Measurable Residual Disease (MRD) as a Surrogate Efficacy-Response Biomarker in AML

In acute myeloid leukemia (AML) many patients experience relapse, despite the achievement of morphological complete remission; therefore, conventional morphologic criteria are currently considered inadequate for assessing the quality of the response after treatment. Quantification of measurable residual disease (MRD) has been established as a strong prognostic marker in AML and patients that test MRD negative have lower relapse rates and better survival than those who test positive. Different techniques, varying in their sensitivity and applicability to patients, are available for the measurement of MRD and their use as a guide for selecting the most optimal postremission therapy is an area of active investigation. Although still controversial, MRD prognostic value promises to support drug development serving as a surrogate biomarker, potentially useful for accelerating the regulatory approval of new agents. In this review, we will critically examine the methods used to detect MRD and its potential role as a study endpoint

Diagnostic analysis of agrarian systems and aspects of family farming in the municipality of Derrubadas, Rio Grande do Sul

A presente pesquisa tem como objetivo explorar e analisar a conjuntura dos sistemas agrários e do sistema de produção de agricultores familiares no município de Derrubadas - RS, assim como verificar a importância da renda de autoconsumo e da reciprocidade na reprodução social dessas famílias, considerando as potencialidades e os limites das condições naturais e socioeconômicas locais. Para tal foi utilizado o método Análise Diagnóstico dos Sistemas Agrários (ADSA). Por meio da estratificação da realidade foi possível realizar um recorte em nível de zona homogênea e identificar os principais sistemas produtivos da região, assim como caracterizar os principais tipos de agricultores. Dessa forma na pesquisa de campo foi possível identificar três tipologias de agricultores, entre elas: agricultores familiares produtores de leite com baixo grau de tecnificação; agricultores familiares sem produção de leite; e agricultores familiares produtores de leite e grãos com alto grau de tecnificação. Por meio da análise das Unidades de Produção Agrícolas - UPAs representativas de cada tipologia, foi possível constatar que a estratégia da agricultura familiar no município se mostrou bastante favorável para a realidade da zona homogênea e que tanto os produtos destinados ao autoconsumo, quanto a questão da reciprocidade possuem papeis fundamentais na reprodução socioeconômica dessas famílias.This research aims to understand and analyze the situation of the agricultural systems and the farmers production system in the city of Derrubadas - RS, as well as check the issue of reciprocity and its importance in social reproduction of these families, considering the potential and limits of natural and socio-economic local conditions. For this, we used the method of Diagnostic Analysis of Farming Systems (ADSA). Through stratification of reality it was possible to make a cut at the level of homogeneous area and identify the main production systems in the region, as well as to characterize the main types of farmers. Thus, in the field research, it was possible to identify three types of farmers, among them: family farmers milk producers with low degree of technification; family farmers without milk production; and family farmers producing milk and grains with high technification. Through the analysis of representative Agricultural Production Units of each type, it was found that the family farming in the county strategy proved favorable to the reality of the homogeneous area and that both products for selfconsumption as the issue of reciprocity, have the key roles of socioeconomic reproduction of these families.Facultad de Ciencias Agrarias y Forestale

Análise diagnóstico dos sistemas agrários e aspectos da agricultura familiar no município de Derrubadas, Rio Grande do Sul

This research aims to understand and analyze the situation of the agricultural systems and the farmers production system in the city of Derrubadas - RS, as well as check the issue of reciprocity and its importance in social reproduction of these families, considering the potential and limits of natural and socio-economic local conditions. For this, we used the method of Diagnostic Analysis of Farming Systems (ADSA). Through stratification of reality it was possible to make a cut at the level of homogeneous area and identify the main production systems in the region, as well as to characterize the main types of farmers. Thus, in the field research, it was possible to identify three types of farmers, among them: family farmers milk producers with low degree of technification; family farmers without milk production; and family farmers producing milk and grains with high technification. Through the analysis of representative Agricultural Production Units of each type, it was found that the family farming in the county strategy proved favorable to the reality of the homogeneous area and that both products for self-consumption as the issue of reciprocity, have the key roles of socioeconomic reproduction of these families.A presente pesquisa tem como objetivo explorar e analisar a conjuntura dos sistemas agrários e do sistema de produção de agricultores familiares no município de Derrubadas - RS, assim como verificar a importância da renda de autoconsumo e da reciprocidade na reprodução social dessas famílias, considerando as potencialidades e os limites das condições naturais e socioeconômicas locais. Para tal foi utilizado o método Análise Diagnóstico dos Sistemas Agrários (ADSA). Por meio da estratificação da realidade foi possível realizar um recorte em nível de zona homogênea e identificar os principais sistemas produtivos da região, assim como caracterizar os principais tipos de agricultores. Dessa forma na pesquisa de campo foi possível identificar três tipologias de agricultores, entre elas: agricultores familiares produtores de leite com baixo grau de tecnificação; agricultores familiares sem produção de leite; e agricultores familiares produtores de leite e grãos com alto grau de tecnificação. Por meio da análise das Unidades de Produção Agrícolas - UPAs representativas de cada tipologia, foi possível constatar que a estratégia da agricultura familiar no município se mostrou bastante favorável para a realidade da zona homogênea e que tanto os produtos destinados ao autoconsumo, quanto a questão da reciprocidade possuem papeis fundamentais na reprodução socioeconômica dessas famílias

The Temporal Modulation of Nocebo Hyperalgesia in a Model of Sustained Pain

Background: The direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain. Methods: Fifty-one healthy participants were allocated to one of three groups. Participants received an inert cream and were instructed that the agent had either hyperalgesic properties setting in after 5 (Nocebo 5, N5) or 30 (Nocebo 30, N30) minutes from cream application, or hydrating properties (No Expectation Group, NE). Pain was induced by the Cold Pressure Test (CPT) which was repeated before cream application (baseline) and after 10 (Test10) and 35 (Test35) minutes. Changes in pain tolerance and in HR at each test point in respect to baseline were compared between the three groups. Results: Tolerance change at Test 10 (Δ10) was greater in N5 (MED = −36.8; IQR = 20.9) compared to NE (MED = −5.3; IQR = 22.4; p < 0.001) and N30 (MED = 0.0; IQR = 23.1; p < 0.001), showing that hyperalgesia was only present in the group that expected the effect of the cream to set in early. Tolerance change at Test 35 (Δ35) was greater in N5 (MED = −36.3; IQR = 35.3; p = 0.002) and in N30 (MED = −33.3; IQR = 34.8; p = 0.009) compared to NE, indicating delayed onset of hyperalgesia in N30, and sustained hyperalgesia in N5. No group differences were found for HR. Conclusions: Our study demonstrated that temporal expectations shift nocebo response onset in a model of sustained pain

Case report: A Saprochaete clavata (Magnusiomyces clavatus) severe infection effectively treated with granulocyte transfusion in a young patient with myeloid sarcoma

Myeloid sarcoma is a hematologic malignancy consisting of extramedullary tissue involvement by myeloid blasts, usually considered as acute myeloid leukemia and treated accordingly. The disease itself, together with chemotherapy and disease-associated factors, may have an impact in increasing the risk of developing severe and frequently life-threatening infections. Herein, we describe the case of a patient with a right breast skin lesion, histologically diagnosed myeloid sarcoma, who developed a severe disseminated fungal infection by Saprochaete clavata (Magnusiomyces clavatus), during the first consolidation course of chemotherapy. Despite maximum antifungal therapy, the infection progressed and the fungus continued to be isolated until granulocyte transfusion therapy was initiated. Our experience suggests that patients with profound and long-lasting neutropenia could benefit from granulocyte transfusions as additional therapy in severe fungal infections resistant to broad-spectrum antimicrobial therapy

The Temporal Modulation of Nocebo Hyperalgesia in a Model of Sustained Pain

Background: The direction and the magnitude of verbal suggestions have been shown to be strong modulators of nocebo hyperalgesia, while little attention has been given to the role of their temporal content. Here, we investigate whether temporal suggestions modulate the timing of nocebo hyperalgesia in an experimental model of sustained pain.Methods: Fifty-one healthy participants were allocated to one of three groups. Participants received an inert cream and were instructed that the agent had either hyperalgesic properties setting in after 5 (Nocebo 5, N5) or 30 (Nocebo 30, N30) minutes from cream application, or hydrating properties (No Expectation Group, NE). Pain was induced by the Cold Pressure Test (CPT) which was repeated before cream application (baseline) and after 10 (Test10) and 35 (Test35) minutes. Changes in pain tolerance and in HR at each test point in respect to baseline were compared between the three groups.Results: Tolerance change at Test 10 (Δ10) was greater in N5 (MED = −36.8; IQR = 20.9) compared to NE (MED = −5.3; IQR = 22.4; p < 0.001) and N30 (MED = 0.0; IQR = 23.1; p < 0.001), showing that hyperalgesia was only present in the group that expected the effect of the cream to set in early. Tolerance change at Test 35 (Δ35) was greater in N5 (MED = −36.3; IQR = 35.3; p = 0.002) and in N30 (MED = −33.3; IQR = 34.8; p = 0.009) compared to NE, indicating delayed onset of hyperalgesia in N30, and sustained hyperalgesia in N5. No group differences were found for HR.Conclusions: Our study demonstrated that temporal expectations shift nocebo response onset in a model of sustained pain

Predictors of Early Thrombotic Events in Adult Patients with Acute Myeloid Leukemia: A Real-World Experience

Information regarding the incidence and the prognostic impact of thrombotic events (TE) in non-promyelocytic acute myeloid leukemia (AML) is sparse. Although several risk factors associated with an increased risk of TE development have been recognized, we still lack universally approved guidelines for identification and management of these complications. We retrospectively analyzed 300 consecutive patients with newly diagnosed AML. Reporting the incidence of venous TE (VTE) and arterial TE (ATE) was the primary endpoint. Secondarily, we evaluated baseline patient- and disease-related characteristics with a possible influence of VTE-occurrence probability. Finally, we evaluated the impact of TE on survival. Overall, the VTE incidence was 12.3% and ATE incidence was 2.3%. We identified three independent predictors associated with early-VTE: comorbidities (p = 0.006), platelets count &gt;50x10e9/L (p = 0.006), and a previous history of VTE (p = 0.003). Assigning 1 point to each variable, we observed an overall cumulative incidence of VTE of 18.4% in the high-risk group (&gt;2 points) versus 6.4% in the low-risk group (0–1 point), log-rank = 0.002. Overall, ATE, but not VTE, was associated with poor prognosis (p &lt; 0.001). In conclusion, TE incidence in AML patients is not negligible. We proposed an early-VTE risk score that could be useful for a proper management of VTE prophylaxis

In BCR-ABL1 Positive B-Cell Acute Lymphoblastic Leukemia, Steroid Therapy Induces Hypofibrinogenemia

Hypofibrinogenemia (HF) in adult acute lymphoblastic leukemia (ALL) of B lineage is uncommon and mostly associated with asparaginase (ASP) delivery. Since we noticed a significant reduction in fibrinogen (FBG) plasma levels even before the first ASP dose, we aim to assess the levels of FBG during induction treatment and explore if the FBG fall correlated with therapies other than asparaginase and/or specific leukemia biological features. We retrospectively analyzed FBG levels in 115 patients with B-ALL. In 74 (64%) out of 115 patients FBG decline occurred during the steroid prephase. In univariate analysis, such a steroid-related HF was significantly associated with BCR-ABL1 rearrangement (p = 0.00158). None of those experiencing HF had significant modifications of liver function tests during induction treatment. Our retrospective study suggests that in B-ALL, steroid therapy can also induce HF and that such an event is preferentially observed in patients carrying BCR-ABL1 rearrangements. The pathogenesis of this phenomenon is still unclear. We attempt to explain it by applying the International Society of Thrombosis and Hemostasis-Disseminated Intravascular Coagulation score (ISTH-DIC score); nonetheless additional studies are needed to clarify further the mechanisms of HF in this subset of patients

FEVER OF UNKNOWN ORIGIN AND MULTIDRUG-RESISTANT ORGANISMS COLONIZATION IN AML PATIENTS.

Abstract. Background: Colonization by multidrug-resistant organisms (MDRO) is a frequent complication in hematologic departments, which puts patients at risk of life-threatening bacterial sepsis. Fever of unknown origin (FUO) is a condition related to the delivery of chemotherapy in hematologic malignancies, in which the use of antibiotics is debated. The incidence, risk factors, and influence on the outcome of these conditions in patients with acute myeloid leukemia (AML) are not clearly defined. Methods: We retrospectively analyzed 132 consecutive admissions of non-promyelocytic AML patients at the Hematology Unit of the University Tor Vergata in Rome between June 2019 and February 2022. MDRO swab-based screening was performed in all patients on the day of admission and once weekly after that. FUO was defined as fever with no evidence of infection. Results: Of 132 consecutive hospitalizations (69 AML patients), MDRO colonization was observed in 35 cases (26%) and resulted independently related to a previous MDRO colonization (p=0.001) and length of hospitalization (p=0.03). The colonization persistence rate in subsequent admissions was 64%. MDRO-related bloodstream infection was observed in 8 patients (23%) and correlated with grade III/IV mucositis (p=0.008) and length of hospitalization (p=0.02). FUO occurred in 68 cases (51%) and correlated with an absolute neutrophilic count <500μ/L at admission (0.04). Conclusion: In our experience, MDRO colonization is a frequent and difficult-to-eradicate condition that can arise at all stages of treatment. Prompt discharge of patients as soon as clinical conditions allow could limit the spread of MDRO. In addition, the appropriate use of antibiotics, especially in the case of FUO, and the contraction of hospitalization length, when feasible, are measures to tackle the further spread of MDRO

CDK4/6 inhibitors in advanced hormone receptor-positive/HER2-negative breast cancer: a systematic review and meta-analysis of randomized trials

Purpose: Combining CDK4/6 inhibitors and endocrine therapy (ET) improved outcomes for the treatment of metastatic HR+/HER2 12 breast cancers. Here, we performed a meta-analysis of randomized clinical trials (RCTs) to better define the benefit and the risk of CDK4/6 inhibitors plus ET for endocrine-sensitive or endocrine-resistant population in metastatic HR+/HER2 12 breast cancer. Method: A systematic literature search of Pubmed, Embase, and the Cochrane Library was carried out up to 30 June 2018. Hazard ratios (HRs) and 95% confidence intervals (CIs) for progression-free survival (PFS), as well as odds ratios (ORs) for objective response rates, 65 G3\u2013G4 adverse events (AEs), and G3\u2013G4 neutropenia were calculated for each trial. A meta-analysis was carried out using the random-effects model. Results: Eight RCTs were eligible including 4578 breast cancer patients. Adding CDK4/6 inhibitors to ET in endocrine-sensitive (HR 0.55, 95% CI 0.50\u20130.62) or endocrine-resistant setting (HR 0.51, 95% CI 0.43\u20130.61) significantly improved the PFS of metastatic HR+/HER2 12 breast cancers regardless of menopausal status and site of metastasis. Moreover, CDK4/6 inhibitors plus ET meaningfully improved objective response rate in endocrine-sensitive (ORs 0.62, 95% CI 0.52\u20130.73) or endocrine-resistant setting (ORs 0.33, 95% CI 0.24\u20130.47). The use of these drugs was characterized by a significant increase of G3\u2013G4 AEs (OR 10.88, 95% CI 6.53\u201318.14). Conclusion: Emerging data provide a new standard treatment for advanced HR+/HER2 12 breast cancer, regardless of menopausal status, prior hormonal/chemotherapy treatments delivered, sites of metastasis. However, benefits should be balanced with longer treatment duration, toxicities, and costs