SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution.

INTRODUCTION: Venetoclax combined with azacitidine (AZA-VEN) constitutes an option for the treatment of acute myeloid leukemia. There are, however, no data on the COVID-19 incidence and outcome in patients treated with AZA-VEN. METHODS: Patients with acute leukemia treated with AZA-VEN at a single institution were included in this prospective observational study. RESULTS: Thirteen patients were enrolled, 46% with treatment-naïve, and 56% with relapsed/refractory disease. Fifty-four percent of patients were males; the median age was 69 years. Six patients (46%) developed COVID-19 during the observation time. The median time to COVID-19 was 24 days from the initiation of AZA-VEN. The 2-month cumulative incidence of COVID-19 was 46.2%. Two patients (33%) succumbed to COVID-19. The 100-day COVID-19-free survival from AZA-VEN initiation was 61%. The median follow-up time was 4.3 months. DISCUSSION/CONCLUSION: COVID-19 constitutes a frequent complication of AZA-VEN treatment in the era of the COVID-19 pandemic, leading to death in a significant proportion of patients.

Azacitidine for relapse of acute myeloid leukemia or myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation, multicenter PALG analysis.

OBJECTIVES: Relapse of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) belongs to the major causes of treatment failure. METHODS: Retrospective multicenter analysis of patients diagnosed with AML or MDS who had hematological relapse after allo-HSCT and were treated with azacitidine for this indication. RESULTS: Twenty-three patients receiving azacitidine as the first treatment of relapse (Group_1) and 8 patients receiving azacitidine after other treatment of relapse (Group_2) were included. There were 68% males, median age at initiation of azacitidine was 53 years (15-66). Median time to relapse was 3.5 months and 6.3 months in Group_1 and Group_2, respectively; median time from relapse to azacitidine 0.2 and 2.3 months. Azacitidine 75 mg/m2 , days 1-7, was administered in 78% and 75% of patients in Group_1 and Group_2, concomitant DLI in 48% and 50%. With median follow-up of 4.7 and 13.6 months, the median overall survival was 5.9 and 9.5 months. 17% and 37.5% patients proceeded to salvage allo-HSCT, with median OS of 11.6 months and not reached respectively. CONCLUSIONS: Azacitidine treatment for hematological relapse is associated with poor outcome; nevertheless, a proportion of patients may benefit from it, including patients receiving subsequent salvage allo-HSCT.

Biomarkers of Neurological Outcome After Aneurysmal Subarachnoid Hemorrhage as Early Predictors at Discharge from an Intensive Care Unit.

BACKGROUND: Subarachnoid bleeding is associated with brain injuries and ranges from almost negligible to acute and life threatening. The main objectives were to study changes in brain-specific biomarker levels in patients after an aneurysmal subarachnoid hemorrhage (aSAH) in relation to early clinical findings, severity scores, and intensive care unit (ICU) outcome. Analysis was done to identify specific biomarkers as predictors of a bad outcome in the acute treatment phase. METHODS: Analysis was performed for the proteins of neurofilament, neuron-specific enolase (NSE), microtubule-associated protein tau (MAPT), and for the proteins of glial cells, S100B, and glial fibrillary acidic protein (GFAP). Outcomes were assessed at discharge from the ICU and analyzed based on the grade in the Glasgow Outcome Scale (GOS). Patients were classified into two groups: with a good outcome (Group 1: GOS IV-V, n = 24) and with a bad outcome (Group 2: GOS I-III, n = 31). Blood samples were taken upon admission to the ICU and afterward daily for up to 6 days. RESULTS: In Group 1, the level of S100B (1.0, 0.9, 0.7, 2.0, 1.0, 0.3 ng/mL) and NSE (1.5, 2.0, 1.6, 1.2, 16.6, 2.2 ng/mL) was significantly lower than in Group 2 (S100B: 4.7, 4.8, 4.4, 4.5, 6.6, 6.8 ng/mL; NSE: 4.0, 4.1, 4.3, 3.8, 4.4, 2.5 1.1 ng/mL) on day 1-6, respectively. MAPT was significantly lower only on the first and second day (83.2 ± 25.1, 132.7 ± 88.1 pg/mL in Group 1 vs. 625.0 ± 250.7, 616.4 ± 391.6 pg/mL in Group 2). GFAP was elevated in both groups from day 1 to 6. In the ROC analysis, S100B showed the highest ability to predict bad ICU outcome of the four biomarkers measured on admission [area under the curve (AUC) 0.81; 95% CI 0.67-0.94, p < 0.001]. NSE and MAPT also had significant predictive value (AUC 0.71; 95% CI 0.54-0.87, p = 0.01; AUC 0.74; 95% CI 0.55-0.92, p = 0.01, respectively). A strong negative correlation between the GOS and S100B and the GOS and NSE was recorded on days 1-5, and between the GOS and MAPT on day 1. CONCLUSION: Our findings provide evidence that brain biomarkers such as S100B, NSE, GFAP, and MAPT increase significantly in patients following aSAH. There is a direct relationship between the neurological outcome in the acute treatment phase and the levels of S100B, NSE, and MAPT. The detection of brain-specific biomarkers in conjunction with clinical data may constitute a valuable diagnostic and prognostic tool in the early phase of aSAH treatment.

Impact of pre-transplantation sinus abnormalities assessed by Lund-Mackay scoring system on sinusitis occurrence after allogeneic hematopoietic cell transplantation in acute leukemia patients.

INTRODUCTION: Screening sinonasal evaluation is routinely performed before allogeneic hematopoietic cell transplantation (allo-HCT), however, data supporting such evaluation is inconsistent. O b j e c t i v e s: Assessment of the utility of screening sinonasal evaluation with computed tomography (CT). METHODS: A retrospective analysis of acute leukemia patients who underwent allo-HCT, for whom screening sinonasal CT scans were reevaluated, and for whom Lund-Mackay score (LMS) was calculated. R e s u l t s: Forty-eight patients, the median age at allo-HCT 38 years (18-58), 52% males, were included. 79% had acute myeloid leukemia (AML), 21% acute lymphoblastic leukemia (ALL). Conditioning intensity was myeloablative in 96% of patients, 21% of patients received total body irradiation. 19% of patients had a history of sinusitis before allo-HCT. Screening sinus CT was performed a median of 22 days before allo-HCT. The median LMS was 1 point (0- 10). The severity of sinus abnormalities was: no abnormalities (31%), mild (67%), moderate (2%), severe (0%). Mucosal thickening was the most frequent abnormality (69%). Eleven patients experienced sinusitis after a median of 93 days (11-607) after allo-HCT. 1-year cumulative incidence of sinusitis was 22%. No threshold of LMS and no type of sinus abnormalities were correlated with sinusitis development after allo-HCT. Mild sinus disease at screening did not negatively impact survival in comparison to no sinus disease. C o n c l u s i o n s: Despite the fact, that majority of analyzed patients had either no or mild sinus disease at screening a significant proportion of patients developed sinusitis after allo-HCT. Evaluation of LMS before allo-HCT did not help predict the development of sinusitis after the procedure.

Soluble Urokinase-Type Plasminogen Activator Receptor Levels as a Predictor of Kidney Replacement Therapy in Septic Patients with Acute Kidney Injury: An Observational Study.

The soluble urokinase-type plasminogen activator receptor (suPAR) is involved in the pathogenesis of acute kidney injury (AKI). Our goal was to establish the optimal suPAR cut-off point for predicting the need for kidney replacement therapy (KRT) use in sepsis patients and to analyze survival rates based on the suPAR level, AKI diagnosis, and the requirement for KRT. In total, 51 septic patients were included (82% septic shock; 96% mechanically ventilated, 35% KRT). Patients were stratified according to the AKI diagnosis and the need for KRT into three groups: AKI(+)/KRT(+), AKI(+)/KRT(−), and AKI(−)/KRT(−). A control group (N = 20) without sepsis and kidney failure was included. Sepsis patients had higher levels of the suPAR than control (13.01 vs. 4.05 ng/mL, p < 0.001). On ICU admission, the suPAR level was significantly higher in the AKI(+)/KRT(+) group than in the AKI(+)/KRT(−) and AKI(−)/KRT(−) groups (18.5 vs. 10.6 and 9.5 ng/mL, respectively; p = 0.001). The optimal suPAR cut-off point for predicting the need for KRT was established at 10.422 ng/mL (area under the curve 0.801, sensitivity 0.889, specificity 0.636). Moreover, patients AKI(+)/KRT(+) had the lowest probability of survival compared to patients AKI(+)/KRT(−) and AKI(−)/KRT(−) (p = 0.0003). The results indicate that the suPAR measurements may constitute an important element in the diagnosis of a patient with sepsis.

Intestinal Fatty Acid Binding Protein (I-FABP) as a Prognostic Marker in Critically Ill COVID-19 Patients.

Gastrointestinal symptoms are common in critically ill COVID-19 patients. There is currently no generally recognized method of assessing gastrointestinal injury in unconscious or sedated intensive care unit (ICU) patients. I-FABP (intestinal fatty acid binding protein) and citrulline have previously been studied as potential biomarkers of enterocyte damage in various gastrointestinal tract diseases, and changes in the levels of these markers may reflect intestinal wall damage in COVID-19. Patients with critical COVID-19, with diagnosed sepsis, or septic shock requiring ICU treatment were included in the study. Blood samples for citrulline and I-FABP were taken daily from day 1 to 5. I-FABP levels were significantly higher in patients who eventually died from COVID-19 than in survivors, and the optimal I-FABP cut-off point for predicting 28-day mortality was 668.57 pg/mL (sensitivity 0.739, specificity 0.765). Plasma levels of I-FABP, but not citrulline, were associated with significantly higher mortality and appeared to be a predictor of poor outcome in multivariate logistic regression analysis. In conclusion, I-FABP seems to be an effective prognostic marker in critically ill COVID-19 patients. Assessing mortality risk based on intestinal markers may be helpful in making clinical decisions regarding the management of intestinal injury, imaging diagnostics, and potential surgical interventions.

Explainable Artificial Intelligence Helps in Understanding the Effect of Fibronectin on Survival of Sepsis.

Fibronectin (FN) plays an essential role in the host's response to infection. In previous studies, a significant decrease in the FN level was observed in sepsis; however, it has not been clearly elucidated how this parameter affects the patient's survival. To better understand the relationship between FN and survival, we utilized innovative approaches from the field of explainable machine learning, including local explanations (Break Down, Shapley Additive Values, Ceteris Paribus), to understand the contribution of FN to predicting individual patient survival. The methodology provides new opportunities to personalize informative predictions for patients. The results showed that the most important indicators for predicting survival in sepsis were INR, FN, age, and the APACHE II score. ROC curve analysis showed that the model's successful classification rate was 0.92, its sensitivity was 0.92, its positive predictive value was 0.76, and its accuracy was 0.79. To illustrate these possibilities, we have developed and shared a web-based risk calculator for exploring individual patient risk. The web application can be continuously updated with new data in order to further improve the model.

Salvage autologous hematopoietic stem cell transplantation for multiple myeloma performed with stem cells procured after previous high dose therapy - a multicenter report by the Polish Myeloma Study Group.

Salvage autologous hematopoietic stem cell transplantation (auto-HSCT) constitutes a therapeutic option for a group of well-selected patients with relapsed multiple myeloma (MM). However, if an insufficient number of stem cells were harvested and stored before the first auto-HSCT, stem cells need to be remobilized. Patients diagnosed with MM who following relapse after auto-HSCT, had remobilization and afterward, auto-HSCT with remobilized cells were included in this retrospective analysis. Thirty-three patients, 61% males, the median age 61 years, were included. With a median follow-up of 1.8 years, 2-year progression-free survival was 56.2%, non-relapse mortality 4.8%. The 2-year cumulative incidence of t-MDS was 4.9%. Factors important for the outcome were: the quality of response, previous radiotherapy, the time between the first and salvage auto-HSCT. To conclude, salvage auto-HSCT performed with cells procured after the previous auto-HSCT can be efficacious in relapsed MM, especially if a sufficiently long response had been obtained to the first auto-HSCT(s).

Downregulation of Polo-like kinase-1 (PLK-1) expression is associated with poor clinical outcome in uveal melanoma patients.

INTRODUCTION: Uveal melanoma (UM) is the most common primary eye tumour in adults. Distant metastases are seen in 50% of cases regardless of treatment, which contributes to high mortality rates. Polo-like kinase-1 (PLK-1) is a protein regulator of mitotic entry and cytokinesis. Increased PLK-1 expression has been shown in different tumours, which makes its inhibition a potential treatment target. To date, no study has been published to discuss the prognostic role of PLK-1 expression in patients with uveal melanoma. MATERIAL AND METHODS: We assessed by immunohistochemistry PLK-1 expression in uveal melanoma cells collected in 158 patients treated by primary enucleation. We determined the correlation between PLK-1 levels evaluated by the immunoreactivity scale (IRS) method and detailed clinical as well as histological parameters. Additionally, we determined the association between PLK-1 expression levels and long-term prognosis. RESULTS: Elevated PLK-1 expression in tumour cells, defined as IRS > 2, was observed in 70% (111/158) of cases, whereas low expression or no expression was seen in the remaining 30% (47/158) of patients. There was a significant correlation between low PLK-1 expression and a higher clinical tumour stage (pT, p = 0.04) as well as a higher AJCC prognostic stage group (p = 0.037). We observed an inverse correlation between PLK-1 expression and tumour cell pigment content (p = 0.0019). There was no correlation between PLK-1 expression and other histological parameters such as mitotic rate or histological subtype. The Kaplan-Meier's analysis demonstrated that low PLK-1 expression was associated with significantly reduced overall survival (p = 0.0058). A similar trend, albeit not significant, was observed for disease-free survival (p = 0.088). CONCLUSIONS: Downregulated PLK-1 expression is a negative prognostic factor in uveal melanoma. It warrants further, multicentre research on prognostic role of PLK-1 expression and possibility of PLK-1 inhibition in uveal melanoma.

Type 2 diabetes mellitus compromises the survival of diffuse large B-cell lymphoma patients treated with (R)-CHOP - the PLRG report.

Comorbidities impair the prognosis of diffuse large B-cell lymphoma (DLBCL). Type 2 diabetes mellitus (DMT2) increases the risk of other comorbidities, e.g., heart failure (HF). Thus, we hypothesized that pre-existing DMT2 may negatively affect the outcome of DLBCL. To verify this, DLBCL patients treated with (R)-CHOP were enrolled. 469 patients were eligible, with a median age of 57 years; 356 patients had advanced-stage DLBCL. 126 patients had high-intermediate and 83 high-risk international prognostic index (IPI). Seventy-six patients had DMT2, 46 HF; 26 patients suffered from both DMT2 and HF. In the analyzed group DMT2 or HF significantly shortened overall survival (OS) and progression free survival (PFS): the 5-year OS for patients with DMT2 was 64% vs 79% and for those with HF: 49% vs 79%. The 5-year PFS for DMT2 was 50.6% vs 62.5% and for HF 39.4% vs 63.2%. The relapse/progression incidence was comparable between groups; the non-relapse/progression mortality (NRPM) was significantly higher solely in DMT2 patients (5-year NRPM 22.5% vs 8.4%). The risk of death was higher in patients with higher IPI (HR = 1.85) and with DMT2 (HR = 1.87). To conclude, pre-existing DMT2, in addition to a higher IPI and HF, was a negative predictor for OS and PFS.

Negative Impact of Borderline Creatinine Concentration and Glomerular Filtration Rate at Baseline on the Outcome of Patients With Multiple Myeloma Treated With Autologous Stem Cell Transplant.

BACKGROUND: Renal impairment (RI) is one of the multiple myeloma (MM)-defining events for initiating therapy. After induction therapy, high-dose chemotherapy followed by autologous peripheral blood stem cell transplant (ASCT) remains the standard of care for transplant-eligible patients with MM. According to the International Myeloma Working Group (IMWG), the organ criterion for kidney damage is defined by a serum creatinine concentration (CrC) > 2 mg/dL or estimated glomerular filtration rate (eGFR) < 40 mL/min. In this long-term study, we evaluated the impact of CrC and eGFR calculated by the Modification of Diet in Renal Disease equation on progression-free and overall survival using a lower threshold than the IMWG criteria. PATIENTS AND METHODS: We studied the longitudinal outcomes as measured by progression-free survival and overall survival in 59 transplant-eligible patients with MM: 38 patients with normal renal function and 21 patients with RI defined as a CrC higher than upper limit of normal (≥ 1.1 mg/dL), eGFR < 60 mL/min, treated with ASCT from 1998 to 2004. RESULTS: The risk of disease progression and death following ASCT increased by 16.5% (P = .005) and 19% (P < .0009) per 1 mg/dL of CrC, respectively. The thresholds for the association of renal insufficiency and negative outcomes were CrC > 1.4 mg/dL and eGFR < 55mL/min. CONCLUSIONS: We observed a negative correlation between minimal renal insufficiency and long-term outcomes. Management of patients with even marginally increased CrC and/or decreased eGFR not fulfilling IMWG RI criteria requires more concentrated effort to reverse even minimal renal insufficiency.