Elevated Serum Lactate Research Articles

Extramedullary Disease in Multiple Myeloma.

Extramedullary disease (EMD) is a rare but recognized manifestation of multiple myeloma (MM), characterized by involvement of several organs including skin, liver, lymphatic system, pleura, and central nervous system. The incidence is about 3-5% in newly diagnosed MM patients, but has been reported in up to 20% patients in the relapsed MM setting. Presence of EMD has been associated with more aggressive phenotype of MM, elevated serum lactate dehydrogenase (LDH) enzyme, and high-risk cytogenetics [deletion 17p, translocation (4;14), translocation (14;16)]. There are several hypotheses of how EMD occurs, including factors leading to bone marrow emancipation and hematogenous spread. The treatment schema usually follows that of high-risk MM. The current review summarizes the disease characterization data, along with available data on clinical activity of available anti-MM agents for this entity.

Cell-free chromatin particles released from dying host cells are global instigators of endotoxin sepsis in mice.

We have earlier reported that cell-free chromatin (cfCh) particles that are released from dying cells, or those that circulate blood, can readily enter into healthy cells, illegitimately integrate into their genomes and induce dsDNA breaks, apoptosis and intense activation of inflammatory cytokines. We hypothesized that sepsis is caused by cfCh released from dying host cells following microbial infection leading to bystander host cell apoptosis and inflammation which are perpetuated in a vicious cycle with release of more cfCh from dying host cells. To test this hypothesis we used three cfCh inactivating agents namely 1) anti-histone antibody complexed nanoparticles which inactivate cfCh by binding to histones; 2) DNase I which inactivates cfCh by degrading its DNA component, and 3) a novel pro-oxidant combination of Resveratrol and Copper which, like DNase I, inactivates cfCh by degrading its DNA component. Female C57 BL/6 mice, 6-8 weeks old, were administered a single i.p. injection of LPS at a dose of 10 mg/Kg or 20 mg/Kg with or without concurrent treatment with the above cfCh inactivating agents. Administration of cfCh inactivating agents concurrently with LPS resulted in prevention of following pathological parameters: 1) release of cfCh in extra-cellular spaces of brain, lung and heart and in circulation; 2) release of inflammatory cytokines in circulation; 3) activation of DNA damage, apoptosis and inflammation in cells of thymus, spleen and in PBMCs; 4) DNA damage, apoptosis and inflammation in cells of lung, liver, heart, brain, kidney and small intestine; 5) liver and kidney dysfunction and elevation of serum lactate; 6) coagulopathy, fibrinolysis and thrombocytopenia; 7) lethality. We conclude that cfCh that are released from dying host cells in response to bacterial endotoxin represents a global instigator of sepsis. cfCh inactivation may provide a novel approach to management of sepsis in humans.

Combined immunotherapy with nivolumab and ipilimumab with and without local therapy in patients with melanoma brain metastasis: a DeCOG* study in 380 patients

BackgroundNivolumab combined with ipilimumab have shown activity in melanoma brain metastasis (MBM). However, in most of the clinical trials investigating immunotherapy in this subgroup, patients with symptomatic MBM and/or prior...

Prophylactic Anti-Cytomegalovirus Hyperimmunoglobulin in Critically Ill Liver Transplant Patients: Impact on Early Immunology and Survival.

Background: Anti-cytomegalovirus hyperimmunoglobulin (CMVIg) was shown to provide beneficial immunodulatory properties beyond antiviral efficacies. The aim of this retrospective study was to assess the impact of prophylactic CMVIg treatment on early outcome following liver transplantation (LT) in critically ill patients. Methods: Forty-three cirrhotic patients requiring pre-LT intensive care due to multiorgan failure were analyzed. Twenty-eight patients with enhanced CMV risk (D+/R+; D+/R−; D−/R+) received prophylactic CMVIg for a minimum of 7 days, while 15 patients (D−/R−) did not. Results: Post-transplantation rates of intra-abdominal infections (28% vs. 61.1%; p = 0.03), Epstein–Barr virus infections (0% vs. 33.3%; p = 0.034), allograft rejections (0% vs. 22.2%; p = 0.013) and sepsis-related mortality (4% vs. 27.8%; p = 0.026) were significantly lower, whereas incidence of CMV infections (4% vs. 22.2%; p = 0.066) tended to be lower in the CMVIg subset. In multivariate analysis, only pretransplant elevated serum lactate level (hazard ratio = 34.63; p = 0.009) and absence of CMVIg therapy (hazard ratio = 21.76; p = 0.023) were identified as independent promoters of 3-month mortality. Conclusion: Prophylactic treatment with CMVIg reduces predisposition for severe immunological and septic events and, thereby, early mortality in critically ill liver recipients.

Abdominal compartment syndrome and decompressive laparotomy in children: a 9-year single-center experience.

Abdominal compartment syndrome (ACS) in children results in 100% mortality if left untreated. Decompressive laparotomy (DL) is the only effective treatment if conservative medical therapies have failed. This study aims to determine the incidence of ACS among pediatric patients who underwent an emergency laparotomy (EL), to describe the effect of DL on clinical and laboratory parameters and, to make a better prediction on fatal outcome, to analyze variables and their association with mortality. This retrospective study includes 418 children up to the age of 16years who underwent EL between January 2010 and December 2018 at our tertiary pediatric referral center. ACS was defined according to the latest guidelines of the World Society of the Abdominal Compartment Syndrome. Fourteen patients had emergency DL for ACS. 6 h preoperatively; median intra-abdominal pressure (IAP) and abdominal perfusion pressure (APP) were 22.5mmHg and 29mmHg, respectively. After DL, IAP decreased and APP increased, both by an average of 60%. Six patients survived, eight patients had a fatal outcome, resulting in a mortality of 57%. An age under 1year, weight under the 3rd percentile, an open abdomen treatment, an intestinal resection and an elevated serum lactate > 1.8mmol/L were associated with an increased relative risk of death. Improving the outcome in pediatric patients with ACS by removing or attenuating risk factors is difficult. This emphasizes the need for early diagnosis and prompt DL once the diagnosis of ACS is made.

Water-Soluble Pristine C60 Fullerenes Inhibit Liver Fibrotic Alteration and Prevent Liver Cirrhosis in Rats.

Liver cirrhosis is an outcome of a wide range of liver chronic diseases. It is attributed to oxidative stress; therefore, antioxidant usage could be a promising treatment of that. So, exploring the impact of effective free radical scavenger pristine C60 fullerenes on liver fibrosis and cirrhosis and their ability to interact with main growth factor receptors involved in liver fibrogenesis was aimed to be discovered. We used N-diethylnitrosamine/carbon tetrachloride-induced simulations of rat liver fibrosis (10 weeks) and cirrhosis (15 weeks). Pristine C60 fullerene aqueous colloid solution (C60FAS) was injected daily at a dose of 0.25 mg/kg throughout the experiment. Liver morphology and functional and redox states were assessed. C60 fullerenes' ability to interact with epidermal, vasoendothelial, platelet-derived, and fibroblast growth factor receptors (EGFR, VEGFR, PDGFR, and FGFR, respectively) was estimated by computational modeling. We observed that C60FAS reduced the severity of fibrosis in fibrotic rats (0.75 vs. 3.0 points according to Ishak score), attenuated the hepatocyte injury, normalized elevated blood serum alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), and mitigated oxidative stress manifestation in liver tissue restoring its redox balance. When applied to cirrhotic animals, C60FAS reduced connective tissue deposition as well (2.4 vs. 5.4 points according to Ishak score), diminished ALP and LDH (by 16% and 61%), and normalized conjugated and nonconjugated bilirubin, restoring the liver function. Altered liver lipid and protein peroxides and glutathione peroxidase activity were also leveled. Within a computer simulation, it was shown that C60 fullerenes can block hinge prohibiting ATP binding for EGFR and FGFR and thus blocking associated signal pathways. This ability in addition to their antioxidant properties may contribute to C60 fullerene's antifibrotic action. Thus, C60FAS may have a substantial therapeutic potential as an inhibitor of liver fibrosis and cirrhosis.

Causes and predictors of early mortality in patients treated with left ventricular assist device implantation in the European Registry of Mechanical Circulatory Support (EUROMACS)

PurposeThe aim of the study was to analyze early mortality after continuous-flow left ventricular assist device (LVAD) implantation which remains high.MethodsWe analyzed consecutive (n = 2689) patients from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS) undergoing continuous-flow LVAD implantation. The primary outcome was early (< 90 days) mortality. Secondary outcomes were differential causes of early post-operative death following LVAD implantation.ResultsUnivariable and multivariable analysis as well as regression analysis were used to examine determinants and differential causes of early (< 90 days) mortality after LVAD implantation. During the first 90 days, 2160 (80%) patients were alive with ongoing LVAD support, 40(2%) patients underwent heart transplantation, and 487(18%) deceased. The main causes of early death were MOF (36%), sepsis (28%), cardiopulmonary failure (CPF; 10%), CVA (9%), and right-sided heart failure (RHF, 8%). Furthermore, MOF and sepsis are 70% of causes of death in the first week. Independent clinical predictors of early death were age, female sex, INTERMACS profile 1 to 3, and ECMO. Laboratory predictors included elevated serum creatinine, total bilirubin, lactate, and low hemoglobin. Furthermore, hemodynamic predictors included elevated RA-to-PCWP ratio, pulmonary vascular resistance, and low systemic vascular resistance. Longer total implantation time was also independent predictor of early mortality. A simple model of 12 variables predicts early mortality following LVAD implantation with a good discriminative power with area under the curve of 0.75.ConclusionsIn the EUROMACS registry, approximately one out of five patients die within 90 days after LVAD implantation. Early mortality is primarily dominated by multiorgan failure followed by sepsis. A simple model identifies important parameters which are associated with early mortality following LVAD implantation.

Prognostic Value of Serum Lactate Levels in Critically Ill Patients in an Intensive Care Unit.

IntroductionThe patient in critical condition, regardless of the cause of admission, continues to be a challenge for health systems due to the high mortality that it reports. There is a need to identify some marker of early obtaining, easy to interpret and with high relevance in the prognosis of these patients.ObjectiveTo determine the prognostic value of serum lactate in an Intensive Care Unit (ICU).MethodOne hundred and forty-five patients admitted to an ICU were enrolled in the study. The Acute Physiology and Chronic Health Evaluation II (APACHE) prognosis score, Sequential Organ Failure Assessment, hemodynamic support need, mechanical ventilation, cause of admission, stay in ICU, analytical and physiological variables were determined. The probability of survival of patients who had elevated and normal serum lactate levels was calculated. The risk of dying was determined using the Cox regression model.ResultsTwenty-eight patients died (19%) in the ICU. The serum lactate value was higher in the group of patients with trauma, infections, APACHE II and high creatinine levels; as well as with decreased mean arterial blood pressure, need for hemodynamic support and mechanical ventilation. The survival capacity was higher in patients who had normal serum lactate. Serum lactate was the sole independent predictor of mortality (AHR 1.28 [1.07-1.53], p = 0.008).ConclusionsPatient assessment through the determination of serum lactate levels provides useful information in the initial evaluation of the critical patient.

Utility of Abdominal Imaging in Peritoneal Dialysis Patients Presenting With Peritonitis

Background:Peritonitis remains a major complication in peritoneal dialysis (PD). Abdominal imaging is often performed in the setting of peritonitis to evaluate for concomitant intra-abdominal processes. However, the usefulness of this procedure is unknown.Objective:The aim of this study was to assess the prevalence of abdominal imaging performed in the setting of PD peritonitis and to evaluate clinical parameters associated with abnormal imaging results to identify clinical situations in which radiographic examinations are informative.Design:This is a retrospective cohort study.Setting:The study was conducted at the Toronto General Hospital, Ontario, Canada.Patients:We studied 166 episodes of PD peritonitis in 114 patients between January 1, 2011, and June 30, 2016.Measurements:Baseline demographics, characteristics of PD peritonitis, and characteristics of abdominal imaging performed.Methods:The association between relevant clinical parameters and abnormal abdominal imaging was examined using a univariate and multivariate logistic regression model.Results:Abdominal imaging (computed tomography [CT] scan or ultrasound) was performed in 68 cases (41%). Patients were more likely to undergo imaging if they required hospitalization, were admitted to the intensive care unit (ICU), had polymicrobial or fungal organisms causing peritonitis, had relapsing/recurrent/refractory peritonitis, had an indication for hemodialysis or PD catheter removal, or presented with hypotension, tachycardia, or an elevated serum lactate. Of the imaging performed, abnormalities were found in 32 cases (47%). The most common findings were bowel obstruction, intra-abdominal collection, and biliary abnormalities. In the univariate analysis, ICU admission (43.3% vs 14.3%, P < .01) and need for temporary or permanent hemodialysis (62.5% vs 30.6%, P < .01) were associated with imaging abnormalities. Importantly, the peritonitis organism was not associated with abnormal imaging results. In a multivariate analysis, ICU admission was the only significant clinical parameter associated with imaging abnormalities with an odds ratio (OR) of 4.4 (95% confidence interval [CI]: 1.1-17.4, P = .04).Limitations:Single-center study, small sample size, and lack of detailed information on the exact indications leading to abdominal imaging.Conclusions:Abdominal imaging is commonly performed in the setting of PD peritonitis. Abnormalities are not infrequent and are present in almost half of the cases, with need for ICU admission being the most significant clinical parameter associated with abnormal findings. Therefore, abdominal imaging should be performed in carefully selected patients with PD peritonitis, especially if there is evidence of hemodynamic instability. While the finding of fungal or polymicrobial peritonitis was a driver for abdominal imaging, the presence of these organisms did not predict radiologic abnormalities.

Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?

The prognosis of patients with advanced melanoma has improved dramatically. However, the clinical outcomes of patients with highly elevated serum lactate dehydrogenase (LDH) remain very poor. The aim of this study was to explore whether patients with normalized LDH after targeted therapy could benefit from subsequent treatment with immune checkpoint inhibitors (ICI). Data from all patients with BRAF-mutant metastatic melanoma with a highly elevated serum LDH at baseline (≥2× upper limit of normal) receiving first-line targeted therapy between 2012 and 2019 in the Netherlands were collected. Patients were stratified according to response status to targeted therapy and change in LDH at start of subsequent treatment with ICI. Differences in overall survival (OS) between the subgroups were compared using log-rank tests. After a median follow-up of 35.1 months, median OS of the total study population (n = 360) was 4.9 months (95% CI 4.4–5.4). Of all patients receiving subsequent treatment with ICI (n = 113), survival from start of subsequent treatment was significantly longer in patients who had normalized LDH and were still responding to targeted therapy compared to those with LDH that remained elevated (median OS 24.7 vs. 1.1 months). Our study suggests that introducing ICI upon response to targeted therapy with normalization of LDH could be an effective strategy in obtaining long-term survival in advanced melanoma patients with initial highly elevated serum LDH.

Central Nervous System Involvement in Patients with Diffuse Large B Cell Lymphoma: Analysis of the Risk Factors and Prognosis from a Single-Center Retrospective Cohort Study.

PurposeThe aim of this study was to identify the risk factors for central nervous system (CNS) involvement in systemic diffuse large B-cell lymphoma (DLBCL) patients and to explore prognostic for DLBCL patients with CNS involvement (relapse or progression).Patients and methodsThis was a retrospective cohort study in our hospital. Data were collected from all DLBCL patients diagnosed in our institutes from January 2013 to June 2018. Clinical information was collected from medical records.ResultsThe participants included 138 patients with DLBCL. Among them, 38 patients were diagnosed as CNS lymphoma, including 15 patients exhibited CNS involvement while DLBCL was pathologically confirmed, and 23 patients developed CNS lymphoma during or after initial chemotherapy. The median disease-free interval to CNS involvement was 13 months. Multivariate analysis identified elevated serum lactate dehydrogenase (LDH) level [hazard ratio (HR)=4.035; 95% confidence interval (95% CI): 1.147–14.195] was an independent predictor of CNS involvement. The median progression-free survival (PFS) and overall survival (OS) time of DLBCL patients with CNS involved were 12.5 months and 22 months, respectively. Multivariate prognostic analysis showed that eastern cooperative oncology group (ECOG) score>2(P=0.018; HR=7.333; 95% CI: 1.424–42.002), elevated serum LDH level (P=0.046; HR=6.510; 95% CI: 1.035–40.949), deep lesion (P=0.005; HR=10.957; 95% CI: 2.050–58.569), and CNS with systemic involvement (P=0.023; HR=2.730; 95% CI: 1.151–6.479) were independent poor prognostic factors for the patients. The cases with lymphocyte absolute count >0.75×109/L (HR=0.047; 95% CI: 0.003–0.732) had better prognosis. The OS of DLBCL patients with secondary CNS lymphoma was inferior to DLBCL patients without CNS involvement. There was no significant difference between the patients with CNS and extra-CNS involvement. There was no significant difference between the patients with CNS involvement and stage III-IV DLBCL cases without CNS lymphoma.ConclusionIn conclusion, elevated serum LDH was independent high-risk factor for secondary CNS lymphoma. For DLBCL patients with CNS involvement, ECOG score>2, elevated serum LDH level, deep lesion, lymphocyte absolute count ≤0.75×109/L and CNS with systemic involvement retained a significant association with outcome.

Arctium lappa Root Extract Prevents Lead-Induced Liver Injury by Attenuating Oxidative Stress and Inflammation, and Activating Akt/GSK-3β Signaling.

Arctium lappa L. (A. lappa) is a popular medicinal plant with promising hepatoprotective activity. This study investigated the protective effect of A. lappa root extract (ALRE) on lead (Pb) hepatotoxicity, pointing to its ability to modulate oxidative stress, inflammation, and protein kinase B/Akt/glycogen synthase kinase (GSK)-3β signaling. Rats received 50 mg/kg lead acetate (Pb(Ac)2) and 200 mg/kg ALRE or vitamin C (Vit. C) for 7 days, and blood and liver samples were collected. Pb(Ac)2 provoked hepatotoxicity manifested by elevated serum transaminases and lactate dehydrogenase, and decreased total protein. Histopathological alterations, including distorted lobular hepatic architecture, microsteatotic changes, congestion, and massive necrosis were observed in Pb(II)-induced rats. ALRE ameliorated liver function and prevented all histological alterations. Pb(II) increased hepatic lipid peroxidation (LPO), nitric oxide (NO), caspase-3, and DNA fragmentation, and serum C-reactive protein, tumor necrosis factor-α, and interleukin-1β. Cellular antioxidants, and Akt and GSK-3β phosphorylation levels were decreased in the liver of Pb(II)-induced rats. ALRE ameliorated LPO, NO, caspase-3, DNA fragmentation and inflammatory mediators, and boosted antioxidant defenses in Pb(II)-induced rats. In addition, ALRE activated Akt and inhibited GSK-3β in the liver of Pb(II)-induced rats. In conclusion, ALRE inhibits liver injury in Pb(II)-intoxicated rats by attenuating oxidative injury and inflammation, and activation of Akt/GSK-3β signaling pathway.

Long-term effect of risk-adaptive therapy for early stage extranodal NK/T cell lymphoma

Objective: This study aimed to evaluate the role of extended involved-field intensity modulated radiation therapy (IMRT) for patients with early stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) in a single center, and to explore the long-term effect of risk-adaptive therapy. Methods: Among 238 patients with early stage NKTCL, there were 191 in high-risk group [any risk factor of age > 60, elevated serum lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG) score≥2, primary tumor invasion, or Ann Arbor stage Ⅱ] and 47 in low-risk group (no risk factor). A total of 204 patients received radiotherapy combined with chemotherapy, 15 received radiotherapy alone and 19 received chemotherapy alone. One-hundred and eighty-six patients had radiotherapy at a dose ≥50 Gy and 159 patients received chemotherapy with asparaginase-based regimen. Results: The 5-year overall survival (OS) rate and progression- free survival (PFS)rate of all patients were 66.2% and 57.5%. Five-year OS and PFS rates in low-risk group were 91.8% and 88.0%, while 59.3% and 49.3% in high-risk group. The survival of patients in low-risk group were better than those in high-risk group (both P<0.001). The five-year OS rate in combined therapy group, radiotherapy group and chemotherapy group were 71.7%, 52.3% and 20.7%, respectively (P<0.001). The five-year PFS rate were 63.5%, 23.3% and 24.1%, respectively (P<0.001). Among 219 patients receiving radiotherapy, the 5-year OS and PFS rate of patients with primary site radiotherapy dose ≥ 50 Gy were 72.6% and 66.1%, higher than those of patients with a dose <50 Gy (57.3% and 30.9%, respectively; P=0.031, P<0.001). In the high-risk group, the 5-year OS and PFS rate of the patients who received radiotherapy combined with more than 4 cycles of chemotherapy were 66.5% and 62.6%, higher than those of patients received less than 4 cycles of chemotherapy (56.7% and 46.4%, P=0.045 and 0.020, respectively). Cox multivariate analysis showed that ECOG score (HR=2.208, P=0.001), primary site (HR=4.887, P<0.001), primary tumor invasion (HR=3.265, P=0.001) and radiation dose (HR=1.895, P=0.011) were independent factors of OS in early NKTCL patients. Conclusion: Extended-involved field IMRT with radiation dose more than 50 Gy was the main treatment for patients with early stage NKTCL. Radiotherapy combined with adequate cycle chemotherapy significantly improved prognosis of high-risk patients.

Risk Factors and Outcomes of Patients with Follicular Lymphoma Who Had Histologic Transformation at First Progression after First-Line Immunochemotherapy in the Gallium Study

Introduction: Predicting the risk of histologic transformation (HT) from indolent follicular lymphoma (FL) to a more aggressive form of lymphoma represents a major challenge in managing patients with FL. We assessed the incidence of HT in the GALLIUM study (NCT01332968) and determined risk factors for transformation and impact on clinical outcomes. Methods: In the Phase III GALLIUM study, patients with previously untreated FL were randomized to receive either the anti-CD20 antibody rituximab (R; 375mg/m² on Day (D) 1 of each cycle) or obinutuzumab (G; 1000mg on D1, 8, and 15 of Cycle 1 and D1 of subsequent cycles) in combination with chemotherapy (CHOP, CVP or bendamustine). Patients who achieved at least a partial response at the end of induction therapy proceeded to maintenance therapy with the same antibody, every 2 months for 2 years, or until progression of disease. Repeat biopsies at progression were not mandatory but carried out in case of clinical suspicion of HT. The rate of HT, as assessed by the local pathologist, in patients with a repeat biopsy at the time of disease progression/relapse was an exploratory endpoint. Results: 1202 patients were enrolled. After a median follow up of 57.3 months, 315 (26.2%) patients progressed (median time to relapse, 25.3 months); of these 315 patients, 46 (14.6%) had a biopsy at first progression due to a clinical suspicion of transformation. Forty patients, corresponding to 3.3% of all patients enrolled in GALLIUM and 12.7% of those that progressed, had biopsy-confirmed HT. Among 153 patients with disease progression within 24 months (POD24), 31/153 (20.3%) had HT. Fewer patients transformed in the G-chemo arm (16/40; 40%) compared with R-chemo (24/40; 60%). In total, 116 patients relapsed in the G-chemo arm versus 159 in the R-chemo arm. Compared with no HT, patients with HT were more likely to be male and have bone marrow involvement, stage 3A FL, high FL International Prognostic Index risk, low hemoglobin (Hb), elevated serum lactate dehydrogenase (LDH), elevated beta-2-microglobulin, and high total metabolic tumor volume (Table). A comparison of chemotherapy backbones showed a trend towards higher HT incidence with bendamustine (5.8% [26/686]) compared with CVP, 4.3% (5/117) and CHOP, 2.3% (9/399). A multivariate cause-specific cox model identified several risk factors for HT, including elevated LDH levels (hazard ratio [HR], 4.27 [95% CI: 2.08─8.78]; p&lt;0.0001), anemia (Hb levels &lt;12 g/dL; HR, 2.01 [95% CI: 0.99─4.11]; p=0.0547) and male gender (HR, 2.36 [95% CI: 1.23─4.55]; p=0.0102). Competing risks were non-progression-related death and relapse without HT. Although there appeared to be a trend towards a higher incidence of HT with bendamustine, the sample size was too small to allow for conclusions. Considering all patients with progressive disease, 16/40 patients with HT and 37/275 relapsed patients overall died within 2 years of relapse (56.0% vs 83.1% post-progression/relapse survival rate, respectively). Of the POD24 patients that died, 19/66 (28.8%) were patients with HT. Among patients with disease progression within 12 months (POD12), overall survival (OS) was unfavorable in patients both with and without transformation: 28/56 FL relapsed POD12 patients died within 2 years of relapse (survival rate, 48.3%; median post-progression survival, 1.88 years) and 13/23 POD12 patients with HT died within 2 years of relapse (survival rate, 41.0%, median post-progression survival, 0.94 years; Figure 1A). Among the 153 POD24 patients, those with HT (n=31) had worse outcomes (16/31 POD24 patients with HT died within 2 years of relapse with a survival rate of 46.8%), compared with 33/122 FL relapsed POD24 patients (survival rate, 72.2%; Figure 1B). Conclusions: In GALLIUM, a low rate of HT was observed over 5 years, with the majority occurring within the first 2 years. Patients with POD12 had poor OS regardless of whether transformation occurred or not. Risk factors for HT included elevated LDH, anemia, and male gender. Patients with HT, especially those with progression of disease within 24 months, had poor OS compared to patients who relapsed with persistent FL. Disclosures Casulo: Celgene: Research Funding; Gilead: Honoraria, Other: Travel, accommodation, expenses; Roche: Other: Travel, accommodation, expenses. Herold:Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; GILEAD: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Hiddemann:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Bayer: Research Funding; Vector Therapeutics: Consultancy, Honoraria. Iyengar:Roche: Honoraria; Abbvie: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Takeda: Honoraria. Marcus:Roche / Genentech: Honoraria, Speakers Bureau; Gilead: Consultancy. Seymour:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy; Acerta: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding. Launonen:F. Hoffmann-La Roche Ltd: Employment. Knapp:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mir:Roche: Other: Previous employment.

Serum Albumin Is an Independent Factor Predicting Survival in Patients with Peripheral T Cell Lymphoma: A Multi-Institutional Study from the Latin American Working Group for Lymphomas (GELL)

Introduction: Peripheral T cell lymphoma (PTCL) is a very heterogenous disease and corresponds to approximately 15% of all non-Hodgkin lymphoma cases. PTCL is divided into several subtypes, however, PTCL not otherwise specified (PTCL-NOS) is the most frequent, with a proportion of 26% of all PTCL cases. There is a lack of demographic and clinical data about PTCL-NOS in middle- and low-income countries, where patients' access to early diagnosis and otherwise standard care might be suboptimal. The objective of this study is to describe the population of PTCL-NOS patients in Latin America, specifically from the countries conforming the "Grupo Latinoamericano de Linfomas" (GELL), in order to better understand clinical behavior and find possible prognostic factors that might prognosticate overall survival (OS). We specifically evaluated the neutrophil/lymphocyte ratio (NLR) and serum albumin as potential prognostic factors. Methods: An observational, retrospective and analytical study was conducted during the period from January 2000 through January 2018. A total of 200 Latin American patients with a pathological diagnosis of PTCL-NOS were included. Clinical data were gathered from clinical records. NLR ≥4 and serum albumin ≤3.5 g/dl were considered adverse prognostic factors. Median Overall Survival (mOS) and 5-year Overall Survival (5y-OS) rates were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional-hazard regression analyses were performed to identify adverse prognostic factors for OS. Data were analyzed and interpreted using STATA 15. Results: A total of 200 patients with a diagnosis of PTCL-NOS were included. 50% of patients were ≥60 years, 57% were male, 50% had ECOG ≥2, 40% had elevated serum Lactate Dehydrogenase (LDH) level, 70% showed stage III/IV disease, bone marrow involvement was present in 37% of patients, B symptoms in 65%, 33% presented with hemoglobin levels &lt;10 g/dL. The International Prognostic Index (IPI) score was high-intermediate in 33% and high in 14% of cases. The Prognostic Index for PTCL-U (PIT) risk score was high-intermediate in 32% and high in 26% of cases. Serum albumin &lt;3.5 mg/dl was seen in 58%, and NLR ≥4 in 37% of patients. Median OS (mOS) for the entire cohort was 0.83 years (95% CI 0.58-1.75) and 5-year OS rate was 31% (95% CI 23-40%). Patients with serum albumin levels &lt;3.5 g/dL had mOS of 0.42 years (95% CI 0.25-0.75) and 5-year OS rate of 20% (95% CI 9-33%), while patients with albumin ≥3.5 g/dL had mOS of 5.1 years (95% CI 0.83-not reached) and 5-year OS rate of 51% (95% CI 36-65%) (log-rank p&lt;0.001). The mOS for NLR &lt;4 was 1.67 years (95% CI 0.75-4.92) with 5-year OS rate of 37% (95% CI 25-48%) while for NLR ≥4, the mOS was 0.58 years (95% CI 0.25-1.00) and 5-year OS rate was 23% (95% CI 12-36%) (log-rank p=0.02). Cox proportional Hazard regression multivariate analyses found serum albumin &lt;3.5 g/dL (HR 1.83, 95% CI 1.10-3.05; p=0.02) and ECOG ≥2 (HR 1.95, 95% CI 1.15-3.30; p=0,01) were associated with a worse OS. Serum albumin remained an adverse prognostic factor for OS after adjustment for the IPI and the PIT scores (HR 1.66, 95% CI 1.01-2.75; p=0.047, and HR 1.70, 95% CI 1.03-2.80; p=0.038, respectively). Conclusion: This multi-institutional Latin American study showed that serum albumin level &lt;3.5 g/dL was an adverse prognostic factor for OS, independent from the IPI and the PIT scores, in Latin American patients with a diagnosis of PTCL-NOS. The survival rates of Latin American patients with PTCL-NOS appear lower than in developed countries. Disclosures M: Merck-Sharp-Dome: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Roche-Mexico: Consultancy, Speakers Bureau. Peña:Novartis: Other: Congress inscription and flights; Tecnofarma: Other: Congress inscription and flights; Roche: Other: Congress inscription and flights; Biotoscana: Other: Congress inscription and flights; Janssen: Other: Congress inscription and flights; Pfizer: Membership on an entity's Board of Directors or advisory committees. Paredes:Tecnofarma: Honoraria. Rojas:ROCHE: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; ABBVIE: Membership on an entity's Board of Directors or advisory committees. Abello:Takeda: Other: Participation in advisory board meeting. Castillo:Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding.

Validation of Hemolytic Anemia Codes in the French Hospital Database

Introduction: Hemolytic anemia is a group of rare diseases. National databases are useful data sources to assess the epidemiology and the management of such diseases. The French national health database covers the entire French population (66 million inhabitants). It links sociodemographic data, out-hospital data including dispensing data and hospital data. As a consequence, this database is very useful for population-based studies on rare diseases. For instance, it has been used for epidemiological and pharmacoepidemiological studies on immune thrombocytopenia. Diseases are identified using the national hospital database (named PMSI) that contains discharge diagnoses for all hospital stays in all private and public hospitals in France. This study was aimed at assessing the positive predictive value (PPV) of hemolytic anemia diagnoses in the French hospital database. Methods: In the PMSI database, every hospital stay contains one primary diagnosis, and possibly one related and several associated diagnoses. They are coded using the International Classification of Diseases, 10th revision (ICD-10) by the physician in charge of the patient or trained nurses from the medical chart. We selected all hospital stays at Toulouse University Hospital, South of France (2860 beds) with a diagnosis of hemolytic anemia (D55.0-D59.9 ICD-10 codes) between January 2017 and December 2017. Medical charts and biological data were reviewed. Hemolytic anemia was defined by anemia with high reticulocyte count (&amp;gt;150 x 109/L), plus at least two of the three following signs of hemolysis: low serum haptoglobin level, hyperbilirubinemia and elevated serum lactate dehydrogenase level. PPVs and their 95% confidence intervals (CI) were calculated by categories of hemolytic anemia: autoimmune hemolytic anemia (AIHA; D59.1 ICD-10 code), enzyme deficiency (D55.0-D55.9 ICD-10 codes), hereditary spherocytosis (D58.0 ICD-10 code) and hemoglobinopathy (D56.0-D57.9 and D58.2 ICD-10 codes). AIHA was defined by positive direct antiglobulin test (DAT); enzyme deficiency was defined by low enzyme dosage and negative DAT; hereditary spherocytosis was defined by negative DAT and either positive flow cytometry osmotic fragility test either positive eosin-5'-maleimide binding test; hemoglobinopathy was defined by compatible blood count and positive hemoglobin electrophoresis. Results: During the study period, 54 patients had at least one hospital stay with a discharge diagnosis of AIHA, 12 with enzyme deficiency, 10 with hereditary spherocytosis, 92 with thalassemia and 285 with sickle cell disease. We further excluded 13 patients due to missing data, precluding disease classification. AIHA was confirmed in 49/53 patients; the PPV was 92.5% (95% CI: 85.3%-99.6%). Enzyme deficiency was confirmed in 8/12 patients (including G6PD deficiency: 7/9) and hereditary spherocytosis in 10/10 patients. Thalassemia was confirmed in 72/83 patients; the PPV was 86.7% (95% CI: 79.5%-94.0%); however, the code of thalassemia type was not adequately coded in most cases (PPV&amp;lt;30%). Sickle cell disease was confirmed in 279/284 patients; the PPV was 98.2% (95% CI: 96.7%-99.8%). Conclusions: Overall, this study confirms high PPV values for hemolytic anemia discharge diagnoses recorded in the French hospital database, allowing epidemiological studies using this source of data. Disclosures Moulis: CSL Behring: Research Funding; Amgen pharma: Research Funding, Speakers Bureau; Novartis pharma: Research Funding, Speakers Bureau.

Early lactate measurement is associated with better outcomes in septic patients with an elevated serum lactate level

BackgroundThe optimal timing of lactate measurement for septic patients in the intensive care unit (ICU) remains controversial, and whether initiating and repeating the lactate measurement earlier could make a difference for septic patients with an elevated lactate level remains unexplored.MethodsThis was a retrospective observational study that included septic patients with an initial lactate level > 2.0 mmol/L after ICU admission, and all data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The main exposure of interest was the early lactate measurement, which was defined as an initial lactate level measurement within 1 h after ICU admission. The primary outcome was 28-day mortality.ResultsA total of 2642 eligible subjects were enrolled, including 738 patients who had initial lactate measurements completed within 1 h (EL group) and 1904 patients who had initial lactate measurements completed more than 1 h after ICU admission (LL group). A significant beneficial effect of early lactate measurement in terms of 28-day mortality was observed: the adjusted odds ratio (OR) was 0.69 (95% CI 0.55–0.87; p = 0.001), and the mediation effect of the time to initial vasopressor administration was significant (average causal mediation effect (ACME) − 0.018; 95% CI − 0.005 approximately to − 0.036; p < 0.001). A strong relationship between delayed initial lactate measurement and risk-adjusted 28-day mortality was noted (OR 1.04; 95% CI 1.02–1.05; p < 0.001). Each hour of delay in remeasuring the lactate level was associated with an increase in 28-day mortality in the EL group (OR 1.09; 95% CI 1.04–1.15; p < 0.001). Further analysis demonstrated that repeating the measurement 3 h after the initial lactate measurement led to a significant difference.ConclusionsEarly lactate measurement is associated with a lower risk-adjusted 28-day mortality rate in septic patients with lactate levels > 2.0 mmol/L. A shorter time to the initial vasopressor administration may contribute to this relationship. Repeating the lactate measurement within 3 h after the initial measurement is appropriate for patients whose lactate levels were measured within 1 h of admission.

Curcumin Ameliorates Lead-Induced Hepatotoxicity by Suppressing Oxidative Stress and Inflammation, and Modulating Akt/GSK-3β Signaling Pathway.

Lead (Pb) is a toxic heavy metal pollutant with adverse effects on the liver and other body organs. Curcumin (CUR) is the principal curcuminoid of turmeric and possesses strong antioxidant and anti-inflammatory activities. This study explored the protective effect of CUR on Pb hepatotoxicity with an emphasis on oxidative stress, inflammation and Akt/GSK-3β signaling. Rats received lead acetate and CUR and/or ascorbic acid (AA) for seven days and samples were collected for analyses. Pb(II) induced liver injury manifested by elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH), as well as histopathological alterations, including massive hepatocyte degeneration and increased collagen deposition. Lipid peroxidation, nitric oxide, TNF-α and DNA fragmentation were increased, whereas antioxidant defenses were diminished in the liver of Pb(II)-intoxicated rats. Pb(II) increased hepatic NF-κB and JNK phosphorylation and caspase-3 cleavage, whereas Akt and GSK-3β phosphorylation was decreased. CUR and/or AA ameliorated liver function, prevented tissue injury, and suppressed oxidative stress, DNA damage, NF-κB, JNK and caspase-3. In addition, CUR and/or AA activated Akt and inhibited GSK-3β in Pb(II)-induced rats. In conclusion, CUR prevents Pb(II) hepatotoxicity via attenuation of oxidative injury and inflammation, activation of Akt and inhibition of GSK-3β. However, further studies scrutinizing the exact role of Akt/GSK-3β signaling are recommended.

The ABC-D score improves the sensitivity in predicting need for massive transfusion in pediatric trauma patients

PurposeEarly and accurate identification of pediatric trauma patients who will require massive transfusion (MT) remains difficult, and MT activation criteria are not well established. In children, the addition of shock index-pediatric age-adjusted (SIPA) to the ABC score (ABC-S) only modestly improves the sensitivity of the ABC score. We hypothesized that the discriminate ability of the ABC-S score would improve with the addition of elevated serum lactate and base deficit (ABCD score). MethodsWe identified children between 1 and 18 years old who received a pRBC transfusion between 2008 and 2018 from our trauma registry. We calculated sensitivity, specificity, and accuracy of the ABC, ABC-S, and ABCD scores to determine the need for MT. ResultsWe included 211 children, of which 66 required MT. The best predictor of MT was achieved by adding BD and lactate to the ABC-S score, with an AUC of 0.805. An ABCD score of 3 or greater was 77.4% sensitive and 78.8% specific at predicting the need for MT. Pediatric trauma patients that required MT had higher injury severity score (p = 0.005), lactate (p = 0.002), base deficit (p = <0.0001). Mortality was higher in the MT group (45.5% vs 15.3%, p = 0.0004). ConclusionsThe ABCD score improves the sensitivity of activating MT in pediatric trauma patients. Study TypeTreatment Study. Level of EvidenceLevel III.

Clinical impact of intraoperative hyperlactatemia during craniotomy.

Patients often develop markedly elevated serum lactate levels during craniotomy although the reason for this is not entirely understood. Elevated lactate levels have been associated with poor outcomes in critically ill septic shock patients, as well as patients undergoing abdominal and cardiac surgeries. We investigated whether elevated lactate in craniotomy patients is associated with neurologic complications (new neurological deficits) as well as systemic complications. We performed a cohort study of elective craniotomy patients. Demographic and intraoperative data were collected, as well as three timed intraoperative arterial lactate values. Additional lactate, creatinine and troponin values were collected immediately postoperatively as well as 12 and 24 hours postoperatively. Assessment for neurologic deficit was performed at 6 hours and 2 weeks postoperatively. Hospital length-of-stay and 30-day mortality were collected. Interim analysis of 81 patients showed that no patient had postoperative myocardial infarction, renal failure, or mortality within 30 days of surgery. There was no difference in the incidence of new neurologic deficit in patients with or without elevated lactate (10/26, 38.5% vs. 15/55 27.3%, p = 0.31). Median length of stay was significantly longer in patients with elevated lactate (6.5 vs. 3 days, p = 0.003). Study enrollment was terminated early due to futility (futility index 0.16). Elevated intraoperative serum lactate was not associated with new postoperative neurologic deficits, other end organ events, or 30 day mortality. Serum lactate was related to longer hospital stay.