Elevated Serum Lactate Dehydrogenase Levels Research Articles

Pemetrexed Plus Lenalidomide for Relapsed/Refractory Primary Central Nervous System Lymphoma: A Prospective Single-Arm Phase II Study.

The prognosis of relapsed/refractory (R/R) primary central nervous system lymphoma (PCNSL) is dismal, and there are limited treatment options for these patients. This was a prospective single-arm phase II study of combined pemetrexed and lenalidomide for salvage treatment of R/R PCNSL. Patients with R/R PCNSL (n = 38) who had undergone two or more different therapeutic regimens and experienced disease progression or recurrence were enrolled. The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Patients were followed up for a median of 18 (range, 1–36) months. ORR was 68.4%, with median PFS and OS of 6 and 18 months, respectively. Adverse events (AEs) included myelosuppression, fatigue, nausea, fever, infection, cardiac disease, and thrombogenesis. Commonly observed grade ≥ 3 AEs included neutropenia (5.3%), leukopenia (2.6%), thrombocytopenia (7.9%), and infection (2.6%). Elevated lactate dehydrogenase (LDH) levels (χ2 = 13.25; P = 0.0003) and bulky disease (P = 0.032; χ2 = 4.580) were associated with short PFS. Elevated serum LDH level (P = 0.011; χ2 = 6.560), abnormal lymphoma cells in the cerebrospinal fluid (CSF) [P = 0.011; χ2 = 6.445], and multiple lesions (P = 0.036; χ2 = 4.404) were significantly associated with poorer OS. Abnormal lymphoma cells in the CSF were an independent predictor of poor prognosis on multivariate analysis (P = 0.034; hazard ratio (HR) = 2.836; 95% confidence interval, 1.082–7.434). Our results indicate that pemetrexed plus lenalidomide is effective for heavily treated R/R PCNSL, with moderate toxicity. Trial registration: #ChiCTR1900028070.

Clinical and chest computed tomography features of patients suffering from mild and severe COVID-19 at Fayoum University Hospital in Egypt

BackgroundIn pandemic COVID-19 (coronavirus disease 2019), the prognosis of patients has been determined using clinical data and CT (computed tomography) scans, but it is still unclear whether chest CT characteristics are correlated to COVID-19 severity.AimTo explore the potential association between clinical data and 25-point CT score and investigate their predictive significance in COVID-19-positive patients at Fayoum University Hospital in Egypt.MethodsThis study was conducted on 252 Egyptian COVID-19 patients at Fayoum University Hospital in Egypt. The patients were classified into two groups: a mild group (174 patients) and a severe group (78 patients). The results of clinical laboratory data, and CT scans of severe and mild patients, were collected, analyzed, and compared.ResultsThe severe group show high significance levels of CRP, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, urea, ferritin, lactate dehydrogenase (LDH), neutrophil percent, and heart rate (HR) than the mild group. Lymphopenia, hypoalbuminemia, hypocalcemia, and decreased oxygen saturation (SpO2) were the most observed abnormalities in severe COVID-19 patients. Lymphopenia, low SpO2 and albumin levels, elevated serum LDH, ferritin, urea, and CRP levels were found to be significantly correlated with severity CT score (P<0.0001).ConclusionThe clinical severity of COVID-19 and the CT score are highly correlated. Our findings indicate that the CT scoring system can help to predict COVID-19 disease outcomes and has a strong correlation with clinical laboratory testing.

Abstract 3537: Pharmacologic inhibition of the glycolytic pathway improves response to immune checkpoint blockade

Abstract Preferential engagement in glycolysis is a hallmark of cancer cells and contributes to the progression and metastasis of many tumor types, including melanoma and triple-negative breast cancer (TNBC). Tumor reliance on glycolysis is emerging as a mechanism of resistance to immunotherapy, due in part to lactate-mediated immunosuppression and competition for glucose between effector T cells and tumor cells within the tumor microenvironment. Elevated serum lactate dehydrogenase (LDH) levels are associated with poor outcomes in cancer patients, and we observed that serum lactate and LDH levels correlate with primary tumor burden in mice. We recently demonstrated that genetic dampening of LDH subunit A in 4T1 TNBC results in improved and long-lasting anti-tumor responses to CTLA-4 blockade in mice. Therefore, we hypothesize that combining LDH inhibitors (LDHi) with CTLA-4 blockade will be an effective strategy to combat resistance to anti-CTLA-4 therapy. Since activated T cells rely on glycolysis, we first determined that glycolytic cancers overexpress LDH (compared with immune cells) by analyzing single-cell transcripts from patient melanoma biopsies. LDHA gene expression is significantly higher in malignant cells than infiltrating CD8+ T cells, and we replicated these findings at the protein level in whole cell lysate from B16-F10 melanoma and 4T1 TNBC tumor cells and tumor-antigen specific T cells in vitro. We show that LDHi reduces tumor lactate production and glucose consumption without inhibiting anti-tumor T-cell killing in vitro. The anti-tumor effect of LDH inhibition requires adaptive immunity, as daily treatment with LDHi results in reduced tumor burden in immunocompetent but not immune-deficient mice. Finally, we show that targeting LDH in combination with CTLA-4 blockade is more effective in slowing B16-F10 growth compared with CTLA-4 blockade alone, and that this combination promotes effector T cell activation while destabilizing regulatory T cell function. Citation Format: Svena Verma, Inna Serganova, Sadna Budhu, Lauren Dong, Myat Ko, Levi Mangarin, Taha Merghoub, Jedd Wolchok, Roberta Zappasodi. Pharmacologic inhibition of the glycolytic pathway improves response to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3537.

MEK inhibitors for pre-treated, NRAS-mutated metastatic melanoma: A multi-centre, retrospective study

BackgroundMEK inhibitors (MEKi) have shown clinical efficacy for NRAS-mutated, metastasized melanoma in randomised controlled trials, yet their clinical use is currently restricted to advanced, pre-treated patients, which is a different situation compared to previous trials. Data on their efficacy in the current real-world use are scarce. MethodsIn this retrospective, multi-centre study, we evaluated the clinical course of disease of patients treated with MEKi with at least one previous treatment line in five German cancer centres. ResultsThirty-three patients were included, 19 males (58%) and 14 females (42%), with a median age of 64 years. Ninety-one percent of patients were pre-treated with immune checkpoint inhibitors, 90% of patients had elevated serum lactate dehydrogenase (LDH) levels at treatment initiation, 33% suffered from cerebral metastases and 30% had an Eastern Cooperative Oncology Group performance status of 2 or higher. The response rate was 18.2%; the disease control rate was 48.5%. Median progression-free survival was 2.8 months (95% confidence interval (CI): 1.6–3.9 months), and median overall survival was 7.1 months (95% CI: 5.8–8.3 months). In subgroup analysis, clinical efficacy was similar also in patients with high LDH levels and cerebral metastases, and there was a better outcome in males and in patients treated with trametinib vs. other MEKi, which may be based on selection bias. Overall, the clinical efficacy was similar compared to previous clinical trials in earlier treatment lines. ConclusionsMEKi fulfil the need for an in-between treatment to stabilise the course of disease in advanced NRAS-mutated melanoma, but expectations regarding ongoing tumour response should be tempered.

Burkitt lymphoma – no impact of HIV status on outcomes with rituximab-based chemoimmunotherapy

We analyzed the prognostic factors for treatment outcomes amongst 34 patients with adult Burkitt lymphoma (BL) who received rituximab with standard first-line chemotherapy. Seven patients had human immunodeficiency virus (HIV)-associated BL. Overall, we observed a complete remission (CR) rate of 91.2%, and 10-year progression-free survival (PFS) and overall survival (OS) was 84.8 and 88.2%, respectively. In patients with concomitant HIV, the prognosis was not different with 10-year PFS of 100% and OS of 88.2%. The majority (71.4%) of HIV-associated BL patients received dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) and had excellent outcomes with 100% CR and no relapses. Central nervous system (CNS) disease, bone marrow involvement and elevated serum lactate dehydrogenase (LDH) levels more than 3 times upper limit of normal (ULN) were associated with poorer survival outcomes. Patients with refractory disease, whilst uncommon (n = 4), had dismal outcomes. Patients with adult BL, including HIV-related cases, harbor generally good prognosis in the modern era.

Clinical characteristics of paroxysmal nocturnal hemoglobinuria (PNH) complicated with ischemic bowel disease

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematopoietic stem cell disease. Gastrointestinal involvement is rarely seen in PNH. This study aims to analyze the clinical features in PNH patients complicated with ischemic bowel disease. Clinical date of 6 patients were collected at Peking Union Medical College Hospital from January 2010 to December 2020. The clinical manifestations, laboratory tests,imaging, endoscopic,and histopathological features and treatment were analyzed.Five in 6 patients were men, with a median age of 31 years old at onset. Most of disease course were recurrent episodes of chronic disease, with abdominal pain (5/6) and gastrointestinal bleeding (5/6). Laboratory examinations showed pancytopenia, reticulocytosis, elevated serum lactate dehydrogenase, high D-dimer and C-reactive protein levels in all patients. Multiple segments of small intestine were the most commonly involved and colon was also affected. Abdominal CT scan showed thickening and roughness or exudation of the intestinal wall (6/6), increased mesenteric density or "comb sign"(4/6), and cholestasis or gallbladder stones (5/6). Endoscopic manifestations included irregular shallow ulcers in the annular cavity (5/6), swelling mucosa with well-defined margins (6/6). Pathological biopsy revealed chronic inflammation of mucosa. The efficacy of steroids combined with anticoagulant therapy was better than that of steroids alone. Ischemic bowel disease in PNH patients is different from typical ischemic enteritis. Young patients, involvement of intestine with multiple segments are common characteristics. The anticoagulant is an essential agent for these patients.

Liver Injury among Coronavirus Disease Patients

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as Coronavirus disease 2019 (COVID-19), is a novel coronavirus first identified in December 2019 and has a broad spectrum of clinical presentations. With the expansion of related research, it was found that in addition to respiratory symptoms, digestive involvements and liver injury were reported among COVID-19 patients. Abnormal liver function was observed in cases of COVID-19, manifesting mainly as isolated elevated serum transaminase and lactate dehydrogenase levels. The current review highlights the possible explanation for liver injury among COVID-19 patients.

Clinicopathological features of syncytial variant nodular sclerosis Hodgkin lymphoma

The syncytial variant of nodular sclerosis Hodgkin lymphoma (SV-NSHL) is uncommon, and its clinicopathological features have not been well analyzed. In this study, we collected 142 cases of SV-NSHL. There were 76 (53.5%) males and 66 (46.5%) females with a median age of 28 years (range, 12-78); 59.9% were younger than 30 years. Patients usually presented with a mediastinal mass (97.6%) and often with bulky (35.7%) and advanced stage disease (3 or 4) (39.7%). Follow-up showed that 61.1% of patients developed relapse after standard therapy. Morphologically, the neoplasms were composed of sheets or large clusters of pleomorphic neoplastic cells with a cohesive appearance that were frequently associated with necrosis. Neutrophils and eosinophils were frequent in the background, whereas small lymphocytes were decreased. Immunohistochemical analysis showed that the following markers were frequently positive: CD30 (100%), MUM1/IRF4 (96%), PAX5 (95%), PD-L1 (91%), and CD15 (80%). CD45 was negative in all cases. Epstein-Barr virus-encoded small RNA (EBER) was detected in 19% of cases. In this cohort, age above 30 years (P=.0430), presence of B-type symptoms (P=.0394), elevated serum lactate dehydrogenase level (P=.0004), and disease relapse (P=.0108) were associated with a poorer overall survival. In contrast, patients with EBER-positive neoplasms had a better survival (P=.0418). Compared with a control group of non-SV-NSHL patients, patients with SV-NSHL were associated with a poorer overall survival (P=.011). These data suggest that SV morphology is associated with a poorer prognosis in patients treated with traditional standard-of-care therapy for classic Hodgkin lymphoma.

Long Term Outcome Patterns and Risk Factors for Early Mortality and Disease Progression in ALK-Positive Anaplastic Large Cell Lymphoma

Long Term Outcome Patterns and Risk Factors for Early Mortality and Disease Progression in ALK-Positive Anaplastic Large Cell Lymphoma

Chronic systemic capillary leak syndrome associated with an intravascular large B-cell lymphoma in a patient undergoing hemodialysis: a case report with literature review

BackgroundSystemic capillary leak syndrome (SCLS) is a rare disorder characterized by hypotension, hemoconcentration, and hypoalbuminemia associated with increased capillary endothelium permeability. Patients with a chronic form of SCLS present with persistent and progressive generalized edema. However, there have been no reports of chronic SCLS in patients undergoing hemodialysis. Herein, we report a case of chronic SCLS associated with an intravascular large B-cell lymphoma (IVLBCL) in a patient undergoing hemodialysis.Case presentationA 71-year-old male had been on hemodialysis for five years due to diabetic nephropathy. Difficulty in body fluid removal was observed during hemodialysis, and the patient was admitted to our hospital due to exacerbated weight gain and lower limb edema. He had elevated serum lactate dehydrogenase (LDH) levels and thrombocytopenia. His blood pressure was low, and his serum brain natriuretic peptide level was relatively low, despite the increase in body fluid volume. His clinical characteristics suggested a chronic form of SCLS. Random skin biopsy revealed IVLBCL; however, the association between IVLBCL and chronic SCLS remained unclear. He underwent chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone, followed by rituximab. After the treatment, his serum LDH level decreased, and the difficulty in body fluid removal during hemodialysis improved. The patient’s chronic SCLS seemed to be complicated by IVLBCL.ConclusionsPatients with chronic SCLS who are undergoing hemodialysis seem to present with difficulties in fluid removal. The frequency of SCLS complications in cases with malignant lymphomas, including IVLBCL, is considered to be extremely low. However, clinicians should be aware of SCLS as a complication of malignant lymphomas.

MM-315: Impact of Stratification of Levels of Serum Lactate Dehydrogenase (LDH) at Diagnosis on Overall Survival (OS) in Newly Diagnosed Multiple Myeloma (NDMM)

Context Elevated serum LDH level is an adverse prognostic factor in NDMM. Quantitative serum LDH levels range from over the upper limit of normal (ULN) to levels 2- or more-fold higher than ULN. Objective The “normal versus elevated” classification of serum LDH level can fail to discriminate between different NDMM disease biology. Thus, we attempted to further stratify NDMM patients by their serum LDH level and determine the impact on OS outcomes. Design and Setting The cohort included patients diagnosed with NDMM from the Mayo Clinic, Rochester, from 2003 to 2017, treated with novel agent induction therapy with measured serum LDH levels at the time of diagnosis. Patients The cohort consists of 1,196 NDMM patients with median age of 65 (22–95) years. R-ISS classification was available for 968 patients and is distributed as follows: 210 (22%) stage 1, 639 (66%) stage 2, and 119 (12%) stage 3. Cytogenetic risk data was available for 970 patients: 215 (22%) high-risk and 755 (78%) standard-risk. Main Outcome Measures The serum LDH levels were stratified into three levels: normal (LDH < 222 U/L), elevated (LDH 223–444 U/L), and very elevated (LDH >444 U/L). Survival analysis was performed using the Kaplan–Meier method and compared via Wilcoxon method. Results Median serum LDH level was 162 U/L (3–1260), and an elevated LDH was present in 199 patients (17%). Median OS for patients with normal (N = 997; 83%), elevated (N = 170; 13%), and very elevated (N = 29; 3%) LDH levels were 76 months, 57 months, and 23 months respectively (P < 0.001). Impact of LDH levels on OS by R-ISS stage and cytogenetic risk was analyzed, and regardless of R-ISS stage/cytogenetic risk, very elevated patients had significantly smaller median OS (discrepancy ranging from 19 months [R-ISS stage 3] to 36 months [R-ISS stage 2] than elevated patients (P ≤ 0.0022 for all classifications). Conclusion A small subset (3%) of NDMM have very elevated LDH levels that confer exceptionally poor OS, irrespective of R-ISS stage and cytogenetic risk. Future studies determining disease biology responsible for such poor OS outcomes are warranted. Acknowledgments Research was supported by the National Cancer Institute [Grant Number CA254961], the Helen Diller Family Foundation, and the Marion Schwartz Foundation for Multiple Myeloma. Elevated serum LDH level is an adverse prognostic factor in NDMM. Quantitative serum LDH levels range from over the upper limit of normal (ULN) to levels 2- or more-fold higher than ULN. The “normal versus elevated” classification of serum LDH level can fail to discriminate between different NDMM disease biology. Thus, we attempted to further stratify NDMM patients by their serum LDH level and determine the impact on OS outcomes. The cohort included patients diagnosed with NDMM from the Mayo Clinic, Rochester, from 2003 to 2017, treated with novel agent induction therapy with measured serum LDH levels at the time of diagnosis. The cohort consists of 1,196 NDMM patients with median age of 65 (22–95) years. R-ISS classification was available for 968 patients and is distributed as follows: 210 (22%) stage 1, 639 (66%) stage 2, and 119 (12%) stage 3. Cytogenetic risk data was available for 970 patients: 215 (22%) high-risk and 755 (78%) standard-risk. The serum LDH levels were stratified into three levels: normal (LDH < 222 U/L), elevated (LDH 223–444 U/L), and very elevated (LDH >444 U/L). Survival analysis was performed using the Kaplan–Meier method and compared via Wilcoxon method. Median serum LDH level was 162 U/L (3–1260), and an elevated LDH was present in 199 patients (17%). Median OS for patients with normal (N = 997; 83%), elevated (N = 170; 13%), and very elevated (N = 29; 3%) LDH levels were 76 months, 57 months, and 23 months respectively (P < 0.001). Impact of LDH levels on OS by R-ISS stage and cytogenetic risk was analyzed, and regardless of R-ISS stage/cytogenetic risk, very elevated patients had significantly smaller median OS (discrepancy ranging from 19 months [R-ISS stage 3] to 36 months [R-ISS stage 2] than elevated patients (P ≤ 0.0022 for all classifications). A small subset (3%) of NDMM have very elevated LDH levels that confer exceptionally poor OS, irrespective of R-ISS stage and cytogenetic risk. Future studies determining disease biology responsible for such poor OS outcomes are warranted.

Evaluation of Tumor Burden for Predicting Survival in Patients with Follicular Lymphoma Receiving First-Line R-CHOP Treatment: Comparison of Different Definition of GELF Criteria

▪Background: The time to treatment initiation is determined by tumor burden in patients with follicular lymphoma (FL). Tumor burden defined by Groupe d'Etude des Lymphomas Folliculaires (GELF) criteria is one of the widely used to define patients in whom immediate therapy is necessary. GELF criteria are, however, developed in the pre-rituximab era. The definition of tumor burden is not uniform in each clinical trial, and prognosis of patients according to tumor burden has not been well studied. Exploratory analyses were conducted to study clinical relevance of tumor burden defined by GELF criteria in the rituximab era.Methods: Patients are identified from the list of patients with newly diagnosed FL at our institute from 1999 to 2011. Patients were included if they were diagnosed as clinical stage II to IV, and received first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) based chemotherapy. Three different types of GELF criteria [GELF criteria reported by Brice et al . (J Clin Oncol 1997), GELF1; reported by Ardeshna et al . (Lancet Oncol 2014), GELF2; and reported by Salles et al . (Lancet 2011), GELF3] were evaluated to determine tumor burden predicting clinical outcomes. In the analyses, multiplicity adjustments were not required based on an exploratory research design.In the group of GELF1, high-tumor-burden was defined if patients had at least the following parameters: tumor mass with a diameter ≥ 7 cm; involvement of three or more nodal sites with a diameter > 3 cm; presence of systemic symptoms; presence of substantial splenic enlargement; presence of serous effusion; presence of local organ compression; or leukemia/cytopenia. In the group of GELF2, high-tumor-burden was defined if at least the following parameters: tumor mass with a diameter ≥ 7 cm; involvement of three or more nodal sites with a diameter > 3 cm; presence of substantial splenic enlargement; presence of serous effusion; or elevated serum lactate dehydrogenase (LDH) levels. In the group of GELF3, high-tumor-burden was defined if at least the following parameters: presence of systemic symptoms; presence of local organ compression; or elevated serum β2-microbloblin in addition to parameters including GELF2.Results: Among 199 patients, data were available for 92 patients. The median age was 57 years (range 39-79 years) and 42 (46%) patients were male. Twenty-seven patients (29%) had poor risk FLIPI scores and 28 (30 %) had poor-risk FLIPI2 scores. According to GELF criteria, 31%, 35%, and 53% patients were diagnosed as high-tumor-burden defined by GELF1, GELF2, and GELF3, respectively.With a median follow-up of 9.3 years, the 5-year overall (OS) and progression-free survival (PFS) rates of all 92 patients were 90% (95%CI: 82 to 95) and 60% (95%CI: 48 to 68). According to three types of criteria, 5-years OS of high-tumor-burden and low-tumor-burden were 77% vs. 97% in GELF1 [hazard ratio (HR) 4.1 (95 % CI 1.3-13.9), P= 0.011]; 77% vs. 98% in GELF2 [HR 4.0 (95 % CI 1.2-13.), P= 0.013]; 83% vs.100% in GELF3 [HR 11.1 (95 % CI 1.4-86.4), P= 0.004]. Five-year PFS of high-tumor-burden and low-tumor burden were 42% vs. 67% in GELF1 [HR 2.5 (95 % CI 1.4-4.5), P= 0.0017]; 43% vs. 68% in GELF2 [HR 2.4 (95 % CI 1.3-4.4), P= 0.0024]; 49% vs. 72% in GELF3 [HR 2.7 (95 % CI 1.4-5.3), P= 0.0021]. Patients with high-tumor-burden showed worse OS and PFS in each of these criteria (Figure 1).We next compared prognostic value of tumor burden defined by each of these criteria. The number of patients with high-tumor-burden in both GELF1 and GELF2 were 28, and the number of patients with low-tumor-burden in both GELF1 and GELF2 were 54. The number of patient with high-tumor-burden in GELF1 and low-tumor-burden in GELF2 were three; on the other hands, the number of patient with high-tumor-burden in GELF2 and low-tumor-burden in GELF1 were seven. Patients with high-tumor-burden in GELF2 and low-tumor-burden in GELF1 had lower OS and PFS rates compared to those with high-tumor-burden in GELF1 and low-tumor-burden in GELF2, however, no statistical significant difference was observed (Figure 2).Conclusions: High-tumor-burden defined by three types of GELF criteria (GELF1-3) was associated with worse OS and PFS in patients with FL who received first-line R-CHOP based chemotherapy. Evaluation of tumor burden would be important clinical relevance toward selecting patients who required immediate therapy in the rituximab era. [Display omitted] DisclosuresKinoshita:Eli Lilly and Kyowa Hakko Kirin: Honoraria. Yamamoto:AbbVie, Celgene, Ono Pharmaceutical, ARIAD Pharmaceuticals, Novartis, Takeda, Eisai, Solasia, MSD, Chugai, Gilead Sciences: Research Funding; ARIAD Pharmaceuticals/CMIC, Celgene, Novartis, Pfizer, Otsuka Pharmaceutical, Takeda, Kyowa Hakko Kirin, Bristol-Myers Squibb, Sumitomo Dainippon Pharma, Ono Pharmaceutical, Mundipharma, Chugai: Honoraria; Ono Pharmaceutical, Meiji Seika Pharma, Novartis, Otsuka Pharmaceutical, Mundipharma, Boehringer Ingelheim: Consultancy.

Impact of stratifying levels of serum lactate dehydrogenase (LDH) at diagnosis on the overall survival (OS) in newly diagnosed multiple myeloma (NDMM).

e20016 Background: An elevated serum LDH level is an adverse prognostic factor in NDMM. However, this category includes quantitative serum LDH levels that range from just over the upper limit of normal (ULN) to levels that may be 2 or more-fold higher than the ULN. This binary classification of serum LDH level of “normal versus elevated” fails to discriminate between the different disease biology that exists among NDMM patients with elevated serum LDH levels. Thus, we attempted to further stratify NDMM patients by the level of their serum LDH and determine its impact on OS. Methods: The cohort included patients diagnosed with NDMM from the Mayo Clinic, Rochester from 2003 - 2017 who were treated with novel agent induction therapy and had serum LDH levels measured at the time of diagnosis. The serum LDH levels were stratified into three levels: Normal (LDH &lt; 222 U/L), Elevated (LDH 223-444 U/L), and Very Elevated (LDH &gt;444 U/L or &gt;2x upper limit of normal). Survival analysis was performed using the Kaplan-Meier survival analysis and compared via the log-rank method. Results: The cohort consists of 1,196 NDMM patients with a median age of 65 (22 – 95). R-ISS classification and cytogenetic risk were available for 968 and 970 patients respectively. The median serum LDH level was (162 U/L (3- 1260)) and an elevated LDH was present in 199 patients (17%). The median OS for patients with normal (N = 997; 83%), elevated (N = 170; 13%) and very elevated (N = 29; 3%) LDH levels were 76 months, 57 months and 23 months respectively (P &lt; 0.001). The impact of these different levels of LDH on OS by R-ISS stage and cytogenetic risk is shown in the Table. Conclusions: A very small subset of NDMM patients has very elevated LDH levels that confer an exceptionally poor OS irrespective of R-ISS stage and cytogenetic risk. Future studies elucidating their disease biology responsible for such poor OS outcomes are warranted.[Table: see text]

27. PREDICTIVE VALUE OF LACTATE DEHYDROGENASE FOR POOR MATERNAL AND PERINATAL OUTCOMES IN PATIENTS WITH PRE-ECLAMPSIA: A META-ANALYSIS

Background: A large number of studies have reported the relationships between serum lactate dehydrogenase (LDH) and prognosis of pre-eclampsia. However, the result is still controversial and no consensus has been reached. Objective: The aim of the study was to find out the role of serum LDH in prediction of poor maternal and perinatal outcomes in patients with pre-eclampsia. Methods: We performed a systematic computerized search for eligible articles from PubMed, Europe PMC, ProQuest, EBSCOhost, and Google Scholar databases from inception to January 2021. The pooled odds ratio (OR) and 95% confidence intervals (CIs) of all events of interest and event-free subjects were obtained to assess the predictive value of serum LDH in predicting composite poor outcomes. Results: A total of 11 studies that assessed patients with pre-eclampsia were included. Overall, elevated serum LDH level in pre-eclamptic patients was associated with poor maternal and perinatal outcomes [pooled OR: 7.92 (95% CI = 5.75–10.93); pooled OR: 8.08 (95% CI = 4.40–14.83) respectively]. Subgroup analyses showed that elevated LDH also increased risk of placental abruption, disseminated intravascular coagulation, acute renal failure, eclampsia, and HELLP syndrome. The resulting P-value showed no heterogeneity among articles (P &gt; 0.01). No evidence of asymmetry was shown in the funnel plot, thus no publication bias existed in the included studies. Conclusions: This meta-analysis demonstrates that elevated serum LDH level is apparently associated with poor outcomes in patients with pre-eclampsia and serum LDH could be a prognostic biomarker for pre-eclamptic patients.

Betanin and Allicin Ameliorate Adriamycin-Induced Cardiotoxicity in Rats by Ameliorating Cardiac Ischemia and Improving Antioxidant Efficiency

Aims: To investigate the protective effects of betanin and allicin against adriamycin (ADR)-induced cardiotoxicity.&#x0D; Study Design: Experimental animal model.&#x0D; Place and Duration of Study: King Abdul-Aziz University, Jeddah, Saudi Arabia; 10 days.&#x0D; Methodology: Adult female Wistar rats were allocated to the following groups (n = 10 per group): Control, received water, a standard diet for 10 days and i.p normal saline on day 8; ADR, intraperitoneal injection with 15 mg/kg ADR as a single dose on day 8; ADR+BE, betanin (20 mg/kg) administration followed by i.p. injection of ADR (15 mg/kg); ADR+ALL, allicin (20 mg/kg) administration followed by i.p. injection of ADR; and ADR+BE+ALL, equal volumes of betanin and allicin followed by ADR (15 mg/kg). Hemodynamic characteristics of the cardiovascular system and electrocardiography were evaluated. Blood samples were obtained to assess cardiac enzymes; cardiac homogenates were processed to analyze oxidative and antioxidant parameters and low-grade inflammatory indicators. Histopathological evaluation of heart tissues was also conducted.&#x0D; Results: Rats pre-administered betanin and allicin were protected from ADR-associated ischemia based on the significant (P &lt; .05) shortening of QT, QTC interval, QRS, and T peak Tend interval compared with the ADR group. Betanin and allicin pre-treatment significantly decreased the ADR-induced elevated serum creatine kinase-MB and lactate dehydrogenase levels. ADR-elevated cardiac oxidative parameters, along with the serum concentrations of the tumor necrosis factor-alpha and the cardiac transforming growth factor-beta, were significantly inhibited by betanin and allicin. Histopathological findings confirmed the biochemical results. Betanin and allicin reduced ADR-induced heart damage by inhibiting several pathways, including those of oxidative stress and inflammation.&#x0D; Conclusion: Betanin and allicin may be promising cardioprotective agents owing to their antioxidant and cytoprotective properties and could thus be used as adjuvant treatment for cancer therapy.

B7-H6 is a new potential biomarker and therapeutic target of T-lymphoblastic lymphoma.

BackgroundB7-H6 is a novel co-stimulatory protein exclusively expressed on a variety of cancer cells and associated with poor prognosis. T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive hematological malignancy whose treatment requires reliable prognostic biomarkers and therapeutic targets. However, the rare nature and delayed progression of T-LBL have limited its clinical management.MethodsThe expression of B7-H6 was analyzed by immunohistochemistry (IHC) in 65 T-LBL samples; the association with the clinicopathological characteristics and prognosis was also investigated. B7-H6-depleted Jurkat cells were also generated to investigate the effect of B7-H6 on cell proliferation, migration, and invasion. RNA sequencing was used to explore differentially expressed genes.ResultsB7-H6 was expressed in 61.5% (40/65) of T-LBL patients; of note, 38.5% (25/65) of patients showed membrane/cytoplasmic expression of B7-H6. Although the expression of B7-H6 varied across samples and did not correlate with patient survival, it was significantly associated with B symptoms, high ECOG scores (3 to 4), elevated serum lactate dehydrogenase level, and reduced complete remission at interim evaluation. B7-H6 underwent translocation into the nucleus of T-LBL cells, showing a specific nuclear localization sequence in the C-terminus. Moreover, the depletion of B7-H6 in Jurkat cells impaired cell proliferation, migration, and invasion. RNAseq showed the differential expression of RAG-1, which may be involved in the tumorigenesis of T-LBL.ConclusionsB7-H6 may serve as a novel prognostic biomarker and therapeutic target of T-LBL.

Preoperative Predictors of Early Mortality Risk in Isocitrate Dehydrogenase-Wild-Type Glioblastoma Patients Treated with Standard Therapy.

PurposeEarly identification of early mortality for glioblastoma (GBM) patients based on laboratory findings at the time of diagnosis could improve the overall survival. The study aimed to explore preoperative factors associated with higher risk of early death (within 1 year after surgery) for isocitrate dehydrogenase (IDH) -wild-type (wt) GBM patients.Patients and MethodsWe conducted a retrospective analysis of 194 IDH-wt GBM patients who underwent standard treatment. The probability of dying within 1 year after gross total resection (GTR) was defined as the end point “early mortality”. Retrospective collection of predictive factors including clinical characteristics and laboratory data at diagnosis.ResultsMedian follow-up time after GTR was 16 months (3–41 months). Forty-two patients died within 1 year after surgery (1‐year mortality rate: 21.6%). All potential predictive factors were assessed on univariate analyses, which revealed the following factors as associated with higher risk of early death: older age (P = 0.013), occurrence of non-seizures symptoms (P = 0.042), special tumor positions (P = 0.046), higher neutrophil-to-lymphocyte ratio (NLR) (P = 0.015), higher red blood cell distribution width (RDW) (P = 0.019), higher lactate dehydrogenase (LDH) (P = 0.005), and higher fibrinogen (FIB) (P = 0.044). In a multivariate analysis, tumor location (P = 0.012), NLR (P = 0.032) and LDH (P = 0.002) were independent predictors of early mortality. The C-index of the nomogram was 0.795. The calibration curve showed good agreement between prediction by nomogram and actual observation.ConclusionTumor location, preoperative elevated NLR and serum LDH level were independent predictors for 1‐year mortality after GTR. We indicate that increased preoperative NLR or LDH may guide patients to review head magnetic resonance imaging (MRI) more frequently and regularly to monitor tumor progression.

Outcome of combination therapy using BRAF and MEK inhibitors among Asian patients with advanced melanoma: An analysis of 112 cases

BackgroundAs most clinical trials evaluating BRAF and MEK inhibitor combination therapy (B + Minh) have been conducted in Western countries, little is known about the effect of B + Minh among East Asian populations. Material and methodsData from patients with advanced melanoma treated using B + Minh (either dabrafenib + trametinib or encorafenib + binimetinib) were retrospectively collected from 16 institutes in Japan. Response rates, adverse events, patterns of failure and survival were analysed. ResultsWe analysed 112 of 144 collected patient records and, of these, 14 had acral/mucosal melanoma. The response rate for the entire cohort was 75.0%. There were no statistical differences in response rates between acral/mucosal and cutaneous melanomas (64.3% versus 76.5%), whereas previous treatment using immune checkpoint inhibitors (ICIs) did not affect response (72.7% versus 73.9%) to B + Minh, response to ICI after B + Minh was only 20%. Patients who achieved complete response had the best overall survival rates at 24 months (94.7%). Elevated serum lactate dehydrogenase levels and 3 or more metastatic sites were independently associated with survival. The most common relapse site was the brain (17.9%). More than half of the patients (58.8%) experienced grade III/IV pyrexia. ConclusionB + Minh was effective among Japanese patients with melanoma, including those with acral/mucosal melanoma. Factors associated with survival were similar to previous Western studies. B + Minh response was not affected by the previous use of ICI; however, vigilance against brain metastasis during B + Minh therapy is required as the brain was our most commonly encountered relapse site.

Immunophenotypic Landscape and Prognosis of Diffuse Large B-Cell Lymphoma with MYC/BCL2 Double Expression: An Analysis of A Prospectively Immunoprofiled Cohort.

Simple SummaryDiffuse large B-cell lymphoma (DLBCL) with MYC/BCL2 double-expression (DE), a recently proposed poor prognostic group, can be easily identified by immunohistochemistry in routine clinical practice. However, clinical outcomes of DE-DLBCL patients vary immensely after R-CHOP immunochemotherapy and prognostic impact of MYC/BCL2-DE was conflicting according to the cell-of-origin, i.e., between germinal center-B-cell (GCB)- and non-GCB-DLBCLs. This implies the heterogeneity within DE-DLBCLs and emphasizes a need for proper risk stratification to select the patients who require more intensive therapy. By analyzing a prospectively immunoprofiled cohort of consecutively diagnosed DLBCL patients, we confirmed the poor prognostic value of MYC/BCL2-DE in DLBCL patients treated with R-CHOP irrespective of the cell-of-origin and international prognostic index. DE-DLBCLs with a concurrent risk factor, especially, elevated serum lactate dehydrogenase (LDH), had the worst survival and DE-DLBCL patients with normal LDH had clinical outcomes similar to those of non-DE-DLBCL patients. Risk stratification of DE-DLBCL based on serum LDH may guide clinical decision-making for DE-DLBCL patients.Diffuse large B-cell lymphoma (DLBCL) patients with MYC/BCL2 double expression (DE) show poor prognosis and their clinical outcomes after R-CHOP therapy vary immensely. We investigated the prognostic value of DE in aggressive B-cell lymphoma patients (n = 461), including those with DLBCL (n = 417) and high-grade B-cell lymphoma (HGBL; n = 44), in a prospectively immunoprofiled cohort. DE was observed in 27.8% of DLBCLs and 43.2% of HGBLs (p = 0.058). DE-DLBCL patients were older (p = 0.040) and more frequently exhibited elevated serum LDH levels (p = 0.002), higher international prognostic index (IPI; p = 0.042), non-germinal-center B-cell phenotype (p < 0.001), and poor response to therapy (p = 0.042) compared to non-DE-DLBCL patients. In R-CHOP-treated DLBCL patients, DE status predicted poor PFS and OS independently of IPI (p < 0.001 for both). Additionally, in DE-DLBCL patients, older age (>60 years; p = 0.017), involvement of ≥2 extranodal sites (p = 0.021), bone marrow involvement (p = 0.001), high IPI (p = 0.017), CD10 expression (p = 0.006), poor performance status (p = 0.028), and elevated LDH levels (p < 0.001) were significantly associated with poor OS. Notably, DE-DLBCL patients with normal LDH levels exhibited similar PFS and OS to those of patients with non-DE-DLBCL. Our findings suggest that MYC/BCL2 DE predicts poor prognosis in DLBCL. Risk stratification of DE-DLBCL patients based on LDH levels may guide clinical decision-making for DE-DLBCL patients.

Identification and Reporting of Cell of Origin, Double-/Triple-Hit and Double Expressor Lymphoma in a Real-World Cohort of Diffuse Large B-Cell Lymphoma Patients

Background The distinction of diffuse large B-cell lymphoma (DLBCL) into cell-of-origin (COO) subgroups (germinal center B-cell-like [GCB] or activated B-cell-like [ABC]) based on gene expression profiling is associated with prognosis and has potential therapeutic implications to mitigate the worse outcome for patients with DLBCL. Other phenotypic and molecular/cytogenetic features such as concurrent translocations of oncogene MYC and BCL2 and/or BCL6 (so-called double-/triple-hit lymphoma, DHL/THL) and coexpression of MYC and BCL2 proteins (so-called double-expressor lymphoma, DEL) are also recognized to have great prognostic impact (Swerdlow SH et al. Blood 2016;127(20):2375-2390). This study investigated the prevalence of COO, DHL/THL and DEL in a real-world cohort of patients with DLBCL who had documented results of diagnostic testing. Methods This study used the Flatiron Health electronic health record-derived de-identified database to abstract information on patients diagnosed with DLBCL between 2011-2019. Information on diagnostic testing from immunohistochemistry (IHC) for expression of MYC, BCL2, BCL6, CD10 or MUM1, and from fluorescence in situ hybridization (FISH) or karyotype analysis for rearrangement of MYC, BCL2 or BCL6 was abstracted from pathology reports or clinical visit notes, where available. We calculated the proportions of COO subgroups (GCB vs. ABC) that were derived from IHC testing results according to Hans algorithm (Hans C et al., Blood 2004;103(1):275-282), DHL/THL, and DEL. We also examined concordance of COO classification derived from IHC testing results with that directly reported by the healthcare providers. Differences in patient characteristics between IHC testing results-derived COO subgroups (GCB vs. ABC) were assessed using chi-square tests. Results 4400 patients had documented results of IHC and 73% (n=3194) can be classified into either GCB or ABC DLBCL (GCB/ABC ratio of 1.38). 3205 patients had documented results of FISH or karyotype analysis and 8% (n=245) were DHL/THL; only 33 patients were DEL. Within the GCB DLBCL patients derived from IHC testing results (n=1854), 163 patients were DHL/THL and 11 were DEL, whereas 24 DHL/THL and 18 DEL were identified within the ABC type (n=1340). When comparing COO classification derived from IHC testing results (n=3194) with that directly reported by the healthcare providers (n=2765), additional 695 and 439 patients can be classified as GCB and ABC DLBCL by IHC, respectively (Table). Univariate analysis showed that patients who were non-White ethnic group, diagnosed in academic centers, with lower body mass index but elevated serum lactate dehydrogenase levels and worse ECOG performance status, and without transformation from a prior indolent lymphoid malignancy, were more likely to be associated with ABC DLBCL (for all variables, p&amp;lt;0.05). There were no clinically meaningful and/or statistically significant differences in IHC testing results-derived COO classification (GCB vs. ABC) by age, gender, year of DLBCL diagnosis, geographic location of residency, type of insurance plan, tumor group stage, documentation of extranodal site or any other primary cancer history at the time of diagnosis. Discussion In this large real-world DLBCL cohort, a lower-than-expected proportion of DEL patients were identified vs. the 20-35% reported in the literature (Karube K and Campo E. Hematology 2015;52(2):97-106). This is likely due to our cohort of patients requiring clear evidence of coexpression for MYC and BCL2 (≥40% and &amp;gt;50%, respectively) that are not related to underlying chromosomal rearrangements, and few pathologists reported levels of percent staining for IHC testing among those with documented positive results of MYC/BCL2 protein coexpression. In addition, results from this study showed that only half of cases had COO classification documented by healthcare providers, despite available IHC results. Although this study indicated lack of details in the reporting of diagnostic testing (e.g. COO identification, levels of percent staining, methods for DLBCL subgroup identification), findings should be interpreted with caution, as patients with DLBCL might have been tested but not documented in the electronic health record system or might have biomarker testing performed at sites outside of the Flatiron Health network. Disclosures Yang: F. Hoffmann-La Roche: Current Employment. Zhang:F. Hoffmann-La Roche: Current Employment. Xiao:F. Hoffmann-La Roche: Current Employment. Hammer:Roche: Consultancy, Honoraria, Research Funding; Caris Lifesciences: Honoraria; PER Med education: Honoraria; PathEdEx: Current equity holder in private company. Prime:F. Hoffmann-La Roche: Current Employment.