Baseline Lactate Dehydrogenase Levels Research Articles

Correlation between LDH levels and response to sorafenib in HCC patients: an analysis of the ITA.LI.CA database.

Lactate dehydrogenase (LDH) is a predictor of clinical outcome in hepatocellular carcinoma (HCC) patients. However, its predictive role in the clinical outcomes of sorafenib treatment has been poorly documented. The correlation between LDH levels and clinical outcomes in HCC patients treated with sorafenib and included in the nationwide Italian database ITA.LI.CA was investigated here. The ITA.LI.CA database contains data for 5,136 HCC patients. All patients treated with sorafenib treatment and with available LDH values were considered. Overall survival (OS) and time to progression (TTP) were compared in patients with LDH levels above and below a defined threshold, determined through an ROC analysis. An explorative analysis investigated the relationship between the variation of LDH levels during treatment and response to sorafenib. Baseline LDH levels were available for 97 patients. The most accurate cutoff value for LDH concentration was 297 U/L. Patients with LDH values above (n=45) and below (n=52) this threshold showed equal OS (12.0 months) and TTP (4.0 months) values. Data on LDH levels during sorafenib treatment were reported for 10 patients. LDH values decreased in 3 patients (mean difference = -219 U/L) who also reported a prolonged OS and TTP versus those with unmodified/increased LDH (OS: NE (not evaluated) vs. 8.0 months, p=0.0083; TTP: 19.0 vs. 3.0 months, p=0.008). The clinical benefits of sorafenib do not seem to be influenced by baseline LDH. According to the results of an explorative analysis, however, a decreased LDH concentration during sorafenib might be associated with improved clinical outcomes.

Ipilimumab in pretreated patients with unresectable or metastatic cutaneous, uveal and mucosal melanoma.

To evaluate the efficacy and tolerability of ipilimumab in an Australian clinical setting, and to assess the association of response with melanoma subtype, BRAF mutation status, absolute lymphocyte count and incidence of serious immune-related adverse events (AEs). Retrospective review of patients with unresectable or metastatic melanoma treated with ipilimumab at an Australian oncology centre between July 2010 and April 2012. Overall survival (OS), progression-free survival (PFS), incidence and severity of AEs. 104 patients were retrospectively followed for a median of 7 months (range 0-30 months). Median OS was 9.6 months (95% CI, 6.6-12.4), and median PFS was 3.0 months (95% CI, 2.7-3.4). The 1- and 2-year survival rates were 42% (95% CI, 32%-52%) and 18% (95% CI, 9%-30%), respectively. Median OS for patients with non-cutaneous (mucosal and uveal) melanomas was almost half that of patients with cutaneous melanoma: 5.8 months (95% CI, 2.8-12.4) v 11.7 months (95% CI, 7.1-13.8); P = 0.11. Raised absolute lymphocyte count was associated with increased PFS (P ≤ 0.005 at all measured time points) but not with OS (P > 0.15). Sex, age, brain metastases, BRAF mutation status, incidence of severe immune-related AEs and baseline lactate dehydrogenase levels did not affect OS or PFS (P > 0.05). Eighteen of 104 patients experienced serious AEs (≥ grade 3), including two treatment-related deaths. In an Australian clinical practice setting, ipilimumab achieved efficacy and tolerability measures similar to those reported in clinical trials. The frequency and severity of ipilimumab-related AEs (including death) are notable, and treatment should occur under the supervision of an experienced clinical team.

Dacarbazine with or without oblimersen (a Bcl-2 antisense oligonucleotide) in chemotherapy-naive patients with advanced melanoma and low–normal serum lactate dehydrogenase

In a previous large randomized, open-label study, retrospective subset analysis revealed that the addition of the Bcl-2 antisense oligonucleotide oblimersen to dacarbazine (Dac) significantly improved overall survival, progression-free survival, and the response rate in chemotherapy-naive patients with advanced melanoma and normal baseline serum lactate dehydrogenase (LDH) levels. To confirm and expand on this observation, we conducted a prospective double-blind, placebo-controlled study to determine whether oblimersen augmented the efficacy of Dac in advanced melanoma patients with low-normal baseline LDH levels. A total of 314 chemotherapy-naive patients were randomly assigned to receive Dac (1000 mg/m(2)) preceded by a 5-day continuous intravenous infusion of either oblimersen sodium (7 mg/kg/day) or placebo every 21 days for less than eight cycles. Co-primary efficacy endpoints were overall survival and progression-free survival. Response and progression of the disease were assessed by independent blinded review of computed tomography scan images. No difference in overall nor progression-free survival was observed between the Dac-oblimersen and Dac-placebo groups. Although the overall (17.2 vs. 12.1%) and durable (10.8 vs. 7.6%) response rates numerically favored Dac-oblimersen over Dac-placebo, they did not differ significantly (P=0.19 and 0.32, respectively). The incidence of hematologic adverse events, particularly thrombocytopenia and neutropenia, was higher in the Dac-oblimersen group than in the Dac-placebo group. Withdrawals from the study because of treatment-related adverse events were low (i.e. <2.5%) in both groups. The addition of oblimersen to Dac did not significantly improve overall survival nor progression-free survival in patients with advanced melanoma and low-normal levels of LDH at baseline.

Looking to possible predictive factors of primary resistance to abiraterone acetate (AA) and enzalutamide (ENZ) in pretreated patients (pts) with castration-resistant prostate cancer (CRPC).

248 Background: Abiraterone acetate (AA) and enzalutamide (ENZ) are new generation hormonal agents (NHA) which demonstrated a survival gain in patients (pts) with castration-resistant prostate cancer (CRPC) pre-treated with docetaxel. Although all patients eventually became resistant to these NHAs, some of them show primary resistance, defined as an early progression within the first 3 months, which leads to an early treatment interruption. In the present analysis we have tried to identify which factor, if any, may predict primary resistance to AA and ENZ. Methods: We evaluated a consecutive series of 57 pts, treated in our hospital in two successive named patient programs conducted in our hospital to allow pre-treated CRPC patients to receive NHAs before their approval in Italy: 26 received AA (1,000 mg po + prednisone 10 mg po daily) and 31 ENZ (160 mg po daily). For each pt we have recorded the pre- and post-NHA clinical history, the treatment details and outcomes. We have also assessed the ability of a series of 24 selected clinical factors to predict NHAs resistance, through a logistic regression analysis. Continuous variables were categorized by quartiles and chosen for the initial model after a univariate chi-square analysis. Results: Among the 24 factors, the presence of pain at baseline, high baseline lactate dehydrogenase levels and prostate-specific antigen (PSA) levels after one month of treatment were predictive of primary NHA resistance at the univariate analysis. However, only PSA levels were confirmed at the multivariate analysis [exp(beta) 0.115; p = 0.007], as patients failing to achieve a 50% or more reduction in baseline PSA levels, were more likely to show primary NHA resistance (48% vs. 15%). Conclusions: Our results suggest that PSA trend may represent a simple and rapid method of identifying patients with primary resistance to NHAs, so patients failing to achieve a 50% or more reduction within the first month of treatment should undergo intensive investigations, to verify whether they have primary resistance to NHAs. These data should be confirmed in a larger patient population.

Eculizumab

Eculizumab is a humanized monoclonal antibody indicated for the treatment of paroxysmal nocturnal haemoglobinuria (PNH). It binds specifically and with high affinity to the complement protein C5, thereby preventing the formation of the terminal complement complex C5b-9, which mediates cell lysis. In patients with PNH, eculizumab inhibits terminal complement mediated intravascular haemolysis. In clinical trials of PNH patients, eculizumab reduced intravascular haemolysis compared with baseline and placebo, as determined by significantly decreased lactate dehydrogenase (LDH) levels. Significant reductions in LDH levels were achieved within the first week of treatment, with near normal levels achieved at week 2 and maintained throughout longer term treatment, including periods of up to 36 months. Eculizumab achieved rapid and sustained efficacy, regardless of baseline LDH levels or platelet counts. In adults with PNH, eculizumab treatment for 26 weeks achieved stabilization of haemoglobin levels in significantly more patients than placebo treatment, and reduced the requirement for packed red cell transfusions to a significantly greater extent than placebo. Half of all patients in the eculizumab group became transfusion independent compared with no patients in the placebo group. Eculizumab was also associated with significant improvements in fatigue and health-related quality-of-life scores in several trials. Over the long term, the survival of PNH patients treated with eculizumab was normalized. Eculizumab was generally well tolerated in clinical trials of PNH patients, including treatment periods of up to 5.5 years. The risk of Neisseria meningitidis is increased with eculizumab and patients must be vaccinated prior to treatment and monitored throughout. Thus, eculizumab, the first targeted terminal complement inhibitor, provides an effective and generally well tolerated treatment for PNH patients, who have previously been without adequate treatment options.

Baseline Serum Lactate Dehydrogenase Levels for Patients Treated With Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: A Predictor of Poor Prognosis and Subsequent Liver Metastasis

To evaluate the prognostic value of baseline serum lactate dehydrogenase (LDH) levels in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Cases of NPC (n = 465) that involved treatment with IMRT with or without chemotherapy were retrospectively analyzed. The mean (±SD) and median baseline serum LDH levels for this cohort were 172.77 ± 2.28 and 164.00 IU/L, respectively. Levels of LDH were significantly elevated in patients with locoregionally advanced disease (p = 0.016). Elevated LDH levels were identified as a prognostic factor for rates of overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS), with p values <0.001 in the univariate analysis and p < 0.001, p = 0.004, and p = 0.003, respectively, in the multivariate analysis. Correspondingly, the prognostic impact of patient LDH levels was found to be statistically significant for rates of OS, DFS, and DMFS (p = 0.028, 0.024, and 0.020, respectively). For patients who experienced subsequent liver failure after treatment, markedly higher pretreatment serum LDH levels were detected compared with patients experiencing distant metastasis events at other sites (p = 0.032). Elevated baseline LDH levels are associated with clinically advanced disease and are a poor prognosticator for OS, DFS, and DMFS for NPC patients. These results suggest that elevated serum levels of LDH should be considered when evaluating treatment options.

Hepatic Artery Chemoembolization in Patients With Ocular Melanoma Metastatic to the Liver

Although hepatic arterial chemoembolization (HACE) has been used for treatment of ocular melanoma metastatic to the liver, the prognostic indicators for survival after HACE have not been studied. We evaluated response rates and survival durations after HACE in such patients and analyzed factors affecting their survival. The medical records of patients with ocular melanoma metastatic to liver who underwent HACE at our institution from 1992 to 2005 were reviewed. The radiologic tumor response rates, and overall survival (OS) and progression-free survival durations were calculated, and patient, tumor, and treatment variables were analyzed to identify factors influencing survival. One hundred twenty-five patients underwent 265 HACE sessions. Of 105 patients in whom radiologic responses could be evaluated, 12 (11%) had partial responses, 17 (16%) had minor responses, 68 (65%) had stable disease, and 8 (8%) had progressive disease. The median OS and progression-free survival durations were 6.7 and 3.8 months, respectively. Multivariate analysis showed that >75% liver involvement and high lactate dehydrogenase levels were associated with short OS. Patients who had radiologic responses to HACE had a longer median OS duration than did patients who did not (15.8 vs. 6.1 months; P = 0.0005). Patients with >75% liver involvement had a median OS duration of only 2.4 months. HACE resulted in radiologic response or disease stabilization in most patients with ocular melanomas metastatic to the liver. The extent of liver involvement, baseline lactate dehydrogenase levels, and response to therapy were found to be significant predictors of OS after HACE.

Predictive value of pretreatment risk group and baseline LDH levels in MDS patients receiving azacitidine treatment

This study analyzed the outcomes of myelodysplastic syndrome patients treated with azacitidine. Between August 2006 and June 2008, a total of 126 patients were treated with azacitidine at a dose of 75 mg/m(2)/day subcutaneously for 7 days, which was repeated every 28 days. The median age of the patients was 64 (range, 20-82) years. Forty-three patients (33.4%) were classified as intermediate-2 and high risk according to International Prognostic Scoring System (IPSS), while 61 patients (47.3%) were classified as high and very high risk according to WHO Prognostic Scoring System (WPSS). Sixty patients (47.6%) exhibited a response at the median of 3 (range, 1-5) cycles. A complete response was observed in 21 patients (16.7%), a partial response in six patients (4.8%), and total hematologic improvement in 61 patients (48.4%). For the IPSS risk group, the median survival for the patients with intermediate-1 was 20.0 months, for intermediate-2 was 14.9 months, and for high risk was 6.3 months (p = 0.008). For the WPSS risk group, the median survival duration was 21.3 months for the very low and low risk patients, 16.5 months for intermediate risk patients, and 14.9 months for the high and very high risk patients (p = 0.003). The patients with higher than normal lactate dehydrogenase (LDH) levels at the time of diagnosis showed a poor survival (p = 0.003). The median survival duration for the patients with high LDH levels was 13.9 months, while that for the patients with normal LDH levels was 20.6 months. The multivariate analyses revealed that high LDH levels [hazard ratio (HR) 4.384, p < 0.001] and high and very high WPSS risk group (HR 3.855, p = 0.014) were significantly associated with a worse survival, whereas a response to azacitidine was identified as a good prognostic factor for survival (HR 0.224, p = 0.019). In conclusion, while the pretreatment risk group and initial LDH levels were both confirmed as important prognostic factors to predict the outcomes for patients treated with azacitidine, more effective therapies are still needed to prevent disease progression.

Effect of ipilimumab at 10 mg/kg on disease control in patients (pts) with M1c-stage melanoma in relation to baseline lactate dehydrogenase (LDH) levels

9041 Background: Ipilimumab, a fully human, anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody, enhances antitumor immunity. Ipilimumab is clinically active in advanced melanoma, with a 1-year survival rate of ∼50% in Phase II studies (Wolchok et al. CRI-CVC annual meeting 2008. Oral presentation). Serum LDH level is an independent prognostic factor for malignant melanoma, and is strongly predictive of reduced survival in stage IV disease (Bedikian et al. J Clin Oncol. 2006;24:4738–4745.). This analysis evaluated the association between baseline LDH levels and disease control (stable or reduced measurable tumor burden) in previously treated pts with M1c-stage melanoma (metastasis to vital organs other than the lungs) who received ipilimumab in 2 recently completed Phase II studies (CA184008 and 022). Methods: Ipilimumab at 10 mg/kg was given every 3 weeks (Q3W) × 4; eligible pts could continue to receive ipilimumab Q12W beginning at Week 24. In study 022, pts were randomized to receive ipilimumab induction dosing at 0.3, 3.0, or 10 mg/kg Q3W × 4; study 008 was a single- arm trial of ipilimumab at 10 mg/kg. Disease control data were pooled from the 2 Phase II studies for pts treated with ipilimumab at 10 mg/kg and stratified by normal and elevated (&gt;1× upper normal limit [UNL]) LDH levels. Elevated LDH was not capped. Results: For 227 pts treated at 10 mg/kg, 123 had M1c-stage disease: 42 had normal LDH and 81 had LDH &gt;1 × UNL (of which 32 had LDH 2 × UNL). Among these 123 pts, 17/81 (21.0%) [95% CI 12.7–31.5] with elevated LDH levels experienced disease control, whereas 12/42 (28.6%) [95% CI 15.7–44.6] with LDH levels at or below the UNL experienced disease control. Conclusions: Our data show that ipilimumab exerts similar disease control in pts with normal and elevated LDH levels. Ipilimumab therefore appears to have clinical activity in the form of disease control in pts with a very poor prognosis, i.e., M1c-stage melanoma and elevated LDH levels. [Table: see text]

Decline in serum carcinoembryonic antigen and cytokeratin 19 fragment during chemotherapy predicts objective response and survival in patients with advanced nonsmall cell lung cancer

The authors assessed the predictive and prognostic role of decline in the serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) during chemotherapy in patients with advanced nonsmall cell lung cancer (NSCLC). Changes in serum levels of CEA and CYFRA 21-1 during first-line, conventional chemotherapy were studied prospectively with an immunometric assay at baseline and every 2 courses in 117 patients with advanced NSCLC. Data were correlated with radiologic objective response (OR) and survival. One hundred seven patients were evaluable for radiologic and serologic response assessment after 2 chemotherapy courses. The radiologic OR rate was 44% overall. The CEA and CYFRA 21-1 responses (> or =20% reduction over baseline level; assessed after the second course of chemotherapy) were 38% and 61%, respectively. Statistically significant correlations were observed between CEA and CYFRA 21-1 responses and OR (P = .01 and P = .004, respectively). The median survival from response assessment (landmark analysis) was 9 months. In a univariate analysis, disease stage, performance status, baseline lactate dehydrogenase level (LDH), OR, CEA response, and CYFRA 21-1 response were correlated significantly with survival. In particular, the median survival was 13 months for patients who had a CEA response and 11 months for patients who had a CYFRA 21-1 response compared with 8 months and 6 months for patients who did not respond, respectively. In a multivariate analysis, performance status (P = .005), baseline LDH level (P = .02), CEA response (P = .03) and CYFRA 21-1 response (P = .01) were confirmed as independent prognostic factors for survival. CEA and CYFRA 21-1 responses appeared to be reliable surrogate markers of chemotherapy efficacy in patients with advanced NSCLC.

Fibrin microbeads (FMB) as a 3D platform for kidney gene and cell therapy

Cell and gene therapy may alter the outcome of renal diseases, such as hereditary nephropathies, acute and chronic glomerulonephritis and allograft nephropathy. However, owing to blockade of many viral and cellular vehicles by the complex glomerular architecture, the exact nature of gene and cell delivery into specific renal compartments remains currently unknown. To study the interaction of viral vectors with a variety of renal cells and mesenchymal stem cells (MSCs), we employed a novel biological three-dimensional (3D) matrix comprised of fibrin microbeads (FMB) in comparison to monolayer cell culture. Our studies showed that renal cells of both established and primary lines can grow efficiently on FMB and differentiate into epithelial structures, as shown by electron microscopy. Gene delivery into renal cells in 3D was observed for several viral vectors and growth in 3D on FMB conferred resistance to renal cancer cells in the context of oncolytic adenoviruses. Finally, MSCs from various rodent species attached to FMB, grew robustly, survived for several weeks and could efficiently be transduced on FMB. Thus, on the basis of growth, differentiation and transduction of renal cells in 3D, FMB emerge as a novel 3D cellular microenvironment that differs substantially from monolayer cell cultures.