Abnormal Lactate Dehydrogenase Levels Research Articles

Association of DNA repair gene XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) polymorphisms with the risk of chronic myeloid leukemia: A case-control study in a South Indian population.

Xeroderma pigmentosum complementation group C (XPC), a DNA repair protein, plays an important role in the maintenance of genomic integrity and is essential for the nucleotide excision repair pathway. Polymorphisms in the XPC gene may alter DNA repair leading to genetic instability and oncogenesis. The present study aimed to assess the relationship between the XPC Ala499Val (rs2228000 C>T) and Lys939Gln (rs2228001 A>C) non-synonymous polymorphisms and susceptibility to chronic myeloid leukemia (CML) pathogenesis, disease progression and the response to targeted therapeutic regimen, imatinib mesylate. This case-control study included 212 cases and 212 controls, and the genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism assays. Our results showed significant association of variant CT (odds ratio = 1.92, 95% confidence interval = 1.21-3.06, p =0.003) and TT (odds ratio = 2.84, 95% confidence interval = 1.22-6.71, p =0.007) genotypes in patients with the XPC Ala499Val polymorphism and CML risk. In addition, these genotypes were associated with CML progression to advanced phases (p =0.006), splenomegaly (p =0.017) and abnormal lactate dehydrogenase levels (p =0.03). XPC Lys939Gln was found to correlate with a poor response to therapy, showing borderline significant association with minor cytogenetic response (p =0.08) and a poor molecular response (p =0.06). Significant association of the Ala499Val and Lys939Gln polymorphisms with prognosis was observed (Hasford high risk, p = 0.031 and p = 0.019, respectively). Haplotype analysis showed a strong correlation of variant TC haplotype with poor therapy responses (minor cytogenetic response, p = 0.019; poor molecular response, p < 0.0001). In conclusion, our results suggest that XPC Ala499Val is a high-penetrance CML susceptibility polymorphism. Both polymorphisms studied are considered as genetic markers with respect to assessing disease progression, therapy response and prognosis in CML patients.

Surgical management for local retroperitoneal recurrence after radical nephrectomy in the targeted therapy era.

431 Background: Isolated local retroperitoneal recurrence (RPR) after radical nephrectomy (RN) for renal cell carcinoma (RCC) poses a therapeutic challenge. We examined the role of aggressive surgical resection of localized RPR in the modern era of targeted therapy for metastatic RCC. Methods: We retrospectively reviewed clinico-pathological data of patients from our RCC database from 2004-2014. We identified 67 patients with localized RPR after radical nephrectomy (RN) who underwent surgical resection. We assessed patient demographics, clinical and pathological features, location of RPR, perioperative complications and outcomes, recurrence free, cancer-specific and overall survival. Results: Median follow up after RPR resection was 33 months (range 3-120). Median recurrence free survival after RPR was 20 months (range 1-120). One, 3 and 5-year cancer specific survival was 95% 77% and 50%, respectively. Neoadjuvant and salvage targeted therapy were administered in 29 (43.3%) and 28 (41.8%) patients, respectively. Multivariate analysis identified that pathological tumor stage and nodal stage at nephrectomy, maximum diameter of RPR mass and abnormal lactate dehydrogenase levels were associated with an increased risk of cancer specific death. Patients with 0, 1, and greater than 1 adverse risk factors demonstrated cancer specific survival of 100%, 74%, 50% at 3 years and 100%, 57%, 19% at 5 years. Conclusions: This study is the largest series of patients to undergo RPR resection in the targeted therapy era. We found that clinic-pathological factors at the time of nephrectomy as well as RPR resection are important prognosticators. Aggressive surgical resection offers potential cure in a substantial number of patients with RPR.

560P - Impact of Pre-Treatment Lactate Dehydrogenase (Ldh) Levels on Prognosis and Bevacizumab Efficacy in Advanced Colorectal Cancer Patients

ABSTRACT Aim: As LDH and pro-angiogenesis factors are regulated by the same HIF1a-driven pathway, high lactate dehydrogenase (LDH) levels are associated with abnormal activation of the VEGF pathway. We assessed the impact of pretreatment LDH levels on the prognosis of advanced colorectal cancer (ACC) patients treated with first-line chemotherapy with or without the anti-VEGF monoclonal antibody, bevacizumab, in a phase 3 randomized trial (NCT01878422). Methods: The relationship between pre-treatment LDH and progression free (PFS) and overall survival (OS) was assessed in 376 patients randomized to receive FOLFOX4 or FOLFIRI with or without bevacizumab. PFS, OS and their 95% confidence intervals (95% CI) were calculated by the Kaplan-Meier method. Results: Information on pre-treatment LDH levels was available for 344 ACC patients; 119 had normal LDH values and 225 had an LDH above the upper limit of the normal range (abnormal LDH). At a median follow up of 36 months (range 1-65), abnormal LDH levels were predictive of a lower median PFS (8.3 months, 95% CI 7.1-8.9 versus 9.8 months, 95% CI 9.1-10.9, p= 0.003) and median OS (19.2 months, 95% CI 16.3-21.1 versus 28.0 months, 95% CI 21.4-36.6, p= 0.0003). In the bevacizumab arm, median PFS was 9.1 (95% CI 7.8-10.2) and 9.7 (95% CI 7.4-12.2) months in patients with abnormal LDH and normal LDH, respectively (p = 0.308), whereas in the chemotherapy-only arm median PFS was 7.2 (95% CI 6.5-8.5) and 9.8 (95% CI 8.9-11.5) months, respectively (p = 0.002). Median OS was significantly associated with LDH levels in both treatment arms. Chemotherapy + bevacizumab Chemotherapy Pre-treatment LDH No. of patients No. of events Median PFS (95% CI) No. of patients No. of events Median PFS (95% CI) p LDH 62 53 9.7 (7.4-12.2) 57 51 9.8 (8.9-11.5) 0.522 LDH ≥ ULN 101 98 9.1 (7.8-10.2) 124 118 7.2 (6.5-8.5) 0.108 p 0.308 0.002 Pre-treatment LDH No. of patients No. of events Median OS (95% CI) No. of patients No. of events Median OS (95% CI) p LDH 62 36 28.0 (17.8-37.6) 57 35 28.6 (21.3-38.7) 0.444 LDH ≥ ULN 101 85 15.8 (13.1-21.1) 124 101 20.2 (17.9-23.2) 0.282 p 0.015 0.007 ULN, upper limit of normal Conclusions: In our study abnormal LDH values were correlated with worse prognosis. Bevacizumab appeared to improve the PFS of this population, but not the OS. Disclosure: All authors have declared no conflicts of interest.

Time-to-treatment of diffuse large B-cell lymphoma in São Paulo

OBJECTIVE:Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma, accounting for nearly 50% of the cases in the Hematology Department of the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo and Instituto do Câncer do Estado de São Paulo. The treatment outcome is influenced by age, abnormal lactate dehydrogenase levels, extranodal infiltration, the disease stage and the patient's performance status. In this study, we sought to report the time-to-treatment of diffuse large B-cell lymphoma in São Paulo's public health system network and its impact on patient outcomes.METHODS:We prospectively followed a cohort of 42 consecutive patients with de novo diffuse large B-cell lymphoma between 2008 and 2012.RESULTS:Our patients had more advanced disease than that reported in the literature (61.9% vs. 46%). In São Paulo's public health system network, it took an average of 7.4 months for a diagnosis to be made and an additional 1.4 months to obtain an appointment with a specialist. Once at our Hematology Department, it took less than 20 days for staging, confirmation of the diagnosis and treatment initiation. An interval from signs or symptoms to treatment of more than 6 months was associated with inferior progression-free survival in 3 years (p = 0.049).CONCLUSION:A delay in the diagnosis of diffuse large B-cell lymphoma is a public health problem and may be associated with worse progression-free survival.

A Single-Institution Validation of the AJCC Staging System for Stage IV Melanoma

Survival of patients with stage IV melanoma is poor. In the current American Joint Committee on Cancer (AJCC) staging system, site of distant disease and lactate dehydrogenase (LDH) are the only prognostic factors included for stage IV disease. We sought to validate the current AJCC staging system in a contemporary, prospectively collected cohort of patients and explore additional factors that may influence prognosis. Our prospective database was searched to identify patients with stage IV melanoma; only patients seen at our institution before developing stage IV disease were included (n = 589). Demographic, clinical, and tumor characteristics were abstracted. Univariate and multivariate assessment of prognostic factors associated with survival were performed by Cox regression. Overall median survival was 9 months. Differential survival by AJCC substage was observed (P < .001). For each site of disease described within the AJCC staging system, an abnormal LDH level was associated with a poorer prognosis. By multivariate analysis, older age at diagnosis (as a continuous variable, hazard ratio [HR] 1.02, 95% confidence interval [95% CI]) 1.01-1.02), an abnormal LDH (HR 1.42, 95% CI 1.11-1.82), site of disease (lung HR 1.22, 95% CI .89-1.66; other viscera 1.61, 95% CI 1.18-2.21), more than one organ involvement (HR 1.27, 95% CI 1.01-1.60), and more than one metastasis (HR 2.27, 95% CI 1.65-3.14) were independently associated with poorer survival. Sex, antecedent stage, and disease-free interval were not statistically significant. In our patient cohort, the AJCC staging system was valid. The strongest predictor of survival-the number of metastases present at the diagnosis of stage IV disease-represents a variable to consider in future staging systems.

A Threefold Dose Intensity Treatment With Ifosfamide, Carboplatin, and Etoposide for Patients With Small Cell Lung Cancer: A Randomized Trial

The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/m(2), paclitaxel at 175 mg/m(2), and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. Median relative dose intensity in the High-ICE arm was 293% (range = 174%-392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% CI = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% CI = 67% to 87%] and n = 48 [68%, 95% CI = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High-ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade > or = 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High-ICE treatment was predictably associated with severe myelosuppression, and five patients (8%) died from toxicity. The long-term outcome of SCLC was not improved by raising the dose intensity of ICE chemotherapy by threefold.

A single-institution validation of the AJCC staging system for stage IV melanoma

8517 Background: We sought to validate the AJCC staging system for stage IV melanoma in a contemporary, prospective, single- institution cohort and explore additional clinical factors that may influence prognosis. Methods: A prospective institutional database identified 1319 patients with stage IV melanoma. To minimize tertiary center referral bias, only patients seen prior to a stage IV diagnosis were included (n=687). Variables were dichotomized: lactate dehydrogenase (LDH) (=200, &gt;200), number of metastases (1, &gt;1), and number of involved organs (1, &gt;1). Kaplan-Meier curves were generated and Cox regression was used to identify factors independently predictive of survival. Results: Demographics are provided in the table . The median age at diagnosis of stage IV was 55 years (range 16–94) and the median disease free interval (DFI) was 12 months (0–181). The overall median survival was 10 months (5–21) with a median follow-up for survivors of 31 months (9–68); 569 deaths were observed. Cox regression analysis ( table ) identified younger age at stage IV diagnosis, a longer DFI, and a normal LDH to be predictive of improved survival. Patients with either distant skin/subcutaneous/nodal or pulmonary disease experienced prolonged survival when compared to patients with metastases to other visceral sites. Survival was improved in patients with a single metastatic site at diagnosis of stage IV. Gender, antecedent stage, and number of involved organs were not associated with outcome. Conclusions: In this single institution cohort of patients with stage IV melanoma, poorer survival in patients with non-pulmonary visceral metastases and/or abnormal LDH levels as described by the AJCC staging system was confirmed. Additionally, the number of metastases at the time of diagnosis of stage IV was the most powerful predictor of poorer survival and may be a variable to consider in future staging systems. No significant financial relationships to disclose. [Table: see text]

First-line phase II trial of sorafenib (BAY 43–9006) in patients with advanced renal cell carcinoma unsuitable for cytokine treatment

15640 Background: Sorafenib (BAY 43–9006) is a serine/threonine and receptor tyrosine kinase inhibitor that prevents tumor cell proliferation and angiogenesis. The objective of this open-label, phase II trial was to determine median progression-free survival (PFS) following sorafenib therapy in patients with renal cell carcinoma (RCC) unsuitable for cytokine treatment. Methods: Eligible patients had cytologically or histologically confirmed clear cell RCC; Eastern Cooperative Oncology Group (ECOG) Performance Status 0–1; adequate renal, liver and medullar function; no active central nervous system metastases; had received no previous treatment with antiangiogenic agents; and had at least one evaluable lesion. Sorafenib was given as first-line treatment in patients unsuitable for cytokine therapy, defined as being intolerant to or ineligible for immunotherapy. Treatment consisted of oral sorafenib 400mg twice daily continuously until disease progression or unacceptable toxicity. The primary endpoint was PFS; secondary endpoints were response rate according to Response Evaluation Criteria in Solid Tumors, tolerability and overall survival. Results: Twenty-six patients were enrolled between March and July 2006 (median age: 68.5 years [48–82]; male/female: 17/9, ECOG Performance Status 0: 11 patients; prior nephrectomy: 19 patients). The main metastatic locations were lung and bone, 14 patients had = 2 metastatic lesions, and 2 patients had abnormal lactate dehydrogenase levels. As of 31 December 2006, with a median follow-up of 6.4 months, the median PFS had not been reached. In 19 patients evaluable for response, the overall clinical benefit rate was 68.4% (1 complete response; 1 partial response; 11 stable disease). Six patients experienced serious adverse events, only one of which was related to treatment. Conclusions: Sorafenib first-line therapy is a tolerable alternative for patients unsuitable for cytokine treatment. Final PFS data will be available in June 2007. No significant financial relationships to disclose.

Clinicopathologic implications of tissue inhibitor of metalloproteinase-1-positive diffuse large B-cell lymphoma

The tissue inhibitor of metalloproteinase-1 (TIMP-1) is a stromal factor that promotes plasmablastic differentiation, and the survival of germinal center B-cells. The expression of TIMP-1 is known to be correlated with a subset of non-Hodgkin lymphoma at the mRNA level, and Epstein–Barr virus infection in vitro. To characterize TIMP-1(+) diffuse large B-cell lymphoma, TIMP-1 expression was investigated in tissue microarrays from 182 cases of de novo diffuse large B-cell lymphoma and compared with prognostic factors, immunophenotypes, and Epstein–Barr virus infection status. TIMP-1 was expressed not only in tumor cells themselves, in 14 of 182 cases (8%), designated as TIMP-1(+) diffuse large B-cell lymphoma, but also in stromal cells like fibroblasts and endothelial cells. In univariate analysis and hierarchical clustering, our findings suggest that TIMP-1 expression may represent a distinct subgroup. In multivariate analysis, TIMP-1(+) diffuse large B-cell lymphoma (n=14) was associated with unfavorable outcomes compared to TIMP-1(−) diffuse large B-cell lymphoma (n=168) (odds ratio=2.5, P=0.049). Together with TIMP-1 expression, age (greater than 60 years), the presence of B-symptoms, abnormal lactate dehydrogenase level, or more advanced stage (III/IV) was correlated with a poor overall survival. However, TIMP-1 expression in diffuse large B-cell lymphoma was not correlated with other prognostic factors including: clinical stage, international prognostic index score, and nongerminal center B-cell phenotype, as well as Epstein–Barr virus infection. Our results suggest that TIMP-1 expression may be an independent negative prognostic factor in patients with diffuse large B-cell lymphoma.

The significance of molecular response of follicular lymphoma to central lymphatic irradiation as measured by polymerase chain reaction for t(14;18)(q32;q21)

Backgound: More than 80% of the patients with follicular lymphoma have a characteristic chromosomal translocation, t(14;18)(q32;q21), at the major breakpoint region (MBR) or minor cluster region (MCR) involving the bcl-2 oncogene. This study was undertaken to assess the significance of the molecular response rate measured by the polymerase chain reaction (PCR) evidence of translocation among patients with Stage I to III follicular lymphoma treated with central lymphatic irradiation (CLI). Methods and Materials: Thirty-three patients with Stage I-III follicular lymphoma were treated with CLI on a prospective protocol. Bone marrow and peripheral blood samples were obtained before CLI for PCR analysis of t(14;18)(q32; q21). PCR-positive patients were followed by PCR analysis at regular intervals during and after CLI, and the results were correlated with clinical outcome. The following pretreatment factors were also investigated for their relationship to relapse and molecular response: gender, age, lactate dehydrogenase (LDH) and β-2 microglobulin (β2 M) levels, Ann Arbor stage, and International Prognostic Index (IPI) for malignant lymphoma. Results: The subjects were 19 men and 14 women, with a median age of 52 years (range 30–69), who started CLI between January 1993 and February 1998. Median follow-up was 44 months (range 12–67), and all but 2 patients were still alive at the last follow-up. Four patients were Stage IA, 8 were Stage IIA, 19 were Stage IIIA, and 2 were Stage IIIB. Two patients had abnormal LDH levels (> 618 U/dL) and 7 patients had abnormal β2M levels (> 2 mg/dL). Nine patients had IPI = 0, 16 had IPI = 1, and 8 had IPI = 2. All patients achieved complete response (CR). Twelve patients have relapsed to date. The median overall time to relapse was 54 months. The actuarial proportion of patients free from relapse at 3 years was 87% (95% confidence interval [CI] 69–95%). A total of 287 PCR results were available, 64 from bone marrow and 223 from peripheral blood. Pretreatment PCR data were available for 27 patients, of whom 21 were positive and 3 were unambiguously negative (in blood and bone marrow for both MBR and MCR). For the 19 PCR positive patients for whom we had post-treatment results, there was a clear and steady decreasing trend toward loss of PCR positivity (49% positive for bone marrow and 32% positive for peripheral blood at 3 years). There was a clear trend for increasing PCR positivity with increasing IPI: 10% for IPI = 0, 31% for IPI = 1, and 63% for IPI = 2 at 3 years for blood. The same trend was also observed for bone marrow. The IPI was the only statistically significant predictor for relapse with a relapse-free survival of 91% at 3 years for IPI < 2 and 75% for IPI = 2 ( p = 0.024, log-rank test). Conclusion: Molecular response to CLI occurs gradually over years. High IPI is a negative predictor for molecular response and relapse-free survival.