Marker Of Tumor Burden Research Articles

Beta-2-Microglobulin Is An Independent Predictor of Progression in Asymptomatic Multiple Myeloma.

Abstract 1796Poster Board I-822The rationale of the study stems from three considerations: i) to date, few clinical predictors of asymptomatic multiple myeloma (MM) progression are available; ii) no study has assessed the role of beta-2-microglobulin (B2M) on risk of asymptomatic MM progression; iii) B2M is a serum marker of tumor burden and represents a key variable of the ISS staging system for symptomatic MM. The study aims at assessing the impact of B2M on risk of asymptomatic MM progression. The study was based on a consecutive series of 148 asymptomatic MM diagnosed according to the IMWG. Cumulative probability of progression to symptomatic MM was calculated from diagnosis of asymptomatic MM to progression to symptomatic disease according to IMWG. Survival analysis was performed by Kaplan-Meier method using log-rank to test for associations. Cox proportional hazard regression was used to build a multivariate model. Harrell's c-statistics was used to evaluate the discriminatory value of the prognostic models. Clinical features at asymptomatic MM diagnosis were as follows: median age 67 years, male:female ratio 1.02, previous MGUS 32/148 (21.6%), IgG monoclonal component (MC) 113/148 (76.4%), IgA MC 32/148 (21.6%), light chain MC 3/148 (2.0%), median serum monoclonal component (sMC) 1.1 g/dl, positive urinary immunofixation 27/148 (18.2%), median urinary monoclonal component (uMC) 98 mg/24h, median bone marrow plasma cell percentage (BMPC%) 15%, median B2M 2.0 mg/l, median albumin 4.3 g/dl, median C reactive protein 0.3 mg/l. After a median follow-up of 48 months, 29/148 asymptomatic MM progressed to symptomatic disease, accounting for a 29.5% 5-year probability of progression. According to Youden's index, best cut-off values for prediction of progression were 2.5 mg/l for B2M, 1.5 g/dl for sMC, 500 mg/24h for uMC, and 20% for BMPC%. Univariate analysis identified B2M >2.5 mg/l (5-year risk: 64.5%; HR=3.85; p<.001), sMC >1.5 g/dl (5-year risk: 49.1%; HR=5.76; p<.001), uMC >500 mg/24h (5-year risk: 68.7%; HR=6.60; p<.001) and BMPC% ≥20% (5-year risk: 50.2%; HR=5.77; p<.001) as predictors of progression to symptomatic MM. Clinical variables not associated with progression to symptomatic MM (p≥0.05 in all cases) were age, sex, sMC type, polyclonal Ig reduction, albumin, C reactive protein, Hb, calcium, creatinine, and previous MGUS. Multivariate analysis identified B2M >2.5 mg/l (HR=3.57; p=.001) as an independent predictor of progression to symptomatic MM, along with sMC >1.5 g/dl (HR=4.07; p=.003), uMC >500 mg/24h (HR=3.66; p=.015) and BMPC% ≥20% (HR=3.20; p=.007). Based on multivariate analysis, B2M, sMC, uMC, and BMPC% were combined into a model for predicting progression to symptomatic MM. This model stratified patients into four risk groups: very low risk (0 risk factors: 5-year risk 0%), low-intermediate risk (1 risk factor: 5-year risk 19.6%), high-intermediate risk (2 risk factors 5-year risk: 60.7%), and high risk (3 or 4 risk factors 5-year risk 80.7%) (Fig. 1). Three lines of evidence suggest that B2M may improve the conventional risk stratification model for prediction of asymptomatic MM progression defined by sMC, uMC, and BMPC%. First, B2M >2.5 mg/l adds prognostic information within the low risk group characterized by sMC '1.5 g/dl, uMC '500 mg/24h and BMPC <20% (p=.005), by segregating a very low risk group of patients with B2M<2.5 mg/l who never progressed (5-year risk: 0%). Second, B2M >2.5 mg/l adds prognostic information within the high risk group defined by sMC >1.5 g/dl and/or uMC >500 mg/24h and/or BMPC ≥20% (p=.034) by segregating a high risk group of patients with B2M >2.5 mg/l who are virtually all projected to progress (5-year risk: 89.0%). Third, based on c-statistics, the prognostic model including B2M along with sMC, uMC, and BMPC% (c-statistics=.760; SE=.045) allowed to predict asymptomatic MM progression better than a model based only on sMC, uMC, and BMPC% (c-statistics=.726; SE=.049). The implications of our results are twofold: i) B2M predicts progression of asymptomatic MM to symptomatic disease independent of conventional risk factors (sMC, BMPC%, light chain burden); ii) B2M refines the conventional model for predicting progression to symptomatic MM by allowing the identification of a very low risk group of patients who never progress and a high risk group of patients who are virtually all projected to progress. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparative Impact of Trastuzumab and Cyclophosphamide on HER-2–Positive Human Breast Cancer Xenografts

Metronomic chemotherapy is a minimally toxic and frequently effective new treatment strategy that is beginning to show promising phase II clinical trial results, particularly for metastatic breast cancer when combined with various molecularly targeted antitumor agents. Here, we assessed a treatment strategy that uses trastuzumab plus daily oral metronomic cyclophosphamide on metastatic Her-2-positive human breast cancer models. Treatments were initiated on orthotopic transplanted primary tumors as well as established visceral metastatic disease of two independent Her-2-positive breast cancer models, both independently derived from the human MDA-MB-231 breast cancer cell line. Outcome was assessed by noninvasive measurements of tumor cell-secreted human choriogonadotropin in the urine as a surrogate marker of relative tumor burden, or by whole body bioluminescent imaging, in addition to prolongation of survival. Orthotopic primary tumors responded to trastuzumab monotherapy with significant growth delays, whereas minimal antitumor effect was observed when mice with metastatic disease were treated. Nevertheless, trastuzumab showed a benefit in this latter setting when combined with metronomic low-dose cyclophosphamide as assessed by prolongation of survival. This benefit was similar to trastuzumab plus maximum tolerated dose cyclophosphamide, but was associated with lesser toxicity. Trastuzumab combined with metronomic cyclophosphamide may be an effective long-term maintenance strategy for the treatment of Her-2-positive metastatic breast cancer.

Autologous Hematopoietic Stem Cell Transplantation May Reverse Renal Failure in Patients with Multiple Myeloma

Approximately 20% of patients with multiple myeloma (MM) have renal failure at diagnosis, and about 5% are dialysis-dependent. Many of these patients are considered ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) because of a high risk of treatment-related toxicity. We evaluated the outcome of 46 patient with MM and renal failure, defined as serum creatinine >2 mg/dL sustained for >1 month before the start of preparative regimen. Patients received auto-HSCT at our institution between September 1997 and September 2006. Median serum creatinine and creatinine clearance (CrCl) at auto-HSCT were 2.9 mg/dL (range: 2.0-12.5) and 33 mL/min (range: 8.7-63), respectively. Ten patients (21%) were dialysis-dependent. Median follow-up in surviving patients was 34 months (range: 5-81). Complete (CR) and partial responses (PR) after auto-HSCT were seen in 9 (22%) and 22 (53%) of the 41 evaluable patients, with an overall response rate of 75%. Two patients (4%) died within 100 days of auto-HSCT. Grade 2-4 nonhematologic adverse events were seen in 18 patients (39%) and included cardiac arrythmias, pulmonary edema, and hyperbilirubinemia. Significant improvement in renal function, defined as an increase in flomerular filtration rate (GFR) by 25% above baseline, was seen in 15 patients (32%). Kaplan-Meier estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 36% and 64%, respectively. In conclusion, auto HSCT can be offered to patients with MM and renal failure with acceptable toxicity and with a significant improvement in renal function in approximately one-third of the transplanted patients. In this analysis, a melphalan (Mel) dose of 200 mg/m(2) was not associated with an increase in toxicity or nonrelapse (Mel) mortality (NRM).

The Value of Squamous Cell Carcinoma Antigen in the Prognostic Evaluation, Treatment Monitoring and Followup of Patients With Penile Cancer

We examined whether squamous cell carcinoma antigen has significant value for prognostic evaluation, treatment monitoring and followup in patients with penile cancer. Serum squamous cell carcinoma antigen was prospectively measured in 63 patients with penile squamous cell carcinoma from 2005 to 2007. The normal range of squamous cell carcinoma antigen was set as less than 1.50 mug/l. Statistical data analysis was done by the nonparametric method. Survival analysis was performed with the log rank test and the Cox proportional hazard model. Of all patients 23.8% had a value of squamous cell carcinoma antigen that was greater than the upper limit of normal. Increased values correlated positively with lymph node metastasis (p = 0.005). However, squamous cell carcinoma antigen could not accurately predict occult inguinal lymph node metastasis in clinically node negative cases. Preoperatively squamous cell carcinoma antigen was an independent prognostic factor for disease-free survival in patients with node positive penile cancer (OR 0.13, p = 0.006). Combining pretreatment squamous cell carcinoma antigen and the percent of decrease after surgery was informative for predicting disease recurrence. The prognostic value of squamous cell carcinoma antigen was also observed in a small number of patients treated with chemotherapy. During followup continuously increasing squamous cell carcinoma antigen indicated tumor progression without a significant lead time effect. Squamous cell carcinoma antigen is not a sensitive marker of tumor burden. However, it has prognostic significance for disease-free survival in patients with penile cancer treated with surgery.

α-Fetoprotein and human chorionic gonadotrophin-β as prognostic markers in neuroendocrine tumour patients

Serum chromogranin A is the most useful general and prognostic tumour marker available for neuroendocrine tumour (NET) patients. The role of other tumour markers is less clear. In order to determine the diagnostic and prognostic value of serum α-fetoprotein (AFP) and human chorionic gonadotrophin-β (hCGβ) in NETs, a database containing biochemical, histological, and survival data on 360 NET patients was constructed. This data was statistically assessed, using Statistical Package for the Social Sciences, to determine the utility of commonly measured tumour markers with particular emphasis on AFP and hCGβ. α-Fetoprotein and hCGβ were raised in 9.5 and 12.3% of patients respectively and jointly raised in 9.1% of patients in whom it was measured. α-Fetoprotein levels associated strongly and positively with tumour grade, serum CgA and hCGβ levels, and worse survival. Human chorionic gonadotrophin-β levels also associated strongly and positively with serum CgA and AFP levels, and worsening survival. α-Fetoprotein and hCGβ are elevated in high-grade NETs, with a rapidly progressive course and poorer survival. They also correlate with chromogranin-A, which is known to be a marker of tumour burden and to have prognostic value. Thus AFP and hCGβ are clinically important in NETs and when elevated are poor prognostic markers.

LDH in solid tumors as a surrogate marker for tumor burden and response to treatment

22164 Background: LDH is a biomarker of cellular turn over. The purpose of our study was to identify serum LDH as a surrogate marker of tumor burden and site of metastatic disease in cancer patients. Methods: Data from 245 cancer patients (mean age: 63.7 years, 53% F, 61.6% adenoca) were retrieved who were treated between July 2005 and December 2007. The pts were risk stratified as stage: stage I: 25, II: 23, III: 92, IV: 105. ECOG performance status was 0–2 in 142 pts, 3–4in 103 pts. All pts had CT scans for tumor staging. LDH, hemoglobin, uric acid, and renal functions were measured at the baseline. Relations between LDH and tumor burden were studied using multivariate analysis. Results: A total of 87 pts (35.5%) had normal LDH (300–600). High LDH was seen in pts as follows: 600–1,000: 80 pts (32.6%), 1,000–2,000: 53 pts (21.6%), 2,000–4,000: 15 pts (6.1%), 4,000–8,000: 7 pts (2.8%), 8,000–16,000: 3 patients (1.2%). The median baseline Hemoglobin, LDH and uric acid levels were 11g/dl, 740IU/L, 5.9mg/dl respectively. None of the pts with normal LDH had liver, brain or lung metastatic disease. Elevated uric acid levels were seen in 41 (16.7%) pts, elevated creatinine >1.5 were seen in 38 pts (15.5%) with high LDH. Increased LDH was the associated with tumor masses: colorectal: 12 pts, kidney: 2 pts, gastric: 8 pts, pelvic: 11 pts. High LDH was associated with extranodal metastatic disease: Liver: 26 pts, lung: 26 pts, and brain: in 6 pts. Elevated LDH did not correlate with stage: Stage 1: 14 pts, stage 2: 11 pts, stage III: 62 pts, stage IV: 70 pts. 90% of long term remitters (30/33) and 80% of pts with stable disease had pretreatment LDH <1000. In contrast, 37.9% of pts with progressive disease had LDH >1,000. No pts received prophylactic allopurinol. Incidence of tumor lysis was 2.8% in all pts (7/245), but with 4.4% (7/158) with high LDH. Conclusions: Incidence of liver and lung metastases was increased in pts with elevated LDH. A pretreatment LDH should always be measured in these pts. Extranodal metastatic sites LDH (IU/L) No.: % pts Liver mets (26) Lung mets (26) Brain mets (7) <600 87 (35.5%) 0 (0%) 0 (0%) 0 (0%) 600-1,000 80 (32.65%) 12 (46.2%) 14 (53.8%) 1 (14.3%) 1,000-2,000 53 (21.6%) 7 (26.9%) 11 (42.3%) 4 (57.1%) 2,000-4,000 15 (6.12%) 3 (11.5%) 0 (0%) 2 (28.6%) >4,000 10 (4.08%) 4 (15.4%) 1 (3.8%) 0 (0%) No significant financial relationships to disclose.

Intravenous Ibandronate Rapidly Reduces Pain, Neurochemical Indices of Central Sensitization, Tumor Burden, and Skeletal Destruction in a Mouse Model of Bone Cancer

Over half of all chronic cancer pain arises from metastases to bone and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Currently, bone pain is treated primarily by opioid-based therapies, which are frequently accompanied by significant unwanted side effects. In an effort to develop nonopioid-based therapies that could rapidly attenuate tumor-induced bone pain, we examined the effect of intravenous administration of the bisphosphonate, ibandronate, in a mouse model of bone cancer pain. Following injection and confinement of green fluorescent protein-transfected murine osteolytic 2472 sarcoma cells into the marrow space of the femur of male C3H/HeJ mice, ibandronate was administered either as a single dose (300 μg/kg), at Day 7 post-tumor injection, when tumor-induced bone destruction and pain were first evident, or in three consecutive doses (100 μg/kg/day) at Days 7, 8, and 9 post-tumor injection. Intravenous ibandronate administered once or in three consecutive doses reduced ongoing and movement-evoked bone cancer pain-related behaviors, neurochemical markers of central sensitization, tumor burden, and tumor-induced bone destruction. These results support limited clinical trials that suggest the potential of ibandronate to rapidly attenuate bone pain and illuminate the mechanisms that may be responsible for limiting pain and disease progression.

Utility of blood DNA levels in diagnosis of breast cancer

Prognostic factors, including both histopathological and biochemical variables, influence the choice of modality and the course of therapy in breast cancer. The biomarkers found in biological fluids, particularly in blood, apparently hold the best promise for the development of screening assays. To find out if any correlation exists between blood DNA level and tumor stage, size and grade. This case-control study was carried out on 52 female patients in the age-group of 18-70 years. The cases comprised 25 patients with histopathologically confirmed malignant breast cancer, while 27 patients with benign breast tumors served as the control group. We used the Student's 't' test to compare the differences between the blood DNA levels in the two groups. Pearson's test was performed to find out the correlation between blood DNA levels and the TNM stage, tumor size and grade. It was observed that blood DNA levels showed statistically significant correlation with the TNM stage, tumor size and grade. The blood DNA level can be utilized as a noninvasive marker to assess tumor aggressiveness. Thus, it can be useful as a prognostic marker and as a marker of tumor burden.

Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenstrom macroglobulinemia

The serum IgM level has been utilised as a marker of tumor progression and to assess response to therapy in patients with Waldenstrom macroglobulinemia (WM). However, there are many limitations to the IgM protein level. The objective of this study was to evaluate the association of known tumor burden markers and prognostic factors with serum free light chain (sFLC) in 98 patients with WM. We demonstrated that sFLC measurement accurately differentiated IgM-MGUS compared with WM reflecting a measurement of tumor burden. In univariate and multivariate analysis, median sFLC at the cut-off at 60 mg/L was higher for WM patients with low hemoglobin and high β2M, when we applied the WM-IPSS cut-offs, but showed no association with IgM level. This study demonstrates that sFLC is a new marker in WM disease. Further analysis is required to prospectively study the role of sFLC in monitoring response to therapy and as a prognostic marker in WM patients.

High CD49d Protein Expression Predicts Short Overall Survival and Early Progression in Chronic Lymphocytic Leukemia Patients.

B-cell chronic lymphocytic leukemia (CLL) is a heterogeneous disease with highly variable clinical courses which can be at least in part foreseen by investigating the expression of known prognosticators, including the IGHV gene mutational status or CD38/ZAP-70 expression. By analysing the coordinated expression of several surface antigens in a series of CLL with known clinical courses, we identified the simultaneous over-expression of CD38 and CD49d as part of the signature characterizing the subgroup with the worst outcome. The aim of the present study was to investigate the relationship between CD49d and other well-established biologic prognosticators (CD38 and ZAP-70 expression, IGHV gene mutational status), or markers of tumor burden (Rai clinical stage, beta2-M, sCD23), and to define the independent prognostic impact of CD49d in predicting overall survival (OS) and disease progression (evaluated as time-to-treatment, TTT) in CLL patients. The study includes samples from 303 patients affected by CLL according to the current diagnostic criteria (median age: 63.5 years, range 32–97). The entire cohort of patients was utilized to investigate the impact of CD49d and other prognosticators (CD38, ZAP-70, IGHV gene mutational status) on OS. TTT information and additional laboratory parameters (beta2-M, sCD23) were available for 232/303 patients, whose therapies were established according to NCI-WG criteria. CD49d expression was determined by three-color flow cytometry combining anti-CD49d, anti-CD19 and anti-CD5 mAbs; its expression was demonstrated to be stable over-time and the 30% of positive CD5+CD19+CLL cells was chosen as cut-off to discriminate CD49dlow from CD49dhigh cases. CD49d, whose expression was strongly associated with that of CD38 (p=2.2×10exp-16) and ZAP-70 (p=2.6×10exp-5), or with IGHV gene status (p=1.1×10exp-6), was independent predictor for OS (HR=4.39; p=0.0081) along with IGHV status (HR=5.54; p=0.0005) or, if this parameter was omitted, with ZAP-70 (HR=2.90; p=0.0092). CD49d also effectively predicted TTT and refined the prognostic relevance of all the investigated prognosticators. Notably, a CD49dhigh phenotype, while not changing the outcome of good prognosis (ZAP-70low, mutated-IGHV) CLL, was necessary to correctly predict the bad clinical courses of ZAP-70high (HR=3.12; p=0.023) or unmutated-IGHV (HR=2.95; p=0.002) cases. These findings support the introduction of CD49d detection in routine prognostic assessment of CLL patients, and suggest both pathogenetic and therapeutic implications for CD49d expression in CLL, e.g. envisioning the use of a humanized anti-CD49d monoclonal antibody, currently employed in multiple sclerosis (Natalizumab), for selcted CLL patients.

Anti-CD25 Targeted Killing of Bicistronically Transduced Cells: A Novel Safety Mechanism Against Retroviral Genotoxicity

Gene therapy for Fabry disease, a deficiency in alpha-galactosidase A (alpha-gal A) activity, has the potential to provide a cure for the disorder with a single treatment. Despite modifications to existing vectors, concerns have arisen regarding the risk of genotoxicity associated with the use of retroviruses. To address safety concerns, we propose that expression of a cell surface protein, human CD25 (huCD25) in a bicistronic format, with any therapeutic gene such as alpha-gal A can provide a target that can be used to kill transduced cells selectively should transformative events occur. We show that an anti-CD25 antibody and immunotoxin can specifically target and eliminate transduced leukemia cells expressing CD25. In a murine leukemia model, antibody treatment reduced tumor burden 32-fold and increased survival compared with untreated mice. Furthermore, after a bone marrow transplant of therapeutically transduced cells into Fabry mice, antibody treatment reduced the number of retrovirally transduced huCD25-expressing cells in the peripheral blood. A systemic loss of transduced cells with functional consequences was also evident in the liver and spleen. This proof-of-principle study demonstrates that a targeted antibody can reduce tumor burden and selectively clear bicistronically transduced hematopoietic cells that express a target antigen, thus acting as a built-in safety mechanism.

Anti-CD25 Targeted Killing of Bicistronically Transduced Cells: A Novel Safety Mechanism Against Retroviral Genotoxicity

Anti-CD25 Targeted Killing of Bicistronically Transduced Cells: A Novel Safety Mechanism Against Retroviral Genotoxicity

Soluble CD30 Can Distinguish Disease Progression from Acute GVHD in Patients with Adult T Cell Leukemia/Lymphoma Who Received Allogeneic Hematopoietic Stem Cell Transplantation.

At present, allogeneic hematopoietic stem cell transplantation (HCST) has been an only curative modality for the treatment of adult T cell leukemia/lymphoma (ATLL). Disease relapse and GVHD are the major causes of mortality after allo-HSCT for ATLL. To achieve better outcome, early detection of disease relapse after allo-HSCT is absolutely crucial for decision-making of interventions such as donor lymphocyte infusion and/or adjuvant chemotherapy, while tumor burden still remains in the level of minimal residual disease (MRD). Serum soluble interleukin-2 receptor alpha (sIL-2R) has been known as a marker of ATLL tumor burden in affected patients, however it increases in patients with acute and chronic GVHD as well. Here we propose a new strategy to distinguish disease progression of ATLL and GVHD at an early stage by measuring serum levels of soluble CD30 antigen (sCD30) and sIL-2R. The surface CD30 is normally expressed by activated B or T cells. It has been known that Hodgkin cells, anaplastic large cell lymphoma and ATLL cells also express surface CD30. The soluble form of CD30 is produced by metalloprotease cleavage. Acute type ATLL patients whose tumor cells express surface CD30 (CD30+ATLL), who underwent allo-HSCT, were included in this study. As control, the serum levels of sCD30 were measured in a healthy donor, an asymptomatic HTLV-I carrier and acute type ATLL patients whose tumor cell were negative for surface CD30 (CD30−ATLL), all were below measurable range. In addition, the level of sCD30 was undetectable in a CD30− ATLL patient with grade II gut acute GVHD as well. Confirming these low backgrounds, both of sCD30 and sIL2R levels were sequentially measured from induction chemotherapy and throughout allo-HSCT. During chemotherapy, the levels of sCD30 and sIL2R are well-correlated along with tumor burden as previously reported, and both markers increase at disease relapse after allo-HSCT as well. In contrast, during GVHD, sIL-2R levels increase along with GVHD status, while sCD30 remained lower or undetectable. In conclusion, serum levels of sCD30 and sIL-2R may predict not only disease progression at an early stage after allo-HSCT, but also distinguish that from GVHD. These findings may help to introduce an early intervention for ATLL progression with DLI and/or adjuvant chemotherapy at the level of minimal residual disease. [Display omitted]

Serum Free Light Chain (SFLC) Elevation Is Associated with High β2-Microglobulin and with a Shorter Time to Treatment in Waldenström Macroglobulinemia (WM).

WM is a rare lymphoproliferative disorder caracterised by bone marrow lymphoplasmacytic infiltration with IgM monoclonal gammopathy. Assessing the tumor burden in WM is challenging and is not directly related to IgM level or bone marrow infiltration. Thus treatment criteria are based on clinical symptoms related to IgM or pancytopenia. SFLC quantification is a useful tool for the diagnosis and follow-up of gammopathies such as amyloidosis and light chain myeloma. So far its quantification has never been studied in WM. We investigated whether SFLC quantification was correlated with monoclonal component value and established prognostic factors, or was predictive of a shorter time to treatment.We analyzed 45 untreated WM patients (IgMκ: 37; IgMλ: 8) at the time of diagnosis (n=23) or during the follow-up (n=22). Patients were assessed for physical examination, body CT scan, serum protein electrophoresis with albumin (g/l) and monoclonal component (g/L) measurements, SFLC level (The Binding Site®, cut-off: SFLCκ 19.4 mg/L and SFLCλ 26.3 mg/L), peripheral blood count and β2-microglobulin (β2-m). Cut-off values of prognostic factors were those defined by the International Prognostic Index for WM (Morel ASH 2006) ie. β2-m > 3mg/L, Hb < 115 g/L, platelets < 100 G/L, albumin < 35 g/L. Treatment was initiated at diagnosis in 7 patients or during the follow-up in 23 patients. Median follow-up for the whole population was 15 months (1 – 74).Median SFLCκ value was 39 mg/L (1.73–399), median SFLCλ was 12.6 mg/L (1.93–19400). 75 % of patients had upper to normal SFLC value (34/45). Table 1 summarizes univariate analysis of (1) the relationship between high SFLC value (SFLC > N) and known biological prognostic factors, and (2) the impact of SFLC > N and other biological parameters on time to treatment. Our results showed that high SFLC correlated with β2-m but not with other biological prognostic factors or with monoclonal IgM value. (2) Patients with SFLC > N had a shorter time to treatment than patients with normal SFLC value. Furthermore, taking SFLC as a continuous variable in patients with SFLC > N, treatment time was strongly correlated to the SFLC quantification (κ: p=0.01; λ: p=0.01). SFLC could thus be used as a new marker of tumor burden in WM and its prognostic value must be tested in larger WM series. The correlation between SFLC variation and response to treatment is still under investigation.Table 1SFLC > N (1)time to treatment (2)SFLC > NNAp=0.03monoclonal IgM valuep=0.08p=0.001β2-m > 3 mg/Lp=0.03p=0.44Hb < 115 g/Lp=0.43p=0.009Platelets < 100 G/Lp=1p=0.36Albumin < 35 g/Lp=0.3p=0.011

Lactate Dehydrogenase, not Vascular Endothelial Growth Factor or Basic Fibroblast Growth Factor, Positively Correlates to Bone Marrow Vascularity in Acute Myeloid Leukemia

Angiogenesis has been extensively studied in acute myeloid leukemia (AML). Lactate dehydrogenase (LDH), a common biochemical marker for tumor burden and anaerobic glycolysis, is a poor prognostic factor for AML. Regulated by hypoxia-induced factor, both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are responsive to cancer-related angiogenesis. To study the roles of serum LDH, VEGF and bFGF in AML angiogenesis, we investigated bone marrow vascularity in untreated AML patients, and analyzed its relationship to serum LDH, VEGF and bFGF levels. Eighteen (11 males, 7 females; mean age, 57.7 years) de novo, untreated AML patients were enrolled. Bone marrow vascularity was evaluated by staining bone marrow core biopsy tissue with endothelial cell marker CD31 or CD34. Serum LDH was determined with the Wroblewski-La Due method. Serum VEGF and bFGF were determined with enzyme-linked immunoassay. The relationship of LDH, VEGF and bFGF level to bone marrow vessel numbers was examined by linear regression. Log LDH significantly correlated to AML bone marrow vascularity (r = 0.61; p = 0.007). VEGF and bFGF concentrations did not correlate with AML angiogenesis. These results suggest that serum LDH, but not VEGF and bFGF concentrations, can be used as a simple parameter for predicting vessel formation in AML bone marrow.

Relationship between pretreatment level of plasma Epstein-Barr virus DNA, tumor burden, and metabolic activity in advanced nasopharyngeal carcinoma

Plasma Epstein-Barr virus DNA (pEBV DNA) is an important prognostic marker in nasopharyngeal carcinoma (NPC). This study tested the hypotheses that pEBV DNA reflects tumor burden and metabolic activity by evaluating its relationship with tumor volume and 18F-fluorodeoxyglucose (18F-FDG) uptake in NPC. Pre-treatment pEBV DNA analysis, 18F-FDG positron emission tomography-computed tomography scan (PET-CT) and magnetic resonance imaging (MRI) of the head and neck were performed in 57 patients. Net volume (cm3) of the primary tumor (T(vol)) and regional nodes (N(vol)) were quantified on MRI. 18F-FDG uptake was expressed as the maximum standardized uptake value (SUV(max)) at the primary tumor (T(suv)) and regional nodes (N(suv)). Lesions with SUV(max) > or = 2.5 were considered malignant. Relationship between SUV(max), natural logarithm (log) of pEBV DNA, and square root (sq) of MRI volumes was analyzed using the Wilcoxon test. A linear regression model was constructed to test for any interaction between variables and disease stage. Log-pEBV DNA showed significant correlation with sq-T(vol) (r = 0.393), sq-N(vol) (r = 0.452), total tumor volume (sq-Total(vol) = T(vol) + N(vol), r = 0.554), T(suv) (r = 0.276), N(suv) (r = 0.434), and total SUV(max) (Total(suv) = T(suv) + N(suv), r = 0.457). Likewise, sq-T(vol) was correlated to T(suv) (r = 0.426), and sq-N(vol) with N(suv) (r = 0.651). Regression analysis showed that only log-pEBV DNA was significantly associated with sq-Total(vol) (p < 0.001; parameter estimate = 8.844; 95% confidence interval = 3.986-13.703), whereas Sq-T(vol) was significantly associated with T(suv) (p = 0.002; parameter estimate = 3.923; 95% confidence interval = 1.498-6.348). This study supports the hypothesis that cell-free plasma EBV DNA is a marker of tumor burden in EBV-related NPC.

Microscopic tumor burden in sentinel lymph nodes (SLNs) best predicts nonsentinel lymph node (NSLN) involvement in patients with melanoma

8004 Background: Therapeutic lymph node dissection (TLND) has long been the standard of care for melanoma metastatic to the regional LNs and is commonly used for patients (pts) with microscopic disease identified by SLN biopsy. We and others have demonstrated that additional histologically positive (pos) nodes are identified in 8%-33% of completion LN dissection (CLND) specimens. The purpose of this study was to determine predictors of additional LN involvement in pts. with pos SLNs. Methods: Pts with clinically node-negative melanoma who underwent SLN biopsy at our institution between 1991 and 2003 and had pos SLNs were identified. Patient and primary tumor factors, number of pos SLNs, and extent of microscopic disease within the SLN were evaluated as potential predictors of pos NSLNs. Results: Overall, 359 (16%) of 2,203 pts had a pos SLN. Pos NSLNs were identified in 48 (14%) of the 343 pts with pos SLNs who underwent CLND. On univariate analysis, several markers of SLN microscopic tumor burden, tumor thickness &gt;2mm, age &gt;50 years, and Clark level &gt;III were predictive of additional pos nodes in the TLND specimen. Primary tumor ulceration was not predictive. On multivariable logistic regression analysis, markers of microscopic tumor burden (large SLN met focus, large SLN tumor square area, presence of SLN extracapsular extension, and synchronous subcapsular and intramedullary SLN deposits) were the most powerful independent predictors of pos NSLNs; tumor thickness &gt;2mm also predicted additional disease. A model was established using tumor thickness and SLN tumor burden to identify pts with low, intermediate, or high risk for NSLN involvement (Table). Conclusions: In melanoma pts with ≥1 pos SLN, SLN tumor burden and primary tumor thickness may be useful in identifying a group at low risk for pos NSLNs. This information is valuable in designing clinical trials in which pts may be randomly assigned to TLND versus observation alone after removal of a pos SLN. [Table: see text] No significant financial relationships to disclose.

Serum insulin‐like growth factor is not elevated in patients with early B‐cell chronic lymphocytic leukemia but is still a prognostic factor for disease progression

Insulin-like growth factor 1 (IGF-1) is an important growth and anti-apoptotic factor for the cancer cells in several malignancies and in multiple myeloma recent studies support the hypothesis of a role for IGF-1 in disease progression; however, clinico-biological relevance of IGF-1 was never studied in B-cell chronic lymphocytic leukemia (CLL). Using a quantitative sandwich immunoassay technique (ELISA) (Quantikine, Human IGF-1 and IGFBP-3, R&D Systems), we measured the concentration of IGF-1 and its major binding protein IGF-binding protein 3 (IGFBP-3) in serum drawn at the time of diagnosis from 77 Binet stage A CLL patients. Either IGF-1 or IGFBP-3 were significantly decreased compared with healthy age- and sex-matched controls (P < 0.0001 for both; Mann-Whitney test). Serum levels of IGF-1 and IGFBP-3 paralleled each other (P = 0.002); in contrast, no significant correlation was found between serum levels of IGF-1 and clinico-hematological variables including age (P = 0.253), sex (P = 0.270), Rai clinical substages (P = 0.140), lactate dehydrogenase (P = 0.956), beta2-microglobulin (P = 0.368), lymphocyte count (P = 0.703) and lymphocyte doubling time (LDT, P = 0.233). When correlation were attempted with circulating levels of angiogenic cytokines such as vascular endothelial growth factor (P = 0.971), basic fibroblastic growth factor (P = 0.695), angiogenin (P = 0.282) or adhesion molecules such as vascular cell adhesion molecule-1 (P = 0.318), intercellular adhesion molecule-1 (P = 0.883) and platelet endothelial cell adhesion molecule-1 (P = 0.772) similar results were found. Serum levels of IGF-1 were further evaluated as a dichotomous variable with respect to progression-free survival (PFS), an endpoint surrogate for overall survival in early B-cell CLL. The best separation of curves was seen with the cutoff point at the 75th percentile of IGF-1 levels (i.e., 93 pg/mL). Median PFS was 63 months in the patient group with low IGF-1, compared with a median PFS of 40 months in the remaining patients (P = 0.03). In the multivariate analysis performed including variables significant at univariate analysis [i.e. Rai substage (P = 0.002); LDT (P = 0.004), IGF-1 (P = 0.01)], only Rai substage retained prognostic significance (P = 0.006). However, after removing from analysis LDT (only six of 77 had an LDT < 12 months), either IGF-1 or Rai substage entered the model at a significant level (P = 0.03 and P = 0.01, respectively). IGF-1 did not correlate with markers of tumor burden or clinical status in CLL thus suggesting that levels of this cytokine do not reflect the intrinsic malignancy of disease. Results of the present study highlight, however, its involvement in mechanisms of disease progression in early CLL.

High Bone Turnover Markers Predict Poor Outcome in Patients With Bone Metastasis

Bone is a frequent site for metastasis in patients with solid tumors such as breast cancer, prostate cancer, and lung cancer. It may be the first, or even the only, site for metastases in these patients. It is estimated that more than 350,000 patients a year in the United States die with bone metastasis. 1 Bone metastasis is responsible for some of the most devastating complications of malignancy, including pathologic bone fractures, spinal cord compression syndromes, excruciating bone pain, and hypercalcemia. These skeletal metastases can require surgery or radiotherapy to bone, in addition to aggressive analgesic therapy. Furthermore, bone metastases have a major impact on the quality of life and even the survival of these patients. This is clearly illustrated by the authors of the current article, who have reported on patients from the placebo arms of their trials. 2 They found that 143 of 454 patients with bone metastasis from prostate or other solid tumors on the placebo arms of thesetrialsexperiencedpathologicfracturesthroughoutthe 21 months of study. 2 Two hundred forty of these 454 patients required radiotherapy to their bone lesions. The median survival for prostate cancer patients on the placebo arm of the trial was 16.8 months and was only 5.6 months for patients with bone metastasis from other solid tumors. These results demonstrate the extreme toll bone metastasis takes on these patients. Inthisissue,Colemanetalexaminedtheabilityofbone turnover markers to predict negative clinical outcomes in a cohort of almost 2,000 patients with baseline bone metastasisfromprostatecancer,breastcancer,myeloma,orother tumors, who were treated with bisphosphonates. 3 Previous reports of the predictive value of bone turnover markers in these types of patients have been conflicting. However, most of the other studies included much smaller numbers of patients. The overwhelming majority of the patients in the current trial received zoledronate, an extremely potent bisphosphonate. Even patients receiving this very potent bisphosphonate still had progression of their bone disease, experiencing one skeletal-related event per year during the 17 months that they were followed up on. These investigators report on two markers of bone turnover, urinary Ntx (N-telopeptide of collagen type 1) and serum bone-specific alkaline phosphatase (BAP). Ntx is a marker of bone degradation by osteoclasts, and BAP is a marker for bone formation. These markers were chosen because patients with solid tumors and bone metastasis have both increased bone destruction and bone formation. In contrast, patients with myeloma have suppressed bone formation. They found that Ntx levels were better predictors of outcome for these patients than BAP. Patients with hormone refractory prostate cancer had the highest Ntx levels, most likely reflecting the combined effects of increased bone turnover from their metastasis, and bone loss due to low testosterone levels. Furthermore, high levels of Ntx at study entry predicted a poor outcome, and the most recent Ntxlevelwasanevenbetterpredictorforoutcome.Patients with high Ntx levels in their urine had a four- to six-fold increased risk of death and a two-fold increase in the risk of future skeletal events compared with patients with low Ntx levels. Interestingly, once patients were on therapy, Ntx levels did not correlate with tumor burden markers suchasprostate-specificantigeninpatientswithprostate cancer, though it is likely that high Ntx levels reflected increased tumor progression in patients compared with those with low Ntx levels. Furthermore, although Ntx levels reflect bone events, it is reasonable to assume those visceral metastases are also progressing in patients with high Ntx levels. Importantly, high levels of bone resorption markers seem to identify ag roup of patients who are not responding to their current therapy and may need additional antiresorptive therapy as well as changes in their chemotherapy, or may be candidates for trials of novel agents.

Correlation between serum CEA level and metabolic volume as determined by FDG PET in postoperative patients with recurrent colorectal cancer

To determine the correlation between serum CEA level and the metabolic volume by FDG PET in postoperative patients with recurrent colorectal cancer, FDG PET was performed in 29 consecutive patients with recurrent or metastatic colorectal cancer whose CEA levels were higher than 5 ng/ml. A whole body emission scan was performed 60 minutes after injecting 370-555 MBq of F-18 FDG. "PET volume" and "PET metabolic volume" of tumors were measured on FDG PET images. Based on an isocontour plot of tumor mass at 2.5 SUV (standardized uptake value), the metabolically active tumor "PET volume" was calculated. "PET metabolic volume" was obtained by multiplying the "PET volume" by the mean SUV of the tumor. All recurrent or metastatic lesions were single or multiple lesions of measurable size (axial diameter > 1 cm, minimum "PET volume" 3.5 cm3), and were verified by operation or by other imaging modalities (CT or MRI). There was a linear associations between "PET volume" and serum CEA level. Further regression analysis by least squares showed a highly significant model with an equation of volume = 41.2 + 0.471 x CEA (r2 = 0.629). However, no such association was found between "PET metabolic volume" and serum CEA level according to the residual normality test. In conclusion, "PET volume" measured by FDG PET and serum CEA level in colorectal cancer are significantly correlated. Tumor volume determined by FDG PET can be used as an effective marker of tumor burden in postoperative patients with colorectal carcinoma.