Relationship between efficacy outcomes and weight gain during treatment of advanced, non-squamous, non-small-cell lung cancer patients.

BACKGROUND: Unintentional weight loss occurs among advanced non-small-cell lung cancer (NSCLC) patients and is associated with worse survival. Small studies have suggested that weight gain during treatment is associated with superior survival. PATIENTS AND METHODS: A retrospective analysis analyzed data from three international phase III studies comprising 2301 advanced, non-squamous NSCLC patients who received a platinum-based, first-line doublet, with or without bevacizumab and maintenance therapy. Body weight was recorded before and after treatment by each study's schedule. The relationship between weight gain and overall survival (OS) and progression-free survival (PFS) was assessed using log-rank test and adjusted Cox modeling. Logistic regression assessed the association between baseline covariates and post-baseline weight gain. RESULTS: Four hundred and twenty-one (18.3%) patients had >5% weight gain after baseline. More than half of the weight gain cohort exhibited initial weight gain by 3 weeks. The median OS was 16.7 months versus 10.7 months for the >5% versus ≤5% weight gain subgroup (n = 1880) (P < 0.001). PFS was 6.9 versus 4.8 months, respectively (P < 0.001). Differences in overall tumor response rate (50.8% versus 25.4%, respectively) and disease control rate (tumor response or stable disease) (91.5% versus 63.6%, respectively) were also significant (P < 0.001). The Cox modeling revealed the >5% subgroup had longer survival [hazard ratio (HR) = 0.54, 95% confidence interval (CI) 0.47-0.62; P < 0.001] than the ≤5% subgroup after adjusting for baseline factors. Similar significant results were found for PFS (HR = 0.59, 95% CI 0.52-0.67; P < 0.001). Unadjusted logistic regression indicated a significant association between weight gain (>5% versus ≤5%) and age, and BMI. CONCLUSIONS: Weight gain during treatment may be an early indicator of clinical benefit. If confirmed in prospective studies, monitoring weight change may provide important information regarding survival outcomes in NSCLC and may provide ideas for new therapeutic strategies.

Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer.

BACKGROUND: Clinical results of a randomized phase III trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC) resulted in trial closure for futility; biomarker analyses using immunohistochemistry (IHC) and single-nucleotide polymorphisms (SNPs) are described herein. PATIENTS AND METHODS: Thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS) were investigated using IHC (n=395). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1 (SLC19A1; n=611). RESULTS: None of the IHC biomarkers (folate pathway or ERCC1) were found to be predictive or prognostic in this setting. rs2838952 (adjacent to SLC19A1) had significant treatment-independent association with overall survival (OS; hazard ratio 0.590, P=0.01). Nine GGH-associated SNPs interacted with rs3788205 (SLC19A1) for OS on the PC arm. rs12379987 (FPGS) interacted with treatment for OS (interaction P=0.036). CONCLUSION: Potential ERCC1 and folate pathway IHC biomarkers failed to predict outcome in either study arm in ED-SCLC. SNPs in regions including FPGS and SLC19A1 and interacting SNPs in GGH and SLC19A1 were associated with differences in OS; however, none of these SNPs predicted for greater survival with PC over EC.

Hyperhomocysteinemia and thrombosis.

Homocysteine has been identified as an independent risk factor for atherosclerotic and thrombotic disease. Both arterial (cerebrovascular, carotid, coronary, and peripheral arterial) and veno-occlusive disease, jointly termed vascular occlusive disease (VOD) in this review, have been associated with hyperhomocysteinemia. In cases of homocystinuria, plasma homocysteine levels are markedly elevated. In this setting, the association between homocysteine and VOD seems clear. However, in cases of mild to moderate homocysteinemia, controversy remains regarding the association between homocysteine and VOD. In part this controversy occurs because VOD has multiple etiologies. Similarly, homocysteine levels are affected by several factors including vitamin status, age and gender, and genotype of the patient. The multiple etiologies of both VOD and hyperhomocysteinemia make controlled studies assessing their interrelationship difficult to perform. This review will attempt to present studies that either support or rebut homocysteine as an independent risk factor for vascular occlusive disease and will show that the study of homocysteine and thrombosis remains an active area of research.

Hyperhomocysteinemia and premature vascular occlusive disease.

Hyperhomocysteinemia has recently been identified as an independent risk factor for arterial and venous occlusive disease. In particular, hyperhomocysteinemia has been associated with premature vascular disease, and may act synergistically with other risk factors. Two young patients with severe premature vascular disease, one venous and one arterial, have significantly elevated homocysteine levels. In addition to appropriate anti-coagulant therapy, these patients receive B6 and folate vitamin therapy which normalizes the homocysteine levels. While this course of therapy is prudent, no prospective clinical trials have yet demonstrated that reduction of homocysteine levels correlates with a decreased cardiovascular risk.

Peripheral stem cell mobilization and engraftment in patients over age 60.

Data from 225 multiple myeloma (MM) patients, undergoing peripheral stem cell (PBSC) mobilization with high-dose cyclophosphamide and hematopoietic growth factors, were analyzed for median CD34+ cell count and median time to post-transplant neutrophil (ANC > 500/microliters) and platelet (> 50,000/microliters) recovery according to age groups (20-49, 50-59 and > or = 60 years) and duration of prior therapy (< or = 12, 13-24, or > 24 months). Fifty-seven of the 225 patients were > or = 60 years. No difference in either the median number of CD34+ cells collected or time to engraftment occurred between age groups, when adjusted for duration of prior therapy. These data support the concept that autotransplants can be performed safely in patients > or = 60 years and that these patients should not be excluded from the most effective treatment modalities.

Hyperhomocysteinemia. An emerging and important risk factor for thromboembolic and cardiovascular disease.

Homocysteine is an important contributing factor to thrombosis, vascular injury, and vascular disease. Mechanisms for homocysteine-induced vascular disease include alterations in coagulation as well as endothelial cell and vessel wall injury. Hyperhomocysteinemia (HH[e]) can occur when homocysteine metabolism is altered by mutations in enzymes responsible for homocysteine metabolism. Characterization of these mutations identifies patient groups at risk for vascular disease. Treatment of HH(e) consists of vitamins and raises the possibility that some forms of vascular disease may be easily, safely, and inexpensively treated.

Granulocyte colony-stimulating factor (G-CSF) production and G-CSF receptor structure in patients with congenital neutropenia.

Congenital neutropenia (Kostmann's syndrome [KS]) is an autosomal recessive syndrome that is characterized by profound neutropenia, resulting in major clinical infections and death. Since the neutropenia and symptoms in KS improve in response to exogenous administration of granulocyte colony-stimulating factor (G-CSF), we studied bone marrow cytokine (G-CSF, granulocyte-macrophage CSF [GM-CSF], and interleukin-6) production under both basal and stimulated conditions. No differences in G-CSF, GM-CSF, or IL-6 gene expression were found in bone marrow stromal cells between normal controls and KS patients, and all three cytokines were detected by enzyme-linked immunosorbent assay (ELISA) in medium conditioned by bone marrow stromal cells from normal donors and patients with KS. Each KS patient tested had detectable, functional G-CSF in their own serum before exogenous G-CSF administration. Since G-CSF production appeared normal in KS patients, we then asked whether we could detect structural defects in the signaling portion of G-CSF receptor genes. Polymerase chain reaction (PCR) amplification of the G-CSF receptor transmembrane region alone, and of the transmembrane plus cytosolic portions of the receptor, yielded the size products predicted from the sequences of the normal G-CSF receptor. Single-strand conformational polymorphism (SSCP) analysis of G-CSF receptor PCR products demonstrated no variance in structural conformation between KS patients and normal subjects. These results demonstrate that bone marrow stromal cells in patients with KS secrete normal concentrations of functional G-CSF and suggest that the neutropenia in KS patients is caused by an inability of neutrophilic progenitor and precursor cells to respond to normal, physiologic levels of G-CSF. Such a defect, clinically responsive to pharmacologic doses of G-CSF, might be caused by defects in the post-G-CSF receptor signal transduction pathway.

Bone marrow stromal fibroblasts secrete interleukin-6 and granulocyte-macrophage colony-stimulating factor in the absence of inflammatory stimulation: demonstration by serum-free bioassay, enzyme-linked immunosorbent assay, and reverse transcriptase polymerase chain reaction.

Bone marrow (BM) stromal fibroblasts produce hematopoietic growth factors (HGFs) in response to inflammatory mediators such as tumor necrosis factor-alpha or interleukin-1 alpha (IL-1 alpha). In the absence of such inflammatory stimuli, production of HGFs by BM stromal cells has been problematic and controversial. In vivo, however, basal hematopoiesis maintains blood counts within a normal homeostatic range even in the absence of inflammation, and HGFs are required for progenitor cell differentiation in vitro. To better ascertain the contribution of BM stromal fibroblasts to basal hematopoiesis, we therefore studied HGF production in quiescent BM stromal fibroblasts by three sensitive assays: serum-free bioassay, enzyme-linked immunosorbent assay, and reverse transcriptase polymerase chain reaction. Stromal fibroblasts were cultured in the presence or absence of normal human serum to determine if serum factor(s) present in the noninflammatory (basal) state induce secretion of HGFs. Human serum was found to induce or enhance transcription and secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhance secretion of constitutively expressed IL-6. In contrast, no secretion of either granulocyte-CSF (G-CSF) or IL-3 was found. These data indicate that factors in normal human serum are active in enhancing GM-CSF and IL-6 production by stromal fibroblasts and suggest that these growth factors contribute to the maintainance of normal, basal hematopoiesis in vivo.

Interferon-alpha restores the deficient expression of the cytoadhesion molecule lymphocyte function antigen-3 by chronic myelogenous leukemia progenitor cells.

Hematopoietic cells from the malignant clone in chronic myelogenous leukemia (CML) maintain and expand a proliferative advantage over normal hematopoietic cells within the bone marrow. This advantage is often ameliorated or reversed in vivo by IFN alpha. Based upon earlier studies suggesting decreased adhesiveness of CML progenitor cells, we asked whether CML progenitor cells are deficient in their expression of the cytoadhesion molecule lymphocyte function antigen-3 (LFA-3, CD58) which is normally expressed on hematopoietic progenitors. Progenitor cells from untreated CML patients showed greatly reduced or absent LFA-3 expression, whereas progenitors from patients treated with IFN alpha in vivo or in vitro expressed surface LFA-3 at more normal levels. LFA-3-deficient CML progenitor cells were unable to stimulate normal regulatory proliferative responses in autologous T cells. We hypothesize that IFN alpha-sensitive LFA-3 deficiency reflects a cell surface cytoadhesion defect which may help explain adhesive abnormalities of CML progenitor cells in vitro and clonal proliferation in vivo.

Regulation of interleukin 3 gene induction in normal human T cells.

The regulation of IL-3 gene induction in human peripheral blood T cells was studied. IL-3 gene expression was inducible by crosslinking of the T cell receptor/CD3 complex using anti-CD3 MAb G19-4. Anti-CD3-induced IL-3 gene expression was found to be limited to the CD28+ T cell subset and could be augmented by costimulating T lymphocytes with antibodies directed against CD28. IL-3 expression could also be induced by costimulation of T cells with both phorbol ester and ionomycin, which are thought to mimic the intracellular effects of T cell receptor-antigen interaction. However, unlike other lymphokines such as IL-2 or granulocyte-macrophage colony-stimulating factor, IL-3 gene expression is not induced by stimulation of cells with phorbol myristate acetate and anti-CD28. We conclude that IL-3 gene regulation is under stringent control since IL-3 gene expression occurs only in the CD28+ subset of T cells, and since IL-3 induction obligately requires increased intracellular calcium.