To examine clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline
-mutated, human epidermal growth factor receptor 2 (HER2)-negative advanced breast ...cancer (ABC).
A retrospective analysis was conducted using medical records from patients with HER2-negative ABC with
mutation who received cytotoxic chemotherapy. Data were stratified into groups with triple-negative breast cancer (TNBC) or hormone receptor-positive (HR+)/HER2-negative diagnoses. Time-to-event outcomes (i.e., real-world progression-free survival rwPFS and overall survival OS) were calculated to summarize health outcomes.
When diagnosed with ABC, most patients were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of
-related cancer (71.5%). A total of 305 patient records were examined; 194 patients (63.6%) had advanced TNBC, and 111 patients (36.4%) had HR+/HER2-negative ABC. Chemotherapy was primarily used as first-line treatment for both subgroups, but the TNBC subgroup received poly (ADP-ribose) polymerase (PARP) inhibitors at triple the rate as a second-line treatment and double the rate as a third-line treatment compared with the HR+/HER2-negative subgroup. Two-year OS rates were similar between the TNBC (73.9%) and the HR+/HER2-negative subgroups (77.0%), and anemia, nausea, and neutropenia were the most commonly reported toxicities across all treatments.
Clinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC given the growing evidence that PARP inhibitors may improve PFS compared with chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life.
To review the available evidence of chemoembolization for unresectable hepatocellular carcinoma (HCC).
Computerized bibliographic searches with MEDLINE and CANCERLIT databases from 1980 through 2000 ...were supplemented with manual searches, with the keywords "hepatocellular carcinoma," "liver cell carcinoma," "randomized controlled trial RCT," and "chemoembolization." Studies were included if patients with unresectable HCC were enrolled and if they were RCTs in which chemoembolization was compared with nonactive treatment (five RCTs) or if different transarterial modalities of therapy (13 RCTs) were compared. Data were extracted from each RCT according to the intention-to-treat method. Five of the RCTs with a nonactive treatment arm were combined by using the random-effects model, whereas all 18 RCTs were pooled from meta-regression analysis.
Chemoembolization significantly reduced the overall 2-year mortality rate (odds ratio, 0.54; 95% CI: 0.33, 0.89; P =.015) compared with nonactive treatment. Analysis of comparative RCTs helped to predict that overall mortality was significantly lower in patients treated with transarterial embolization (TAE) than in those treated with transarterial chemotherapy (odds ratio, 0.72; 95% CI: 0.53, 0.98; P =.039) and that there is no evidence that transarterial chemoembolization is more effective than TAE (odds ratio, 1.007; 95% CI: 0.79, 1.27; P =.95), which suggests that the addition of an anticancer drug did not improve the therapeutic benefit.
In patients with unresectable HCC, chemoembolization significantly improved the overall 2-year survival compared with nonactive treatment, but the magnitude of the benefit is relatively small.
Unconjugated monoclonal antibodies have emerged as important therapeutic agents for selected malignancies. One mechanism by which antibodies can exert cytotoxic effects is antibody-dependent cellular ...cytotoxicity (ADCC). In an effort to increase the efficiency of ADCC at tumor sites, we have focused on the construction of bispecific antibodies specific for the tumor antigen HER2/neu and the FcγRIII-activating receptor (CD16) found on NK cells, mononuclear phagocytes, and neutrophils. Here, we describe the production of bispecific minibodies in two distinct binding formats. The parent minibody was constructed such that the IgG1 CH3 constant domain serves as the oligomerization domain and is attached to an anti-CD16 and an anti-HER2/ neu single-chain Fv via 19- and 29-amino acid linkers, respectively. This molecule can be expressed in mammalian cells from a dicistronic vector and has been purified using sequential affinity purification techniques. Analysis by surface plasmon resonance shows that the bispecific minibody can bind to HER2/neu and CD16, both individually and simultaneously. Furthermore, cytotoxicity studies show that the minibody can induce significant tumor cell lysis at a concentration as low as 20 nm. A trimeric, bispecific minibody (TriBi) that binds dimerically to HER2/neu and monomerically to CD16 induces equivalent cytotoxicity at lower antibody concentrations than either the parent minibody or the corresponding single-chain dimer. Both minibody constructs are stable in mouse and human serum for up to 72 h at 37 °C. These minibodies have the potential to target solid tumors and promote tumor lysis by natural killer cells and mononuclear phagocytes.
We tested the hypothesis that bispecific Abs (Bsab) with increased binding affinity for tumor Ags augment retargeted antitumor cytotoxicity. We report that an increase in the affinity of Bsab for the ...HER2/neu Ag correlates with an increase in the ability of the Bsab to promote retargeted cytotoxicity against HER2/neu-positive cell lines. A series of anti-HER2/neu extracellular domain-directed single-chain Fv fragments (scFv), ranging in affinity for HER2/neu from 10(-7) to 10(-11) M, were fused to the phage display-derived NM3E2 human scFV: NM3E2 associates with the extracellular domain of human FcgammaRIII (CD16). The resulting series of Bsab promoted cytotoxicity of SKOV3 human ovarian carcinoma cells overexpressing HER2/neu by human PBMC preparations containing CD16-positive NK cells. The affinity for HER2/neu clearly influenced the ability of the Bsab to promote cytotoxicity of (51)Cr-labeled SKOV3 cells. Lysis was 6.5% with an anti-HER2/neu K(D) = 1.7 x 10(-7) M, 14.5% with K(D) = 5.7 x 10(-9) M, and 21.3% with K(D) = 1.7 x 10(-10) M at 50:1 E:T ratios. These scFv-based Bsab did not cross-link receptors and induce leukocyte calcium mobilization in the absence of tumor cell engagement. Thus, these novel Bsab structures should not induce the dose-limiting cytokine release syndromes that have been observed in clinical trials with intact IgG BSAB: Additional manipulations in Bsab structure that improve selective tumor retention or facilitate the ability of Bsab to selectively cross-link tumor and effector cells at tumor sites should further improve the utility of this therapeutic strategy.
Previous studies have shown that the C protein of 40 S hnRNP complexes contains a leucine-zipper domain, residues 180-207, and that a 40 residue highly basic domain, immediately preceding the zipper, ...is responsible for almost all of the free energy of RNA binding to C protein. Because this domain arrangement is like that seen in the bZIP transcription factors it has been termed the bZIP-like-motif or bZLM. We report here that the zipper domain drives C protein oligomerization through its spontaneous assembly into an anti-parallel four-helix bundle approximately 50 Å in length. The anti-parallel nature of the four-helix bundle positions the tetramer’s four high-affinity RNA binding domains at opposing ends of a rigid core formed by the helix bundle. This domain topology is ideally suited to accommodate and direct a double wrapping of RNA around the tetramer and is fully consistent with C protein’s ability to bind and order 230 nt lengths of pre-mRNA through a highly cooperative RNA binding mode. We have used a novel sequence-specific
13C/
15N labeling strategy and multidimensional NMR spectroscopy to define the anti-parallel orientation of the four-helix bundle and its molecular dimensions.
In vitro reconstitution and hydrodynamic studies on native C protein, on several C protein fragments, and on various synthetic peptides, are consistent with the proposed model and indicate that C protein’s canonical RNA recognition motifs probably function in tetramer-tetramer interactions during 40 S hnRNP assembly.
Inhibitors of the vascular endothelial growth factor (VEGF) pathway frequently induce hypertension when used to treat patients with advanced renal cell carcinoma (RCC). This analysis characterizes ...hypertension and hypertension-related events in patients treated with the VEGF pathway inhibitors axitinib or sorafenib in the AXIS trial. AXIS was a randomized phase III study of axitinib versus sorafenib in patients with metastatic RCC following failure of one prior systemic regimen. Patients with uncontrolled hypertension were excluded, but patients with hypertension controlled with antihypertensive medication were allowed to participate. Guidelines for hypertension management included adjustment or addition of antihypertensive medications and/or axitinib or sorafenib dose reductions, interruptions, or discontinuations. Treatment-emergent all-causality hypertension occurred in 145 (40.4 %) axitinib-treated patients (
N
= 359) and 103 (29.0 %) sorafenib-treated patients (
N
= 355), with grade 3 hypertension reported in 55 (15.3 %) and 38 (10.7 %) patients, respectively, and grade 4 hypertension reported in one (0.3 %) patient in each arm. Hypertension-related events led to axitinib dose interruptions (
n
= 46; 12.8 %), dose reductions (
n
= 16; 4.5 %), or discontinuations (
n
= 1; 0.3 %). Approximately 50 % of axitinib-treated patients with grade 3 or 4 hypertension continued treatment for ≥ 9 months. Hypertension-related sequelae occurred in <1 % of axitinib-treated patients. Hypertension was more frequently observed during treatment with axitinib than sorafenib in patients with RCC, but axitinib-induced hypertension rarely led to treatment discontinuation or cardiovascular sequelae. Recommendations for monitoring blood pressure and managing hypertension during axitinib therapy are presented.
When and how to treat acute hepatitis C? Licata, Anna; Di Bona, Danilo; Schepis, Filippo ...
Journal of hepatology,
12/2003, Letnik:
39, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background: Appropriate treatment of acute hepatitis C is still a matter of controversy due to the lack of large controlled trials.
Aim: To assess the effectiveness of interferon as treatment for ...acute hepatitis C by meta-analysis.
Methods: MEDLINE search (1985–2002) was supplemented with manual searches of reference lists. Studies were included if they were controlled trials comparing interferon to no treatment and if they included patients with either post-transfusion or sporadic acute hepatitis C. Twelve trials were analyzed (414 patients). The outcome assessed was the sustained virological response (SVR) rate (undetectable hepatitis C virus RNA in serum at least 6 months after cessation of therapy).
Results: Interferon significantly increased the SVR (risk difference 49%; 95% confidence interval 32.9–65%) in comparison to no treatment. The risk difference of SVR increased from 5 to 90% when trials were ordered by increasing interferon weekly dose. Delaying therapy by 8–12 weeks after the onset of disease does not compromise the SVR rate.
Conclusions: Current evidence is sufficient to recommend interferon treatment of patients with acute hepatitis C. A later initiation of therapy yields the same likelihood of response as early treatment. A daily induction dose during the 1st month is the best option of treatment.
Based on UV cross-linking experiments, it has been reported that the C protein tetramer of 40 S heterogeneous nuclear ribonucleoprotein complexes specifically interacts with stem-loop I of U2 small ...nuclear RNA (snRNA) (Temsamani, J., and Pederson, T. (1996)J. Biol. Chem. 271, 24922–24926), that C protein disrupts U4:U6 snRNA complexes (Forne, T., Rossi, F., Labourier, E., Antoine, E., Cathala, G., Brunel, C., and Tazi, J. (1995) J. Biol. Chem. 270, 16476–16481), that U6 snRNA may modulate C protein phosphorylation (Mayrand, S. H., Fung, P. A., and Pederson, T. (1996) Mol. Cell. Biol. 16, 1241–1246), and that hyperphosphorylated C protein lacks pre-mRNA binding activity. These findings suggest that snRNA-C protein interactions may function to recruit snRNA to, or displace C protein from, splice junctions. In this study, both equilibrium and non-equilibrium RNA binding assays reveal that purified native C protein binds U1, U2, and U6 snRNA with significant affinity (∼7.5–50 nm) although nonspecifically. Competition binding assays reveal that U2 snRNA (the highest affinity snRNA substrate) is ineffective in C protein displacement from branch-point/splice junctions or as a competitor of C protein's self-cooperative RNA binding mode. Additionally, C protein binds snRNA through its high affinity bZLM and mutations in the RNA recognition motif at suggested RNA binding sites primarily affect protein oligomerization.
CNTO 95 is a fully human monoclonal antibody that recognizes αv integrins. Previous studies have shown that CNTO 95 exhibits both anti-tumor and anti-angiogenic activities (Trikha M et al., Int J ...Cancer 110:326–335, 2004). In this study we investigated the biological activities of CNTO 95 on breast tumor cells both in vitro and in vivo. In vitro treatment with CNTO 95 decreased the viability of breast tumor cells adhering to vitronectin. CNTO 95 inhibited tumor cell adhesion, migration, and invasion in vitro. CNTO 95 treatment also induced tyrosine dephosphorylation of focal adhesion kinase (FAK), and the docking protein paxillin that recruits both structural and signaling molecules to focal adhesions (Turner CE, Int J Biochem Cell Biol 30:955–959, 1998; O’Neil GM et al., Trends Cell Biol 10:111–119, 2000). These results suggest that CNTO 95 inhibits breast tumor cell growth, migration and invasion by interruption of αv integrin mediated focal adhesions and cell motility signals. In vivo studies of CNTO 95 were conducted in an orthotopic breast tumor xenograft model. Treatment with CNTO 95 resulted in significant inhibition of both tumor growth and spontaneous metastasis of MDA-MB-231 cells to the lungs. CNTO 95 also inhibited lung metastasis in a separate experimental (tail vein injection) model of metastasis. The results presented here demonstrate the anti-tumor and anti-metastatic activities of CNTO 95 in breast cancer models and provide insight into the cellular and molecular mechanisms mediating its inhibitory effects on metastasis.
Studies performed to discover genes overexpressed in inflammatory diseases identified dermokine as being upregulated in such disease conditions. Dermokine is a gene that was first observed as ...expressed in the differentiated layers of skin. Its two major isoforms, α and β, are transcribed from different promoters of the same locus, with the α isoform representing the C terminus of the β isoform. Recently, additional transcript variants have been identified. Extensive in silico analysis and reverse transcriptase (RT)-PCR cloning has confirmed the existence of these variants in human cells and tissues, identified a new human isoform as well as the γ isoform in mouse. Recombinant expression and analysis of the C-terminal truncated isoform indicate that the molecule is O-linked glycosylated and forms multimers in solution. In situ hybridization and immunohistochemistry has shown that the gene is differentially expressed in various cells and tissues, other than the skin. These results show that the dermokine gene is expressed in epithelial tissues other than the skin and this expression is transciptionally and posttranscriptionally complex.
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