Disease-free Advantage Research Articles

Prognostic Significance of TWEAK Expression in Colorectal Cancer and Effect of Its Inhibition on Invasion

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been implicated in tumor development and progression. The aim of this study was to investigate the role of TWEAK in colorectal cancer (CRC) progression. To investigate the involvement of TWEAK in the progression of human CRC, normal, and tumor specimens from 174 patients were analyzed immunohistochemically for the expression of TWEAK. TWEAK recombinant protein treatment, transfection of expression plasmids, and small interfering RNA to knockdown TWEAK expression were performed to test invasive ability with a Boyden chamber. The mRNA expression profile in recombinant TWEAK treatment was compared to a control group by microarray analysis. To identify downstream effectors, Raf kinase inhibitor (RKIP) and its correlation with TWEAK in vitro and in vivo were examined by quantitative real-time polymerase chain reaction and invasion assays. CRC patients whose tumors displayed high TWEAK expression had a statistically significantly higher overall survival and a disease-free advantage over those with a low TWEAK expression. In in vitro invasion assays, alterations in TWEAK expression in CRC cell lines inversely modulated their invasive ability. By means of integrated genomics, we identified RKIP as a downstream effector in TWEAK-mediated invasion inhibition. Knockout of RKIP expression in HCT116 cells by short hairpin RNA (shRKIP) resulted in increased invasiveness. Clinically, RKIP and TWEAK mRNA expression showed strong positive correlations in CRC patient samples. Our results implicate TWEAK as a key regulator of CRC invasion, and it appears to be a useful prognostic factor for patients with CRC.

Long-term follow-up of a comparison of nonmyeloablative allografting with autografting for newly diagnosed myeloma

AbstractBefore the introduction of new drugs, we designed a trial where treatment of newly diagnosed myeloma patients was based on the presence or absence of HLA-identical siblings. First-line treatments included a cytoreductive autograft followed by a nonmyeloablative allograft or a second melphalan-based autograft. Here, we report long-term clinical outcomes and discuss them in the light of the recent remarkable advancements in the treatment of myeloma. After a median follow-up of 7 years, median overall survival (OS) was not reached (P = .001) and event-free survival (EFS) was 2.8 years (P = .005) for 80 patients with HLA-identical siblings and 4.25 and 2.4 years for 82 without, respectively. Median OS was not reached (P = .02) and EFS was 39 months (P = .02) in the 58 patients who received a nonmyeloablative allograft whereas OS was 5.3 years and EFS 33 months in the 46 who received 2 high-dose melphalan autografts. Among patients who reached complete remission in these 2 cohorts, 53% and 19% are in continuous complete remission. Among relapsed patients rescued with “new drugs,” median OS from the start of salvage therapy was not reached and was 1.7 (P = .01) years, respectively. Allografting conferred a long-term survival and disease-free advantage over standard autografting in this comparative study.

Are aromatase inhibitors superior to antiestrogens?

Aromatase inhibitors (AIs) have been in use to treat metastatic breast cancer for over 25 years. Recently potent and specific AIs have been introduced, which, because of their low toxicity profile, are being used in the adjuvant and neoadjuvant situation and also for the prevention of breast cancer. The two non-steroidal AIs, anastrozole and letrozole, and the steroidal AI, exemestane, have all shown superiority to tamoxifen as first-line treatment for advanced breast cancer. Interestingly, the oestrogen receptor downregulator, fulvestrant, was shown to be equivalent to anastrozole when compared as second-line therapy after the failure of tamoxifen. The first adjuvant AI trial began in 1996 and recruited over 9000 patients (ATAC trial). Anastrozole was compared with tamoxifen and a combination of the two drugs. There were no significant differences between tamoxifen and the combination. However, anastrozole showed about a 20% improvement in disease-free survival in ER+ disease compared with the other treatments. An overall survival analysis will be reported later this year. Two trials have compared 5 years of tamoxifen with 2–3 years of tamoxifen, followed by 2–3 years of AI (one trial (ITA) used anastrozole and another (intergroup) exemestane). Both trials show a disease-free advantage for the switch to AI. In another study (MA17) 5 years of tamoxifen was followed by a randomisation to letrozole or placebo and showed a significant disease-free advantage to the AI. Both letrozole and anastrozole show superiority to tamoxifen when used as a neoadjuvant therapy. Anastrozole significantly reduced contralateral breast cancer compared with tamoxifen, and this has led to two prevention trials: one in women at risk comparing anastrozole with placebo and the other after excision of DCIS comparing anastrozole with tamoxifen (IBIS II). The NCI Canada has also just initiated a trial of exemestane for prevention. Nearly all data available indicate that AIs are superior to tamoxifen. The important question is whether survival is improved when they are used as adjuvant therapy?

Connective tissue growth factor inhibits metastasis and acts as an independent prognostic marker in colorectal cancer

Connective tissue growth factor (CTGF) has been shown to be implicated in tumor development and progression. The aim of this study was to investigate the role of CTGF in progression of colorectal cancer (CRC). Immunohistochemical staining of specimens from 119 patients with CRC was performed. Liposome-mediated transfection was used to introduce a CTGF expression vector into CRC cell lines. Transfectants were tested in invasive ability and experimental hepatic metastasis in BALB/c mice. Furthermore, a FOPflash/TOPflash reporter assay was performed to investigate CTGF on the beta-catenin/T-cell factor signaling pathway. Patients with stage II and stage III CRC whose tumors displayed high CTGF expression had a significantly higher overall survival and a disease-free advantage over patients with CRC with low CTGF expression. Alterations in the CTGF level in CRC cell lines modulated their invasive ability with an inverse correlation. In addition, a reduction in the CTGF level of CT26 cells after stable transfection with antisense CTGF resulted in increased liver metastasis in BALB/c mice. The activity of the beta-catenin/T-cell factor signaling pathway and its downstream effector gene matrix metalloproteinase 7 in these CTGF-transfected cells was strongly attenuated. Blockage of matrix metalloproteinase 7 with its neutralizing antibodies inhibited increased invasiveness in antisense CTGF-transfected CT26 cells. Our results implicate CTGF as a key regulator of CRC invasion and metastasis, and it appears to be a useful and better prognosis factor for patients with stage II and stage III CRC.

Isolation of Georgia Variant (Georgia Isolate 1992) Infectious Bronchitis Virus but Not Ornithobacterium rhinotracheale from a Kentucky Broiler Complex

Integrated broiler production operations in western Kentucky have been very successful. The reason for this success includes the fact that flocks are free of many endemic diseases for a period of time, often years, because birds are raised in virgin, disease-free territory. This case report documents that importation of birds from an area with endemic Georgia variant (GA-92) infectious bronchitis virus and Ornithobacterium rhinotracheale (ORT) bacterial infection resulted in introduction of GA-92, but not ORT, to Kentucky farms. As more broiler production units locate in western Kentucky, in the early phases of operation, they may not experience the "virgin territory," disease-free advantage.

Survival superiority of females with melanoma. A multivariate analysis of 6383 patients exploring the significance of gender in prognostic outcome.

To evaluate the effects of gender on prognostic outcome of patients with melanoma. Retrospective cohort study, including 20 years of follow-up. Duke University Melanoma Clinic, Durham, NC, a referral center for patients with melanoma. Patients with melanoma (N = 6383), consisting of 45% females and 55% males, obtained from a referred sample. Eligibility requirements were nonocular melanomas and white race. Time to metastases and survival. Females with melanoma demonstrated a superior prognostic outcome over males, with a 34% survival advantage and a 28% disease-free advantage. When each of the variables of age, site, Clark's level, histologic type, and tumor thickness was explored for possible influences on prognostic outcome, female survival advantage persisted, although modified by independent variables. The greatest influence came from the variables of site, Clark's level, and Breslow's thickness. Age, specifically in premenopausal vs postmenopausal age groups, was not significant in altering females' prognostic advantage. A multivariate analysis combining the effects of all the variables resulted in females still maintaining a 22% survival advantage and a 17% disease-free advantage. Females with melanoma have a significant prognostic advantage over their male counterparts that cannot be fully explained by influences from the variables of age, site, Clark's level, histology, and Breslow's thickness. This superior prognostic outcome does not appear to be associated with menstrual status. Evidence does suggest that the protective factor for females occurs at the level of metastases.