Early Local Therapy for the Primary Site in De Novo Stage IV Breast Cancer: Results of a Randomized Clinical Trial (EA2108).

PURPOSE: Distant metastases are present in 6% or more of patients with newly diagnosed breast cancer. In this context, locoregional therapy for the intact primary tumor has been hypothesized to improve overall survival (OS), but clinical trials have reported conflicting results. METHODS: Women presenting with metastatic breast cancer and an intact primary tumor received systemic therapy for 4-8 months; if no disease progression occurred, they were randomly assigned to locoregional therapy for the primary site (surgery and radiotherapy per standards for nonmetastatic disease) or continuing sysmetic therapy. The primary end point was OS; locoregional control and quality of life were secondary end points. The trial design provided 85% power to detect a 19.3% absolute difference in the 3-year OS rate in randomly assigned patients. The stratified log-rank test and Cox proportional hazards model were used to compare OS between arms. Cumulative incidence of locoregional progression was compared using Gray's test. Quality-of-life assessment used standard instruments. RESULTS: Of 390 participants enrolled, 256 were randomly assigned: 131 to continued systemic therapy and 125 to early locoregional therapy. The 3-year OS was 67.9% without and 68.4% with early locoregional therapy (hazard ratio = 1.11; 90% CI, 0.82 to 1.52; P = .57). The median OS was 53.1 months (95% CI, 47.9 to not estimable) in the systemic therapy arm and 54.9 months (95% CI, 46.7 to not estimable) in the locoregional therapy arm. Locoregional progression was less frequent in those randomly assigned to locoregional therapy (3-year rate: 16.3% v 39.8%; P < .001). Quality-of-life measures were largely similar between arms. CONCLUSION: Early locoregional therapy for the primary site did not improve survival in patients presenting with metastatic breast cancer. Although it was associated with improved locoregional control, this had no overall impact on quality of life.

Cross-lagged relations between motives and substance use: Can use strengthen your motivation over time?

Motives for substance use have garnered considerable attention due to the strong predictive utility of this construct, both in terms of use and problems associated with use. The current study examined the cross-lagged relations between alcohol use and motives, and marijuana use and motives over three yearly assessment periods in a large sample (N=526, 48% male) of college students. The relations between substance use and motives were assessed at each time point, allowing for the examination of these inter-relations over time. Results indicated different trends based on the type of substance. For alcohol use, cross-lagged trends were found between freshman and sophomore year for coping, social, and conformity motives with cross-lagged relations between enhancement motives and alcohol use across all years. However, outside of enhancement motives, cross-lagged relations were not found between sophomore and junior year. In contrast, cross-lagged effects were found for marijuana use and coping, enhancement, and expansion motives between sophomore and junior year, but not freshman year. These results suggest that people's expectations that drinking or smoking marijuana makes activities more reinforcing and helps them cope with distress may perpetuate use. In turn, use itself may enhance these expectations over time. Results have direct implications for treatment, with recommended focus on motives, behavior activation, and healthy coping skills in order to interrupt the cycle of substance use.

Mortality rates, life expectancy, and causes of death in people with hemophilia A or B in the United Kingdom who were not infected with HIV.

Since the 1970s, mortality in the hemophilia population has been dominated by human immunodeficiency virus (HIV) and few reports have described mortality in uninfected individuals. This study presents mortality in 6018 people with hemophilia A or B in the United Kingdom during 1977 to 1998 who were not infected with HIV, with follow-up until January 1, 2000. Given disease severity and factor inhibitor status, all-cause mortality did not differ significantly between hemophilia A and hemophilia B. In severe hemophilia, all-cause mortality did not change significantly during 1977 to 1999. During this period, it exceeded mortality in the general population by a factor of 2.69 (95% confidence interval [CI]: 2.37-3.05), and median life expectancy in severe hemophilia was 63 years. In moderate/mild hemophilia, all-cause mortality did not change significantly during 1985 to 1999, and median life expectancy was 75 years. Compared with mortality in the general population, mortality from bleeding and its consequences, and from liver diseases and Hodgkin disease, was increased, but for ischemic heart disease it was lower, at only 62% (95% CI: 51%-76%) of general population rates, and for 14 other specific causes it did not differ significantly from general population rates. There was no evidence of any death from variant Creutzfeldt-Jakob disease or from conditions that could be confused with it.

Synovial sarcoma mimicking haemophilic pseudotumour.

This is a case of a 36-year-old gentleman with haemophilia A who was presented with an acute atraumatic soft tissue swelling in the right thigh. Open biopsy was performed with the resultant diagnosis of a synovial cell sarcoma. Although the clinical findings were nonspecific they could easily have been found in a bleeding haemophilic pseudotumour. The findings reported on MRI scan initially were highly consistent with those present in patients with mild haemophilia. An important part of orthopaedic management in haemophilia is concerned with intraarticular and intramuscular bleeding. Haematomas are common and sarcomas are rare. However the absence of trauma should alert the clinician to the possibility that the abnormality may represent haemorrhage into a tumour and not just haematoma, even in a haemophilic patient.

Versatile peptide dendrimers for nucleic acid delivery.

Dendrimers are nonviral vectors that have attracted interest on account of a number of features. They are structurally versatile because their size, shape, and surface charge can be selectively altered. Here we examine the functions of a new family of composite dendrimers that were synthesized with lipidic amino acid cores. These dendrimers are bifunctional because they are characterized by positively charged (lysine) modules for interaction with nucleic acids and neutral lipidic moieties for membrane lipid-bilayer transit. We assessed their structure-function correlations by a combination of molecular and biophysical techniques. Our assessment revealed an unexpected pleitropy of functions subserved by these vectors that included plasmid and oligonucleotide delivery. We also generated a firefly luciferase cell line in which we could modulate luciferase activity by RNA interference. We found that these vectors could also mediate RNA suppression of luciferase expression by delivering double-stranded luciferase transcripts generated in vitro. The structural uniqueness of these lipidic peptide dendrimers coupled with their ease and specificity of assembly and the versatility in their choice of cargo, puts them in a new category of macromolecule carriers. These vectors, therefore, have potential applications as epigenetic modifiers of gene function.

The effect of highly active antiretroviral therapy for HIV on the anti-HCV specific humoral immune response.

The effect of highly active antiretroviral therapy (HAART) on HCV replication is controversial, with some studies reporting no effect and others increases, reductions and even clearances of HCV RNA after treatment. In this study, the effect of HAART was investigated on the titre of anti-HCV specific antibodies and on the relationship between these antibodies and HCV RNA level in a cohort of 24 patients with inherited bleeding disorders. A significant inverse correlation between antibodies to both total HCV proteins and HCV RNA (R = -0.42, P = 0.05) and between antibodies to HCV envelope glycoproteins and HCV RNA (R = -0.54, P = 0.01) was observed pre-HAART. The relationship disappeared or was obscured after therapy (R = 0.24, P = 0.30 and R = 0.16, P = 0.50, respectively). Thus, we show that HAART affects the HCV specific humoral immune responses without affecting the HCV RNA level.

NKT cell subsets in infection and inflammation.

We recently identified two stably expressed cell surface markers, IL-18R and ST2L, which are selectively expressed on T1/NK1 and T2/NK2 cells, respectively. Here we use these molecules in direct ex vivo analysis of PBMCs from patients with AIDS, psoriasis (PS) atherosclerosis and to show the importance of these markers as determinants of the functional dichotomy of lymphocyte subsets, in particular NKT. In a cohort of 22 HIV patients made up of a mixture of long term non-progressors, seroconvertors, progressors and asymptomatics, we found a clear NKT1 to NKT2 shift (P=0.001) in the HIV-infected individuals. We also show a predominance of NKT2 cells over NKT1 cells in the PBMCs of patients with mild to moderate PS (N=13, P=0.005) but not in atopic dermatitis or healthy controls. However, in patients (N=6) requiring surgery for aneurysm, a predominance of Type 1 (IL-18R(+)) NKT lymphocytes over NKT2 was detected among infiltrating lymphocytes isolated from atherosclerotic plaques. Our data therefore demonstrate that ST2L and IL-18R could serve as important determinants of the immune status of human diseases.

The incidence of lymphoma in the UK haemophilia population between 1978 and 1999.

OBJECTIVE: To determine the incidence of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) in the UK haemophilia population during the 22 year period 1978-1999. DESIGN AND METHODS: An analysis of patient data included on the UK Haemophilia Centre Doctors' Organisation lymphoma register. The number of cases of NHL and HD occurring in HIV-positive and negative patients in each 3-year period were compared with the expected incidence in the general male population. RESULTS: Eighty-nine cases of lymphoma were identified. Seventy-two cases (81%) occurred in HIV-positive patients (67 NHL, five HD), and 17 cases (19%) in HIV-negative patients (nine NHL, eight HD). The incidence of NHL in the HIV-positive cohort was significantly increased, with a ratio of observed to expected cases of 83.92 (P < 0.001) in the period 1985-1996. The ratio reduced to 42.15 during the period 1997-1999, presumably as a consequence of the introduction of highly active antiretroviral therapy (HAART). There was a significant excess of HD in HIV-positive patients, with an observed to expected ratio of 10.50 between 1985 and 1999 (based on five cases, P < 0.001). During the whole observation period, there was a significant excess of HD in HIV-negative patients, with an observed to expected ratio of 2.66 (based on eight cases, P < 0.05). CONCLUSION: The incidence of lymphoma is significantly higher in HIV-positive UK haemophilia patients compared with HIV-negative individuals. Since the introduction of HAART, the incidence of lymphoma has tended to fall in the HIV-positive group.