Foveal relocation by redistribution of the neurosensory retina

AIM: To describe a new surgical technique for foveal relocation, and to report the outcome in nine patients treated with this procedure. METHODS: Nine consecutive patients with subfoveal choroidal neovascular membranes (CNVMs) secondary to age related macular degeneration underwent foveal relocation surgery by redistribution of the neurosensory retina (RNR). The technique involved induction of a retinal detachment via a single retinotomy, relocation of the fovea by "sweeping" the retinal tissue with a retinal brush, and stabilisation of the retina in its new location using perfluorocarbon liquid peroperatively and silicone oil postoperatively. RESULTS: In eight of nine eyes successful relocation of the fovea was achieved; in one eye the CNVM remained in a subfoveal location postoperatively. Visual acuity improved in two eyes, remained unchanged in three, and decreased in four eyes after a median follow up of 4 months (range 2.5-6 months). Complications included rupture of a foveal cyst with the development of a macular hole in one eye and epimacular membrane formation in another eye. In two eyes, macular retinal vessel closure occurred at the time of laser photocoagulation; one of these eyes later developed cystoid macular oedema and the other an epiretinal membrane. Recurrence of the CNVM was observed in one eye, but was controlled with further laser treatment. CONCLUSIONS: Foveal relocation by RNR appears to be feasible, obviating the need for extensive retinotomies or scleral shortening.     

Alendronate treatment for osteoporosis: a review of the evidence

Alendronate, a bisphosphonate indicated for the management of osteoporosis, is an antiresorptive agent that directly inhibits osteoclast activity. It reduces bone turnover and increases spine and hip BMD. Equivalent effects on turnover and BMD have been reported with once-weekly dosing, using seven times the daily dose. Among 3658 women with osteoporosis enrolled in the Fracture Intervention Trial (FIT), there was a 53% reduction in hip fractures, a 48% reduction in morphometric vertebral fractures, a 45% reduction in clinical vertebral fractures, and a 30% reduction in all clinical fractures. Each of these differences was already statistically significant within 12 months of starting treatment. The drug is safe and well tolerated.     

External pneumatic compression does not increase urokinase plasminogen activator after abdominal surgery

External pneumatic compression (EPC) devices prevent lower extremity deep venous thrombosis (DVT) by reducing stasis. There is a widely held belief that they also enhance endogenous fibrinolysis; however, recent studies of tissue plasminogen activator (the primary activator of fibrinolysis) and plasminogen activator inhibitor-1 (the primary inhibitor of fibrinolysis) failed to confirm this. The hypothesis of this study was that EPC devices increase the level of urokinase plasminogen activator (uPA), a second activator of fibrinolysis. This was a prospective trial in which 44 subjects who underwent major abdominal surgery were randomized to receive unfractionated heparin injections, thigh-length sequential EPC devices, or both for DVT prophylaxis. Prophylaxis was begun immediately before surgical incision and continued until postoperative day 5 or discharge. Venous blood samples were collected from an antecubital vein for measurement of systemic uPA levels and from the common femoral vein for measurement of regional uPA levels. Samples were collected the day before surgery, after induction of anesthesia but before surgical incision, and on postoperative days 1, 3, and 5. uPA levels (ng/mL) were measured with an enzyme-linked immunoassay. Baseline uPA levels (0.41 to 0.56 ng/mL; P >.05, analysis of variance with repeated measures) were similar among the three groups. uPA levels did not change after surgery in systemic or regional blood samples in any group. There were no significant differences in systemic or regional uPA levels in the groups treated with EPC devices relative to those treated with heparin at any time point (P >.05, analysis of variance with repeated measures). Enhancement of fibrinolysis with EPC devices remains unproven; the findings reported here suggest that effective DVT prophylaxis can only be assured when the devices are used in a manner that reduces venous stasis.     

Fundus autofluorescence in patients with age-related macular degeneration and high risk of visual loss

PURPOSE: To describe fundus autofluorescence (AF) patterns and their change over time in patients with age-related macular degeneration (AMD) and high risk of visual loss participating in the drusen laser study (DLS). DESIGN: Randomized clinical trial. METHODS: The study population consisted of 29 patients (35 eyes) participating in the DLS, which is a prospective, randomized, controlled clinical trial of prophylactic laser therapy in patients with AMD and high risk of neovascular complications. The intervention consisted of 16 eyes having prophylactic laser and 19 receiving no treatment. The main outcome measures were changes in the distribution of drusen and AF. Patients were reviewed for a median follow-up or 24 months (range 12-36 months). RESULTS: At baseline, four patterns of fundus AF were recognized: focal increased AF (n = 18), reticular AF (n = 3), combined focal and reticular AF (n = 2), and homogeneous AF (n = 12). At last follow-up, fundus AF remained unchanged in 15 untreated (78%) and in seven treated (43%) eyes. In only one untreated eye, focal areas of increased AF returned to background levels and were no longer detectable at last follow-up, compared with six treated eyes. This difference was statistically significant (P =.03). Only large foveal soft drusen (drusenoid pigment epithelium detachments) consistently corresponded with focal changes in AF, whereas no obvious correspondence was found between small soft drusen located elsewhere and changes in AF. CONCLUSION: The lack of obvious correspondence between the distribution of drusen and of AF found in this study appears to indicate that drusen and AF represent independent measures of aging in the posterior pole.     

Sexual abuse among women entering methadone treatment

Women who enter drug abuse treatment programs are likely to report histories of sexual abuse that may impact psychosocial functioning, retention, and outcomes. This study investigates differences at admission between women with and without sexual abuse histories who entered an outpatient methadone treatment program in Texas. In a sample of 137 women, 39% reported prior sexual abuse. Findings show that women with sexual abuse histories were more likely also to have experienced physical and emotional abuse, to report poorer family-of-origin relationships, and to report more drug-related problems. These clients also reported more depression, anxiety, thoughts of suicide, trouble concentrating, and trouble controlling violent behavior. Results are discussed in terms of the need for adequate assessment of abuse history at intake and the need for targeted outcome studies to better define the impact of past abuse on treatment participation and outcome.     

Quality assessment of a collaborative approach for decreasing drug-related morbidity and achieving therapeutic goals

BACKGROUND: Collaboration between physicians and pharmacists is one approach to address drug-related morbidity and achieve therapeutic goals. A collaborative practice of pharmaceutical care has been used in the Fairview Clinics System of Minneapolis-St Paul since 1999. METHODS: The quality of therapeutic determinations made by pharmacists within this collaborative practice of pharmaceutical care was studied by a 12-member panel of physicians and pharmacists who used randomly selected patient records. This was a quality improvement and care process validation component of a study evaluating the effects of drug therapy management in patients receiving prepaid medical assistance. An implicit review process was used to evaluate the clinical credibility of therapeutic determinations made by pharmaceutical care practitioners. RESULTS: A total of 5780 drug therapy problems were resolved for 2524 patients receiving pharmaceutical care. The rate of therapeutic goals achieved increased from 74% at the time of patients' initial pharmaceutical care encounters to 89% at patients' latest encounters. In this quality assessment analysis panel members performed a total of 4779 evaluations of clinical decisions. Panelists indicated agreement with the evaluations in 94.2% of cases, expressed a neutral opinion in 3.6% of cases, and disagreed in 2.2% of cases. Intraclass correlation coefficients ranged from 0.73 to 0.85. CONCLUSIONS: The decisions made by pharmaceutical care practitioners working in collaboration with physicians to provide drug therapy management services are clinically credible based on the evaluations and comments of a peer review panel. This study provides information on the quality of care provided by pharmacists when collaborating with physicians to provide drug therapy management services.     

Presence of active gelatinases in endometrial carcinoma and correlation of matrix metalloproteinase expression with increasing tumor grade and invasion

BACKGROUND: The actions of the extracellular-matrix degrading enzymes, matrix metalloproteinases (MMPs), are implicated in tumorigenesis. The cellular localization of MMP-2, MMP-9, membrane type 1 (MT1)-MMP, tissue inhibitors of metalloproteinases (TIMPs) 1-3, and the presence of active gelatinases were investigated in endometrial carcinoma. METHODS: Endometrial carcinomas were grouped according to histologic grade (Grades 1-3), depth of myometrial invasion (0, < 50%, > 50%) and the presence of vascular/lymphatic invasion. Twenty-nine endometrial carcinoma biopsies were investigated immunohistochemically to determine the tissue localization of MMP-2 (gelatinase A), MMP-9 (gelatinase B), MT1-MMP, and TIMPs 1-3. In situ hybridization was performed to localize MMP-2 and MMP-9 mRNA. The presence of active gelatinases was assessed using in situ zymography. RESULTS: Epithelial tumor cells were the main site of MMP-2, MMP-9, and MT1-MMP protein. Variable stromal cell localization was also observed, particularly in areas adjacent to tumor nests. Semiquantitative analysis revealed increases in MMP-9 and MMP-2 but not MT1-MMP staining scores in tumor epithelial cells in the transition from histologic Grade 1 to Grades 2 and 3. Matrix metalloproteinase-9 and MT1-MMP staining scores in tumor cells were significantly associated with the presence of myometrial invasion and vascular/lymphatic invasion, while MMP-2 did not correlate with these factors. In addition, MT1-MMP was co-localized with MMP-2, supporting its role in the activation of proMMP-2. Tumor cells from all histologic grades stained intensely for TIMP-2 and TIMP-3 proteins, while variable stromal staining was observed. In Grade 1 carcinomas TIMP-1 was predominantly immunolocalized to the stromal compartment with variable tumor cell localization being observed in Grades 2 and 3 carcinomas. Matrix metalloproteinase-9 and MMP-2 mRNAs were predominantly observed in tumor epithelial cells as well as in the stroma to varying degrees. In situ zymography revealed active forms of gelatinases at the cellular surface and in association with tumor epithelial cells within endometrial carcinoma tissues. CONCLUSIONS: These data suggest that increasing expression of MMPs and endometrial carcinoma progression are closely related. Active gelatinases are present in endometrial carcinoma, resulting in alterations to the microenvironment that promote tumor invasion and metastasis.     

Inhibition of the mammary carcinoma angiogenic switch in C3(1)/SV40 transgenic mice by a mutated form of human endostatin

Cancer therapies based on the inhibition of angiogenesis by endostatin have recently been developed. We demonstrate that a mutated form of human endostatin (P125A) can inhibit the angiogenic switch in the C3(1)/Tag mammary cancer model. P125A has a stronger growth-inhibitory effect on endothelial cell proliferation than wild-type endostatin. We characterize the angiogenic switch, which occurs during the transition from preinvasive lesions to invasive carcinoma in this model, and which is accompanied by a significant increase in total protein levels of vascular endothelial growth factor (VEGF) and an invasion of blood vessels. Expression of the VEGF(188) mRNA isoform, however, is suppressed in invasive carcinomas. The VEGF receptors fetal liver kinase-1 (Flk-1) and Fms-like tyrosine kinase-1 (Flt-1) become highly expressed in epithelial tumor and endothelial cells in the mammary carcinomas, suggesting a potential autocrine effect for VEGF on tumor cell growth. Angiopoietin-2 mRNA levels are also increased during tumor progression. CD-31 (platelet-endothelial cell adhesion molecule [PECAM]) staining revealed that blood vessels developed in tumors larger than 1 mm The administration of P125A human endostatin in C3(1)/Tag females resulted in a significant delay in tumor onset, decreased tumor multiplicity and tumor burden and prolonged survival of the animals. Endostatin treatment did not reduce the number of preinvasive lesions, proliferation rates or apoptotic index, compared with controls. However, mRNA levels of a variety of proangiogenic factors (VEGF, VEGF receptors Flk-1 and Flt-1, angiopoietin-2, Tie-1, cadherin-5 and PECAM) were significantly decreased in the endostatin-treated group compared with controls. These results demonstrate that P125A endostatin inhibits the angiogenic switch during mammary gland adenocarcinoma tumor progression in the C3(1)/Tag transgenic model.     

Therapy-associated solid tumors

As survival after a diagnosis of cancer improves, characterization of the late sequelae of treatment becomes critical. The development of second malignant neoplasms represents one of the most serious side effects of treatment with radiation and chemotherapy. Although secondary leukemia was the first reported carcinogenic effect resulting from cancer treatment, solid tumors now comprise the largest second tumor burden in some populations of survivors. It should be recognized, however, that solid cancers do not necessarily represent an adverse effect of therapy, but may also reflect the operation of shared etiologic factors, host determinants, gene-environment interactions, and other influences. Quantification of second cancer risk is important in terms of patient management, enabling clinicians to make informed decisions with regard to optimal treatment of the initial cancer, balancing efficacy against acute and chronic sequelae. This article focuses on selected highlights and recent developments in treatment-associated solid malignancies, with emphasis on radiotherapy and chemotherapy in adults, and summarizes areas for future research. Although cancer therapy represents a double-edged sword, it should always be recognized that it is advances in treatment that are largely responsible for the tremendous improvement in patient survival. Thus, the benefit derived from many cancer therapies far outweighs any risk of developing a second cancer.