Principles of treatment of choroidal neovascularization with photodynamic therapy in age-related macular degeneration

Age-related macular degeneration (AMD) is a common cause of legal blindness in the developed countries in people older than 50 years of age. AMD complicated by choroidal neovascular membranes (CNV) accounts for 12% of AMD, but for 88% of legal blindness cases. Because of the progressive aging of the population, it is expected that AMD will be one of the greater public health problems in ophthalmology in the first half of the next century. Laser photocoagulation remains the only proven treatment for CNV in AMD, but unfortunately, is applicable only to a minority of patients presenting with CNV in AMD. Photodynamic therapy (PDT) is a new experiment treatment for CNV that combines the application of low-intensity light with a photosensitizing agent in the presence of oxygen to produce tissue effects. It uses the noninvasive potential of the laser light to cause a nonthermal localized chemotoxic reaction and obtain highly selective occlusion of the neovascular channels, with sparing of the overlying photoreceptors. Animal studies showed that PDT accounts for the effective closure of experimentally induced CNV. Phase I-II clinical studies showed that PDT using BPD can safely stabilize leakage from CNV in a majority of patients for up to 3 months. Phase III clinical studies to assess the long term prognosis of PDT-treatment of CNV in AMD are ongoing.     

Properties of fibres,endplates and acetylcholine receptors in the diaphragm,masseter, laryngeal,abdominal and limb muscles in the goat

Purpose

Although differences in fibre composition, fibre size or acetylcholine receptor (AChR) density between muscles have often been proposed to explain the unequal sensitivities of muscles to muscle relaxant drugs, it is not clear whether or how these parameters differ among muscles or are related to one another. In this study, several muscles were examined to determine the composition and cross-sectional area (CSA) of types I and II fibres, the surface area of their motor endplates (ESA), and their AChR density.

Methods

Biopsies from the thyroarytenoideus, cricoarytenoideus dorsalis, masseter, diaphragm, transversus abdominis, rectus abdominis, gastrocnemius and soleus muscles of goats were processed by muscle histochemistry and morphometry and the ESA:CSA ratio was computed. The number and density of AChRs per endplate were estimated by¹²⁵I-α-bungarotoxin binding studies.

Results

The mean type 1 fibre composition (range: 0–100%), fibre diameter (28–50 μm) and the ESA:CSA ratio (0.27–1.01) differed among muscles (P = 0.0001), but there were no significant differences (P > 0.05) in the mean endplate size (577–725 μm²), AChR number (6.6?14.5 × 10⁶) or AChR density (8,900–22,300 μm^?2) probably because of marked individual variations. Fibre size increased and the ESA:CSA ratio decreased in the order laryngeal, diaphragm, jaw, limb and abdominal muscles.

Conclusion

It is concluded that between muscles fibre size varies more than endplate size or AChR number.     

Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide.

BACKGROUND: Effective adjuvant or neoadjuvant regimens of chemotherapy have dramatically improved the prognosis of patients with high-grade osteosarcoma of the extremity, localized at diagnosis. Currently, little is known about patients with metastatic disease at presentation. PATIENTS AND METHODS: From May 1995 to May 2000, 57 patients with osteosarcoma of the extremity, metastatic at presentation, were treated according to the following scheme: primary chemotherapy, restaging, simultaneous resection of primary tumor and metastatic lesions, and maintenance chemotherapy. RESULTS: Thirty-five patients achieved remission. At a follow-up ranging from 2 to 7 years, seven remained continuously free of disease, one died of chemotherapy-related toxicity and 27 patients relapsed. Twenty-one of the 22 patients who never achieved remission died as a result of the tumor, as well as 20 of the 27 who achieved remission but then relapsed. Of the remaining seven relapsing patients, six are alive with uncontrolled disease, while one is alive and free of disease 24 months after the last post-relapse treatment. Two-year event-free survival (EFS) and overall survival (OS) were 21% and 55%, respectively. These results are significantly poorer than those achieved in 128 contemporary patients with non-metastatic disease at presentation, treated with the same chemotherapy protocol (2-year EFS and OS of 75% and 94%, respectively). CONCLUSIONS: The results of our study confirm that the prognosis of patients with osteosarcoma of the extremity, metastatic at presentation, remains poor, despite the use of aggressive treatments.     

Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants

Objectives: A prospective study comparing the efficiacy and side-effects of oral sulindac with intravenous indomethacin in clinically stable preterm infants (<1750 g) requiring non-invasive closure of haemodynamically significant patent ductus arteriosus.
Methodology: As maturity and birthweight are the two major determinants of ductal closure, infants were matched as closely as possible for these parameters. An eligible patient was first assigned to the sulindac group and a subsequent patient with similar gestational age (± 1 week) and birthweight (±100 g) to the previously recruited infant would automatically receive indomethacin. A total of eight infants were enrolled in each group.
Results: The ductus arteriosus was successfully closed in all eight infants receiving indomethacin, and in seven of eight infants receiving sulindac. No significant differences were found with regards to the ductal size between the two groups at diagnosis or on each of the consecutive days of treatment ( P >0.25). More renal adverse effects were encountered in the indomethacin group. Significant differences in changes from baseline value for urine output, plasma sodium, urea and creatinine concentrations were noted at 24, 48 and 72 h after commencement of treatment between the two groups ( P <0.05). All the parameters returned to normal or pre-treatment levels 48 h after stopping therapy. Unexpectedly, severe gastrointestinal complications were encountered in the sulindac group.
Conclusions: Sulindac is capable of promoting ductal constriction in clinically stable preterm infants without compromising the renal function. The spectrum of gastrointestinal complications observed in sulindac treated infants were similar to those described for indomethacin. The use of sulindac for ductal closure in the preterm infant should remain experimental.     

Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy

McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994) and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the striking similarity in lifestyle risk factors for colorectal cancer and insulin resistance, proposed that the hyperinsulinemia, glycemia and hypertriglyceridemia associated with insulin resistance promotes colon cancer. To compare the effect of diet on colon cancer promotion and insulin resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids and energy in pairwise comparisons on average size of aberrant crypt foci (ACF) and on glucose intolerance in the same animals in a single experiment. Diets high in fat and energy increased and diets with increased n-3 fatty acids and calorie restriction decreased both ACF growth and glucose intolerance compared with control diets. The measures of promotion of colon cancer and insulin resistance were strongly correlated (n = 98, r = 0.67, P < 0.001). In addition, both were highly correlated with daily energy intake (r = 0.62 and 0.66) and were also correlated with basal (post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P < 0.01). We concluded that ACF growth and glucose intolerance are correlated for a wide range of diets and that increased circulating energy (glucose and triglycerides) may lead to both colon cancer promotion and insulin resistance.      

Angiogenesis is an early event in the development of chemically induced skin tumors

In this study we have analyzed the vascular response induced in the two- stage carcinogenesis model in SENCAR mice. The role of angiogenesis has not been explored in this model, which is the paradigm of multistage carcinogenesis and a model for neoplastic lesions derived from exophytic premalignant lesions (e.g. colon carcinoma, bladder papilloma). We investigated if angiogenesis is involved in the formation of papillomas and in the progression from papilloma to carcinoma. To this end we analyzed the vasculature of normal and hyperplastic skin, focal epidermal hyperplasias that are precursors of papillomas, papillomas at different stages and squamous cell carcinomas. We also analyzed the vascularization of papillomas induced in two strains of mice that differ in their susceptibility to malignant progression. We show here that angiogenesis is turned on in the earliest stages of papilloma formation. In late stages, regardless of state of progression, the predominant response is an increase in the size of blood vessels. Thus, in the SENCAR mouse model, representative of exophytic tumors, the angiogenesis switch is a very early event, probably mechanistically related to the development of the primarily exophytic lesions. Therefore, the density of blood vessels cannot be used as a predictor of malignant progression in this model.      

Massive bone allograft reconstruction in high-grade osteosarcoma

From 1986 to 1994, 112 bone allograft reconstructions were performed in patients with high-grade osteosarcoma in whom neoadjuvant chemotherapy was administered. The allograft reconstruction was used in arthrodesis in 44 cases (41 knees, three ankles), as an intercalary graft in 39 (28 femurs, 11 tibias), as an osteoarticular graft in 22 (three proximal and/or distal humeri, six distal femurs, 13 proximal tibias), and as an allograft and prosthesis composite in seven (two proximal humeri, one proximal femurs, four proximal tibias). In 20 patients an autologous vascularized fibula was used to augment the allograft. Functional results were excellent or good in 74% of the patients after the primary surgery, and in 83% of the patients after secondary surgery. Complications include delayed union (49%) and fracture (27%), although there were no cases of deep infection. The incidence of delayed union, but not infection or fracture, was increased by the use of chemotherapy.     

Posterior lumbar interbody fusion a mid-term review of 60 cases

It is the purpose of this study to evaluate the clinical and radiographic medium-term results of a series of 60 patients submitted to intersomatic lumbar fusion by posterior approach, using a system constituted by carbon wedges to be associated with bone grafts for intersomatic fusion, and by steel or titanium plates or bars used for posterior pedicle osteosynthesis. Satisfactory clinical results were obtained in 88.2% of cases and complete radiographic fusion in 91.4% of cases. Complications were generally observed in 8.3% of cases. In light of these results, we may consider intersomatic lumbar fusion by posterior approach a method that is perhaps aggressive, but effective in the treatment of severe lumbar spondylolysis. The use of carbon wedges brings several advantages that favor intersomatic fusion, its progressive control, and the restoration of normal lordosis of the lumbar spine.     

Treatment of uterine fibromyoma with bilateral uterine artery embolization: state of the art

Uterine fibroids are common tumors of the female pelvis. Uterine artery embolization (UAE) is a minimally invasive alternative procedure in appropriate candidates to conventional myomectomy and hysterectomy for symptomatic uterine leiomyoma, reducing or eliminating leiomyoma-related symptoms of bleeding, bulk, and/or pain. In order to completely block the arterial blood supply to the fibroid, UAE is typically performed in both uterine arteries. At 1 year follow-up, the uterus may shrink by up to 55%, however, a re-growth of the fibroid may occur. The rate of major complications and amenorrhea following this procedure is low, ranging in most series from 1% to 3.5% and 1% to 7%, respectively. Nevertheless, the rate of amenorrhea in women over 45 seems to be higher. Women who wish to become pregnant should be cautioned about potential complications during pregnancy. Despite the lack of controlled studies that compared UAE with conventional surgery, and despite limited extended outcome data, UAE has gained rapid acceptance, primarily because this procedure preserves the uterus, is less invasive, and has less short-term morbidity than most surgical options. This review focuses on recent publications evaluating UAE and concludes that it is a safe treatment option, providing substantial improvement in both health-related quality of life and symptom control for most patients, with a very low rate of major complications. Any centre that offers UAE should adhere to published clinical guidelines, maintain ongoing assessment of quality improvement measures, and observe strict criteria to obtain procedural privileges. The gynecologist is likely to be the primary initial consultant to patients who present with myomas symptoms. Therefore, they must be familiar with the indications, exclusions, outcome expectations, and complications of UAE. When hysterectomy is the only option, UAE should be seriously taken into consideration. At this particular moment in time, data are needed from randomized controlled trials comparing UAE with surgical procedures. Current efforts to provide prospective objective assessment of treatment outcomes and complications after UAE will help to optimize women options and clinical guidelines.     

Therapeutic studies in NZB/W mice. I. Synergy of azathioprine,cyclophosphamide and methylprednisolone in combination

This study compares different immunosuppressive regimens in the treatment of the lupus-like nephritis of NZB/W mice. Groups of 5-month-old female NZB/W mice were given azathioprine, cyclophosphamide and methylprednisolone in all one-, two- and three-drug regimens, each drug in the relatively low dose of 1.5 mg/kg/day. Treatment for 3 months with one or two drugs resulted in modest suppression of NZB/W disease. Mice receiving all three drugs had significantly less proteinuria, lower titers of anti-DNA antibody and less severe, histologically evident renal involvement than mice treated with one or two drugs. Survival at 1 year was 10% for untreated controls, 44% for one-drug-treated, 37% for two-drug-treated and 86% for the three-drug-treated mice. The survival for the three-drug regimen was significantly longer than any other group (P < 0.01). The three-drug regimen was synergistic, since mice treated with each drug at three times the dose had significantly more proteinuria after 3 months of treatment and lowered 1 year survival (33%). The beneficial effects of triple-drug therapy were attained without increased toxicity. This study represents the first controlled evaluation of single versus combination therapy in a model of autoimmune disease. Based on these results, a controlled evaluation of triple-drug therapy in human systemic lupus erythematosus appears warranted.