Major joint replacement. A model for antithrombotic drug development: from proof-of-concept to clinical use.

AIM: Development of antithrombotic compounds has traditionally been performed in patients undergoing total hip and knee replacement surgery. A high number of asymptomatic deep-vein thromboses are radiologically detectable, and bleeding and other adverse events (AE) are easy to observe. However, standardization of study procedures and endpoints in early proof-of-concept studies and late pure clinical endpoint studies has been lacking. This has made comparison between studies difficult, economic analyses speculative and potential benefits of applying the drug regimen in non-selected patients uncertain. In this paper, the International Surgical Thrombosis Forum proposes a strategy for the clinical investigation of new pharmacological agents for the prophylaxis of postoperative thrombotic events. METHODS: First, dose titration safety studies of short duration, in highly selected patients using objective venographic endpoints are recommended. Bleeding should be divided into the quantified volume of surgical bleeding and other adjudicated clinical bleeding events. The number of AE should be described for each dose step and classified according to International Coding of Diagnoses (ICD). Second, a dose confirmatory study of moderate exposure period and sufficient follow-up time is recommended. The exclusion criteria should be restricted to contraindications of the compared drugs and technical procedure. RESULTS: The efficacy, bleeding and AE should be similar to those used in dose-titration studies. In addition, the failure rate of the drug to exert its effect and the net clinical benefit should be calculated. CONCLUSION: Finally, trials with simple clinical endpoints and long follow-up should be conducted to evaluate the potential benefits of the drug-regimen in non-selected populations.

The effect of thrombocytopenia on experimental arteriosclerotic lesion formation in rabbits. Smooth muscle cell proliferation and re-endothelialization.

This study was designed to investigate the mechanisms involved in fibromusculoelastic lesion formation produced by selective de-endothelialization by the intra-arterial balloon catheter technique in thrombocytopenic rabbits. Thrombocytopenia was induced and maintained for up to 30 days by daily injections fo highly specific sheep anti-rabbit platelet sera (APS). Evidence for re-endothelialization was obtained by i.v. Evans blue dye 30 min before sacrifice. Rabbits received daily injections of APS, which reduced the mean platelet count to 5,600/cm3; control animals received identically treated normal sheep sera on the same schedule, and had mean daily platelet counts of 363,000/cm3. Evaluation of intimal thickness was assessed by counting cell layers in semithin sections. Intimal thickening in aortae from rabbits treated with APS was strikingly suppressed, in contrast to those from normal sheep sera-treated animals which showed a mean intimal thickness of 18 cell layers within 28 days often after de-endothelialization. Re-endothelialization was not affected by APS treatment. These results indicate that the proliferation of smooth muscle cells is dramatically inhibited by reduction of platelets.

The effect of supplemental oral phosphate on the bone mineral changes during prolonged bed rest.

Five healthy young men were studied during 24-30 wk of continuous bed rest. During the first 12 wk of bed rest, untreated subjects increased calcium excretion in the urine by 109 mg/day and in the feces by 147 mg/day. The rate of total body calcium loss was 0.5-0.7% per month. Losses of central calcaneus mineral, assessed by gamma ray transmission scanning, occurred at a tenfold higher rate, whereas the mineral content of the radius did not change. Changes in phosphorus balance resembled the calcium pattern, and increased excretion of nitrogen and hydroxyproline also occurred during bed rest. Upon reambulation, the subjects' calcium balance became positive in 1 month and recovery of their calcaneus mineral was complete within 10-20 wk. Treatment with potassium phosphate supplements (1327 mg P/day) entirely prevented the hypercalciuria of bed rest, but fecal calcium tended to increase. During the first 12 wk, calcium balance was slightly less negative (mean - 193 mg/day) than during bed rest without added phosphate (mean - 267 mg/day). This effect was not seen during the second 12 wk of bed rest. The patterns of magnesium excretion were similar to those of calcium. Fecal and urinary phosphorus excretions were doubled, and phosphorus balance became positive (+ 113 mg/day). Mineral loss from the central calcaneus was similar to that of untreated subjects. It is concluded that this form of phosphate supplementation reduces urinary calcium excretion but does not prevent bone loss during bed rest.

Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry.

Patients who have undergone total hip or knee replacement (THR and TKR, respectively) are at high risk of venous thromboembolism. We aimed to determine the time courses of both the incidence of venous thromboembolism and effective prophylaxis. Patients with elective primary THR and TKR were enrolled in the multi-national Global Orthopaedic Registry. Data on the incidence of venous thromboembolism and prophylaxis were collected from 6639 THR and 8326 TKR patients. The cumulative incidence of venous thromboembolism within three months of surgery was 1.7% in the THR and 2.3% in the TKR patients. The mean times to venous thromboembolism were 21.5 days (sd 22.5) for THR, and 9.7 days (sd 14.1) for TKR. It occurred after the median time to discharge in 75% of the THR and 57% of the TKA patients who developed venous thromboembolism. Of those who received recommended forms of prophylaxis, approximately one-quarter (26% of THR and 27% of TKR patients) were not receiving it seven days after surgery, the minimum duration recommended at the time of the study. The risk of venous thromboembolism extends beyond the usual period of hospitalisation, while the duration of prophylaxis is often shorter than this. Practices should be re-assessed to ensure that patients receive appropriate durations of prophylaxis.

Alexia without agraphia associated with spleniogeniculate infarction.

Pure alexia, following an infarction in the distribution of the left posterior cerebral artery, is attributed to damage of the left occipital lobe and the splenium of the corpus callosum. We describe a case of pure alexia in a 57-year-old woman with infarction of the left lateral geniculate body and the splenium of the corpus callosum, a variation on this classic disconnection syndrome.

Inhibition of injury induced thromboatherosclerotic lesions by anti-platelet serum in rabbits.

We have previously shown that repeated or continuous intimal injury caused by an indwelling aortic catheter causes a variety of lesions in rabbits maintained on a diet unsupplemented by lipid. These include fatty streaks, lipid-free fibrous plaques and lipid-rich raised thromboatherosclerotic plaques. Whether lipid-rich raised lesions are a result of injury or co-existing thrombosis or both is not clear. The present experiment was designed to answer this question. Anti-platelet serum (APS) to washed sonicated rabbit platelets was raised in sheep. PE 60 polyethylene catheters were placed in the aortas of 35 rabbits by way of a femoral artery. The animals were randomly divided into 2 groups. The experimental group (17 rabbits) received an intravascular injection of 1.0 ml of APS followed 8 hours later by a subcutaneous injection of 0.5 ml. Thereafter, 0.5 ml APS was given subcutaneously each day for 13 additional days. The control group (18 rabbits) received no APS. Platelet counts were done prior to surgery, at 5 minutes following surgery, at 4 days, 8 days and just prior to killing. Extent of lesions was estimated by photographing the opened aortas, projecting the photographs on cardboard, cutting out the areas occupied by the different lesions and weighing the cardboard. The mean weight of raised lesions in the control group was 6 to 7 times greater than in the experimental groups. Statistical analysis of this difference based on Welsh's "t" test for unequal variances was highly significant (P less than 0.001). Platelet counts in the experimental groups varied from 0 to 20,000 at 14 days. In animals with platelet counts less than or equal to 1,000 mm3 raised lesions were completely prevented. In a second experiment the effect of APS was compared with normal sheep serum (NSS). A similarly significant inhibition of raised lesions occurred in the APS group. The extent of lesions in the NSS control was similar to that in the No-APS group of the first experiment. These findings indicate that thrombosis is more important than injury in the development of lipid-rich raised lesions.

Silicone breast prostheses implantation and explanation.

Breast implants have been used for augmentation and reconstruction for a 30-year period. Standard techniques have been used for the successful placement of mammary prostheses to enhance or replace breast tissue. All breast implants are surrounded by a capsule. The most common complication of breast implant surgery is hardening and contracture of the capsule. Explanation of implants is indicated for implant rupture, infection, extrusion, siliconoma, breast pain, painful capsular contracture, malposition, significant patient fear, and systemic symptoms thought secondary to implants. A number of alternatives are available for postexplant reconstruction, including myocutaneous flaps and free tissue transfers.

Pre-clinical in vivo evaluation of orthopaedic bioabsorbable devices.

The presence of bioabsorbable materials in orthopaedics has grown significantly over the past two decades with applications in fracture fixation, bone replacement, cartilage repair, meniscal repair, fixation of ligaments, and drug delivery. Numerous biocompatible, biodegradable polymers are now available for both experimental and clinical use. Not surprisingly, there have been a wealth of studies investigating the biomechanical properties, biocompatibility, degradation characteristics, osteoconductivity, potential toxicity, and histologic effects of various materials. Promising results have been reported in the areas of fracture fixation, ligament repair, and drug delivery. In this article we review the pre-clinical in vivo testing of bioabsorbable devices with particular emphasis on implants used for these applications.

Long-term compressive property durability of carbon fibre-reinforced polyetheretherketone composite in physiological saline.

In total hip arthroplasty, concerns such as corrosion and stress shielding associated with stiff metallic femoral components have led to the development of low stiffness advanced fibre-reinforced polymer (FRP) composite femoral components. Carbon fibre-reinforced polyetheretherketone (CF/PEEK) composite material is now one of the primary material systems being considered for composite hip stem development. As a hip stem, a composite material must be able to support a complex state of stress in the in vivo environment without failure. Considering the loading conditions of a hip stem (superimposed compression and bending), and the fact that FRP composites typically possess lower compressive than tensile strength, the compressive behaviour of FRP composites becomes very important for femoral component design. This paper presents an investigation of the long-term durability of 0 degree and 90 degrees compressive strengths of CF/PEEK composite following physiological saline saturation. 0 degree and 90 degrees compressive moduli and Poisson ratio (v12) properties are also reported. Samples were tested following conditioning in physiological saline at 37, 65 and 95 degrees C for time periods from 0 to 5000 h. Dry samples were tested as controls. Results show no significant loss in compressive property values of the saline-saturated or the dry control samples as a function of conditioning time or temperature.

Revision total knee arthroplasty in patients with osteoarthritis.

Total knee replacement (TKR) is a technically demanding surgical procedure, which is becoming more reliable and durable than total hip replacements. The authors describe the mechanisms of failure, the clinical evaluation of the painful TKR, the surgical planning techniques, and the overall results of revision TKR to date.

Prognostic significance of hypopigmentation in malignant melanoma.

It has been suggested that the presence of cutaneous hypopigmentation favorably influences the prognosis of patients with malignant melanoma (MM). To examine this possibility, we have compared the actual with the predicted survival of 46 patients with MM and hypopigmentation who were among 1130 patients with MM entered in a long-term prospective study of MM at the New York University Medical Center. The actual average five-year survival rate of the patients with MM and hypopigmentation (86.3%) was significantly better than predicted (74.8%) on the basis of the risk factors present in each patient at the time of entry into the study. The findings suggest that hypopigmentation is a factor that beneficially influences the prognosis of MM, and that the mechanisms that inhibit or destroy normal melanocytes in patients with MM may also slow the growth of this cancer.

Stress steroids are not required for patients receiving a renal allograft and undergoing operation.

BACKGROUND: It is commonly believed that patients receiving exogenous glucocorticoids have hypothalamic-pituitary-adrenal (HPA) axis suppression and require exogenous, supplemental, high-dose stress glucocorticoids to meet the demands of operative or other stress. Several recent reports suggest both that clinically important HPA axis suppression is extremely uncommon and that the levels of glucocorticoids required for stress are much lower than previously believed. In addition, the high doses of steroids currently used for stress prophylaxis may actually increase morbidity and mortality. STUDY DESIGN: To test the need for stress steroids, a prospective study of 52 recipients of a renal allograft who underwent 58 operative procedures was conducted. No patient received stress steroids but only baseline, immunosuppressive doses of glucocorticoids. Clinical (hypotension, myalgias, arthralgias, ileus, and fever) and laboratory (serum sodium, eosinophil count, and 24-hour urinary-free cortisol from perioperative and nonstressed time periods) data were obtained to document evidence for adrenocortical insufficiency. RESULTS: There was no clinical or laboratory evidence for adrenocortical insufficiency in any of the patients. Twenty-four hour urinary-free cortisol levels showed that all patients had endogenous adrenocortical function and, combined with clinical outcome, this function was sufficient to meet the demands of stress. CONCLUSIONS: Adrenocortical insufficiency is much less common in recipients of a renal allograft than previously thought. Supplemental exogenous stress glucocorticoids are not required to meet the demands of operative stress in these patients. While biochemical testing of HPA axis function may sometimes reveal evidence for adrenal insufficiency, these tests do not predict clinical outcome and are far too sensitive to guide therapy.

Prevalence of congenital-nevus-like nevi, nevi spili, and café au lait spots.

To determine the clinical prevalence of medium-sized (1.5- to 19.9-cm-diameter) congenital-nevus-like nevi (CNLN), a consecutive series of 601 patients (mostly adults) had total cutaneous examinations. In this series, 15 (2.5%) were found to have such lesions. In addition, 14 (2.3%) had nevi spili and 83 (13.8%) had café au lait spots. All three types of lesions were equally represented in both sexes and tended to spare the head, neck, and upper extremities. Compared with CNLN, nevi spili were found to have significantly larger diameters and lower mean age, suggesting that these are different types of lesions. Some recommend the surgical removal of all congenital nevocytic nevi because of their malignant potential. Since it is not possible to clinically distinguish congenital nevocytic nevi and CNLN and since the observed prevalence of these lesions in adults is over four times that previously reported in newborns, such a recommendation becomes less feasible.

Effect of anatomical location on prognosis in patients with clinical stage I melanoma.

A study of the influence of the anatomical location of malignant melanoma on the prognosis of 971 patients with stage I disease disclosed specific high-, intermediate-, and low-risk sites. High-risk sites included scalp, mandibular area, midline of trunk (anterior and posterior), upper medial thighs, hands, feet (except the arches), popliteal fossae, and genitalia. The life-table-adjusted five-year disease-free survival was 54% in the high-risk locations, 79% in intermediate-risk locations, and 93% in low-risk sites. A Cox proportional hazards analysis demonstrated that the grouping of lesions by their anatomical risk location had prognostic value that was significant in a model of eight other known predictive variables (thickness, sex, age, type, level, mitotic index, ulceration, and presence of preexistent nevus). The results indicate that anatomical location of the primary melanoma is significantly associated with five-year disease-free survival.

Relationship of lumbosacral nevocytic nevi to sun exposure in dysplastic nevus syndrome.

In 104 consecutive Caucasian patients who had histologically proved dysplastic nevi, the number and diameter of nevocytic nevi were determined in two equally sized contiguous rectangles in the lumbosacral region. The cephalad (superior) rectangle was in a relatively sun-exposed site, whereas the caudad (inferior) rectangle was in a relatively sun-protected site. Many of the nevocytic nevi identified in these rectangles had the clinical features of dysplastic nevi. Significantly, more nevi were found in the cephalad rectangle compared with the caudad rectangle. Men greater than or equal to 40 years of age had significantly larger nevi in the cephalad rectangle compared with the caudad rectangle. These data are consistent with the hypothesis that sunlight promotes development of more and larger nevocytic nevi in individuals afflicted with dysplastic nevus syndrome.

Hazard-rate analysis in state I malignant melanoma.

Hazard-rate analysis provides a unique means of assessing prognosis in patients with malignant disease. The hazard rate is the probability of a patient dying within a particular unit of time after definitive therapy. Hazard-rate analysis was performed on a series of 719 consecutive patients with clinical stage I cutaneous malignant melanoma (MM). The peak hazard rate for death from metastatic MM occurred during the 48th month of follow-up. Thereafter, the hazard rate declined and approached zero by the 120th month. When the patients were stratified by the thickness of their primary MM, thicker lesions reached their peak hazard-rate month earlier than thinner lesions. We conclude that after 120-month survival, the risk of dying from MM is virtually zero. However, since rare late deaths from MM occur, lifetime follow-up is recommended.

Risk of cutaneous malignant melanoma in patients with 'classic' atypical-mole syndrome. A case-control study.

BACKGROUND AND DESIGN: There is an increased risk of developing cutaneous malignant melanomas (MMs) in patients with classic atypical-mole syndrome (AMS). This study compares the incidence of newly diagnosed MMs in patients with classic AMS (cases) with the incidence of newly diagnosed MMs developing in a population without classic AMS (control patients). The charts of 287 white patients with AMS and 831 white patients without AMS were reviewed for the occurrence of newly diagnosed invasive MMs during follow-up. Both cases and control patients were followed up regularly by total-body cutaneous examinations. The cumulative 10-year risk for developing newly diagnosed invasive MMs was calculated (life-table method) for each cohort. RESULTS: Of the 287 AMS cases, 10 developed a newly diagnosed invasive MM, resulting in a 10-year cumulative risk of 10.7%. Of the 831 control patients, two developed a newly diagnosed invasive MM, resulting in a 10-year cumulative risk of 0.62%. CONCLUSION: Patients with classic AMS, regardless of the presence of a personal and/or family history of MM, are at significantly increased risk of developing invasive MMs compared with control patients.

Favorable prognosis for malignant melanomas associated with acquired melanocytic nevi.

In a clinicohistopathologic study of 557 patients with primary cutaneous malignant melanoma, there were fewer metastases and/or deaths from melanoma when histologic evidence of a coexisting acquired melanocytic nevus was found. A total of 130 patients with melanocytic nevus and 427 cases of melanoma without histologic evidence of a nevus (denovo) were studied. Clinical follow-up evaluation for evidence of metastases and/or death was obtained. Only ten of the patients (7.7%) with nevus-associated melanoma had metastases and/or death v 78 (18.3%) with de novo melanoma. When stratified by lesion thickness, the logrank test for survival revealed a statistically significant difference between the two groups. An overall favorable outcome seen in patients with malignant melanomas associated with acquired melanocytic nevi was found, therefore, to be independent of lesion thickness as well as six other variables reported to be related to the biologic behavior of malignant melanoma. Thus, the presence of nevus cells in a specimen of malignant melanoma portends a better prognosis and may have important implications in the biology of this neoplasm.

Influence of biomaterial surface texture on bone ingrowth in the rabbit femur.

The purpose of this study was to examine both the histologic and the mechanical characteristics of bone apposition to an experimental surface, arc-deposited titanium, in a rabbit model and to compare them with those of four previously studied surfaces: one layer of cobalt-chromium beads, three layers of cobalt-chromium beads, plasma-sprayed cobalt-chromium, and uncoated titanium alloy. Bilateral cylindrical implants were press-fit into the lateral femoral condyles of 70 adult New Zealand White rabbits, which were allowed unrestricted activity and then killed at 6 or 12 weeks. The distal femora were harvested, radiographed, and prepared for either mechanical or histologic evaluation. All of the implants with coated surfaces had significantly greater shear strength than the implants of grit-blasted titanium alloy after both 6 and 12 weeks. After 6 weeks, maximum bone apposition occurred in the beaded surfaces. After 12 weeks, the shear strengths and bone apposition of implants of arc-deposited titanium and of one and three layers of cobalt-chromium beads were significantly greater than those of implants of plasma-sprayed cobalt-chromium and grit-blasted titanium alloy. The histologic studies correlated with the mechanical results. After 12 weeks, the bone apposition and mechanical stability of arc-deposited titanium were similar to those of a single layer of beads. There appeared to be no advantage to multiple layers of beads, and the plasma-sprayed cobalt-chromium and grit-blasted titanium surfaces showed lower shear strength and bone apposition than the other groups.

Bone ingrowth to implant surfaces in an inflammatory arthritis model.

Many studies have shown enhanced bone apposition to implants coated with hydroxyapatite, but the optimum implant texture, especially in abnormal trabecular bone, is unclear. The purpose of this project was to evaluate the histological and mechanical properties of cylindrical implants with three different surface textures that were placed in the cancellous bone of the distal femur of the rabbit after the production of an inflammatory knee arthritis. The three implant surfaces included a beaded surface (Group A), a beaded surface coated with hydroxyapatite (Group B), and a smooth surface coated with hydroxyapatite (Group C). The right knees of 36 rabbits were injected with carrageenan twice a week for 2 weeks. Then bilateral implantations were performed, with 12 rabbits in each group receiving identical implants in the right and left knees. The rabbits were killed 6 weeks after surgery. Mechanical (push-out test) and histomorphometric analyses were performed to determine the quality and quantity of bone ingrowth. In Group A, there was virtually no direct contact (a 20-60-microm clearance) between the bone and the beaded surfaces. Direct contact between the bone and the implant surfaces was seen in Groups B and C. The thickness and number of trabeculae were smaller on the arthritic side than on the control side for all groups but were not different between groups for either the control or the arthritic side. Mechanical testing showed that the shear strength of the interface was weaker on the arthritic side in all groups. The results suggest that inflammatory arthritis induced by carrageenan may influence the quality of local bone (osteopenic changes) and hence compromise the bone apposition and mechanical stability of the interface between the implant and bone.