Interim 1-Year Radiographic and Clinical Outcomes Following Anterior Cervical Discectomy and Fusion Using Hydroxyapatite-Infused Polyetheretherketone Interbody Cages.

BACKGROUND: This is a multicenter observational registry analysis of 1-year radiographic and clinical outcomes following anterior cervical discectomy and fusion (ACDF) using hydroxyapatite (HA)-infused polyetheretherketone (PEEK) intervertebral cages. METHODS: Radiographic and clinical outcome data were collected preoperatively and at 6 weeks, 3 months, 6 months, and 12 months postoperatively. To assess fusion, dynamic flexion-extension radiographs were independently evaluated with a validated method. Clinical outcomes were assessed using the following disease-specific measures: Neck Disability Index (NDI) and visual analog scale (VAS) for neck, left arm, and right arm pain. Patient satisfaction was also evaluated. RESULTS: A total of 789 ACDF patients (men: 51.5%/women: 48.5%; mean body mass index: 29.9 kg/m2) were included at the time of analysis, and 1565 segments have been operated. Successful fusion was confirmed in 91.3% of all operated levels after 6 months and 92.2% after 12 months. Mean NDI scores improved significantly (P < 0.01) preoperatively (46.3, n = 771) to postoperatively (12 months: 25.2, n = 281). Consistently, mean VAS neck (preoperative: 64.2, n = 770; 12 months: 28.6, n = 278), VAS right arm (preoperative: 42.6, n = 766; 12 months: 20.4, n = 277), and VAS left arm (preoperative: 41.1, n = 768; 12 months: 20.8, n = 277) decreased significantly (P < 0.01). Patients reported high satisfaction rates after surgery with no significant changes in postoperative patient satisfaction between 6 weeks and 12 months (95.1%, n = 273). CONCLUSIONS: ACDF with HA-infused PEEK cages demonstrates promising radiographic and clinical outcomes, supporting the potential benefits of incorporating HA into PEEK cages to enhance fusion rates and improve patient outcomes. CLINICAL RELEVANCE: This study demonstrates a >90% fusion rate by level with reliable improvements in patient reported outcomes, along with a high rate of patient satisfaction, in a large patient cohort undergoing ACDF with HA-infused PEEK cages. LEVEL OF EVIDENCE: 2 .

Erythrocytosis after renal transplantation represents an abnormality of insulin-like growth factor-I and its binding proteins.

BACKGROUND: Secondary erythrocytosis is classically defined by an increase in erythropoietin (EPO) production. Despite increased levels of EPO often seen in secondary erythrocytosis, some of these forms such as that seen after renal transplantation remain undefined. Our group has recently investigated the in vivo function of insulin-like growth factor-I (IGF-I) in erythropoiesis both in humans and in a murine model of chronic renal failure. These data, and the recently recognized role of IGF-I in polycythemia vera, suggested that IGF-I might be involved in secondary erythrocytosis. METHODS: Renal transplant recipients who developed erythrocytosis after transplantation were compared to normal individuals and to renal transplant recipients without erythrocytosis. We measured fasting serum EPO and IGF-I in all three groups. Because binding proteins may modify IGF-I function, IGF-I-binding proteins (IGFBP) 1 and 3, major binding proteins of IGF-I, were also measured. RESULTS: Renal transplant recipients have significantly elevated serum of IGF-I and IGFBP3 compared to normal individuals. When transplant recipients with and without posttransplant erythrocytosis were compared, similar levels of IGF-I were found; however, the group with erythrocytosis had significantly elevated IGFBP1 and IGFBP3. No other significant differences including EPO levels were found between the groups. CONCLUSIONS: Erythrocytosis after renal transplantation represents an anomaly of both IGF-I and its major binding proteins. Further studies are under way to better define this dysregulation and determine whether IGF-I can play a more generalized role in secondary forms of erythropoiesis.

Successful treatment of acquired factor VIII inhibitors with cyclosporin.

The treatment of Factor VIII inhibitors remains controversial and no standard therapy exists. We describe in this report two consecutive patients with this inhibitor that responded to cyclosporin. Clinical improvement of the bleeding diathesis, a return to normal of the PTT, a decrease in the level of the inhibitor, and a return to normal of the factor VIII level followed use of this drug. We believe that cyclosporin is effective in the treatment of factor VIII inhibitors and deserves further investigation.

Effect of chronic renal failure on the expression of erythropoietin message in a murine model.

The anemia of chronic renal failure (CRF) is largely due to decreased production of erythropoietin (EPO) by the kidney. A small amount of EPO also originates from extra-renal sources, and this would be expected to assume a more important role in maintaining erythropoiesis when renal production is impaired. In this study, we examined the production of EPO mRNA by RT-PCR in kidney, liver, and bone marrow tissues isolated from normal mice, mice rendered acutely anemic by phlebotomy, and from mice with surgically induced CRF. The induction of acute anemia results in an expected increase in the expression of EPO mRNA in renal and hepatic tissue. In contrast, while the expression of EPO mRNA was expectedly reduced in the kidney from CRF mice, it was completely absent in the liver of these same animals. EPO mRNA expression was also absent in the bone marrow in both states of acute anemia and CRF. These results show that CRF can directly or indirectly can suppress the extrarenal production of EPO by the liver and that this effect may further aggravate the anemia of CRF.

Subtherapeutic erythropoietin and insulin-like growth factor-1 correct the anemia of chronic renal failure in the mouse.

Chronic renal failure (CRF) is associated with a hyporegenerative anemia, which is caused primarily by inadequate production of erythropoietin (EPO) by the diseased kidneys and is responsive to exogenous EPO administration. Little is known about compensatory mechanisms that might supervene in anemia with low levels of EPO. Multiple investigations in vitro suggest an important role for insulin-like growth factor-1 (IGF-1) as well as EPO in erythropoiesis. Recently, both EPO and IGF-1 in vitro have been found to stimulate erythroid colony forming units in the mouse. However, no studies have examined the effect of IGF-1, singly and in combination with EPO, in CRF in vivo. This study examined mice with surgically-induced renal failure of six weeks duration that were treated for three weeks with the combination of subtherapeutic doses of both EPO and IGF-1. The single administration of each cytokine caused no significant change in hemoglobin in all CRF mice. In marked contrast the combined administration of the two cytokines produced a striking rise in hemoglobin, resulting in anemia correction in the majority of animals. The response to the combination therapy was comparable to the maximal response obtained with a single EPO dose (10 U) in a dose-finding study. Although the data are limited to utilizing one dose of each cytokine and one preparation of IGF-1, the large increase in hemoglobin observed with the combination therapy indicates that these two cytokines work in concert to stimulate erythroid precursors in CRF. In addition, untreated CRF mice showed markedly increased serum levels of low molecular weight binding proteins for IGF-1, potentially reducing the bioavailability of IGF-1. These findings taken together suggest that the anemia of CRF may represent both an EPO and a functional IGF-1 deficient state.

Control of construction-associated nosocomial aspergillosis in an antiquated hematology unit.

OBJECTIVE: To determine the incidence of aspergillosis in patients with leukemia or bone marrow transplants during a construction-associated outbreak, and the effect of an environmental control program for Aspergillus. DESIGN: Clinical, microbiological, and pathological records were reviewed retrospectively once the outbreak was appreciated, and prospectively thereafter, to determine the presence or absence of aspergillosis and duration of neutropenia. SETTING: A university tertiary-care center with a single designated hematology-oncology unit. PATIENTS: From January 1988 to September 1993, there were 141 patients with leukemia or bone marrow transplants identified as being neutropenic during 231 admissions to this specialized unit. INTERVENTIONS: Installation of wall-mounted portable high-efficiency particulate air (HEPA)-filter air purifiers, application of copper-8-quinolinolate-formulated paint, replacement of perforated ceiling tiles with nonperforated type, sealing of all windows, replacement of horizontal, dust-accumulating blinds with vinyl, opaque, roller shades, and systematic and regular cleaning of surfaces. RESULTS: Thirty-six cases of nosocomial aspergillosis were diagnosed during this period. The incidence density (ID) in the preconstruction period was 3.18 per 1,000 days at risk. During construction activity-before the implementation of a control strategy-the ID increased dramatically to 9.88 per 1,000 days at risk. With infection control measures implemented and continued construction work, the ID decreased to 2.91 per 1,000 days at risk, comparable to the preconstruction baseline rate. CONCLUSIONS: An environmental control strategy incorporating widely available technology may have played an important role in controlling this outbreak of construction-associated invasive aspergillosis.

Anemia of chronic renal failure: characterization in the mouse and correction with human recombinant erythropoietin.

Anemia is a cardinal feature of chronic renal failure (CRF) which contributes significantly to the clinical syndrome of chronic uremia. We have conducted a detailed examination of the hematological changes in CRF in the inbred mouse strain C57BL/6J. As in the human situation, CRF mice presented major hematological changes affecting primarily the erythroid cell series. Despite the presence of abundant iron stores in the bone marrow, the CRF mice developed a hypoproliferative anemia of a severity commensurate with the degree of renal impairment. The levels of circulating erythropoietin (EPO) in CRF mice were not significantly different from those in normal control littermates and were therefore inappropriately low for the degree of anemia. In contrast acutely bled control mice with normal renal function showed a significant inverse correlation between the serum EPO level and hemoglobin concentration, indicating an appropriate response to anemia. The chronic administration of recombinant human EPO raised the hemoglobin concentration of CRF mice, a therapeutic effect which was independent of the initial degree of anemia. These observations suggest that this animal model has wide applicability for the study of anemia secondary to CRF.

Pharmacokinetics of Pamidronate Disodium in Cancer Patients after a Single Intravenous Infusion of 30-, 60- or 90-mg Dose over 4 or 24 Hours.

The objective of this study was to determine the pharmacokinetics of pamidronate disodium in plasma and urine after a single intravenous infusion of the drug to cancer patients at risk for developing bone metastases. Thirty-six patients were randomized into six treatment groups to receive 30-, 60- or 90-mg doses of the drug by 4- or 24-h intravenous infusions. Plasma and urine samples were collected at intervals for up to 144 h after drug administration and were assayed for pamidronate disodium using validated reversed-phase HPLC methods. The percentage of the administered dose excreted in urine following a 4- or 24-h infusion of 30-, 60- or 90-mg pamidronate disodium ranged from 30% to 60% except for one individual who excreted 96% by this route of elimination. There was a linear relationship between amount of drug excreted in urine and dose. Curve fitting of ARE (amount of drug to be excreted in urine) data indicated that the disposition kinetics of the drug was consistent with a biexponential process with overall mean plus minus S.D. half-life values of 2.1 plus minus 1.8 and 26.9 plus minus 8.7 h for the alpha and beta phases, respectively. The results of this study showed that the drug exhibited dose proportionality in its pharmacokinetic behavior over the 30--90-mg range regardless of whether it was infused over a 4- or 24-h interval.

Non-Hodgkin's lymphoma of the spleen.

Although the spleen is frequently involved in disseminated non-Hodgkin's lymphoma (NHL), splenic presentation as the initial or only site of disease is uncommon. The true incidence of splenic lymphoma is difficult to estimate because of the variable definition of this disease, however, the diagnosis of primary lymphoma of the spleen should be limited to involvement of only the spleen and splenic hilum. Using this restricted definition, our experience suggests that the prognosis of NHL of the spleen, when pathologically staged, may have a favorable prognosis which approximates that seen with limited stage NHL at other sites. The influence of pathologic subtype on natural history and the impact of adjuvant therapy are discussed.

Urinary excretion of aminohydroxypropylidene bisphosphonate in cancer patients after single intravenous infusions.

The effect of the rate of infusion of disodium aminohydroxypropylidene bisphosphonate (APD; CGP 23339A), an inhibitor of bone resorption, on urinary excretion of this agent was studied in a randomized open-label study in 20 cancer patients. Ten patients received 60 mg of APD over 4 h, and the remaining 10 patients received the same dose over 24 h. Urine collected during specified intervals for 72 h after the start of the infusion was analyzed by high-performance liquid chromatography for unchanged APD. Mild and transient adverse experiences were observed in 12 (60%) patients; the most common were headache, fever, and phlebitis at the infusion site. No clinically significant laboratory abnormalities were observed, and none of the experiences were serious enough to require discontinuation of treatment. Cumulative urinary excretion of APD was a linear function of time, increasing rapidly after both the 4- and 24-h infusions were started. The mean (+/- standard deviation) cumulative urinary excretion of APD was 51.1 +/- 13.0% of the dose in the 20 patients, 55.0 +/- 15.0% in the 10 patients given the 4-h infusion, and 47.2 +/- 9.9% in the 10 patients receiving the 24-h infusion. Thus, the rate of infusion of the 60-mg dose did not influence retention of APD at 72 h after the start of therapy. Similarly, the presence or absence of bone metastases did not influence cumulative urinary excretion or the retention of APD.

Primary non-Hodgkin lymphoma of the spleen.

Primary splenic lymphoma is a relatively infrequent cause of splenomegaly, its reported incidence being less than 1%. Nonetheless, various series have reported on its occurrence and its unfavorable prognosis, but these series have reported data on heterogenous populations, including many patients with nodal or hepatic disease. We report on a series of nine patients with primary splenic lymphoma. None of these patients had biopsy-proven evidence of extrasplenic disease and were categorized as involving spleen only (stage 1) or spleen and splenic hilum (stage 2). In this series, classified by the recent N.C.I. working formulation, four patients had intermediate or high-grade histology and five patients had low-grade histology. There was no correlation between histological subtype and prognosis, nor could other factors be delineated to explain their favorable prognosis. The median survival in this group of patients was 7.48 years, and no evidence of relapse has been documented. The data suggest that primary splenic lymphoma, treated by splenectomy alone or combination therapy, may be potentially curative. Further studies should address the question of aggressive accurate staging in hopes of obtaining homogenous patient populations so that appropriate treatment in primary splenic lymphoma can be better defined.

The N-terminal sequence of the major erythropoietic factor of an anephric patient is identical to insulin-like growth factor I.

The erythropoietic factors present in an anephric patient with nearly normal hematocrit were isolated from plasma by reversed-phase and gel permeation HPLC. The most active fraction was purified and the analysis of its N-terminal sequence was identical to the published sequence of the human insulin-like growth factor I (IGF I). Recombinant human IGF I had identical elution positions as the isolated erythropoietic factor on reversed-phase HPLC and the same molecular weight on gel permeation HPLC. Furthermore, hrIGF I stimulated erythroid colony formation in human bone marrow cultures as was previously shown for the isolated human erythropoietic factor. These results suggest that IGF I may replace erythropoietin as a stimulator of erythropoiesis in some patients with anemia and renal failure.

Identification and characterization of an 8-kd peptide stimulating late erythropoiesis.

Chronic renal failure is often associated with severe anemia, subnormal levels of erythropoietin (EPO), and the presence of erythropoietic inhibitors. We studied an anephric patient with polycystic kidney disease maintaining a hemoglobin level of 13-14 g. Biochemical, endocrine, and hematological parameters were all within normal limits. EPO levels examined on two occasions during the clinical investigation were found to be low to subnormal. Plasma of this patient supported human bone marrow erythroid colony formation without the addition of exogenous EPO. Following reversed-phase high pressure liquid chromatography (HPLC) and gel filtration HPLC of the patient's plasma, a small polypeptide was identified that stimulated thymidine incorporation into fetal calf liver cells and supported erythroid colony formation of human marrow cells. This molecule is different from EPO with respect to its molecular weight and its functional and chromatographic properties. In this report we provide evidence of a human plasma-derived peptide of an anephric patient regulating late erythropoiesis.

Treatment of idiopathic thrombocytopenic purpura with ascorbate.

The treatment of idiopathic thrombocytopenic purpura (ITP) includes corticosteroids, danazol, splenectomy and various immunosuppressives. Treatment can be difficult for those patients refractory to these modalities and/or those patients intolerant of the secondary effects. In this paper we report on the use of ascorbate in the treatment of ITP and its successful use in seven of 11 patients studied. We found that therapy with ascorbate appeared to improve the platelet count and the intravascular survival of platelets. Because of excellent patient compliance and its lack of toxicity, it may be an alternative for the treatment of ITP. The exact role of ascorbate in the treatment of ITP, as well as its mechanism of action, await further study.

Hemolytic anemia following intravenous gamma globulin administration.

A young homosexual man with immune thrombocytopenia recently had transient intravascular hemolysis during intravenous gamma globulin treatment. The hemolysis, manifested by a sharp decrease in hemoglobin and by a direct Coombs' test with a positive result, was mediated by anti-A antibody present in the gamma globulin preparation. In view of the increasing use of intravenous gamma globulin in the treatment of patients with immune cytopenia, this problem may result in crossmatching difficulties and should be recognized as a potential complication of therapy.

Expression of common acute lymphoblastic leukemia-associated antigen on germ cell tumor.

A mediastinal germ cell tumor is described that reacts with the anti-common acute lymphoblastic leukemia-associated antigen antibody J5 using both immunofluorescence and immunoperoxidase techniques. This antigen has been reported recently on various cell lines including melanoma, colon, and breast. It has also been seen on normal fibroblasts and peripheral granulocytes. This is believed to be the first description of a solid nonlymphoid neoplasm possessing this antigen, and the implications regarding prognosis and therapy are discussed.

An antigen related to the phenotype of multi-drug resistance can be induced in vivo and used as a target for immunotherapy of rat leukemia.

Several laboratories have reported that new plasma membrane peptides appear in rodent and human cells after induction of in-vitro resistance to vinca alkaloids, anthracyclines and other anti-neoplastic drugs. Recently, murine monoclonal antibodies have been produced that recognize surface components of such drug-resistant cells. The work presented here describes the development of an in-vivo animal model of this phenomenon using a rat myeloid leukemia. Brown Norway rats were made leukemic with promyelocytes of the BNML line and subsequently were treated with 7.7 mg kg-1 of daunorubicin. After eight cycles of passage-treatment-regrowth, the resulting cells reacted with this antibody in immunofluorescence and cytotoxicity assays. Animals injected with cells that had been pre-incubated with antibody in the absence of complement survived significantly longer than did the controls. Further prolongation of survival occurred when the cells were treated with a second antibody of a different specificity. These results demonstrate that some of the changes associated with in-vitro drug resistance occur also in vivo and potentially may be exploited as a focus for immunotherapy.

Blastic variants of rat promyelocytic leukemia produce neurologic disease.

The characteristics of tumor cells that enable invasion into normal tissues are not well understood. We have derived variants of the promyelocytic leukemia of the Brown Norway rat (BNML) that exhibit a high incidence of growth in the epidural space and produce paralysis of the hind limbs. This unique animal model mimics a major cause of morbidity in human cancer and provides a reproducible system in which to study the determinants of metastasis localization.