Citations

Abstract We hypothesized that the presence of monoclonal free kappa or lambda immunoglobulin light chains in monoclonal gammopathy of undetermined significance (MGUS), as detected by the serum free light chain (FLC) assay increases the risk of progression to malignancy. Of 1384 patients with MGUS from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 1148. At a median follow-up of 15 years, malignant progression had occurred in 87 (7.6%) patients. An abnormal FLC ratio (kappa-lambda ratio < 0.26 or > 1.65) was detected in 379 (33%) patients. The risk of progression in patients with an abnormal FLC ratio was significantly higher compared with patients with a normal ratio (hazard ratio, 3.5; 95% confidence interval [CI], 2.3-5.5; P < .001) and was independent of the size and type of the serum monoclonal (M) protein. Patients with an abnormal serum FLC ratio, non–immunoglobulin G (non-IgG) MGUS, and a high serum M protein level (≥ 15 g/L) had a risk of progression at 20 years of 58% (high-risk MGUS) versus 37% with any 2 of these risk factors (high-intermediate risk), 21% with one risk factor (low-intermediate risk), and 5% when none of the risk factors were present (low risk).

Purpose There is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification. Patients and Methods Clinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies. Results Serum beta 2 -microglobulin (Sβ 2 M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sβ 2 M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sβ 2 M less than 3.5 mg/L plus serum albumin ≥ 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sβ 2 M ≥ 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system. Conclusion The new ISS is simple, based on easy to use variables (Sβ 2 M and serum albumin), and recommended for early adoption and widespread use.

Extracellular proteolysis plays a key role in many pathophysiologic processes including cancer, inflammatory diseases, and cardiovascular conditions such as atherosclerosis and restenosis. Whereas matrix metalloproteinases are their best known member, many others are becoming better known. The extracellular proteases are a complex and heterogeneous superfamily of enzymes. They include metalloproteinases (matrix metalloproteinases, adamalysins, or pappalysins), serine proteases (elastase, coagulation factors, plasmin, tissue plasminogen activator, urokinase plasminogen activator), and the cysteine proteases (such cathepsins). In addition to their matrix degradation capabilities, they have other less well known biologic functions that include angiogenesis, growth factor bioavailability, cytokine modulation, receptor shedding, enhancing cell migration, proliferation, invasion, and apoptosis. This review discusses extracellular proteases relevant to the vasculature, their classification and function, and how protease disorders contribute to arterial plaque growth, including chronic atherosclerosis, acute coronary syndromes, restenosis, and vascular remodeling. These broad extracellular protease functions make them potentially interesting therapeutic targets.

Abstract OBJECTIVE: To evaluate the efficacy and toxicity of radiosurgery in the treatment of cranial base chordoma and chondrosarcoma. METHODS: We reviewed 29 patients with cranial base chordoma (n = 25) or chondrosarcoma (n = 4) who underwent stereotactic radiosurgery between September 1990 and December 2002. The median patient age was 45 years (range, 10–81 yr). Nineteen patients also had radiation therapy before or in conjunction with radiosurgery (median dose, 50.4 Gy). The median tumor volume was 14.4 cm3 (range, 0.6–65.1 cm3). The median tumor margin dose was 15 Gy (range, 10–20 Gy); the median maximum radiation dose was 30 Gy (range, 20–40 Gy). Median clinical and imaging follow-up periods were 4.8 and 4.5 years, respectively. RESULTS: Seven chordoma patients (28%) had tumor progression (in-field, n = 3; out-of-field, n = 4), whereas 18 had stable disease or tumor shrinkage. No patient with a chondroid chordoma had tumor enlargement. The actuarial tumor control rates were 89 and 32% at 2 and 5 years, respectively. All 4 patients with chondrosarcoma had tumor control. Clinically, 7 patients (24%) had improvement of pretreatment symptoms, 16 (55%) remained stable, and 6 (21%) worsened. Three patients with tumor progression died. Ten patients (34%) had radiation-related complications. Complications included cranial nerve deficits (n = 6), radiation necrosis (n = 5), and pituitary dysfunction (n = 3). Patients having radiosurgery alone had no toxicity. CONCLUSION: Cranial base chordomas and chondrosarcomas remain a formidable management challenge. Radiosurgery as an adjunct to surgical resection provides in-field tumor control for some patients, but radiation-related complications are relatively high, especially when radiosurgery is combined with fractionated radiation therapy.

There are theoretical and practical advantages to modular rather than monoblock designs of prostheses for shoulder arthroplasty, but there are no reported studies which specifically compare the clinical and radiological results of their use. We have compared the results of unconstrained total shoulder arthroplasty for osteoarthritis using both types of implant. The monoblock design was used between 1992 and 1995 and the modular design after 1995. Both had cemented all-polyethylene glenoids, the monoblock with matched and the modular with mismatched radii of curvature. There were 34 consecutive shoulders in each group with a mean follow-up of 6.1 years in the first and 5.2 years in the second. There were no significant differences in improvement of pain scores, active elevation, external rotation, internal rotation, patient satisfaction, or the Neer ratings between the two groups. Two of 28 glenoid components in the first group and six of 30 in the second met the criteria for being radiologically at risk for loosening (p = 0.25). There were no significant differences in clinical outcome or radiological changes between the first- and second-generation designs of implant for shoulder arthroplasty.

Abstract Background: The quantitative assay for free light chains (FLCs) is a recently introduced commercial test reported to be sensitive and specific for detecting FLC diseases such as primary systemic amyloidosis (AL), light chain deposition disease (LCDD), nonsecretory multiple myeloma (NSMM), and light chain multiple myeloma. We evaluated its diagnostic performance in clinical practice. Methods: All FLC clinical test results generated in 2003 were abstracted from the Laboratory Information System. Diagnoses were obtained from the Dysproteinemia database and the patient medical history. Results: In 2003, we received samples for FLC assays from 1020 Mayo Clinic patients. The majority of these patients (88%) had bone marrow-derived monoclonal plasma cell disorders (PCDs). The 121 patients who did not have monoclonal gammopathy all had FLC κ/λ ratios within the range of values obtained for a reference population in our laboratory. Among the patients with monoclonal gammopathies were patients with multiple myeloma (330), AL (269), monoclonal gammopathy of undetermined significance (114), smoldering multiple myeloma (72), plasmacytoma (22), NSMM (20), macroglobulinemia (9), LCDD (7), and a variety of other PCDs. Among the 110 AL patients who had not been previously treated and who had a FLC assay performed within 120 days of diagnosis, the FLC κ/λ ratio was positive in 91% compared with 69% for serum immunofixation electrophoresis (IFE) and 83% for urine IFE. The combination of serum IFE and serum FLC assay detected an abnormal result in 99% (109 of 110) of patients with AL. Conclusion: The performance of the FLC assay in this analysis of clinical laboratory data is consistent with results from published retrospective validation studies.

The corpus cavernosum of the penis is one of the few vascular beds in which there is a change in oxygen tension with function (blood PO225-40mm Hg in the flaccid state, and 90-100mm Hg in the erect state). This change in oxygen tension exposes the components of the corpus cavernosum to a variety of cytokines, humoral, vasoactive, and growth factors which may affect the structure and function of the endothelial cells, smooth muscle cells, neurons and extracellular matrix. Among these cell types, endothelial cells are the first line of defense to blood-borne stress and can affect the underlying smooth muscle via paracrine mechanisms. Impotence is defined as the inability to obtain or sustain an erection sufficient for vaginal penetration and can result from a variety of pathological conditions, vascular disease, endocrine disease, neurological disease, and psychogenic disorders. The penis is a vascular organ and as such is susceptible to the effects of vascular diseases. This review will discuss the basic etiology of erection and vasculogenic erectile dysfunction and explore the role oxygen tension in regulating various cellular and humoral factors as well as trabecular structure and function.

Purpose Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. Patients and Methods In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. Results The cytotoxic target exposure for mafosfamide was 10 μmol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 μmol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. Conclusion The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.