Fritz Lipmann--Nobel Prize in discovery of coenzyme A.
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Biomedical subjects
Publications and source records attributed to R A Kyle.
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OBJECTIVE: To evaluate the presentation and prognosis of primary localized amyloidosis of the urinary bladder. PATIENTS AND METHODS: The medical records of 31 patients with primary localized amyloidosis of the urinary bladder were reviewed. Immunohistochemical amyloid typing was performed on bladder biopsy specimens from 27 patients. RESULTS: The median age of the 22 men and 9 women was 55 years. Twenty-four patients (77%) presented with gross hematuria (associated with irritative urinary tract symptoms in 6 patients), and 7 (23%) had only irritative lower urinary tract symptoms. Multiple bladder areas were involved in 20 patients (65%), a single area was involved in 8 (26%), and diffuse involvement was present in 3 (10%). Twenty-four patients had immunoglobulin light chain, and 3 had transthyretin-related amyloid. Local recurrences were common. None of the patients developed systemic amyloidosis. CONCLUSION: Primary localized amyloidosis of the urinary bladder can be easily confused with a neoplasm. Immunohistochemical amyloid typing is important. Transthyretin-related amyloid of the bladder requires no further work-up. Repeated work-ups for systemic amyloidosis are unnecessary for patients with light chain-related amyloidosis of the urinary bladder. Early eradication with fulguration or laser therapy is indicated. Cystoscopic follow-up is necessary.
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OBJECTIVE: To describe the efficacy of therapy with thalidomide, a drug that has antiangiogenic properties, in patients with relapsed multiple myeloma. PATIENTS AND METHODS: We studied 16 patients (median age, 64 years) who received thalidomide for relapsed myeloma at the Mayo Clinic in Rochester, Minn, between November 1998 and August 1999. Treatment consisted of thalidomide given orally at a dose of 200 mg/d for 2 weeks, then increased by 200 mg/d every 2 weeks, up to a maximal dose of 800 mg/d. RESULTS: The stage of myeloma at treatment was Durie-Salmon IIIA in 9 patients (56%) and IIIB in 7 (44%). The median time from myeloma diagnosis to initiation of thalidomide therapy was 32 months. In 4 patients (25%) prior stem cell transplantation had failed, and 14 (88%) had received 2 or more prior chemotherapeutic regimens before institution of thalidomide. All patients were evaluable for response. Four (25%) achieved a partial response to therapy, with a greater than 50% reduction in the serum or urine M protein level. Responses lasted 2, 4+, 8, and 10+ months. Major adverse effects included constipation, sedation, rash, and peripheral neuropathy. CONCLUSION: Thalidomide is an active agent in the treatment of patients with advanced myeloma.
BACKGROUND: Minimal criteria for the diagnosis of multiple myeloma are provided. Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, primary systemic amyloidosis and metastatic carcinoma must be included in the differential diagnosis. Patients with multiple myeloma should not be treated unless they have an increasing M-protein in the serum or urine, development of anemia, hypercalcemia, renal insufficiency, lytic lesions, fractures or extra-medullary plasmacytomas. PATIENTS AND METHODS: This is a review of patients treated with chemotherapy, autologous stem-cell transplantation and allogeneic transplantation. RESULTS: Comparisons of melphalan and prednisone with a variety of combinations of therapeutic agents produces a higher response rate than with melphalan and prednisone but no significant difference in overall survival. Autologous stem-cell transplantation produces a higher response rate and some prolongation of survival but is not curative. Allogeneic transplantation is associated with a mortality of 40% and is not curative. CONCLUSIONS: If the patient is younger than 70 years, the physician should consider the possibility of an autologous peripheral blood stem-cell transplant. Ideally, this should be done as part of a prospective study. Hematopoietic stem cells are damaged by alkylating agents so they must be collected before these agents are given. Autologous stem-cell transplantation does not produce a cure and most patients will relapse. The appropriate timing of an autologous stem-cell transplant has not been ascertained. Hopefully, better preparative regimens and the removal of contaminated tumor cells from the peripheral blood will make an autologous transplant more effective. Another major question is whether double (tandem) transplants are superior to a single autologous stem-cell transplant. A current French Myeloma Group Study randomized study should answer this question. Allogeneic transplantation for multiple myeloma must be made safer because the transplant-related mortality is 40%. The relapse of multiple myeloma following allogeneic transplant is a major problem and consequently the preparative regimens must be improved. The infusion of donor lymphocytes following relapse after an allogeneic transplant is useful. New approaches with immunologic aspects including the use of dendritic cells and vaccines are of potential importance for the future.
We studied the prognostic value of angiogenesis grading and microvessel density estimation in newly diagnosed multiple myeloma. Seventy-five patients with newly diagnosed myeloma, treated on Eastern Cooperative Oncology Protocol E9486 and Intergroup study 0141 (S9321) at the Mayo Clinic, were studied. Bone marrow microvessels were examined using immunohistochemical staining for von Willebrand factor. Determination of microvessel density and angiogenesis grading was done in a blinded manner. There was a strong correlation between microvessel density and the plasma cell labeling index, rho 0.42, P < 0.001. Angiogenesis grade was also significantly associated with the plasma cell labeling index. Fifteen % of patients with low-grade angiogenesis had a high labeling index (>1%). In contrast, 47% of patients with intermediate or high-grade angiogenesis had high labeling indices (P = 0.02). Overall survival was significantly different among those with high-, intermediate-, and low-grade angiogenesis, with median times of 2, 4, and 4.4 years, respectively (P = 0.02). Similarly, patients with microvessel density >50/x400 field had poorer survival compared with those with 50 or fewer microvessels/field, median survival 2.6 versus 5.1 years, respectively (P = 0.004). There was a strong association between angiogenesis grade and microvessel density (P < 0.001). We conclude that bone marrow angiogenesis is a predictor of poor survival in newly diagnosed myeloma. Angiogenesis is correlated with the plasma cell labeling index but not the bone marrow plasma cell percentage. A simple visual grading of angiogenesis is an efficient alternative to microvessel density estimation.
BACKGROUND: Interferon (IFN) has demonstrated activity in the treatment of patients with multiple myeloma. A previous Eastern Cooperative Oncology Group (ECOG) study suggested that the rates of complete response (CR) and survival were increased with a regimen that alternated IFN with chemotherapy. The current study was designed to evaluate the effect of adding alternating cycles of IFN or early intensification with high dose cyclophosphamide (HiCy) to the VBMCP regimen for the treatment of multiple myeloma patients. METHODS: From February 1988 to May 1992, the ECOG entered previously untreated patients with active multiple myeloma on a study in which they were randomized to VBMCP (vincristine 1.2 mg/m(2) administered intravenously [i.v.] on Day 1, BCNU 20 mg/m(2) i.v. on Day 1, melphalan 8 mg/m(2) administered orally [p.o.] on Days 1-4, cyclophosphamide 400 mg/m(2) i.v. on Day 1, and prednisone 40 mg/m(2) p.o. on Days 1-7; 5-week cycles) or VBMCP + rIFN(alpha2), the latter given at 5 Mu/m(2) 3 times a week starting on Day 22 of each 6-week cycle after 2 initial cycles of VBMCP. Patients younger than 70 years were also randomized to a third treatment that substituted cyclophosphamide 600 mg/m(2) i.v. on Days 1-4 and prednisone 100 mg/m(2) p.o. on Days 1-4 for cycles 3 and 5 of VBMCP (VBMCP + HiCy). Treatment was continued for 2 years. RESULTS: Of the 653 patients entered, 628 were eligible for the study. All were evaluated for response. With median follow-up for surviving patients of 54 months, the median survival duration was 42 months-1 year longer than usually reported for melphalan combined with prednisone. A comparison of the three regimens revealed no significant difference in the rates of survival or objective response (OR). However, CRs were increased among patients treated with VBMCP + rIFN(alpha2) compared with VBMCP alone (18% vs. 10%, P = 0.03). Patients treated with VBMCP + rIFN(alpha2) had a longer response duration than patients treated with VBMCP alone (30 vs. 25 months, P = 0.035). There was a greater response rate with the IFN regimen among elderly patients (OR and CR = 67% and 31%, respectively) and patients with immunoglobulin A (IgA) myeloma (OR and CR = 83% and 29%, respectively). Severe infections were seen as often with VBMCP as with VBMCP + rIFN(alpha2) (13% vs. 15%), but they were more frequent with VBMCP + HiCy (25%). CONCLUSIONS: VBMCP + rIFN(alpha2) yields a higher rate of CR and a longer response duration than VBMCP alone but appears to make no difference in the rates of overall response or survival compared with VBMCP or VBMCP + HiCy. The superior ability of VBMCP + rIFN(alpha2) induction therapy to produce CR and more durable responses, as well as its activity in older patients and in those with IgA myeloma, suggest that this therapy has important biologic activity in myeloma and merits further clinical investigation.
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