A Phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease.

BACKGROUND: Bone metastases typically are associated with osteolytic bone destruction, resulting in bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. Bisphosphonates are potent inhibitors of normal and pathologic bone resorption and represent a significant therapeutic improvement in the management of patients with lytic bone metastases. Zoledronic acid is a new-generation, highly potent, nitrogen-containing bisphosphonate that to the authors knowledge is the most potent inhibitor of bone resorption currently in clinical trials. The objectives of the current study were to assess the safety and tolerability of increasing doses of zoledronic acid and to determine its activity with respect to reducing biochemical markers of bone resorption in cancer patients with bone metastases. METHODS: Forty-four cancer patients with bone metastases or primary bone lesions were enrolled sequentially into 1 of 5 fixed ascending-dose treatment groups. Each patient received a single intravenous bolus injection of 1, 2, 4, 8, or 16 mg of zoledronic acid over 30-60 seconds. Patients were monitored for 8 weeks for the evaluation of clinical findings, adverse events, vital signs, electrocardiograms, markers of bone resorption, and urinary N-acetyl-beta-D-glucosaminidase. RESULTS: Zoledronic acid was safe and well tolerated at all dose levels tested. Commonly reported adverse events included bone pain, fever, anorexia, constipation, and nausea, which were experienced by a similar proportion of patients in each treatment group. Seven patients reported serious adverse events, none of which appeared to be related to the study drug. Zoledronic acid effectively suppressed biochemical markers of bone resorption, including the highly specific markers N-telopeptide and deoxypyridinoline, for up to 8 weeks in the 2-16-mg dose groups and for a shorter duration in the 1-mg group. CONCLUSIONS: In the current study, zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption. The authors believe it may improve the treatment of metastatic bone disease.

Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients.

Kaposi's sarcoma-associated herpesvirus (KSHV) was found in the bone marrow dendritic cells of multiple myeloma patients but not in malignant plasma cells or bone marrow dendritic cells from normal individuals or patients with other malignancies. In addition the virus was detected in the bone marrow dendritic cells from two out of eight patients with monoclonal gammopathy of undetermined significance (MGUS), a precursor to myeloma. Viral interleukin-6, the human homolog of which is a growth factor for myeloma, was found to be transcribed in the myeloma bone marrow dendritic cells. KSHV may be required for transformation from MGUS to myeloma and perpetuate the growth of malignant plasma cells.

An association between renal cell carcinoma and lymphoid malignancies. A case series of eight patients.

BACKGROUND: Second primary malignancies have been described in patients with both solid tumors and hematologic malignancies. However, an association between renal cell carcinoma and lymphoid malignancies has rarely been described. Eight patients with both disorders are described and possible explanations for the association are reviewed. METHODS: A retrospective review of records from patients with renal cell carcinoma, lymphoma, leukemia, or myeloma discharged from the University of California at Los Angeles between July 1, 1993 and June 30, 1995 was performed. Renal cell carcinoma was diagnosed in 186 patients, whereas 405 had a lymphoid malignancy. Eight patients with both disorders were identified. RESULTS: In four of the eight patients, the renal cell carcinoma was diagnosed prior to their hematologic malignancy, whereas in the remaining four patients, the lymphoid malignancy was diagnosed first. Renal cell carcinoma is observed in the general population in 12.5 persons per 100,000 and hematologic malignancies in 31.8 per 100,000. The number of cases of lymphoid malignancies expected in the 186 renal cell carcinoma patients is lower than the 4 cases actually observed (P < 0.01). Likewise, the number of renal tumors expected in the 405 patients with hematologic malignancies is fewer than the 4 cases observed (P < 0.01). CONCLUSIONS: The incidence of renal cell carcinoma and lymphoid malignancy occurring in the same patient is higher than that expected in the general population. This association cannot be explained by treatment-related development of a second malignancy. A common genetic mutation or an immunomodulatory role of the first malignancy predisposing to the second are possibilities but further investigation is warranted.