Todd J. Alekshun

Diseases of Large Granular Lymphocytes

BACKGROUND Clonal diseases of large granular lymphocytes (LGLs) are rare lymphoproliferative malignancies that arise from either mature T-cell (CD3+) or natural killer (NK)-cell (CD3-) lineages. They manifest a distinct biologic behavior that ranges from indolent to very aggressive. METHODS We discuss four distinct diseases involving LGLs: indolent T-cell LGL leukemia, aggressive T-cell LGL leukemia, chronic NK-cell leukemia, and aggressive NK-cell leukemia. Furthermore, we present an up-to-date systematic review of therapies for each entity. RESULTS Sustained LGLs, characteristic immunophenotype, clonal origin of leukemic cells, and clinical presentation are the most important features that distinguish indolent from aggressive subtypes of LGL leukemia and guide the selection of therapy. Patients with symptomatic indolent T-cell or NK-cell LGL leukemia are usually treated with immunosuppressive therapies in contrast to aggressive T-cell and NK-cell LGL leukemia, which require intensive chemotherapy induction regimens. Novel targeted therapies using monoclonal antibodies against receptors, including CD2, CD52, the beta subunit of the interleukin-2 receptor, and small molecules such as tipifarnib, are undergoing evaluation in clinical trials. CONCLUSIONS Future scientific advances focusing on the delineation of molecular pathogenic mechanisms and the development of new targeted therapies for each distinct LGL leukemia entity should lead to improved outcomes of patients with these disorders.

Targeted Therapies in the Treatment of Colorectal Cancers

BACKGROUND In solid organ malignancies, no tumor type has seen a greater impact from the development of novel targeted therapies in 2004 than metastatic colorectal cancer. METHODS We review the current progress to date with the use of monoclonal antibodies in colorectal cancer and look at newer therapies under investigation. RESULTS Two monoclonal antibodies received Food and Drug Administration approval in early 2004, both for the indication of advanced, metastatic colorectal cancer. A large, randomized, placebo-controlled study demonstrated that the addition of a monoclonal antibody to vascular endothelial growth factor, bevacizumab, led to a statistically significant improvement in overall survival, with tolerable additional toxicity. Chimeric monoclonal antibody therapy directed at the epidermal growth factor receptor was associated with radiographic responses in a significant minority of patients with irinotecan-refractory colon cancer in a randomized phase II study of patients with irinotecan-refractory disease. CONCLUSIONS These dramatic successes have led to further clinical studies of targeted therapy in colorectal cancer, making it one of the most promising areas of cancer research.

Bortezomib salvage followed by a Phase I/II study of bortezomib plus high-dose melphalan and tandem autologous transplantation for patients with primary resistant myeloma

We conducted a Phase 1/2 study of bortezomib administered in combination with high‐dose melphalan followed by tandem autologous transplants in patients with primary resistant multiple myeloma. Thirty patients received two cycles of salvage bortezomib followed by stem cell mobilization with granulocyte colony‐stimulating factor and harvest. Melphalan 100 mg/m2 per day on two consecutive days was administered, immediately followed by one dose of bortezomib (dose escalation) and stem cell infusion. The median beta 2‐microglobulin was 4·35 mg/l (range: 1·8–11·4); albumin was 37 g/l (range: 3·1–4·9); high‐risk karyotypes were noted in 45% of patients. The maximum planned dose of bortezomib at 1·3 mg/m2 was well tolerated and a formal maximum tolerated dose was not determined. The peak of best overall response (≥partial response) and complete response rates after tandem transplants were 84% and 36%, respectively. With a median follow‐up of 48 months, the median progression‐free survival was 15 [95% confidence interval (CI): 11–21] months and the median overall survival was 35 (95% CI: 22–43) months. Correlative studies demonstrated decreased expression of BRCA2 (P = 0·0072) and FANCF (P = 0·0458) mRNA following bortezomib treatment. Bortezomib combined with high‐dose melphalan is a well‐tolerated conditioning with some activity in patients with resistant myeloma.

Management of hot flashes in men with prostate cancer being treated with androgen deprivation therapy.

The use of androgen deprivation therapy (ADT) to treat prostate cancer has favorably impacted outcomes for men with prostate cancer. Androgen deprivation therapy is effective in reducing painful bony metastases and soft tissue visceral disease in advanced-stage prostate cancer. The use of ADT has expanded beyond the metastatic setting and can also be used as adjuvant therapy for patients with locally advanced prostate cancer who received surgery or localized radiation therapy. Luteinizing hormone-releasing hormone agonists are the most common medical therapy used to deprive men of androgen production. Despite the beneficial effects that ADT has on prostate cancer, ADT causes side effects that can impair quality of life. This article will review the impact and treatment of hot flashes in men treated for prostate cancer.