Gene Expression and Serum Cytokine Profiling of Low Stage CLL Identify WNT/PCP, Flt-3L/Flt-3 and CXCL9/CXCR3 as Regulators of Cell Proliferation, Survival and Migration.

Gene expression profiling (GEP) of 8 stage 0/I untreated Chronic Lymphocytic Leukemia (CLL) patients showed over-expression of Frizzled 3 (FZD3)/ROR-1 receptor tyrosine kinase (RTK), FLT-3 RTK and CXCR3 G-protein coupled receptor (GPCR). RT-PCR of 24 genes in 21 patients of the WNT pathway corroborated the GEP. Transforming growth factorß, fibromodulin, TGFßRIII and SMAD2 are also over-expressed by GEP. Serum cytokine profiling of 26 low stage patients showed elevation of IFNγ, CSF3, Flt-3L and insulin-like growth factor binding protein 4. In order to ascertain why CLL cells grow poorly in culture, a GEP of 4 CLL patients cells at 0 hr and 24 hr in culture demonstrated over expression of CXCL5, CCL2 and CXCL3, that may recruit immune cells for survival. Treatment with thalidomide, an immunomodulatory agent, showed elevation of CCL5 by GEP but was not cytotoxic to CLL cells. Our data suggest an interplay of several oncogenic pathways, cytokines and immune cells that promote a survival program in CLL.

Utility of fine-needle aspiration as a diagnostic technique in lymphoma.

PURPOSE: To evaluate, from a clinician's perspective, the sensitivity and specificity of fine-needle aspiration (FNA) as a technique for the diagnosis of lymphoma. PATIENTS AND METHODS: Medical records of 470 new patients seen in one lymphoma specialist's clinic from January 1998 through December 2002 were reviewed. Ninety-nine (21%) of the 470 patients underwent a total of 115 FNA procedures, which were assessed by more than 70 different pathologists in 32 different pathology departments. Subsequent excisional biopsies were performed in 67 of these patients and interpreted by a single hematopathology group without independent review. RESULTS: Of 115 FNA procedures, 93 were completed for the initial evaluation of lymphoma and 22 were done for assessment of relapsed disease. Of the 93 FNA attempts at initial diagnosis, only 27 (29%) were given a specific and complete histologic diagnosis using an accepted classification system (Working Formulation, Revised European-American Classification of Lymphoid Neoplasms, WHO). For the 22 FNAs done for recurrent disease, only nine (41%) were classified using an accepted system. Sixty-seven (72%) of the 93 FNAs performed for the evaluation of initial disease had subsequent excisional biopsies. Among these paired comparisons, only eight (12%) of 67 FNA diagnoses were correlated with the subsequent excisional biopsy diagnosis. Immunophenotyping was completed on 24 of the 67 paired FNAs. Seven of the 24 FNAs with immunophenotyping (29%) were correlated with subsequent histology on excisional biopsy. Only one (2%) of 43 FNA diagnoses, based on morphology alone, was correlated with subsequent excisional biopsy diagnosis. CONCLUSION: Overall, FNA for lymphoma diagnosis is not helpful, not cost effective, and in addition may misguide treatment.

What is the treatment of choice for advanced-stage Hodgkin's lymphoma: ABVD, Stanford V, or BEACOPP?

The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is the most commonly used chemotherapy regimen in North America for the treatment of advanced-stage Hodgkin's lymphoma. Although 60% to 70% of patients with stages III and IV Hodgkin's lymphoma may be cured with ABVD, many patients relapse or progress despite standard therapy. Two new regimens, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and Stanford V (vinblastine, doxorubicin, vincristine, bleomycin, mustard, etoposide, and prednisone), have shown short-term (3-5 years) overall survival results of 90% or better. Although the results of pilot studies using these regimens and one randomized trial with BEACOPP look promising, the toxicities are substantial. To evaluate overall benefit, two large intergroup trials are underway comparing ABVD versus BEACOPP (European Organization for Research and Treatment of Cancer 20012) and ABVD versus Stanford V (E2496) in advanced Hodgkin's lymphoma.

Mood alterations in patients treated with chlorambucil.

The alkylating agent chlorambucil produces dose-limiting myelosuppression but can also cause rare central nervous system toxicities, including seizures, when given in high doses. Patients with lymphoma who were receiving intermittent pulsed oral doses of 10-12 mg/m2 chlorambucil per day for 5 days experienced marked mood alterations during therapy. These effects, which have not been reported previously, involved sleep alterations, anxiety and restlessness, irritability, and depression. All effects remitted immediately after the final day of the dosing regimen. Mood alterations should be added to the known list of chlorambucil-related toxicities and can occur with commonly used oral dosing schedules.