Lack of c-kit (CD117) expression in CD30+ lymphomas and lymphomatoid papulosis.

c-Kit receptor (CD117) is expressed by erythroid, megakaryocytic, and myeloid precursors and mature mast cells and has been reported to be expressed in CD30+ lymphomas such as Hodgkin's disease and anaplastic large-cell lymphoma. Imatinib mesylate, a well-established inhibitor of bcr-abl tyrosine kinase, and currently used for the treatment of patients with chronic myeloid leukemia, also inhibits c-kit receptor kinase activity. In view of the possible use of imatinib as experimental therapy for patients with c-kit-positive tumors, we assessed c-kit expression in CD30+ cell lines and lymphomas. The cell lines were assessed using multiple methods (RT-PCR, flow cytometry, and Western blot). c-Kit expression was also immunohistochemically assessed in 168 CD30+ lymphomas including 87 classical Hodgkin's disease, 63 anaplastic large-cell lymphoma, and 15 cutaneous anaplastic large-cell lymphoma. We also studied 18 cases of lymphomatoid papulosis, a CD30+ lesion closely related to cutaneous anaplastic large-cell lymphoma. Neither c-kit mRNA nor protein was detected in any of the cell lines assessed. Furthermore, treatment with imatinib did not inhibit proliferation of cell lines in vitro. Using immunohistochemistry, only one of 183 (0.5%) lesions was positive for c-kit, the positive case being an ALK-negative anaplastic large-cell lymphoma. Our data demonstrate that expression of c-kit receptor is exceedingly rare among CD30+ lymphomas and lymphomatoid papulosis, suggesting that c-kit receptor is unlikely to be an appropriate target for therapeutic options such as imatinib in patients with these tumors.     

Positron emission tomography in breast cancer: a clinicopathological correlation of results

We conducted a retrospective study to evaluate the sensitivity, specificity and accuracy of positron emission tomography (PET) scans in 109 patients with primary recurrent or metastatic breast cancer. All patients had a PET scan, X-ray or CT scan of the chest, an ultrasound or CT scan of the liver and a bone scan. Mammography was available for 86 patients. Correlation between the PET scan result and histological findings were made. The sensitivity, specificity and accuracy of the PET scan were calculated for both the primary tumour (T) and lymph nodes (N). In patients with metastasis (M) the accuracy of the PET scan was compared with other imaging modalities. Histological results of the site in question were available in only 105 patients. Information for the primary tumour was available for 93 patients and for nodes in 74. The PET scan was accurate in 89.2% for (T), with 3.2% false positive and 7.6% false negative. For (N) the PET scan was accurate in 90.5% with 9.5% false negative. In the 86 patients who underwent both mammography and PET scanning, the PET scan was more accurate in 89.5% versus 72% (p = 0.0003). In the 19 patients with metastasis, the PET scan was in agreement with other imaging modalities in 100% of cases. PET scanning is the only non-invasive imaging procedure that will detect tumours in the breast, lymph nodes, lung, liver, bone and bone marrow with high sensitivity, specificity and accuracy. It is a valuable tool in the management of patients in all stages of breast cancer for diagnosis, staging and following treatment response.     

Phase II study of denileukin diftitox for relapsed/refractory B-Cell non-Hodgkin's lymphoma.

PURPOSE: Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL. PATIENTS AND METHODS: Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 microg/kg once daily for 5 days every 3 weeks, up to eight cycles. RESULTS: Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25- histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient. CONCLUSION: Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25- B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.     

Induction of cell cycle arrest and apoptosis by the proteasome inhibitor PS-341 in Hodgkin disease cell lines is independent of inhibitor of nuclear factor-kappaB mutations or activation of the CD30, CD40, and RANK receptors.

PURPOSE: The malignant Hodgkin and Reed-Sternberg cells of Hodgkin disease (HD) are known to constitutively express high levels of activated nuclear factor kappaB (NF-kappaB), which plays an important role in their survival. The proteasome inhibitor PS-341 has been recently shown to modulate tumor cell proliferation and survival by inhibiting NF-kappaB and modulating critical cellular regulatory proteins, but its activity in cells carrying IkappaBalpha gene mutations has not been reported previously. Experimental Design: The activity of PS-341 in four well-characterized, HD-derived cell lines. Cell proliferation and apoptosis were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium (MTS) and Annexin-V binding methods, respectively. Cell cycle analysis was determined by flow cytometry. Intracellular protein levels were determined by Western blot. RESULTS: PS-341 demonstrated a strong antiproliferative activity, which was irrespective of the status of mutations in IkappaBalpha and even the presence of CD30, CD40, or RANK receptor activation. This effect was attributable to the induction of apoptosis and cell cycle arrest at the G(2)-M phase. PS-341 not only inhibited nuclear localization of NF-kappaB but also activated the caspase cascade, increased p21 and Bax levels, and decreased Bcl-2 levels. Furthermore, PS-341 enhanced the effect of gemcitabine chemotherapy and potentiated the effect of tumor necrosis factor-related apoptosis-inducing ligand/APO2L and two agonistic antibodies to tumor necrosis factor-related apoptosis-inducing ligand death receptors R1 and R2. CONCLUSIONS: The in vitro activity of PS-341 against HD-derived cell lines suggests that PS-341 may have a therapeutic value for the treatment of HD.     

Emerging applications of the tumor necrosis factor family of ligands and receptors in cancer therapy.

Abnormalities of the tumor necrosis factor (TNF) family members have been linked to several human diseases, including cancer. Novel treatment strategies for cancer are emerging based on an understanding of the function of TNF family members. The advantage of these strategies is their potential to selectively target cancer cells, while sparing normal cells. Combining these new strategies with currently available treatments such as chemotherapy and radiation therapy is under investigation, with promising results. However, because some TNF family members are toxic to normal mammalian cells when administered systemically, only a few TNF family members have potential therapeutic value. This concise review focuses on the clinical implications of four TNF family members for cancer treatment: CD30/CD30 ligand, CD40/CD40 ligand, receptor activator of nuclear factor-kappaB (RANK)/RANK ligand, and TNF-related apoptosis-inducing ligand (TRAIL) Apo-2L/TRAIL receptors.