David S. Eilender

Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

PURPOSE To define, in a phase I study in relapsed non-Hodgkins lymphoma (NHL) and chronic lymphocytic leukemia (CLL), the maximum-tolerated dose (MTD), major toxicities, and possible antitumor activity of bryostatin 1, a macrocyclic lactone. PATIENTS AND METHODS Bryostatin 1 was delivered by 72-hour continuous infusion every 2 weeks to patients with relapsed NHL or CLL, at doses that ranged from 12 microg/m2 to 180 microg/m2 per course. Correlative investigations included evaluations of total protein kinase C (PKC) in peripheral blood and lymphoid differentiation in patient tumor tissue. RESULTS Twenty-nine patients were treated, including three patients with CLL and 26 with NHL. Generalized myalgia was the dose-limiting toxicity (DLT) and occurred in two of three patients treated with bryostatin 1 at 180 microg/m2 per course. Myalgias were dose-related and cumulative, and often started in the thighs and calves, improved with activity, were somewhat responsive to analgesics, and often took weeks to resolve once taken off study. Six patients were treated at the MTD of 120 microg/m2 per course. Myalgia, headache, and fatigue were common. Hematologic toxicity was uncommon. Total cumulative doses of bryostatin 1 up to 1,134 microg/m2 have been administered without untoward toxicity. Eleven patients achieved stable disease for 2 to 19 months. An in vitro assay for total PKC evaluation in patient peripheral-blood samples demonstrated activation within the first 2 hours with subsequent downregulation by 24 hours, which was maintained throughout the duration of the 72-hour infusion. CONCLUSION This phase I study defined the MTD and recommended phase II dose of bryostatin 1, when administered over 72 hours every 2 weeks, to be 120 microg/m2 (40 microg/m2/d for 3 days). Generalized myalgia was the DLT. Future studies will define the precise activity of bryostatin 1 in subsets of patients with lymphoproliferative malignancies and its efficacy in combination with other agents.

Blastic natural killer cell lymphoma/leukemia: A report of seven cases

Only a few blastic natural killer (NK) cell leukemias and lymphomas have been reported. As such, the clinicopathologic spectrum of this disease is incompletely understood. We report 7 cases of blastic NK cell lymphoma/leukemia. All patients were men, 5 white and 2 Arab American. All cases exhibited blastic morphologic features and were CD3- and CD56+ with germline T-cell receptor genes. Five cases were CD4+ and involved the skin. Both CD4- cases never involved the skin. Other markers of mature NK cells such as CD16, CD57, and TIA-1 were expressed infrequently. Three cases were CD33+. One CD33+ case had a clonal rearrangement of the immunoglobulin heavy chain gene. Skin and lymph nodes were involved most often, with frequent evolution to a leukemic phase. Initial responses to therapy were achieved in most patients, but the tumors invariably recurred.

CD56+/CD4+ Lymphomas and Leukemias Are Morphologically, Immunophenotypically, Cytogenetically, and Clinically Diverse

CD56, a neural adhesion molecule, is a marker of natural killer (NK) lymphocytes as well as a subgroup of CD8+ T cells. Normal lymphocytes with a CD56/CD4 phenotype are scarce. Physiologic increases may occur in patients with immunosuppression, chronic inflammation, and autoimmune disorders. We report 4 cases of lymphomas/leukemias with the unusual CD56/CD4 phenotype. Two were of T-cell and 2 of true NK-cell origin. The T-cell lymphomas had large granular lymphocyte morphologic features and splenomegaly. One patients had a benign course; the other died within months of the leukemia diagnosis. The 2 NK cell lymphomas had blastic morphologic features, initially involved skin, and had a very aggressive clinical course; 1 patient died of acute leukemia, and 1 had recurrence after bone marrow transplantation. Cytogenetic analyses did not show a consistent pattern of abnormalities. The NK lymphoma with acute leukemia had a t(2;5) but was CD30- and anaplastic lymphoma kinase negative. Although CD56+/CD4+ lymphomas/leukemias are a heterogeneous group, there may be a distinct subgroup of NK lymphoblastoid lymphomas of the skin, judging from our cases, as well as those previously reported.

Blastic Natural Killer Cell Lymphoma/Leukemia

Only a few blastic natural killer (NK) cell leukemias and lymphomas have been reported. As such, the clinicopathologic spectrum of this disease is incompletely understood. We report 7 cases of blastic NK cell lymphoma/leukemia. All patients were men, 5 white and 2 Arab American. All cases exhibited blastic morphologic features and were CD3- and CD56+ with germline T-cell receptor genes. Five cases were CD4+ and involved the skin. Both CD4- cases never involved the skin. Other markers of mature NK cells such as CD16, CD57, and TIA-1 were expressed infrequently. Three cases were CD33+. One CD33+ case had a clonal rearrangement of the immunoglobulin heavy chain gene. Skin and lymph nodes were involved most often, with frequent evolution to a leukemic phase. Initial responses to therapy were achieved in most patients, but the tumors invariably recurred.

Blastic Natural Killer Cell Lymphoma/LeukemiaA Report of Seven Cases

Only a few blastic natural killer (NK) cell leukemias and lymphomas have been reported. As such, the clinicopathologic spectrum of this disease is incompletely understood. We report 7 cases of blastic NK cell lymphoma/leukemia. All patients were men, 5 white and 2 Arab American. All cases exhibited blastic morphologic features and were CD3- and CD56+ with germline T-cell receptor genes. Five cases were CD4+ and involved the skin. Both CD4- cases never involved the skin. Other markers of mature NK cells such as CD16, CD57, and TIA-1 were expressed infrequently. Three cases were CD33+. One CD33+ case had a clonal rearrangement of the immunoglobulin heavy chain gene. Skin and lymph nodes were involved most often, with frequent evolution to a leukemic phase. Initial responses to therapy were achieved in most patients, but the tumors invariably recurred.

Behavior of breast cancer in young women: A Surveillance Epidemiology and End Results (SEER) database review.

6 Background: Advanced age is a major risk factor for breast cancer in women. Small sized studies have reported variable outcome of breast cancer in young women. Our study was done to evaluate tumor characteristic and cancer specific survival among young women. METHODS The 1973-2009 SEER database was reviewed for women with breast cancer diagnosed between 2004 and 2009. Patients were grouped by age into: A (≤35 years), B (36-50 years) and C (>50 years). Age, ethnicity, staging, lymph nodes status, micrometastasis in negative lymph nodes, tumor size, tumor grade, hormone receptor status were extracted. Data and survival were analyzed using chi square, Kaplan-Meier, Life table, and Cox proportional hazard model. The primary outcome was 5-year cancer-specific survival. RESULTS A total of 248,280 patients were included in the study, group A, B and C making 2.8%, 25.5% and 71.7% of study subjects respectively. The median tumor size was 2.4, 1.9, and 1.6 cm in groups A, B and C respectively (p=0.0001). Positive lymph nodes were seen in 52.5%, 43% and 34% in groups A, B and C respectively (p=0.0001). Regional disease was seen in 47.5%, 39.5% and 29.9% in groups A, B and C respectively (p=0.0001). Higher Grade histology was seen in 63.5%, 44.3% and 33.8% in groups A, B and C respectively (p=0.0001). ER-PR negative were found in 42.1%,26.4%, 22.6% of Groups A, B and C respectively (p=0.0001). Five year cancer specific survival was 82%, 89%, 86% in groups A, B and C respectively (p=0.0001). Independent prognostic factors are given in the table. CONCLUSIONS Breast cancer is uncommon among young women (age <35). Compared to other age groups, breast cancer in young women presents with bigger tumor, higher nodal positivity, an advanced stage, higher tumor grade, higher hormone receptor negativity, and worse 5-year cancer-specific survival. [Table: see text].

Does lobular carcinoma in situ (LCIS) affect biology of future breast cancer? Surveillance Epidemiology and End Results (SEER) database review.

37 Background: Lobular carcinoma in situ (LCIS) is a recognized risk factor of breast cancer. Data evaluating the behavior of breast cancer arising after LCIS is lacking. Our study compared the characteristics of breast cancer arising after LCIS with the breast cancer arising de novo. METHODS From the 1973-2009 SEER database, women with breast cancer who were diagnosed and treated between 1990 and 2009 were abstracted. Patients were divided to group A: breast cancer after LCIS, group B: de novo breast cancer. Age, ethnicity, staging, tumor size, grade and hormone receptor status were reviewed. Data were analyzed using chi square, Kaplan-Meier, Life table, and Cox proportional hazard model. RESULTS Patients with LCIS were 7,258 with 547 (7.5%) developing breast cancer subsequently. The mean (SD) time to develop breast cancer after LCIS was 68 (2.14) months. Of the total 557,309 patients with breast cancer, group A had 547 patients and group B had 556,762 patients. The median tumor size was 1.3 and 1.8 cm in groups A and B respectively (p<0.0001). Grade 1 and 2 tumors were 78.5% and 60.8% in groups A and B respectively (p<0.0001). Local disease alone was seen in 70% and 61% of groups A and B respectively (p<0.0001). ER-PR negative tumor was seen in 14.9% and 24.5 % in groups A and B (p<0.0001). On univariate analysis, 5 year cancer specific survival was 91% and 85% in groups A and B respectively (p< 0.0001). Unlike grade, hormone receptor status and stage, prior history of LCIS was not an independent predictor of survival on multivariate analysis (see Table). CONCLUSIONS Breast cancer diagnosed after prior LCIS has favorable features like smaller tumor, lower grade, earlier stage and less ER-PR negativity. Some of these might be a result of more diligent subsequent screening. A history of LCIS per se is not an independent prognostic factor in breast cancer. [Table: see text].