Andre M. Kallab

Mifepristone induces growth arrest, caspase activation, and apoptosis of estrogen receptor-expressing, antiestrogen-resistant breast cancer cells

Purpose: A major clinical problem in the treatment of breast cancer is the inherent and acquired resistance to antiestrogen therapy. In this study, we sought to determine whether antiprogestin treatment, used as a monotherapy or in combination with antiestrogen therapy, induced growth arrest and active cell death in antiestrogen-resistant breast cancer cells. Experimental Design: MCF-7 sublines were established from independent clonal isolations performed in the absence of drug selection and tested for their response to the antiestrogens 4-hydroxytamoxifen (4-OHT) and ICI 182,780 (fulvestrant), and the antiprogestin mifepristone (MIF). The cytostatic (growth arrest) effects of the hormones were assessed with proliferation assays, cell counting, flow cytometry, and a determination of the phosphorylation status of the retinoblastoma protein. The cytotoxic (apoptotic) effects were analyzed by assessing increases in caspase activity and cleavage of poly(ADP-ribose) polymerase. Results: All of the clonally derived MCF-7 sublines expressed estrogen receptor and progesterone receptor but showed a wide range of antiestrogen sensitivity, including resistance to physiological levels of 4-OHT. Importantly, all of the clones were sensitive to the antiprogestin MIF, whether used as a monotherapy or in combination with 4-OHT. MIF induced retinoblastoma activation, G1 arrest, and apoptosis preceded by caspase activation. Conclusions: We demonstrate that: (a) estrogen receptor+progesterone receptor+, 4-OHT-resistant clonal variants can be isolated from an MCF-7 cell line in the absence of antiestrogen selection; and (b) MIF and MIF plus 4-OHT combination therapy induces growth arrest and active cell death of the antiestrogen-resistant breast cancer cells. These preclinical findings show potential for a combined hormonal regimen of an antiestrogen and an antiprogestin to combat the emergence of antiestrogen-resistant breast cancer cells and, ultimately, improve the therapeutic index of antiestrogen therapy.

Autoimmune thrombocytopenia following autologous hematopoietic cell transplantation: review of literature and treatment options

Autoimmune thrombocytopenia after high-dose chemotherapy and autologous bone marrow/peripheral blood stem cell transplantation occurs infrequently and only six cases meeting the criteria have been reported in the literature. All six of these patients had either acute myelogenous leukemia (AML) or lymphoblastic lymphoma (LBL). Immune thrombocytopenia following autologous transplantation in solid tumors has not been reported. We report the first case of autoimmune thrombocytopenia after high-dose chemotherapy and peripheral blood stem cell transplantation in a patient with breast cancer. A review of the literature has been conducted and treatment options are discussed. In two patients the condition resolved with treatment and in a third patient it improved. Immune-mediated thrombocytopenia in the post-transplant period is one of the causes of a low platelet count. It should be recognized promptly and treated. Bone Marrow Transplantation (2000) 26, 925–927.

Leukemic Leptomeningeal Involvement in Stage 0 and Stage 1 Chronic Lymphocytic Leukemia

Central nervous system (CNS) involvement in early (Rai Stage 0 and Stage 1) chronic lymphocytic leukemia (CLL) is rare, with only five cases reported. We present the sixth reported case, a 77-year-old male with a 4 year history of Stage 0 CLL who presented with sudden onset of diplopia and headache. Workup revealed a leukemic involvement of his CNS and he responded well to treatment with intrathecal (IT) methotrexate. After his third IT treatment, he developed a change in his mental status, consistent with a chemotherapy induced encephalopathy, which was effectively treated with IT hydrocortisone. In addition to the case presentation, we review the previously reported cases in an effort to determine any characteristics common among the Stage 0/1 CLL patients with reported CNS involvement.

Tumor lysis syndrome in small cell lung cancer.

Tumor lysis syndrome, resulting from the abrupt release of intracellular ions into the blood stream due to sudden tumor cell death, is a serious complication of chemotherapy treatment. This syndrome occurs more frequently in hematologic malignancies and lymphomas. Its incidence in solid tumors is rare, but has a high mortality rate owing to the lack of prophylactic therapy to prevent this complication. We report a case of tumor lysis syndrome accompanied by death in a patient with extensive stage small cell lung cancer who was treated with cisplatin and etoposide, and review the risk factors associated with the syndrome in solid tumor patients who are likely to respond to chemotherapy.

Infectious complications in patients receiving mobilization chemotherapy for autologous peripheral blood stem cell collection

The purpose of this retrospective study was to evaluate infectious complications in patients receiving mobilization chemotherapy for stem cell collection prior to autologous peripheral blood stem cell transplantation. An additional goal was to evaluate risk factors associated with the development of infectious complications. At the Medical College of Georgia BMT center, 54 patients were administered mobilization chemotherapy for the purpose of collecting stem cells between June, 1997, and May, 2002. All patients received Filgrastim in addition to chemotherapy, and 50 of 54 patients received prophylactic acyclovir, fluconazole, and ciprofloxacin until neutrophil recovery. The median duration to neutrophil recovery was 11 days. Fourteen of 54 (26%) patients developed fever/infections during the mobilization phase. One patient developed both a catheter-related infection and Clostridium difficile colitis, increasing the total number of infectious episodes to 15. Twelve patients had a documented site of infection whereas 2 patients had neutropenic fever with no identifiable source. Eight of the 15 (55%) infections were Gram-positive catheter infections. All the patients were treated successfully with antibiotics. No systemic fungal infections were identified and none of the patients died from complications related to mobilization chemotherapy. Logistic regression was applied for univariate and multivariate analysis and showed that age, sex, diagnosis, neutrophil recovery, disease status, use of salvage chemotherapy, and mobilization regimen used did not affect the infection rate. In our series of 54 patients, 14 patients developed fever/infections during mobilization. Although there is a substantial risk of infectious complications among patients who receive mobilization chemotherapy, it is not clear that prophylactic antibiotics decrease infectious complications. Because the vast majority of infections are Gram-positive catheter infections, it appears reasonable to employ Gram-positive prophylaxis. Controlled studies should be conducted to define the optimum mobilization regimens as well as the optimum combination of prophylactic antibiotics.

Rheumatoid Arthritis and Immune Thrombocytopenia: A Report of Two Cases

Abstract:

Non-Hodgkin's Lymphoma Presenting as Anasarca: Probably Mediated by Tumor Necrosis Factor Alpha (TNF-α)

Two patients presented with anasarca, fevers and sweats. Subsequent evaluation revealed aggressive lymphoproliferative disease. Both patients were treated with CHOP chemotherapy. One patient responded with spontaneous, vigorous diuresis and complete resolution of the edema. She relapsed two months later with recurrent edema that responded a second time to salvage chemotherapy. The second patient died of gram positive sepsis a week after diagnosis. As anasarca is an unusual presenting symptom of non-Hodgkins lymphoma, we postulated that the malignant cells were secreting a cytokine that resulted in “vascular leakage” of fluid and development of diffuse edema. Several serum cytokine levels were tested. Both patients had elevated TNF-α levels, which could have been the cause of the edema; or there might be yet another unidentified mediator that was responsible for the anasarca. We report these two cases to bring to attention the unusual nature of this presentation.

A phase II study of weekly paclitaxel and carboplatin in previously untreated patients with advanced non-small-cell lung cancer

AbstractPurpose: Both paclitaxel (P) and carboplatin (C) have a significant activity in non-small cell lung cancer (NSCLC). Weekly administration of P is active, is dose intense, and has a favorable toxicity profile. To evaluate the efficacy and toxicity of weekly P and C in advanced-stage NSCLC, we initiated this phase II study in patients with advanced NSCLC (III B with pleural effusion and stage IV). Patients and Methods: Eligible patients were treated with paclitaxel 100 mg/m2 intravenously (iv) over 1 h followed by carboplatin AUC 2 iv over 30 min. This treatment was administered weekly for 3 of every 4 wk until disease progression or intolerable toxicities. Results: Of the 30 patients enrolled in the study, one patient did not meet the eligibility criteria. Of the remaining 29 patients, 6 did not complete at least two cycles of treatment and hence were not assessable for response. The overall response rate was 43.5% (10/23) (all partial responses). An additional 43.5% had stable disease. The median time to progression was 162 d and the median duration of response was 169 d. Overall survival at 1 yr on intent-to-treat analyses was 44% and median survival was 10.8 mo. We observed the following grade 3/4 toxicities: hypersensitivity to paclitaxel (13%), hypersensitivity to carboplatin (3%), neutropenia (31%), thrombocytopenia (7%); 31% experienced grade 1 neuropathy and 17% experienced grade 2 neuropathy. Conclusions: We conclude that weekly paclitaxel and carboplatin is active and very well tolerated in patients with advanced NSCLC.

Adult T-cell leukemia/lymphoma: a rare case in the USA and review of the literature.

Adult T-cell leukemia/lymphoma (ATLL), in its acute stage, is a uniformly fatal disease. ATLL is caused by the human T-cell lymphotropic virus I (HTLV-1), a retrovirus endemic in numerous areas throughout the world including Japan, the Caribbean, Central and South America and certain areas of the United States. Although the progression from HTLV-1 carrier status to ATLL occurs only rarely, ATLL is incurable and thus prevention of HTLV-1 transmission should be a primary goal. With the development of new anti-retroviral and monoclonal therapies, there exist potential cures or at least prolonged remissions for patients diagnosed with ATLL. We present a case of ATLL that, to our knowledge, is only the third reported case in Georgia. In addition, we present a brief review of the literature, including potential new treatment regimens that appear to have promise in the treatment of ATLL.

Ototoxicity after high-dose chemotherapy with cyclophosphamide, thiotepa and carboplatin followed by stem cell transplantation in patients with breast cancer.

Our purpose was to determine the risk of ototoxicity in breast cancer patients receiving a myeloablative regimen consisting of cyclophosphamide 6000 mg/m2, thiotepa 500mg/m2 and carboplatin 800mg/m2 (CTCb) followed by stem cell transplantation.Fourteen consecutive patients with breast cancer were treated with high dose chemotherapy consisting of the CTCb regimen followed by stem cell transplantation. A pretransplant complete hearing study was obtained which consisted of hearing case history, audiometry and tympanometry. In addition, DPOAE (Distortion Product Otoaccoustic Emissions) was done to evaluate measurable changes in the cochlear (outer hair cell) functioning.Pre-transplant, all patients had no clinical evidence of hearing impairment and hearing studies were normal. Eleven patients had hearing studies and a telephone interview posttransplant. One patient was lost to follow-up and two patients died. One of the 11 patients tested had an abnormal post-transplant hearing study but none of them had clinically detectable hearing impairment.In our prospective study of breast cancer patients treated with the CTCb regimen, we did not observe clinically detectable hearing impairment in any of the patients tested.