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The naturally occurring compound 3[beta],16[beta],17[alpha]-trihydroxycholest-5-en-22-one 16-O-(2-O-4-methoxybenzoyl-[beta]-D-xylopyranosyi)-(1[right arrow]3)-(2-O-acetyl-[alpha]-L-arabinopyranoside) (OSW-1) is found in the bulbs of Ornithogalum saudersiae and is highly cytotoxic against tumor cell lines. Using various human cancer and nonmalignant cell lines, we investigated the anticancer activity and selectivity of OSW-1 and its underlying mechanisms of action. OSW-1 exhibited extremely potent cytotoxic activity against cancer cells in vitro. Nonmalignant cells were statistically significantly less sensitive to OSW-1 than cancer cells, with concentrations that cause a 50% loss of cell viability 40-150-fold greater than those observed in malignant cells. Electron microscopy and biochemical analyses revealed that OSW-I damaged the mitochondrial membrane and cristae in both human leukemia and pancreatic cancer cells, leading to the loss of transmembrane potential, increase of cytosolic calcium, and activation of calcium-dependent apoptosis. Clones of leukemia cells with mitochondrial DNA defects and respiration deficiency that had adapted the ability to survive in culture without mitochondrial respiration also were resistant to OSW-1. In vitro analysis revealed that OSW-1 effectively killed primary leukemia cells from chronic lymphocytic leukemia patients with disease refractory to fludarabine. The promising anticancer activity of OSW-1 and its unique mechanism of action make this compound worthy of further investigation for its potential to overcome drug resistance. [J Natl Cancer Inst 2005;97:1781-5]

Stripped-down, compact cars--Renaults and Peugeots, primarily--move and swerve, race and cut in, clogging the streets, endangering passersby. Even intersections are legitimate parking places: Cars squeeze catty-corner against the curb. Pedestrians [...]

Background: Fludarabine, a purine analogue with activity in chronic lymphocytic leukemia, is usually well tolerated. Although serious infections after fludarabine therapy have been described, a systematic analysis of the risk factors for such infections in chronic lymphocytic leukemia is lacking. Objective: To determine the risk factors for major infection in patients with chronic lymphocytic leukemia treated with fludarabine. Design: Retrospective review of medical records. Setting: Cancer center. Patients: 402 patients with chronic lymphocytic leukemia not previously treated or treated with chlorambucil (with or without prednisone) who received fludarabine (30 mg/ [m.sup.2] of body surface area per day for 5 days) with or without prednisone at 4-week intervals. Results: Infections occurred more often in previously treated (144 of 248 [58%]) than in previously untreated (53 of 154 [34%]) patients (P [is less than] 0.001). Listeriosis or pneumocystosis occurred in 12 of 170 (7%) previously treated patients receiving fludarabine plus prednisone, 0 of 78 previously treated patients receiving fludarabine alone, and 2 of 154 (1%) previously untreated patients receiving fludarabine plus prednisone (P = 0.003). Univariate analysis identified previous chemotherapy, advanced disease, failure to respond to fludarabine, elevated serum [[Beta].sub.2]-microglobulin level (P [is less than] 0.001), low serum albumin level (P = 0.024), elevated serum creatinine concentration (P = 0.008), and low granulocyte count (P = 0.003) as risk factors for infection. Multivariate analysis identified Rai stage III or IV (odds ratio, 1.98 [95% CI, 1.17 to 3.94]), previous treatment (odds ratio, 2.24 [CI, 1.43 to 3.51]), and elevated serum creatinine concentration (odds ratio, 1.98 ICI, 1.09 to 3.67]) as statistically significant independent risk factors for major infection. A baseline granulocyte count of more than 1000 cells/[micro]L was protective (odds ratio, 0.54 [CI, 0.29 to 0.99]). Five (26%) of 19 patients with a CD4 count less than 50 cells/mL developed cutaneous zoster compared with 9 (6%) of 139 patients with a CD4 count greater than 50 cells/mL (P = 0.01). Conclusions: Fludarabine used in previously treated patients with chronic lymphocytic leukemia may be associated with infections involving T-cell dysfunction, such as listeriosis, pneumocystosis, mycobacterial infections, and opportunistic fungal and viral infections. Prophylaxis or presumptive therapy should be initiated in the appropriate setting., Patients with chronic lymphocytic leukemia who take fludarabine may have an increased risk of developing infection, especially if they have had other chemotherapy. In a study of 402 patients with this type of leukemia who were taking fludarabine, 58% of those who had other chemotherapy developed infections compared to 34% of those who had never had chemotherapy. Risk factors for infection included previous chemotherapy, severe disease, failure to respond to fludarabine and a poorly functioning immune system.

Background. The efficacy of granulocyte colony-stimulating factor (G-CSF) in reducing neutropenia and its associated complications in adults with acute lymphocytic leukemia (ALL) undergoing intensive chemotherapy in first remission was evaluated. Methods. Fourteen adult patients with ALL in first remission received intensive chemotherapy consisting of mitoxantrone 5 mg/[m.sup.2] intravenously (IV) over 1 hour daily for 3 days, cytosine arabinoside (ara-C) 3 g/[m.sup.2] IV over 2 hours every 12 hours X 4 on days 1 and 2, vincristine 2 mg IV on day 1, solumedrol 50 mg IV twice daily for 5 days, and G-CSF 4 [mu]g/kg subcutaneously daily starting on day 4 until granulocyte recovery. Their outcome was compared with that of 14 consecutive patients who received the same intensification chemotherapy, but without G-CSF. The latter patients had been entered on the same ALL protocol from April 1990 through June 1991. Results. G-CSF administration was associated with a significant shortening in the duration of neutropenia. The number of days to granulocyte recovery above 0.5 X [10.sup.3]/[mu]l was 14 in th G-CSF group versus 18 days in the historical group (P < 0.001). Two episodes of documented infections were observed in the G-CSF group compared with four episodes in the historical group. Death during intensification therapy occurred in 2 of 14 patients in the historical group, but in none of the 14 patients receiving G-CSF. Conclusions. G-CSF as an adjunct to intensive chemotherapy in adults with ALL in first remission yielded positive results. Future studies incorporating growth factors supportive care during remission, induction, and consolidation may reduce treatment-related morbidity and mortality, increase the dose-intensity delivery of therapy, and potentially improve patient outcome.

PURPOSE: To assess the response rate, remission duration, and survival of patients with Waldenstrom's macroglobulinemia treated with the adenine nucleoside analogue fludarabine. PATIENTS AND METHODS: Twenty-eight patients with Waldenstrom's macroglobulinemia, of whom only 2 were previously untreated, received fludarabine at a dose of 20 to 30 mg/[m.sup.2] intravenously daily for 5 days (20 patients) or 30 mg/ml intravenously daily for 3 days (8 patients). Treatment was continued until maximum response was achieved. Responding patients were followed with no further treatment until relapse. RESULTS: Ten patients responded (36%), including the 2 previously untreated patients and 8 of 26 patients (31%) who were resistant to prior therapies. Unmaintained remissions lasted for a median of 38 months. There were no fatalities associated with this treatment. Previously untreated patients and those with a primary resistant disease of relatively short duration were more likely to benefit from this treatment. CONCLUSION. Fludarabine is an effective salvage agent for the treatment of patients with resistant Waldenstrom's macroglobulinemia. Further investigations of fludarabine in untreated patients and in combination with other active agents are warranted

* Objective:To evaluate the activity of 2-chlorodeoxyadenosine (2CdA) in the treatment of patients with Waldenstrom macroglobulinemia. * Design: Uncontrolled phase II trial. * Setting: Tertiary, referral cancer center. * Patients: Twenty-nine consecutive, symptomatic patients with Waldenstrom macroglobulinemia, of whom 9 were previously untreated. * Intervention:2-Chlorodeoxyadenosine was administered as a continuous intravenous infusion at a dose of 0.1 mg/kg body weight per day for 7 days. Only two courses of 2CdA were given and responding patients were then followed without further treatment. * Measurements and Main Results: A total of 17 (59%) patients responded, including all of those who were newly diagnosed and 40% of those who had failed previous therapies. Treatment was well tolerated except for one death in a patient who had presented with severe pancytopenia. With a median follow-up of 7 months, only one responding patient has relapsed. * Conclusion: 2-Chlorodeoxyadenosine is a nucleoside analog that was effective in most patients with Waldenstrom macroglobulinemia and was associated with little toxicity., Treating patients with Waldenstrom macroglobulinemia with 2-chlorodeoxyadenosine (2CdA) may reduce tumor size and relieve symptoms of the disease. Waldenstrom macroglobulinemia is a lymphatic malignancy that primarily affects the elderly and is characterized by weakness, fatigue and bleeding disorders. Of 29 patients with Waldenstrom macroglobulinemia, 17 (59%) experienced significant tumor reduction and marked relief of symptoms. All previously untreated patients went into remission after 2CdA therapy, and three of four patients who had relapsed while off of another form of treatment went into remission. Overall, 40% of the patients who had not responded to previous treatment responded to 2CdA. After an average of seven months of follow-up, only one patient who had responded to 2CdA relapsed. Side effects associated with 2CdA therapy were minimal.

PURPOSE: Elevated serum beta-2 microglobuli([beta]2M) levels are associated with poor prognosis in several lymphoproliferative disorders including multiple myeloma and lymphoma. Their prognostic relevance in acute lymphocytic leukemia (ALL) is unknown. We analyzed the associations of serum [beta]2M levels at diagnosis with pretreatment characteristics and with prognosis in adult ALL. PATIENTS AND METHODS: One hundred fifty-nine adults with newly diagnosed ALL. were investigated. Serum [beta]2M levels were determined at diagnosis, on fresh peripheral blood samples, using a radioimmunoassay, the Pharmacia [beta]2 Micro RIA (Pharmacia Diagnostics, Uppsala, Sweden). Statistical correlations were assessed by standard methods, and further independent prognostic value of serum [beta]2M was determined by multivariate analysis. RESULTS: Patients with [beta]2M levels of 4.0 mg/L or above had a lower complete response rate (61% versus 80%; p: 0.02), a significantly worse survival (p (0.01), and a significantly higher association with development of central nervous system (CNS) leukemia (p (0.01). High [beta]2M levels were more common among patients with older age, with elevated Creatinine, bilirubin, and alkaline phosphatase levels, with low albumin levels, and with B-cell disease. Multivariate analysis for survival indicated the [beta]2M level to be an independent prognostic variable (after adjusting for pretreatment creatinine level and age). The evaluation of [beta]2M levels within low-and high-risk groups for CNS disease suggested an association of elevated [beta]2M levels with a worse incidence of CNS disease in the high-risk patients. CONCLUSION: Monitoring serum [beta]2M levels may provide significant prognostic information in adults with A T ,L and should be included in their pretreatment evaluation. Its importance in childhood ALL requires investigation.

* Background.--Neutropenic patients with cancer are traditionally treated with empiric antibiotic combinations when they become febrile. The availability of broad-spectrum antibiotics such as ceftazidime and imipenem has made it possible to initiate therapy with a single agent (monotherapy). The objectives of this trial were to compare ceftazidime and imipenem as single agents for the therapy of febrile episodes in neutropenic patients and to ascertain whether the addition of an aminoglycoside (amikacin) to either or these agents would provide an advantage. Methods.--A prospective clinical trial was conducted in which eligible neutropenic patients with cancer were randomized to one of four treatment arms: ceftazidime alone; imipenem alone; ceftazidime plus amikacin; and imipenem plus amikacin. Efficacy analysis was done for 750 assessable episodes. A multivariate logistic-regression analysis was also performed to examine the unique contribution of various prognostic factors. Results.--The overall response rates were 76% with imipenem plus amikacin, 72% with imipenem, 71% with ceftazidime plus amikacin, and 59% with ceftazidime alone. Single-organism gram-positive infections occurred in 101 of 750 episodes. Without a change in antibiotics, the response rates were 50% with imipenem, 40% with imipenem plus amikacin, 39% with ceftazidime plus amikacin, and 38% with ceftazidime. Most responded to vancomycin or other antibiotics, and the mortality associated with gram-positive infections was only 5%. Regardless of the antibiotic regimen, the majority of uncomplicated gram-negative infections responded to therapy and the majority of complicated gram-negative infections failed to respond. Multivariate logistic-regression analysis showed that recovery of the neutrophil count was the most favorable prognostic factor in a patient's response to infection, whereas the presence of gram-positive infection, acute leukemia, pulmonary or enteric infection, and therapy with ceftazidime were unfavorable factors. Conclusions.--Single-agent therapy with imipenem is as effective as more conventional combination antibiotic therapy for the empirical treatment of febrile episodes in neutropenic patients with cancer. (Arch Intern Med. 1992;152:283-291)

PURPOSE: To describe the results of fludarabine therapy in patients with prolymphocytic leukemia (PLL) and the prolymphocytoid variant of chronic lymphocytic leukemia (CLL-Pro). PATIENTS AND METHODS: Seventeen patients with a diagnosis of PLL or CLL-Pro received fludarabine 30 mg/m[sup. 2] over 30 minutes daily for 5 days every 4 weeks alone (12 patients), or with prednisone (five patients). Previously defined criteria for response were used. Differences in response rates according to various characteristics were evaluated by chi-square test. RESULTS: Three patients (18%) achieved complete remission, and three (18%) had a partial remission, for an overall response rate of 35%. Responses were durable and occurred in all involved organ sites. Lower response rates were observed in patients with anemia, thrombocytopenia, advanced Rai stages, and primary resistance to prior therapy. Toxicities were minimal except for febrile episodes associated with therapy. CONCLUSION: Fludarabine has shown encouraging results in these patients and deserves further investigation in combination with other active agents, and in the setting of front-line therapy., Prolymphocytic leukemia (PLL) is a type of cancer of the blood cells that is associated with proliferation of prolymphocytes, a type of white blood cell, in the blood and bone marrow; involvement of the spleen; less frequent accumulation of cancer cells in the lymph nodes and liver; and a poor outcome. An intermediate form of PLL is chronic lymphocytic leukemia (CLL-Pro), in which there is a lower percentage of prolymphocytes as compared with that in PLL. Patients with more than 30 percent prolymphocytes had a higher death rate than patients with fewer prolymphocytes. The anticancer agents chlorambucil, cyclophosphamide, and fludarabine monophosphate, and steroids have been used to treat patients with CLL. The effectiveness of fludarabine in treating 17 patients with PLL and CLL-Pro was assessed. Remission was complete in three patients and partial in three other patients, producing an overall response rate of 35 percent. The response to treatment was enduring and evident in all affected tissues. Patients with anemia (decreased numbers of red blood cells), thrombocytopenia (abnormal decrease in blood platelets, involved in clotting), advanced cancer, and initial resistance to prior therapy were less responsive to treatment with fludarabine. Side effects of fludarabine were few and included the development of fever. These results show that fludarabine may be beneficial in treating patients with PLL and CLL-Pro, and should be tested in additional studies. (Consumer Summary produced by Reliance Medical Information, Inc.)

PURPOSE: The prognostic importance of pretreatment bone marrow cytogenetic studies in adults with acute lymphocytic leukemia treated at a single institution, with an identical treatment program, is described. PATIENTS AND METHODS: A total of 105 patients with a documented morphologic diagnosis of acute lymphocytic leukemia were reviewed for the purpose of this analysis. All patients had an extensive workup at presentation, and cytogenetic analysis was performed in 103 patients, using the Giemsa banding technique with trypsin pretreatment on 24-hour cultured cells. RESULTS: The specific cytogenetic classification in the 103 patients who had the karyotypic analysis was as follows: diploid 27%; Philadelphia chromosome-positive 13%; hyperdiploid 12%; B-cell karyotype 6%; 6q- and 14q+ abnormalities 4%; pseudodiploid 8%; hypodiploid 2%; and insufficient metaphases 28%. B-cell, 6q- or 14q+, and Philadelphia chromosome-positive karyotypes tended to correlate with other known negative prognostic factors. Patients with diploid, hyperdiploid, pseudodiploid, and hypodiploid karyotypes or with insufficient metaphases could be combined into one group with a favorable prognosis. In this group, the remission rate with induction chemotherapy was 89%, the median complete remission duration was 26 months, and the median survival was 25 months, with a 3-year survival rate of 45%. Patients with Philadelphia chromosome-positive, B-cell, and 6q- or 14q+ abnormalities collectively had an unfavorable prognosis. Their response rate to induction chemotherapy was 65%, the median response duration was 7 months, and the median survival was 8 months, with a 3-year survival rate of less than 10%. CONCLUSION: We conclude that the pretreatment bone marrow karyotype is an important part of the evaluation of adults with acute lymphocytic leukemia and provides significant prognostic information., Cytogenetic studies involve the analysis of a karyotype, a photographic representation of a single cell at a stage in cell division that shows the chromosomes in descending order by size. Chromosomes are structures within the cell nucleus that carry genetic information. Cytogenetic studies have been used to examine disease variation and to determine the prognosis of several types of cancer. One study showed that specific abnormalities in the karyotype were associated with rates of remission and prognosis in patients with adult acute lymphocytic leukemia (ALL), a type of blood cancer. In this study, the usefulness of cytogenetic studies in determining the prognosis of 103 patients with ALL was assessed. Patients were classified into cytogenetic groups based on analysis of their karyotype. Certain classifications were associated with a poor prognosis, including diploid, hyperdiploid, pseudodiploid, and hypodiploid karyotypes; whereas classifications of Philadelphia chromosome-positive, B-cell, and 6q- or 14q+ abnormalities were associated with a less favorable outcome. Patients with a good prognosis had an average remission rate of 89 percent after chemotherapy; an average remission of 26 months; an average survival of 25 months; and an overall survival rate of 45 percent at three years. Patients with a poor prognosis had a response rate to chemotherapy of 65 percent; an average duration of response of seven months; an average survival of eight months; and an overall survival rate of less than 10 percent at three years. These findings suggest that analysis of bone marrow cell karyotype helps to evaluate and predict the outcome of patients with adult ALL. (Consumer Summary produced by Reliance Medical Information, Inc.)

The treatment of relapsed cancer patients poses a problem for the clinician; conservative treatment is likely to fail, and aggressive treatment brings with it more severe side effects. This is the case in acute and chronic leukemia, for which intermediate- and high-dose cytosine arabinoside have become popular in recent years. In an evaluation of the use of high-dose cytosine arabinoside in the treatment of relapsed acute leukemia or chronic myeloid leukemia, 103 patients were treated. They received three grams per square meter of body area over a two-hour period every 6 to 12 hours for 6 to 12 doses, or two 2-hour infusions followed by a continuous infusion of 1.5 grams per square meter per day for three or four days. Thirteen patients developed adult respiratory distress syndrome. This syndrome includes the development of pulmonary edema (fluid accumulation) without a recognized cause. Only four of the patients recovered; the condition was fatal for nine. Pathological examination revealed exudate without any signs of inflammation, and pathological signs seen in other tissues, such as the intestines, hinted at a problem involving capillary leakage in these patients. The data suggest that the pulmonary edema in these patients may be the result of capillary leakage stemming from the high dose of cytosine arabinoside. While previous studies have reported sporadic incidents of pulmonary failure associated with aggressive cytosine arabinoside treatment, only one noted an incidence similar to that seen in this study. The reason for the discrepancy is uncertain, but may involve the schedule on which the drug is administered. Since the pathogenesis of pulmonary failure among these patients is unclear, the high rate of mortality demands awareness of the problem and the investigation of possible pathogenic mechanisms. (Consumer Summary produced by Reliance Medical Information, Inc.)

Although great advances in the treatment of acute lymphocytic leukemia (ALL) have been made over the past two decades, its prognosis still depends strongly on several host and tumor attributes. Characteristics like patient age, degree of leukocytosis, and chromosome abnormalities of the tumor cells all influence the relative chances for long-term remission, which range from 40 to 50 percent in patients at average risk and less than 20 percent for patients with greater risk factors. Refractory ALL, which doesn't respond to conventional treatment, has been treated with high doses of cytosine arabinoside (ara-C), and response rates of between 20 and 60 percent have been reported. Likewise, mitoxantrone has been used in these patients and similar response rates have been found. Since the toxic effects of ara-C and mitoxantrone do not overlap, there is little reason not to try both drugs simultaneously, and there may, in fact, be some beneficial antileukemic effects as a result of combining them. To examine this combination of drugs, 25 patients with a diagnosis of refractory ALL were treated with 5mg per square meter (of body surface) mitoxantrone over one hour daily for five days, and 3mg ara-C over two hours every twelve hours for six doses. For purposes of this study, complete remission was defined on the basis of bone marrow examination. A percentage of blast cells, immature, undifferentiated cells, under 5 percent was regarded as complete remission (CR). Complete remission was observed in 9 of 25 patients (36 percent). Eight patients had disease which was resistant to this treatment, and another eight died during the treatment, primarily of complications induced by chemotherapy. The overall median survival time for the 25 patients was 10 weeks, while among the patients achieving remission, the median survival period was 16 weeks. Although the improvement in survival seems promising, the deaths due to the suppression of the bone marrow were higher than seen with some other treatments, suggesting that some sort of additional support for immune function be provided patients treated with mitoxantrone and high-dose cytosine arabinoside. (Consumer Summary produced by Reliance Medical Information, Inc.)