Microcirculation in hypertensive patients.

Regardless of the mechanisms that initiate the increase in blood pressure, functional and structural changes in the systemic vasculature are the final result of long-standing hypertension. These changes can occur in the macro- but also in the microvasculature. The supply of the tissues with oxygen, nutrients, and metabolites occurs almost exclusively in the microcirculation (which comprises resistance arterioles, capillaries and venules), and an adequate perfusion via the microcirculatory network is essential for the integrity of tissue and organ function. This review focuses on results from clinical studies in hypertensive patients, which have been performed in close cooperation with different clinical groups over the last three decades. Intravital microscopy was used to study skin microcirculation, microcatheters for the analysis of skeletal muscle microcirculation, the slit lamp for conjunctival microcirculation and the laser scanning ophthalmoscope for the measurement of the retinal capillary network. The first changes of the normal microcirculation can be found in about 93% of patients with essential hypertension, long before organ dysfunctions become clinically manifest. The earliest disorders were found in skin capillaries and thereafter in the retina and the skeletal muscle. In general, the disorders in the different areas were clearly correlated. While capillary rarefaction occurred mainly in the retina and the conjunctiva bulbi, in skin capillaries morphological changes were rare. A significant decrease of capillary erythrocyte velocities under resting conditions together with a marked damping of the postischemic hyperemia was found, both correlating with the duration of hypertension or WHO stage or the fundus hypertonicus stage. Also the mean oxygen tension in the skeletal muscle was correlated with the state of the disease. These data show that the microcirculatory disorders in hypertension are systemic and are hallmarks of the long-term complications of hypertension. There is now a large body of evidence that microvascular changes occur very early and may be important in their pathogenesis and progression.

Randomized double-blind phase II trial comparing gemcitabine plus LY293111 versus gemcitabine plus placebo in advanced adenocarcinoma of the pancreas.

BACKGROUND: LY293111 (LY) is a novel oral anticancer agent with leukotriene B4 receptor antagonist and peroxisome proliferator-activated receptor gamma agonist properties, producing promising results alone and in combination with gemcitabine in pancreatic cancer xenograft models. A phase I study proved that the combination (gemcitabine plus LY) is safe and well tolerated. PATIENTS AND METHODS: Chemotherapy-naive patients with histologically confirmed locally advanced or metastatic adenocarcinoma of the pancreas were randomly assigned to gemcitabine 1000 mg/m on days 1, 8, and 15 of a 28-day cycle and continuously administered LY 600 mg twice daily or gemcitabine 1000 mg/m on days 1, 8, and 15 of a 28-day cycle and daily oral placebo. Arms were balanced for Eastern Cooperative Oncology Group performance status and disease stage. The primary end point was 6-month survival; secondary objectives include response rate (RR), progression-free survival, and overall survival. RESULTS: Six-month survival was not different between groups (P>0.2, 1-sided); progression-free survival and RR were not different (P>0.05, 2-sided). RR was also not impacted. LY did not increase grades 3-4 hematologic toxicities, but was associated with a trend toward more, grades 3-4 diarrhea. CONCLUSIONS: These results do not demonstrate any benefit to adding LY to gemcitabine in unpretreated patients with advanced pancreatic carcinoma.

Enhancing drug discovery through in silico screening: strategies to increase true positives retrieval rates.

Computational chemistry software for lead discovery has become well established in pharmaceutical industry and has found its way to the desktop computers of medicinal chemists for different purposes, providing insight on the mode of action and binding properties, and creating new ideas for lead structure refinement. In this review we investigate the performance and reliability of recent state-of-the-art data modeling techniques, as well as ligand-based and structure-based modeling approaches for 3D virtual screening. We discuss and summarize recently published success stories and lately developed techniques. Parallel screening is one of these emerging approaches allowing for efficient activity in silico profiling of several compounds against different targets or anti-targets simultaneously. This is of special interest to medicinal chemists, as the approach allows revealing unknown binding modes ('target-fishing') as well as integrated ADME profiling or--more generally--the prediction of off-target effects.

Delphi-panel analysis of appropriateness of high-dose chemotherapy and blood cell or bone marrow autotransplants in women with breast cancer.

BACKGROUND: There is controversy whether high-dose chemotherapy and a blood cell or bone marrow autotransplant is a better treatment than conventional-dose chemotherapy for women with local/regional or metastatic breast cancer. Subject selection and time-to-treatment biases make definitive comparison impossible. Recent results of randomized trials are contradictory. OBJECTIVE: Determine appropriateness of high-dose chemotherapy and a blood cell or bone marrow autotransplant in women with breast cancer. PANELISTS: Nine breast cancer experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of 'breast cancer' and 'chemotherapy' and/or 'blood cell' or 'bone marrow transplants'. PROCESS: We used a modified Delphi-panel group judgement process. Clinical variables were permuted to define 2058 clinical settings. Each panelist rated appropriateness of high-dose therapy and an autotransplant versus conventional therapy on a 9-point ordinal scale (1: most inappropriate, 9: most appropriate). An appropriateness index was developed based on median rating and amount of disagreement. The relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. CONCLUSIONS: In women with local/regional breast cancer autotransplants were rated: 1) appropriate in those with > or = 10 cancer-involved lymph nodes; 2) uncertain in those with 4-9 cancer-involved nodes; and 3) inappropriate in women with < or = 3 cancer-involved lymph nodes. In women with metastatic breast cancer autotransplants were rated: 1) appropriate in those with metastases to 'favorable' sites (skin, lymph node, pleura) and a complete or partial response to chemotherapy; 2) uncertain in women with metastases to 'unfavorable' sites (lung, liver, or central nervous system) and a complete response to chemotherapy or those with bone metastases and a complete or partial response or stable disease after chemotherapy; and 3) inappropriate in other settings.

Factors correlated with progression-free survival after high-dose chemotherapy and hematopoietic stem cell transplantation for metastatic breast cancer.

CONTEXT: Women with breast cancer are the most frequent recipients of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (autotransplants) in North America. Despite widespread use, controversy exists about the benefits of and appropriate patients for this therapy. OBJECTIVE: To determine factors associated with disease progression or death after autotransplantation in women with metastatic breast cancer. DESIGN: Analysis of data collected retrospectively (January 1989 to 1992) and prospectively (1992 through January 1995) for the Autologous Blood and Marrow Transplant Registry. SETTING: Sixty-three hospitals in North America, Brazil, and Russia. PARTICIPANTS: A total of 1188 consecutive women aged 18 to 70 years receiving autotransplants for metastatic or locally recurrent breast cancer, with a median follow-up of 291/2 months. MAIN OUTCOME MEASURE: Time to treatment failure (disease progression, disease recurrence, or death) after autotransplantation. RESULTS: Factors associated with significantly (P<.05) increased risk of treatment failure in a Cox multivariate analysis included age older than 45 years (relative hazard, 1.17; 95% confidence interval [CI], 1.02-1.33), Karnofsky performance score less than 90% (1.27; 95% CI, 1.07-1.51), absence of hormone receptors (1.31; 95% CI, 1.15-1.51), prior use of adjuvant chemotherapy (1.31; 95% CI, 1.10-1.56), initial disease-free survival interval after adjuvant treatment of no more than 18 months (1.99; 95% CI, 1.62-2.43), metastases in the liver (1.47; 95% CI, 1.20-1.80) or central nervous system (1.56; 95% CI, 0.99-2.46 [approaches significance]) vs soft tissue, bone, or lung, 3 or more sites of metastatic disease (1.32; 95% CI, 1.13-1.54), and incomplete response vs complete response to standard-dose chemotherapy (1.65; 95% CI, 1.36-1.99). Receiving tamoxifen posttransplantation was associated with a reduced risk of treatment failure in women with hormone receptor-positive tumors (relative hazard, 0.60; 95% CI, 0.47-0.87). Women with no risk factors (n = 38) had a 3-year probability of progression-free survival of 43% (95% CI, 27%-61 %) vs 4% (95% CI, 2%-8%) for women with more than 3 risk factors (n = 343). CONCLUSION: These data indicate that some women are unlikely to benefit from autotransplantation and should receive this treatment only after being provided with prognostic information and in the context of clinical trials attempting to improve outcome.

Hydroxyethylstarch sedimentation by gravity ex vivo for red cell reduction of granulocyte apheresis components.

BACKGROUND: When selecting only leukocyte compatible donors, the requirement of ABO compatibility limits the investigation and application of granulocyte transfusion therapy by reducing the pool of potential donors. Ex vivo hetastarch (HES) sedimentation was evaluated as a method of red blood cell (RBC) reduction of granulocyte components. The objective was to determine if this procedure consistently resulted in reduction of component packed RBC (PRBC) volume to < 5 ml, the range acceptable for infusion of ABO incompatible blood components based on guidelines set forth by the American Association of Blood Banks (AABB). STUDY DESIGN AND METHODS: HLA-matched, ABO-compatible sibling marrow donors were selected to donate granulocyte components, which were transfused into the allogeneic bone marrow transplant (BMT) recipient as prophylaxis against infection. Three granulocyte components were collected from each of 5 donors receiving G-CSF (daily x 5). Leukapheresis (LA) began 1 day after the first G-CSF dose (Day 1), and was repeated on Days 3 and 5. LA were performed using a continuous-flow blood cell separator, with 7L blood processed during each procedure. RBC sedimentation was facilitated by administration of a 6% HES solution to the donor line. The 5 granulocyte components collected on Day 1 were not manipulated after collection. The 10 components collected on Days 3 and 5 were manipulated by ex vivo gravity sedimentation for 60 minutes followed by transfer of the buffy coat (red cell poor [RCP] fraction) to a transfer bag with residual RBCs retained in the collection bag (red cell rich [RCR] fraction). The PRBC volume and cellular composition of the components and fractions were determined. RESULTS: When data for the 10 manipulated components were combined, the fraction of the components with < 5 ml PRBC was 0.4 in the RCP and 0.1 in the RCR fractions. All unmanipulated components contained > 5 ml PRBC. The mean PRBC volume (ml) of the RCP and RCR fractions were 6.3 and 16.4, respectively (P = .06). The mean number of RBC (x10(11)) in the RCP and the RCR fractions were .41 and 1.73, respectively (P = .03). The average proportion of cells in the manipulated components lost to the RCR fraction was 19.2% of granulocytes and 18.6% of platelets. CONCLUSION: Ex vivo HES sedimentation, as performed, significantly reduced the number of RBCs from granulocyte components, but did not consistently result in PRBC volumes in the RCP fraction within the range acceptable for infusion of ABO incompatible blood components based on the AABB guidelines. Moreover, significant numbers of granulocytes were lost to the RCR fraction.

Autologous CD34-selected blood progenitor cell transplants for patients with advanced multiple myeloma.

Fifty-five patients with advanced multiple myeloma received purified CD34-selected peripheral blood progenitor cell transplants following myeloablative chemotherapy. A median of 4.1 x 10(6) CD34 cells/kg (range 1.2-30.7) were infused after busulfan (14 mg/kg) and cyclophosphamide (120 mg/kg); granulocyte-macrophage colony-stimulating factor was used until hematopoietic recovery. Median time to neutrophils >0.5 x 10(9)/l and platelets >20 x 10(9)/l were 12 days (range 10-16 and 8-184 days, respectively). Median follow-up of survivors from the time of transplantation is 33 months (range 7 to 44 months). Thirty-one patients are alive, 19 progression-free. Median progression-free survival is 14 months. Actuarial 3-year progression-free and overall survival are 29+/-14% and 47+/-17%. CD34-selection of peripheral blood progenitor cells provides effective hematopoietic support with significant progression-free and overall survival.

A phase II study of repetitive cycles of dose-intense carboplatin plus paclitaxel chemotherapy and peripheral blood stem cells in metastatic breast cancer.

To assess the feasibility of administering sequential cycles of dose-intensive therapy, 14 patients without prior chemotherapy for metastatic breast cancer were registered to be treated with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) at an initial dose of 250 mg/m2 over 24 hours (day 1), followed by carboplatin dosed to an area under the concentration-time curve of 16 (calculated according to the Calvert formula), every 3 weeks for four cycles. This combination was supported with peripheral blood stem cells collected following granulocyte colony-stimulating factor with or without cyclophosphamide and paclitaxel. One patient failed to peripheralize CD34 cells after cyclophosphamide/paclitaxel therapy and was taken off protocol. The remaining 13 patients entered the paclitaxel/carboplatin phase of the program, and nine completed all four cycles. The median duration of severe neutropenia (absolute neutrophil count < 100/microL) was 6 days, despite the absence of routine use of granulocyte colony-stimulating factor. Only five of a total of 42 chemotherapy cycles (12%) were associated with febrile neutropenia requiring hospitalization. Most patients did not require platelet transfusions. The most significant nonhematologic toxicity was gastrointestinal (grade 3 in three patients, two of whom had received local radiation for relapse before chemotherapy). Most patients developed grade 1 or 2 sensory neuropathy by the final cycle. Of the nine patients who entered the paclitaxel/carboplatin phase and were evaluable for response, five achieved a complete remission. This doublet of high-dose therapy can be given in an entirely ambulatory setting and is associated with modest hematologic toxicity. The value of this option in the treatment of metastatic breast cancer compared with more conventional approaches to high-dose therapy will require a greater number of patients evaluable for response and longer follow-up.

Transfusions of granulocyte-colony-stimulating factor-mobilized granulocyte components to allogeneic transplant recipients: analysis of kinetics and factors determining posttransfusion neutrophil and platelet counts.

BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) is a safe and effective agent for mobilization of neutrophils in normal donors, consistently resulting in cell yields per leukapheresis (LA) procedure that are superior to those with other agents. LA components also contain platelets, whose clinical relevance is unknown. STUDY DESIGN AND METHODS: This study describes the kinetics of and analyzes the factors determining the ANC and platelet count increments seen with each of three transfusions of granulocytes collected from HLA-matched sibling donors receiving G-CSF (n = 10; maximum of 3 LA procedures/donor). The transfusions were given to recipients (n = 10) on alternate days beginning. Day 1 after allogeneic bone marrow transplant (BMT). RESULTS: Significant, sustained increments in the recipient ANCs were observed after the transfusion of G-CSF-mobilized LA components. The mean peak posttransfusion increments in the ANCs were 1195, 729, and 631 per microL with transfusion of donor LA components on Days 1, 3, and 5, respectively. The length of time that the mean posttransfusion ANC was at or above the baseline (pretransfusion) value was 25 to 37 hours, depending on the post-BMT day when the component was administered. No consistent relationship was observed between LA component granulocyte dose, baseline recipient ANC, or temperature elevation and post-transfusion ANC increments. Large numbers of platelets (mean, 2.55 x 10(11)) were present in LA components, and this resulted in significant increments from baseline in the mean platelet count 1 hour after LA component transfusions. Between Days 1 and 7, the duration of severe neutropenia was shorter and the percentage of patients requiring nondonor platelet transfusions was less in study patients who received LA component transfusions than in a similar historical control group who did not. CONCLUSION: The transfusion of G-CSF-mobilized, HLA-matched LA components to allogeneic BMT recipients resulted in significant and sustained increments in the ANC and the platelet count. Within the range examined, a relationship between neutrophil dose and an increment in the ANC was not demonstrated.

High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America.

PURPOSE: To identify trends in high-dose therapy with autologous hematopoietic stem-cell support (autotransplants) for breast cancer (1989 to 1995). PATIENTS AND METHODS: Analysis of patients who received autotransplants and were reported to the Autologous Blood and Marrow Transplant Registry. Between January 1, 1989 and June 30, 1995, 19,291 autotransplants were reviewed; 5,886 were for breast cancer. Main outcomes were progression-free survival (PFS) and survival. RESULTS: Between 1989 and 1995, autotransplants for breast cancer increased sixfold. After 1992, breast cancer was the most common indication for autotransplant. Significant trends included increasing use for locally advanced rather than metastatic disease (P < .00001) and use of blood-derived rather than marrow-derived stem cells (P < .00001). One-hundred-day mortality decreased from 22% to 5% (P < .0001). Three-year PFS probabilities were 65% (95% confidence intervals [Cls], 59 to 71) for stage 2 disease, and 60% (95% Cl, 53 to 67) for stage 3 disease. In metastatic breast cancer, 3-year probabilities of PFS were 7% (95% Cl, 4 to 10) for women with no response to conventional dose chemotherapy; 13% (95% Cl, 9 to 17) for those with partial response; and 32% (95% Cl, 27 to 37) for those with complete response. Eleven percent of women with stage 2/3 disease and less than 1% of those with stage 4 disease participated in national cooperative group randomized trials. CONCLUSION: Autotransplants increasingly are used to treat breast cancer. One-hundred-day mortality has decreased substantially. Three-year survival is better in women with earlier stage disease and in those who respond to pretransplant chemotherapy.

Indium-labeled white blood cells apheresed from donors receiving G-CSF localize to sites of inflammation when infused into allogeneic bone marrow transplant recipients.

G-CSF administration to normal donors results in granulocyte apheresis yields generally greater than those observed with other neutrophil mobilizing agents. In vitro, neutrophils cultured with G-CSF exhibit prolonged survival; however, the random migration of neutrophils exposed to this agent is inhibited. Although transfused neutrophils mobilized with agents other than G-CSF migrate to sites of inflammation or infection in vivo, this has yet to be demonstrated with infusion of G-CSF-mobilized neutrophils into neutropenic human subjects. Five neutropenic allogeneic bone marrow transplant (BMT) patients each received a fresh infusion of G-CSF-mobilized indium-labeled irradiated white blood cells (WBC) apheresed from HLA-matched normal donors on day +5 post-transplant. Localization of activity on delayed scintigraphic images of indium-labeled WBC scans to sites of tissue damage (oral/nasopharynx in two patients with mucositis and terminal ileum/cecum in one with diarrhea) occurred, and supports the hypothesis that G-CSF-mobilized HLA-matched donor neutrophils which have been irradiated are functional after infusion into neutropenic recipients.

Randomized comparison of G-CSF + GM-CSF vs G-CSF alone for mobilization of peripheral blood stem cells: effects on hematopoietic recovery after high-dose chemotherapy.

Fifty patients with either lymphoid or selected solid tumor malignancies were apheresed an identical number of times for PBSC collection after being randomized to receive either G-CSF 10 microg/kg/day alone (arm I), or G-CSF at the same dose with GM-CSF 5 microg/kg/day (arm II). Growth factor(s) was/were given as the stem cell mobilizing agent for 5 days before the start of PBSC collection, and were continued throughout the 4 days of apheresis. Aspiration and cryopreservation of autologous bone marrow occurred on day 3 or 4 of growth factor(s). Thirty-one of 50 patients received one cycle only at time of evaluation, and 19 patients received two cycles of HDCT, each supported with PBSC with or without autologous bone marrow. No patients received growth factors post-autologous stem cell transplant, unless the absolute neutrophils count (ANC) failed to recover to > or = 100/microl by day +18 post-transplant. The median number of days to recovery of ANC to 100/microl, 500/microl and 1000/microl, and of platelet counts to 20000/microl, 50000/microl and 100000/microl after either cycle 1 or cycle 2 of HDCT and the number of febrile days and platelet and PRBC transfusion requirements was not significantly different between the two arms of the study. The duration of hospitalization was similar between study arms for cycle 1 of HDCT, but was 3.5 days less with arm II compared to arm I (P = 0.0248) for cycle 2 of HDCT. The bone marrow buffy coat and PBSC product mononuclear cell count (x 10(8)/kg) and CD34+ cell count (x 10(6)/kg) collected by each method of stem cell mobilization was not significantly different. There is questionable clinical benefit with PBSC products mobilized with the combination of G-CSF and GM-CSF vs G-CSF alone. Perhaps different dosages, schedules, or other growth factor combinations with G-CSF might enhance these differences.

Antifungal effects of yeast-derived rhu-GM-CSF in patients receiving high-dose chemotherapy given with or without autologous stem cell transplantation: a retrospective analysis.

Systemic fungal infections (SFI) in patients receiving high-dose chemotherapy (HDC) are a frequent cause of morbidity and mortality. Preclinical studies have reported augmented antifungal activity of monocytes, macrophage cells, and neutrophils exposed to certain colony-stimulating factors (CSF), including GM-CSF. We conducted a retrospective descriptive epidemiologic study to examine the characteristics of 145 consecutive patients receiving HDC administered with or without autologous stem cell transplantation (ASCT) and who subsequently received either GM-CSF and G-CSF, G-CSF alone, GM-CSF +/- IL-3 or no CSF. The analysis of this patient population sought to define the incidence of SFI and its relationship to therapy with monocyte/macrophage-stimulating (MMS group) cytokines (GM-CSF and G-CSF; GM-CSF +/- IL-3) or to cytokines which do not result in monocyte/macrophage stimulation (NMMS group, G-CSF alone or no CSF). Risk factors for the development of SFI were balanced between the MMS (n = 70) and NMMS (n = 75) groups. Two patients (2.9%) in the MMS and nine patients (12%) in the NMMS groups developed SFI. The risk ratio for developing SFI in the NMMS group compared to the MMS group was 4.20 (P = 0.023). This relationship was confounded, however, by the diagnosis of hematologic tumor or solid tumor (RR = 3.15, P = 0.082). SFI was the primary cause or major contributing factor in five of the 10 total deaths in our study population. Four SFI-related deaths occurred in the NMMS group and one SFI-related death occurred in the MMS group. Our data suggest a protective role for GM-CSF, IL-3 or other MMS cytokines in preventing SFI in patients receiving HDC. This should be further investigated as a potential complementary approach to conventional strategies in antifungal prophylaxis for patients receiving HDC.

Transplantation of CD34+ peripheral blood progenitor cells after high-dose chemotherapy for patients with advanced multiple myeloma.

A major potential problem of autologous transplantation in the treatment of advanced malignancy is the infusion of tumor cells. A multi-institutional study of purified CD34-selected peripheral blood progenitor cell (PBPC) transplantation was conducted in 37 patients with advanced multiple myeloma receiving myeloablative chemotherapy. Fourteen days after intermediate-dose cyclophosphamide, prednisone, and granulocyte colony-stimulating factor (G-CSF), a median of 3 (range, 2 to 5) 10-L leukaphereses yielded 9.8 x 10(8)/kg (range, 3.7 to 28.3) mononuclear cells. The adsorbed (column-bound) fraction contained 5.9 x 10(6) cells/kg (range, 1.6 to 25.5) with 4.65 x 10(6) CD34 cells/kg (range, 1.2 to 23.3). Using Poisson distribution analysis of positive polymerase chain reactions with patient-specific complementarity-determining region 1 (CDR1) and CDR3 Ig-gene primers, tumor was detected in leukapheresis products from 8 to 14 unselected patients and ranged from 1.13 x 10(4) to 2.14 x 10(6) malignant cells/kg. After CD34 selection, residual tumor was detected in only three patients' products. Overall, a greater than 2.7- to 4.5-log reduction in contaminating multiple myeloma cells was achieved. CD34 PBPCs were infused 1 day after busulfan (14 mg/kg) and cyclophosphamide (120 mg/kg), and granulocyte-macrophage colony-stimulating factor was used until hematologic recovery. The median time to both neutrophil and platelet recovery was 12 days (range, 11 to 16 days and 9 to 52 days, respectively). The median number of erythrocyte and platelet transfusions was 7 (range, 2 to 37) and 3 (range, 0 to 85), respectively. Patients receiving fewer than 2 x 10(6) CD34 cells/kg had significantly prolonged neutropenia, thrombocytopenia, and an increased red blood cell and platelet transfusion requirement. Thus, CD34 selection of PBPCs markedly reduces tumor contamination in multiple myeloma and provides effective hematopoietic support for patients receiving myeloablative therapy.

Allogeneic bone marrow transplantation for leukemia following piperazinedione and fractionated total body irradiation.

Between 1980 and 1988, 126 patients with leukemia were treated with piperazinedione and fractionated total body irradiation (TBI) followed by allogeneic bone marrow transplantation from HLA matched siblings. Sixty-one patients had acute myelogenous leukemia, 46 acute lymphoblastic leukemia, and 19 chronic myelogenous leukemia. Patients with acute leukemia in first complete remission were transplanted only if perceived to have a low probability of remaining in remission with conventional therapy. The toxicity from the preparative regimen was similar to that of cyclophosphamide and TBI except that none of the patients in the study had hemorrhagic cystitis or veno-occlusive disease. After a median follow up of 114 months, 29 patients (23%) are still alive without relapse. The survival of patients with acute myelogenous or lymphoblastic leukemia transplanted in their first remission were 35% and 43%, respectively. The survival of patients transplanted in their first chronic phase of chronic myelogenous leukemia was 60%. The results of this preparative regimen are comparable to those of cyclophosphamide and TBI.

Factors predicting long-term survival for metastatic breast cancer patients treated with high-dose chemotherapy and bone marrow support.

BACKGROUND: Poor prognosis of Stage IV breast cancer patients have at best a 10% 3-year survival rate with conventional chemotherapy. Dose-intensive chemotherapy improved survival rates for some of these patients. METHODS: All patients were Stage IV estrogen receptor-negative or estrogen receptor-positive hormonal refractory and received conventional chemotherapy (induction phase) to the point of achieving maximal response; if disease was stable or the patients responded, they entered high-dose chemotherapy (intensive phase). Seventy-six percent of the patients received two high-dose treatments with cyclophosphamide (4.5-6.0 g/m2), etoposide (750-1500 mg/m2), and cisplatin (120-180 mg/m2). Patients were randomized to receive or not receive autologous marrow. To identify prognostic factors for survival, univariate statistical analysis and multivariate models were applied to patient subsets. RESULTS: Univariate analysis identified a number of factors whose presence indicates improvement in overall survival rates. These include: (1) absence of liver relapse (P = 0.001); (2) absence of soft tissue relapse (P = 0.001); (3) a smaller number of metastatic sites at the time of detecting Stage IV disease (P = 0.026); and (4) disease-free interval greater than 1 year from initial diagnosis to Stage IV disease (P = 0.011). Multivariate models were fitted to the data, and three variables were identified as independent negative predictors for overall survival: (1) liver site (P = 0.001); (2) soft tissue site (P = 0.039); and (3) prior adjuvant chemotherapy (P = 0.028). CONCLUSIONS: Shorter survival after high-dose chemotherapy is predicted independently by patients pretreated with adjuvant chemotherapy, by disease distributed to the liver or the soft tissue.

Randomized study of growth factors post-peripheral-blood stem-cell transplant: neutrophil recovery is improved with modest clinical benefit.

PURPOSE: To evaluate the clinical value of growth factors (GFs) with peripheral-blood stem cells (PBSC) collected following mobilization with GFs, we randomized patients to receive or not to receive GFs following transplant. PATIENTS AND METHODS: Thirty-seven patients were apheresed after receiving the combination of granulocyte colony-stimulating factor (G-CSF) with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses of 10 micrograms/kg/d and 5 micrograms/kg/d, respectively, for 6 days before apheresis and during a median of 4 days of collections. One day after the infusion of autologous marrow and PBSC, patients were randomly assigned to receive no GFs or a combination of G-CSF (7.5 micrograms/kg/d) and GM-CSF (2.5 micrograms/kg/d), both as a 2-hour intravenous (i.v.) infusion twice per day until the neutrophil count was greater than 1,500/microL. RESULTS: The median days to recovery to an absolute neutrophil count (ANC) of 100/microL (9 v 11.5, P = .0005), 500/microL (10 v 16, P = .0004), or 1,000/microL (12 v 21, P = .0008) was shortened with the use of GFs, post-PBSC infusion. In addition, the duration of hospitalization was shorter (19 v 21 days, P = .0112) in the arm receiving GFs post-PBSC infusion. There was no significant difference between the two study arms in the duration of fever, documented septic episodes, or RBC or platelet transfusion requirements. CONCLUSION: Despite faster neutrophil recovery and shortened duration of hospitalization with GFs administered after PBSC transplantation, the measured clinical variables of febrile days, septic episodes, and transfusion requirements were similar between the study arms. The use of GFs post-PBSC transfusion is associated with a modest clinical benefit.

Irreversible, severe congestive cardiomyopathy occurring in association with interferon alpha therapy.

Interferon alpha is a biologic agent with demonstrated anti-tumor activity in a variety of hematologic and solid malignancies. Many patients treated with interferon experience acute toxicity manifested as a flu-like syndrome of fever, chills, myalgias, and malaise. However, fatigue, anorexia, bone marrow suppression, nausea, vomiting, dizziness, and confusion may also occur. Cardiotoxicity is a rare complication of interferon therapy that most frequently presents as transient episodes of hypotension and tachycardia, with few significant life-threatening cardiovascular effects reported. A small number of cases of suspected interferon-induced cardiomyopathy, all of which improved after discontinuing interferon, have recently been documented. We report a patient with multiple myeloma who developed severe congestive cardiomyopathy while receiving interferon alpha that did not reverse subsequent to discontinuation of interferon therapy. Although the patient had previously received doxorubicin, the presence on endomyocardial biopsy of a prominent intracellular lipid accumulation within myocytes and only grade 2 anthracycline cardiotoxicity suggested that other or additional factor(s) contributed to the severity of this patient's cardiomyopathy. Etiologies of cardiac dysfunction other than interferon and doxorubicin were excluded. While a direct cause-effect relationship between interferon alpha and irreversible congestive cardiomyopathy cannot be firmly established in this case report, patients who either concurrently or sequentially receive interferon and anthracyclines should be carefully monitored for evidence of cardiac toxicity.

Persistent problems of neutropenia and thrombocytopenia with peripheral blood stem cell transplantation.

We describe potential problems that may limit the usefulness of peripheral blood stem cells (PBSC) to facilitate the delivery of multiple cycles of high-dose chemotherapy. These include (1) cumulative myelotoxicity and (2) recurrent episodes of febrile neutropenia and a requirement for frequent platelet transfusions as a result of the stubborn persistence of a minimum of 7-9 days of absolute neutropenia and even longer durations of severe thrombocytopenia, despite utilization of PBSC. However, some of these problems may be overcome by shortening the duration of administration of the high-dose regimen with subsequent earlier reinfusion of the stem cell product. The adverse consequences of severe neutropenia could be overcome by the development of prophylactic neutrophil transfusions. These concepts are discussed with presentation of some preliminary data.