Randomized comparison of progenitor-cell mobilization using chemotherapy, stem-cell factor, and filgrastim or chemotherapy plus filgrastim alone in patients with ovarian cancer

PURPOSE: This was the first randomized study to investigate the efficacy of peripheral-blood progenitor cell (PBPC) mobilization using stem-cell factor (SCF) in combination with filgrastim (G-CSF) following chemotherapy compared with filgrastim alone following chemotherapy. PATIENTS AND METHODS: Forty-eight patients with ovarian cancer were treated with cyclophosphamide and randomized to receive filgrastim 5 microg/kg alone or filgrastim 5 microg/kg plus SCF. The dose of SCF was cohort-dependent (5, 10, 15, and 20 microg/kg), with 12 patients in each cohort, nine of whom received SCF plus filgrastim and the remaining three patients who received filgrastim alone. On recovery from the WBC nadir, patients underwent a single apheresis. RESULTS: SCF in combination with filgrastim following chemotherapy enhanced the mobilization of progenitor cells compared with that produced by filgrastim alone following chemotherapy. This enhancement was dose-dependent for colony-forming unit-granulocyte-macrophage (CFU-GM), burst-forming unit-erythrocyte (BFU-E), and CD34+ cells in both the peripheral blood and apheresis product. In the apheresis product, threefold to fivefold increases in median CD34+ and progenitor cell yields were obtained in patients treated with SCF 20 microg/kg plus filgrastim compared with yields obtained in patients treated with filgrastim alone. Peripheral blood values of CFU-GM, BFU-E, and CD34+ cells per milliliter remained above defined threshold levels longer with higher doses of SCF. The higher doses of SCF offer a greater window of opportunity in which to perform the apheresis to achieve high yields. CONCLUSION: SCF (15 or 20 microg/kg) in combination with filgrastim following chemotherapy is an effective way of increasing progenitor cell yields compared with filgrastim alone following chemotherapy.     

Early dopaminergic drug-induced hallucinations in parkinsonian patients

OBJECTIVE: To characterize patients who develop hallucinations early in the course of dopaminergic therapy for Parkinson's disease (PD) and contrast them with patients developing hallucinations after chronic drug treatment. METHODS: Parkinsonian patients who met diagnostic criteria for PD, experienced hallucinations, had a detailed hallucination interview at the onset time of their first hallucination, and had a 5-year clinical follow-up or an autopsy in those 5 years were identified and divided into two groups for comparison: 12 patients who developed early hallucinations within 3 months of starting levodopa therapy and 58 PD patients who developed hallucinations after 1 year of dopaminergic therapy. We contrasted the quality, content, diurnal nature, and emotional elements of the hallucinations, as well as the 5-year follow-up data on diagnosis, disease course, community home or nursing home outcome, and mortality. RESULTS: Both groups experienced a predominance of visual hallucinations, visions of people and animals, and vivid colors and definition. Features distinctive to the early onset hallucinating patients included visions that persisted in daytime as well as nighttime, frightening content with paranoia, and accompanying nonvisual hallucinations, either auditory, olfactory, tactile, or combinations thereof. At the 5-year follow-up, none of the early onset hallucinators had PD as their sole disorder. Four of the 12 had an underlying psychiatric illness that included hallucinations or psychosis preceding their parkinsonism by several years. In the other eight patients at the 5-year follow-up, their parkinsonism evolved to include additional signs that were no longer consistent with PD. The primary diagnoses were diffuse Lewy body disease and Alzheimer's disease (AD) with extrapyramidal signs. Patients with early drug-induced hallucinations had significantly greater placement to nursing homes and greater mortality. CONCLUSIONS: Early onset drug-related hallucinations are not typical of PD. Their presence should signal an investigation of two alternative diagnoses, either a comorbid psychotic illness (often unrevealed by the patient initially) or an evolving parkinsonism-plus syndrome.     

Peripheral blood progenitor cell mobilization using stem cell factor in combination with filgrastim in breast cancer patients

The safety and optimal dose and schedule of stem cell factor (SCF) administered in combination with filgrastim for the mobilization of peripheral blood progenitor cells (PBPCs) was determined in 215 patients with high-risk breast cancer. Patients received either filgrastim alone (10 microg/kg/d for 7 days) or the combination of 10 microg/kg/d filgrastim and 5 to 30 microg/kg/d SCF for either 7, 10, or 13 days. SCF patients were premedicated with antiallergy prophylaxis. Leukapheresis was performed on the final 3 days of cytokine therapy and, after high-dose chemotherapy and infusion of PBPCs, patients received 10 microg/kg/d filgrastim until absolute neutrophil count recovery. The median number of CD34+ cells collected was greater for patients receiving the combination of filgrastim and SCF, at doses greater than 10 microg/kg/d, than for those receiving filgrastim alone (7.7 v 3.2 x 10(6)/kg, P < .05). There were significantly (P < .05) more CD34+ cells harvested for the 20 microg/kg/d SCF (median, 7.9 x 10(6)/kg) and 25 microg/kg/d SCF (median, 13.6 x 10(6)/kg) 7-day combination groups than for the filgrastim alone patients (median, 3.2 x 10(6)/kg). The duration of administration of SCF and filgrastim (7, 10, or 13 days) did not significantly affect CD34+ cell yield. Treatment groups mobilized with filgrastim alone or with the cytokine combination had similar hematopoietic engraftment and overall survival after PBPC infusion. In conclusion, the results of this study indicate that SCF therapy enhances CD34+ cell yield and is associated with manageable levels of toxicity when combined with filgrastim for PBPC mobilization. The combination of 20 microg/kg/d SCF and 10 microg/kg/d filgrastim with daily apheresis beginning on day 5 was selected as the optimal dose and schedule for the mobilization of PBPCs.     

Anesthesia in two patients with essential thrombocythemia

Case 1. The patient was a 69-year-old man with essential thrombocythemia (ET), who underwent urgent laparotomy. On admission he was dehydrated and the platelet count was more than 160 x 10(4).microliter-1, with hematocrit of 50%. Anesthesia was induced with ketamine i.v. and maintained with nitrous oxide and sevoflurane in oxygen. Postoperative care included the administration of gabexate mesilate (GM) which is an antiplatelet agent. Case 2. An 84-year-old woman with ET was diagnosed as gastric cancer and elective gastrectomy was scheduled. The platelet count was more than 100 x 10(4).microliter-1. The patient was anesthetized with nitrous oxide and oxygen supplemented with fentanyl and mepivacaine via epidural catheter. Intravenous infusion of GM was performed at a rate of 1 mg.kg-1.hr-1 during surgery. PF-4 and beta-TG were measured. These are platelet releasing factors. The level of PF-4 decreased to normal level during this procedure. In conclusions, it will be important to use GM during anesthesia in order to avoid the complications such as myocardial or pulmonary infarction caused by thrombocythemia.     

Rapidly cycled courses of high-dose alkylating agents supported by filgrastim and peripheral blood progenitor cells in patients with metastatic breast cancer

Our purpose was to determine the feasibility of a regimen of multiple, rapidly cycled courses of high-dose alkylating agents, including paired courses of escalating doses of thiotepa, supported by peripheral blood progenitor cells and filgrastim, in patients with responding stage IV breast cancer. The regimen consisted of two courses of cyclophosphamide (3.0 g/m2/course) followed by two courses of thiotepa (500-700 mg/m2/course). All courses were supported by filgrastim. Leukaphereses were performed after each cyclophosphamide course to harvest peripheral blood progenitors (PBPs) for use as rescue following thiotepa administration. The planned interval for all courses was 14 days. Forty-two patients were enrolled. Thirty-eight received all four courses, and four did not receive the second thiotepa cycle due to poor PBP mobilization. The maximum dose of thiotepa that was administered was 700 mg/m2 x 2. At this dose, one patient developed encephalopathy, which resolved over several weeks. The median number of days to an absolute neutrophil count of 0.5 x 10(9)/liter after PBP reinfusion for cycles 1 and 2 of thiotepa were 9 (range, 7-16) and 9 (range, 8-13) days, respectively. The corresponding values for platelet recovery to >20 x 10(9)/liter were 11 (range, 8-39) and 12 (range, 10-28) days, respectively. There were no treatment-related deaths. Hospitalization was required following 28 of 84 cyclophosphamide courses and 76 of 80 thiotepa courses. Four patients developed grade III-IV mucositis. The median interval between courses of treatment was 15 (range, 13-29) days. Of 19 patients who entered the protocol with measurable disease in partial response from prior therapy, 8 (42%) achieved complete response following the high-dose therapy. Nine (21%) of 42 remain progression free at a median follow-up of 28 (range, 20-32) months. Therefore, we concluded that the administration of multiple, rapidly cycled courses of high-dose alkylating agents is feasible.     

Pilot trial of infusional cyclophosphamide, doxorubicin, and etoposide plus didanosine and filgrastim in patients with human immunodeficiency virus-associated non-Hodgkin's lymphoma

PURPOSE: To determine the following: (1) the feasibility of combining the antiretroviral didanosine (ddl) with a 96-hour continuous intravenous (IV) infusion of cyclophosphamide (800 mg/m2), doxorubicin (50 mg/m2), and etoposide (240 mg/m2) (CDE) plus filgrastim in patients with non-Hodgkin's lymphoma (NHL) associated with human immunodeficiency virus (HIV) infection; (2) the effect of ddl on CDE-induced myelosuppression and CD4 lymphopenia; and (3) the effect of CDE on serum p24 antigen and quantitative HIV blood cultures. METHODS: Twenty-five patients with HIV-related NHL received CDE every 28 or more days. Consecutive patients were assigned in an alternating fashion to group A (ddl given at a standard dose during cycles one, two, five, and six) or group B (ddl given during cycles three, four, five, and six). RESULTS: ddl use was associated with less leukopenia (mean nadir, 3.33 v 1.49 x 10(3)/microL; p = .03), neutropenia (2.38 v 1.07 x 10(3)/microL; p = .03), and thrombocytopenia (76 v 48 x 10(3)/microL; p = .059), and fewer RBC (1.6 v 3.1 per cycle; p < .01) and platelet transfusions (0.7 v 1.5 per cycle; p < .01), but had no significant effect on CD4 lymphopenia. Furthermore, lymphomatous bone marrow involvement and low CD4 count were associated with significantly greater myelosuppression. Although there was no substantial change in serum p24 antigen, the HIV blood culture became quantitatively more positive or converted from negative to positive in seven patients (64%). Complete response (CR) occurred in 58% of patients (95% confidence interval, 38% to 78%), median CR duration exceeded 18 months, tumor-related mortality was 20%, and median survival was 18.4 months. CONCLUSION: Our results suggest that the CDE and filgrastim regimen is tolerable and effective for patients with HIV-associated NHL, and that combination with ddl is feasible and may result in less myelosuppression.     

Nizatidine in therapy and prevention of non-steroidal anti-rheumatic drug-induced ulcers in rheumatic patients

269 patients with various rheumatic disorders who had been treated with non-steroidal anti-inflammatory drugs (NSAID) for at least three weeks, were enrolled in this randomised double-blind multicenter trial. Entry criteria were both the presence of an ulcer in gastric and/or duodenal mucosa (> 3 mm and < 20 mm in diameter) as well as dyspeptic symptoms. The patients had been treated with 150 mg nizatidine nocte (n = 86), 2 x 150 mg/d (n = 93) and 2 x 300 mg/d (n = 90) nizatidine. All patients continued to take their original NSAID-medication. The three nizatidine-groups had been well matched with respect to important patient characteristics. After 8 weeks of treatment more than 90% of gastric and duodenal ulcers had been healed under all three nizatidine-dosages. There was a tendency for higher healing rates in case of gastric ulcers after 4 weeks following the higher dose of nizatidine. Erosions in stomach and duodenum as well as esophagitis had been improved to a similar degree with all nizatidine doses. The same holds with respect to improvement of clinical symptoms such as epigastric pain, heartburn etc. Consumption of additional antacids was similar in all three groups. In the subsequent prophylactic trial 237/221 patients had been followed for 3/6 months. 116/107 received in addition to their continued antirheumatic medication nizatidine 150 mg nocte and 121/114 patients 2 x 150 mg nizatidine daily. The cumulative relapse rates within 6 months averaged 5.5% in the low and 1.8% in the high dose group (n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal failure in two patients with Wolfram syndrome

BACKGROUND/OBJECTIVE: Aluminium is produced from the mineral bauxite. Occupational exposure is reported during the industrial processing of aluminium and is associated with pulmonary and neurotoxicity. However, data on exposure and toxicity of workers in the open bauxite mining industry do not exist. Therefore, a study was performed to explore aluminium exposure in employees involved in this bauxite mining process in a Surinam mine. METHODS/DESIGN: A group of workers occupationally exposed to aluminium in an open bauxite mine were compared with a group of nonexposed wood processors. Serum aluminium was analyzed using atomic absorption spectrometry Data from the clinical chemistry of the blood and a questionnaire were used to explore determinants for aluminium exposure. RESULTS: No significant difference between serum aluminium in the exposed (4.4 +/- 2.0 micrograms/L, n = 27) and control group (5.1 +/- 1.5 micrograms/L, n = 27) was detected. For the serum concentration of the clinical chemical variables (calcium, citrate, and creatinine), a statistically significant difference was computed (p < or = 0.02) between the exposed and control group. All levels were slightly higher in the exposed group; no statistically significant correlations with serum aluminium were found. CONCLUSIONS: In this study, serum aluminium values were in the normal range, no significant difference between the groups could be detected despite long-term occupational exposure.     

A family of infantile genetic agranulocytosis

A survey was performed of the mold flora in the air and on the surfaces inside twelve homes throughout four seasons. There were significant variations of the mold flora in homes associated with the outdoor spore count, various rooms, carpeting, central air-conditioning and pets. We conclude that homes may be a source of perennial mold exposure.     

Phase I study of pharmacologically based dosing of carboplatin with filgrastim support in women with epithelial ovarian cancer

PURPOSE: The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA). PATIENTS AND METHODS: A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle. RESULTS: We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level. CONCLUSION: An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.     

Efficiency of two pancreatic extracts in patients with cystic fibrosis

Mechanical cell damage was studied in vitro with three types of prostheses: Starr-Edwards, Kay-Shiley and Bj?rk-Shiley valves. Mechanical cell damage was found to be closely related to the flow characteristics in the prosthesis. Considering valves of similar orifice diameter, Bj?rk-Shiley valves produced the lowest rate of haemolysis. This is due to the improved haemodynamic characteristics of the valve which resulted from the laminar type of flow. With Starr-Edwards valves, smaller sizes produced unacceptably high rates of haemolysis. Increasing the mean forward flow across the valve resulted in a disproportionate rise in the energy loss and the rate of haemolysis when compared with Bj?rk-Shiley valves of similar annulus diameters.     

A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group

OBJECTIVE: The aims of the study were to follow prospectively the intrasubject progression of idiopathic PD in a cohort of patients using levodopa kinetic-dynamic modeling and to assess the relation between the rate of progression of the disease and patients' different clinical characteristics. METHODS: Thirty-four patients (Hoehn and Yahr stages 1 to 3) enrolled in the longitudinal follow-up. Each patient was examined at 1-year intervals over a median 4 years by a standardized oral levodopa test. The primary measure outcome was the computed half-life of levodopa in the "effect compartment" (t1/2eq), a proposed indicator of nigrostriatal dopaminergic functionality and integrity. RESULTS: Values of levodopa t1/2eq correlated negatively with severity of symptoms (r = -0.652, p < 0.0001) and decreased over the years together with a worsening of patients' clinical stage (p < 0.001). The rate of reduction in drug t1/2eq was more rapid in patients at the earlier stages of the disease compared with the more advanced ones, falling from a median annual reduction of 37 minutes in patients at initial Hoehn and Yahr stage 1 to 6.5 minutes in stage 3 patients (p < 0.001). Patients without tremor at onset, otherwise comparable to patients with tremor for baseline values of levodopa t1/2eq, disease severity, duration, and daily dose of levodopa, tended to show a higher rate of reduction in levodopa t1/2eq than patients with tremor. Overall, patients' annual reduction in levodopa t1/2eq over baseline values averaged 17+/-9%. CONCLUSIONS: These results are in keeping with PET findings on the objective assessment of idiopathic parkinsonism evolution, and they support the suggestion that levodopa pharmacodynamic modeling may offer a practical clinical tool to assess indirectly the functional integrity of the nigrostriatal dopaminergic system over time in parkinsonian patients.     

Palliative intubation of esophageal prosthesis in two patients with lung cancer

PURPOSE: Severe eye burns often result in extensive necrosis of the conjunctiva and episcleral tissue. Video fluorescein angiography was performed to reveal the perfusion of the anterior eye segment after severe eye burns. METHODS: A scanning laser ophthalmoscope was used for anterior segment fluorescein angiography in 12 patients (14 eyes) with severe burns grade III-IV and in 7 healthy volunteers. RESULTS: Necrotic tissues occurred as non perfused areas and remained dark throughout the whole angiogram. In general, the borders from healthy to necrotic conjunctival tissue were sharply demarcated. Thus, the extent of scleral and limbal ischemia could be determined exactly. Injured vessels showed hyperfluorescence with late leakage. Damage of the subconjunctival tissue appeared as a deep weak fluorescence in the early angiography and exhibited patchy leakage in the late angiogram. CONCLUSIONS: Anterior segment angiography provides a basis for deciding the extent of surgical debridement of necrotic tissue in the acute phase of the burn. The determination of the extent of limbal and scleral ischemia may give useful information for early plastic-reconstructive procedures.