Biomedical subjects
Publications and source records attributed to Z Rahman.
We present a case of pancreatic malignancy which presented as chronic pancreatitis. The diagnostic difficulties are discussed. We recommend that when there is any doubt about a diagnosis of chronic pancreatitis with a pancreatic mass, then early resection is appropriate.
The development of anthracycline/paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combinations has gone through several phases or generations. The first dose escalation studies used prolonged infusions of doxorubicin (48 to 72 hours) and paclitaxel (24 hours). Myelosuppression, mucositis, and neutropenic fever were dose limiting, and a sequence-dependent interaction was noted. In a second phase, doxorubicin was administered by bolus, without changing the schedule of the taxane. More recently, bolus doxorubicin was combined with 3-hour paclitaxel infusions. Higher doses of both agents were administered in this latter schedule, with higher overall response rates reported. Excessive cardiac toxicity was reported with the initial trials that used this schedule. Confirmatory studies are under way pursuing several alternatives to reduce the risk of cardiac toxicity; these include limiting the cumulative dose of doxorubicin, inserting an interval between the administration of the two drugs, and adding a cardioprotective agent to the combination. The high degree of antitumor activity of this combination is quite encouraging, and additional evaluation of this regimen in controlled trials is warranted in metastatic and high-risk primary breast cancer.
The objective of this study was to compare the antitumor activity of single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) with that of the 5-fluorouracil/doxorubicin/cyclophosphamide (FAC) combination by evaluating the extent of residual disease in the breast and regional lymph nodes of patients with breast cancer following four cycles of induction chemotherapy. Patients with histologically confirmed invasive but noninflammatory carcinoma of the breast stages T2-3, N0-1, M0 were eligible to enter the study. Patients were treated with four cycles of either FAC or single-agent paclitaxel before local therapy. Following local therapy, treatment of the two arms was identical. Of 104 operable breast cancer patients who were treated with either regimen, 78 were evaluable for response to preoperative chemotherapy and had undergone local therapy. Age, TNM classification, and estrogen receptor status of the patients were similar in the two groups. Following induction chemotherapy, the extent of disease in the breast and the distribution and number of positive nodes were similar between the two treatment arms. Disease progressed in two patients in the FAC arm and in none in the paclitaxel arm during the induction phase of therapy. A higher fraction of patients had neutropenic fever during the paclitaxel treatment. Initial data from this ongoing randomized study show that paclitaxel alone has comparable anticancer activity with FAC in patients with early breast cancer. The degree of cytoreduction was similar with both induction therapies.
Since both doxorubicin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have substantial antitumor activity in advanced breast cancer, the combination of these two agents was a logical extension of the clinical development of paclitaxel. Early attempts used long infusions of both drugs, limiting the dose of both agents because of limiting gastrointestinal and myelosuppressive toxicity. Bolus doxorubicin combined with 3-hour infusion paclitaxel was reported to have dramatic antitumor activity, but clinically relevant cardiac toxicity in up to 20% of patients in two recent reports. In our current study the same schedules and doses of administration were used, limiting the total doxorubicin dose of 360 mg/m2. In-depth monitoring of cardiac function with noninvasive tests and endomyocardial biopsy were performed. Preliminary results suggest that, at these doses and schedule, the two-drug combination is safe, without unexpected toxicity. Limiting doxorubicin dose to 360 mg/m2 limits cardiac toxicity to levels expected from single-agent doxorubicin at similar cumulative doses.
Relapse following complete remission achieved with a single course of high-dose chemotherapy continues to be the main cause of treatment failure in patients with metastatic breast cancer. A phase I/II trial was initiated that combined the two most active drugs against breast cancer, doxorubicin and paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), with cyclophosphamide, and delivered four cycles of these drugs with peripheral blood progenitor cells (PBPCs) and granulocyte colony-stimulating factor support in an outpatient setting. Patients with untreated metastatic breast cancer received two cycles of doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2. During recovery from the second cycle, PBPCs were harvested. Responding patients were then admitted for a day to receive escalating-dose doxorubicin, paclitaxel, and cyclophosphamide followed by PBPC reinfusion on day 3 as outpatients. Seventeen patients have been enrolled to date. Ten patients completed treatment and received 34 cycles of high-dose chemotherapy every 21 days (range, 21 to 28 days). The median age was 47 years (range, 26 to 56 years) and the median number of metastatic sites was two (range, one to three). Five patients had received adjuvant chemotherapy (four cyclophosphamide/methotrexate/5-fluorouracil and one mitoxantrone-based). The most common toxic reactions were nausea and vomiting (75% of courses) and neurosensory (50% of courses). No patients had a decreased ejection fraction or overt congestive heart failure. Ten patients underwent cardiac biopsy (median doxorubicin, 253 mg/m2; range, 120 to 312 mg/m2); only one showed grade 1 cytotoxic changes with doxorubicin 240 mg/ m2. Six patients were admitted for neutropenic fever. Eight of 10 patients responded (two pathologically confirmed complete remissions in liver). At these doses, four cycles of doxorubicin, paclitaxel, and cyclophosphamide with PBPC and granulocyte colony-stimulating factor support every 21 days was well tolerated and showed evidence of activity. Enrollment at higher dose levels continues so that maximum tolerated dose can be defined.
To formally test the hypothesis that the granulocyte/macrophage colony-forming unit (GM-CFU) cells can contribute to early hematopoietic reconstitution immediately after transplant, the frequency of genetically modified GM-CFU after retroviral vector transduction was measured by a quantitative in situ polymerase chain reaction (PCR), which is specific for the multidrug resistance-1 (MDR-1) vector, and by a quantitative GM-CFU methylcellulose plating assay. The results of this analysis showed no difference between the transduction frequency in the products of two different transduction protocols: "suspension transduction" and "stromal growth factor transduction." However, when an analysis of the frequency of cells positive for the retroviral MDR-1 vector posttransplantation was carried out, 0 of 10 patients transplanted with cells transduced by the suspension method were positive for the vector MDR-1 posttransplant, whereas 5 of 8 patients transplanted with the cells transduced by the stromal growth factor method were positive for the MDR-1 vector transcription unit by in situ or in solution PCR assay (a difference that is significant at the P = 0.0065 level by the Fisher exact test). These data suggest that only very small subsets of the GM-CFU fraction of myeloid cells, if any, contribute to the repopulation of the hematopoietic tissues that occurs following intensive systemic therapy and transplantation of autologous hematopoietic cells.
Chronic lymphocytic leukemia (CLL) is characterized by delayed senescence and slow accumulation of monoclonal, small lymphocytes. Basic fibroblast growth factor (bFGF) is a pleiotropic cytokine that plays a role in hematopoiesis and apoptosis. Elevated bFGF levels have been detected in urine from patients with a variety of neoplastic diseases including various leukemias; however, the cellular source of the bFGF has not been determined. In this study, the intracellular bFGF level in lymphocytes of 36 patients with B-CLL and 15 normal donors was determined using an enzyme-linked immunoassay. In cells derived from patients with high-risk disease, the median level of intracellular bFGF was 381.5 pg/2 x 10(5) cells, compared with a median of 90.5 pg/2 x 10(5) cells in patients with intermediate disease. In patients with low-risk disease, the median bFGF level was 4.9 pg/2 x 10(5) cells, and in normal controls, it was 6.0 pg/2 x 10(5) cells. The difference in the bFGF levels was significant for the comparison between low- and intermediate-risk (P = .00119), low- and high-risk (P < .0001), and intermediate- and high-risk disease (P = .0001). Immunofluorescent stains of peripheral blood mononuclear cells confirmed CLL lymphocytes as a cellular source of bFGF. To evaluate the potential contribution of elevated intracellular bFGF levels to the phenotype of CLL cells, leukemic cells were cultured in vitro with an apoptotic stimulus (fludarabine). CLL cells with high intracellular levels of bFGF appeared to be more resistant to fludarabine treatment. The addition of bFGF to fludarabine-treated CLL cells resulted in a delay of apoptosis and prolonged survival. These data suggest that bFGF may contribute to the resistance of CLL cells to an apoptotic stimulus.
Stem cell factor (SCF) and basic fibroblast growth factor (bFGF) are hematopoietic cytokines produced by bone marrow stromal cells. It is known that, although SCF and bFGF have limited clonogenic activity on their own, they can augment colony-stimulating factor (CSF)-mediated progenitor cell growth. Because these factors are both sequestered by stromal cells, we examined their interaction on progenitor cell growth in conjunction with granulocyte-macrophage-CSF (GM-CSF). In this study, we show that clonogenic growth derived from low-density bone marrow cells stimulated by GM-CSF is significantly augmented (P < .001) in the presence of maximal (100 ng/mL) concentrations of SCF in combination with 100 ng/mL of bFGF. When CD34+ cells are used, the synergistic effect of bFGF and SCF for GM-CSF-mediated progenitor cell growth is further increased, resulting in as much as a sevenfold increase in detectable colony-forming units granulocyte-macrophage (P < .001). These data suggest that the synergistic activity of bFGF and SCF is mediated directly on hematopoietic precursors. These observations suggest that bFGF and SCF, concentrated locally on stromal cell surfaces, might interact in concert with other hematopoietic cytokines to regulate stem cell proliferation and differentiation in hematopoietic niches in the bone marrow.
Virulence determinants of nineteen strains of Plesiomonas shigelloides isolated from stool samples of diarrhoeal children were studied. Heat-labile toxin was detected in seven strains using rat ileal loop model and in none of the strains using Chinese hamster ovary cell assay system and by Enzyme-linked immunosorbent assay. Rat ileal loop model was used for the first time to assay toxin in P. shigelloides and is suggested to be a cheap and effective method of detecting labile toxin in the organism. Heat stable toxin, cytotoxin, hemolysin and hemagglutinin were not detected in the strains tested. Invasiveness could not be established by using HEp-2 cell assay system. The results of this study provide some experimental support for an etiological role for P. shigelloides in the production of diarrhoea.
Maximum oxygen consumption (VO2max) has been shown to be reduced after periods of simulated weightlessness. To assess the role of the sympathetic nervous system in these reductions, Sprague-Dawley rats were either chemically sympathectomized (SYMX) or injected with saline (SHAM) and assigned to head-down suspension (HDS), horizontal restraint with the hindlimbs weight bearing (HWB), or cage-control (CC) conditions. VO2max, run time (RT), and mechanical efficiency (ME) were measured before suspension and on days 7 and 14. Male and female SHAM HDS groups exhibited reduced measures of VO2max (12-13%) after 7 and 14 days, and this decrease was attenuated in the SYMX and HWB rats. HDS resulted in a significant reduction in RT (9-15%) in both the male and female rats, and ME was significantly reduced after HDS in male and female SYMX and male SHAM rats (23-33%) but not in the female SHAM rats. Lesser reductions in ME were observed in the HWB rats. HDS and HWB were associated with lower body, fat-free, and fat masses, which were similar in male and female rats as well as for the SHAM and SYMX conditions. In a related HDS experiment with normal rats, plasma norepinephrine and epinephrine were increased by 53 and 42% after 7 days, but only epinephrine returned to baseline after 14 days. It was concluded that chemical sympathectomy and/or a weight-bearing stimulus will attenuate the loss in VO2max associated with simulated weightlessness in rats despite similar changes in body mass and composition. The mechanism(s) remains unclear at this time.
To determine the time course of changes in maximal oxygen consumption (VO2max) and its relationships with body composition, a 29-d simulated microgravity study was initiated with 30 adult female rats (230-280 g) randomly assigned to one of three experimental groups; namely, head-down suspension (HDS) at 45 degrees, horizontal suspension (HS) at 0 degree, or cage control (CC). Five separate exercise performance tests with measurements related to VO2max, treadmill run time, and mechanical efficiency were conducted before suspension and on days 7, 14, 21, and 28. The animals were sacrificed and chemically analyzed for fat and fat-free free mass (FFM) between days 22 and 29. When oxygen consumption results were expressed on an absolute basis (ml.min-1), both suspension groups had significant decreases at day 7. Thereafter, the HDS rats remained significantly decreased, while the HS rats returned to values not significantly different than the presuspension values by day 28. When oxygen consumption was expressed on a relative basis (ml.kg-1.min-1), all groups exhibited significant reductions between 6-8%. Both suspended groups had significantly less fat than the CC rats but had similar values for FFM (p greater than 0.05). When VO2max was evaluated on a FFM basis, the HDS rats had a group mean that was 6% lower than the other two groups, but the difference was not statistically significant. Treadmill run time was significantly reduced in all groups after 28 d with the reduction from pre-suspension values being more pronounced with HDS animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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Trypsinization (WT) was employed to disaggregate urothelial cells from normal human urinary bladder mucosa for the preparation of primary cultures. Urinary bladders of two male adults both 25 years old were obtained autopsy 1-2 h after death. The mucosa was incubated in HBSS containing 0.25% trypsin at 37 degrees C. Mean cell yield, viability, and attachment were 14.6 X 10(7), 76%, and 42.5% after WT. In histologic sections of treated mucosa, most of the urothelium was removed by WT. Following plating and attachment, cells obtained by WT formed a monolayer of flattened epithelial-like cells. When stained with polyclonal antikeratin antibody using the indirect immunoperoxidase technique, all of the cells were immunoreactive indicating an epithelial origin. In conclusion, based on morphology and immunocytochemistry, WT removed virtually all of the urothelial cells from the mucosa and no contamination by mesenchymal cells resulted from this procedure. Thus, WT is an appropriate technique for the isolation of urothelial cells and initiation of primary cultures of normal human urothelial cells for subsequent study.
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