Diffuse large cell lymphoma: a teaching hospital experience.
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Antigens, CD↗
Biomedical subjects
R M Fox
Publications and source records attributed to R M Fox.
Clinical experience with recombinant human granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor.
Bacterially synthesized human granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage colony-stimulating factor (GM-CSF) have been studied to determine if they could prevent or reduce the neutropenia caused by chemotherapy. Our studies suggest that 10 micrograms/kg/day of G-CSF administered as a continuous subcutaneous infusion abrogates the neutropenia associated with a standard dose of melphalan. G-CSF produced a rapid increase of neutrophil levels, was well-tolerated, and was associated with only one frequent adverse effect: bone pain. GM-CSF, administered in doses ranging from 3 to 15 micrograms/kg/day subcutaneously, appeared to be useful in abrogating the neutropenia associated with chemotherapy, producing elevations in neutrophils, eosinophils, and monocytes. Although GM-CSF was relatively well-tolerated, several adverse effects, including bone pain, rashes, and fluid retention, were observed. The initial dose of GM-CSF in some patients produced a reaction that was characterized by hypoxia.
Clinical Trials as Topic↗
Hashimoto's disease, thyroid lymphoma and splenic atrophy.
An elderly woman is described who developed Hashimoto's thyroiditis and, subsequently, thyroid lymphoma more than 15 years after the onset of splenic atrophy. This case supports the concept that splenic atrophy predisposes to the development of autoimmune thyroid disease. The relationship between splenic atrophy and autoimmune thyroid disease is reviewed.
Aged↗
Rapid infusion amphotericin B: effective and well-tolerated therapy for neutropenic fever.
A retrospective analysis was carried out of the results of 115 intensively-treated cancer inpatients receiving 91 treatment courses of amphotericin B given in an empirical fashion. Amphotericin B was administered over 1.5 to 2 hours at a dose of 0.6 to 0.7 mg/kg/day. Median duration of neutropenic fever before amphotericin B administration was 5 days (range 1 to 32 days) and median total amphotericin B dose was 480 mg (range 10 to 2450 mg). In 56 (61%) of 91 amphotericin B courses, neutropenic fevers resolved; this occurred a median of 3 days (range 1 to 15 days) after amphotericin B was begun and at a median dose of 120 mg (range 10 to 850 mg). Response to amphotericin was independent of positive cultures for fungus or sites of positive culture. Adverse reactions to amphotericin B included rigors (89% of courses), fever (23%), bronchospasm (9%), and transient hypotension (9%). Median increase above baseline serum creatinine in patients given amphotericin B was 0.5 mg/dl (range 0 to 2.6 mg/dl) compared to a median of 0.1 mg/dl (range 0 to 2.9 mg/dl) in a similar group of intensively-treated cancer patients who did not receive amphotericin B. Amphotericin B was well tolerated when given by rapid infusion and was associated with prompt resolution of neutropenic fever in the majority of patients.
Adolescent↗
Plasma membrane lipid composition of vinblastine sensitive and resistant human leukaemic lymphoblasts.
Plasma membranes purified 32- to 45-fold were isolated from leukaemic T-lymphoblasts, both sensitive and resistant to the Vinca alkaloid vinblastine. On development of drug resistance there was a very significant elevation of ether lipid content. 1-0-alkyl phospholipid increased by 200% with a smaller 30% increase in 1-0-alkenyl phospholipid. Cholesterol and phospholipid levels were also found to increase by 50% and 30% respectively, while the lipid to protein ratio increased by 60%. More modest changes were observed in the fatty acid composition of the membranes, with an alteration in the double bond index from 35.3 to 41.2. These lipid changes may have important implications in the changes to membrane permeability that develop with drug resistance.
Cell Line↗
Ribonucleotide reductase M1 subunit in cellular proliferation, quiescence, and differentiation.
Ribonucleotide reductase catalyzes the first unique, rate-limiting step in DNA synthesis; both its large (M1) and small (M2) subunits are necessary for activity. While direct studies of M2 expression have previously shown a tight correlation with S phase, the kinetic features of M1-expressing cells have remained ill defined. Therefore we have, using immunofluorescence flow cytometry, analyzed changes in whole cell M1 levels and DNA content during various cell cycle and differentiation events. In asynchronous cultures M1 levels are sustained throughout the cell cycle, including G1 phase when M2 levels and ribonucleotide reductase catalytic activity are known to be very low. In contrast M1 is virtually absent from quiescent lymphocytes but is expressed following mitogen stimulation, shortly before S phase cells appear. M1 declines to low levels in "plateau phase" cultures, the major reduction occurring in cells with 2n (G0/G1) DNA content. HL-60 promyelocytic leukemia cells, induced into either myeloid or monocyte-macrophage differentiation, show a similar marked decrease in M1 levels concomitant with the cessation of cell division. We conclude that the M1 subunit of ribonucleotide reductase is constitutively expressed by cycling cells. It is acquired during stimulated transition from G0 to G1 and is lost during exit to G0 or terminal differentiation. This pattern of expression suggests that determination of cellular M1 content may be useful in distinguishing proliferating (including G1) and quiescent (including G0) cells in vivo.
Cell Differentiation↗
Metastatic adenocarcinoma of unknown primary site. A randomized study of two combination chemotherapy regimens.
Of 101 patients with symptomatic adenocarcinoma or undifferentiated carcinoma of unknown primary site, 95 were evaluable for the effects of two randomized chemotherapy regimens. Forty-eight patients received combination doxorubicin and mitomycin C (DM) and 47 received combination cisplatin, vinblastine and bleomycin (PB). Response rates were not significantly different between the two treatment groups, 42% for DM and 32% for PVB, with an overall response rate of 37.1%. Survival differences for DM and PVB treated groups were not significantly different, with 18 weeks and 25 weeks median survivals respectively. Toxicities were unequal for the two treatment groups with increased haematological toxicity for DM and greater gastrointestinal toxicity for PVB. The authors conclude both therapies were of limited efficacy in the treatment of ACUP patients and emphasize that only symptomatic patients should be considered for such therapies.
Adenocarcinoma↗
Chemotherapy for small cell lung cancer: induction and reinduction with VOCA.
Sixty-five patients with small cell lung cancer were treated with VP16, vincristine, cyclophosphamide, and doxorubicin (VOCA) intravenously at three-week intervals. Patients with limited disease received four cycles with responders receiving radiation to the primary site and prophylactic cranial irradiation. Patients with extensive disease received chemotherapy only. Of 59 patients evaluable for chemotherapy response, eight (14%) achieved complete remission and 30 (51%) partial remission. Major side-effects included myelosuppression, alopecia, nausea, and vomiting. Reinduction with VOCA at relapse yielded objective or subjective response in four of seven patients. This regimen is active in small cell lung cancer and was well tolerated by patients. Reinduction of response was possible in a small number of patients retreated and may provide useful palliation for those who relapse when treatment is discontinued.
Adult↗
Improved survival after brain metastases in non-seminomatous germ cell tumours with combined modality treatment.
Long-term disease-free survival (78 + and 31 + months) has been achieved in two of four patients treated for brain metastases from non-seminomatous germ cell tumours between 1980 and 1984. The incidence of cerebral metastases among 101 patients seen over the 5-year period was 4%. The encouraging results from the use of combined modality treatment, incorporating cisplatin-based chemotherapy, whole brain irradiation and surgery, are reviewed.
Adult↗
Chemotherapy of adult soft tissue sarcoma with combination of doxorubicin and methotrexate.
Thirty-six adult patients with measurable advanced soft tissue sarcoma were treated with a combination of doxorubicin (70 mg/m2) and methotrexate (50 mg/m2) iv every 21 days. Partial remission was seen in ten of 33 evaluable patients (30%). Median duration of remission was 23 weeks, and median survival was 42 weeks. Bone marrow toxicity was the main toxic effect; 23% of the patients had a nadir leukocyte count less than 2.0 X 10(9)/L during therapy. These results do not suggest any therapeutic advantage in adding methotrexate to doxorubicin in this context.
Adult↗
Classification of human tumours by high-resolution magnetic resonance spectroscopy.
Malignant tumours yield a high-resolution proton magnetic resonance (MR) spectrum. Fifty-one tumour biopsy specimens from patients with cancer of the ovary or colon were examined by magnetic resonance spectroscopy (MRS) to determine whether it was possible to identify tumour subtypes with metastatic potential. Relaxation parameters (T2) for visible lipid methylene protons were within the range of those measured for three animal metastasis models. Primary carcinomas with metastases gave T2 values greater than 350 ms, whereas carcinomas not associated with known metastases at the time of tumour excision gave a range of values from 150 to 1500 ms. All but two carcinomas gave a long T2 (greater than 350 ms) indicating metastatic potential. The MRS method designated five of six histologically borderline epithelial ovarian tumours as malignant with metastatic potential. MRS may be sensitive enough to detect malignant cells in a tumour which is of intermediate or borderline malignancy by light microscopy. Malignancy without a potential for metastasis is uncommon.
Colonic Neoplasms↗
Assignment of methylene proton resonances in NMR spectra of embryonic and transformed cells to plasma membrane triglyceride.
Some biological characteristics of cancer cells and solid tumors are identifiable by the high resolution NMR relaxation behavior of their nonaqueous components. Chemical analysis and two-dimensional scalar correlated (COSY) NMR spectroscopy show these resonances arise from neutral lipid in the plasma membrane. Triglyceride is shown to be the main plasma membrane component giving rise to the NMR spectrum, while soluble nonmembrane components account for 90% of the remaining resonances in the spectrum of intact cells. The presence of triglyceride has been detected by chemical analysis in highly purified plasma membranes from two different cell lines. The COSY spectra of cancer cells are comparable with that obtained for the triglyceride-rich very low density human lipoprotein.
Adenocarcinoma↗
Extraskeletal Ewing's sarcoma: a clinical, morphological and ultrastructural analysis of five cases with a review of the literature.
In 1969 it was recognised that tumors with light microscopic appearances indistinguishable from Ewing's sarcoma of bone may arise in extraskeletal sites (extraskeletal Ewing's sarcoma). Here, we review the available literature and report five new cases. All five received combined modality therapy with combination chemotherapy and radiotherapy to the primary site followed by surgical excision in two. All attained complete remission; after a median follow-up of 26 months, three remain disease-free but two have relapsed and died. Our experience, in accord with previous series, suggests that extraskeletal Ewing's sarcoma compared with its bony counterpart tends to occur in older subjects, has a similar incidence in males and females, usually presents with a painless mass and readily responds to combined modality therapy. We detected no light or electron microscopic features to denote a histogenetic origin. However, we suspect extraskeletal Ewing's sarcoma may occur more frequently than previously supposed.
Adult↗
Deoxyadenosine triphosphate as a mediator of deoxyguanosine toxicity in cultured T lymphoblasts.
The mechanism by which 2'-deoxyguanosine is toxic for lymphoid cells is relevant both to the severe cellular immune defect of inherited purine nucleoside phosphorylase (PNP) deficiency and to attempts to exploit PNP inhibitors therapeutically. We have studied the cell cycle and biochemical effects of 2'-deoxyguanosine in human lymphoblasts using the PNP inhibitor 8-aminoguanosine. We show that cytostatic 2'-deoxyguanosine concentrations cause G1-phase arrest in PNP-inhibited T lymphoblasts, regardless of their hypoxanthine guanine phosphoribosyltransferase status. This effect is identical to that produced by 2'-deoxyadenosine in adenosine deaminase-inhibited T cells. 2'-Deoxyguanosine elevates both the 2'-deoxyguanosine-5'-triphosphate (dGTP) and 2'-deoxyadenosine-5'-triphosphate (dATP) pools; subsequently pyrimidine deoxyribonucleotide pools are depleted. The time course of these biochemical changes indicates that the onset of G1-phase arrest is related to increase of the dATP rather than the dGTP pool. When dGTP elevation is dissociated from dATP elevation by coincubation with 2'-deoxycytidine, dGTP does not by itself interrupt transit from the G1 to the S phase. It is proposed that dATP can mediate both 2'-deoxyguanosine and 2'-deoxyadenosine toxicity in T lymphoblasts.
B-Lymphocytes↗
Analysis of a prospectively randomized comparison of doxorubicin versus 5-fluorouracil, doxorubicin, and BCNU in advanced gastric cancer: implications for future studies.
A multi-institutional cooperative study of patients with locally advanced, recurrent, or metastatic gastric adenocarcinoma who had not previously received chemotherapy was conducted, prospectively randomizing patients to receive either doxorubicin or the three-drug combination, 5-fluorouracil (5-FU), doxorubicin (Adriamycin; Adria Laboratories, Columbus, Ohio), and BCNU (FAB). The 187 evaluable patients were initially stratified according to the presence of measurable or evaluable disease and performance status. There was a significantly higher response rate observed for FAB (40%) compared with doxorubicin (13%) among the 145 measurable-disease patients. Duration of response and survival were significantly longer for FAB in the measurable-disease group, but for the total patient population an early advantage for FAB in time to disease progression and survival was lost with continued follow-up. Median survival was 33 weeks for patients receiving FAB and 19 weeks for those receiving doxorubicin. Significant pretreatment factors adversely affecting survival included poor performance status, weight loss of greater than 10%, and more than two sites of metastases. Toxicity was not severe in either treatment arm, and only thrombocytopenia occurred significantly more often with FAB. It is contended that in the treatment of advanced gastric cancer, chemotherapy only exerts a relatively short-term and modest beneficial effect, most apparent in patients with intermediate tumor bulk. 5-FU remains the most active single agent, and combination chemotherapy has not yet proven its overall worth. Further studies are indicated comparing the most active combinations with 5-FU using optimal doses and schedules, and consideration must be given to the incorporation of no-treatment controls.
Adenocarcinoma↗
Coronary artery cardiomyopathy. Hemodynamic and prognostic implications.
To assess the prevalence and significance of left ventricular dilatation in patients with severe left ventricular dysfunction secondary to coronary artery disease (or coronary artery cardiomyopathy), we studied 70 patients with an ejection fraction of 35 percent or less and one-vessel coronary artery disease (n = 14) or with multivessel coronary artery disease (n = 56). None had had a recent myocardial infarction or valvular heart disease. Patients who underwent myocardial revascularization during follow-up were excluded. The left ventricular end-diastolic volume (measured by contrast ventriculography) was less than 110 ml/sq m in 14 patients (20 percent) (group 1), and was 110 ml/sq m or more in 56 patients (80 percent) (group 2). There were no differences between the two groups in age, sex, diabetes mellitus, hypertension, extent of coronary artery disease, or left ventricular asynergy. Patients in group 1 had lower pulmonary arterial wedge pressure (13 +/- 6 vs 22 +/- 10 mm Hg; p = 0.0008), lower left ventricular end-diastolic pressure (21 +/- 6 vs 27 +/- 9 mm Hg; p = 0.007), and higher left ventricular ejection fraction (31 +/- 2 vs 25 +/- 7 percent; p = 0.001) than patients in group 2. At a mean follow-up of 27 months, 24 patients had died of cardiac causes, all of whom were in group 2. Survival was significantly better in group 1 than in group 2 (Mantel-Cox, p = 0.009). Survival analysis (Cox models) of 20 clinical, hemodynamic, and angiographic variables showed that ejection fraction (chi2 = 13.6; p less than 0.001) and end-diastolic volume chi2 = 4.7; p = 0.03) were the most significant predictors of death. Thus, minimally dilated coronary artery cardiomyopathy is a distinct entity with favorable hemodynamics. Prognostically, the end-diastolic volume adds significant predictive information to the ejection fraction among conservatively treated patients.
Adult↗
Lipid domain in cancer cell plasma membrane shown by 1H NMR to be similar to a lipoprotein.
Human blood lipoproteins have been characterised by 1H NMR methods and chemical analysis, and comparisons made with the properties of the triglyceride-rich plasma membrane domain found in cancer cells. By means of selective and non-selective T1 experiments, the lipids in HDL and LDL are shown to be in diffusive exchange. In contrast, the lipids of chylomicra and VLDL do not exhibit lipid diffusion, and therefore resemble the neutral lipids of cancer cell plasma membranes. 2D scalar correlated NMR (COSY) spectra of cancer cells or solid tumours are similar to those obtained from VLDL and LDL. The long T2 relaxation value observed for neutral lipid methylenes in metastatic cancer cells (greater than 300 ms) was not observed for any of the 4 lipoproteins studied. None of the lipoprotein classes gave a T2 longer than 250 ms.
Adenocarcinoma↗
Changes in deoxynucleoside triphosphate pools induced by inhibitors and modulators of ribonucleotide reductase.
Changes in dNTP pools have been studied by a number of investigators, in a wide range of cell types. The in vitro pertubations in dNTP pool levels induced, in particular, by deoxynucleosides which act as allosteric modulators, are not totally consistent with current 'in vitro models' of ribonucleotide reductase function. This problem has also been addressed by Henderson et al. (1980) who stress the profusion of such models. Possible explanations, apart from the technical problems of the range of different experimental conditions (e.g. concentration of modulator used, time of incubation, etc.) for the various cell lines include: Modulators presumably have unpredictable 'network' effects by inhibiting or stimulating many other enzymes involved in the de novo and salvage synthesis of purines and pyrimidines. It is possible there are two separate forms of ribonucleotide reductase, one specifically reducing CDP/UDP, the other ADP/GDP. This, in particular, would explain the lack of decrease in dCTP levels after elevation of the dATP pool. There may be variations in ribonucleotide function which in vivo are cell specific, e.g. in thymic-derived compared with non-T-cell types. Peculiarities of T-cells include: Their ability to elevate their dNTP pools on exposure to very low exogenous concentration of deoxynucleoside. This may reflect very low rates of dNTP catabolism. The biological response of T-cells to elevation of the dATP or dGTP pool is reflected by a G1 block compared to an S phase block in cell-cycle progression in non-T-cell lines. The possibility that, in thymic cells, ribonucleotide reduction is restricted to ADP/GDP while pyrimidine dNTPs are synthesized by salvage pathways. As well, possible variation in the pool localization of dNTPs depending on production by either de novo or salvage synthesis could produce dNTP pool changes not clearly in accord with in vitro models. Clearly, the solution to these problems (although not easy) requires systematic comparative study, using cells of various origin (particularly T vs non-T), of dNTP pool responses to deoxynucleoside modulators, with an attempt to explore the factors described above. However, in the detailed pursuit of such an analysis the concept, that these variations in the control of nucleotide metabolism in T and non-T-cell systems may reflect quite significant differences in growth control and cell-cycle progression, should not be lost.
Animals↗