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Biomedical subjects

J Showel

Publications and source records attributed to J Showel.

16 recordsLinked to original sources
PubMed1997

Cell cycle kinetic studies in 68 patients with myelodysplastic syndromes following intravenous iodo- and/or bromodeoxyuridine.

Sixty-eight patients with myelodysplastic syndromes (MDS) received sequential infusions of iodo- and/or bromodeoxyuridine for cell kinetic analysis. Bone marrow biopsy sections were treated by appropriate antibodies and a labeling index (LI), duration of S-phase (Ts), and total cell cycle time (Tc) of myeloid cells were determined. The mean LI was 28.4%, Ts was 11.8 hours and Tc was 40.7 hours. The %LI decreased as the disease evolved from refractory anemia toward transformation to acute leukemia (p = 0.04). Double-labeling of biopsy sections for apoptosis and proliferation showed that 30-90% of S-phase cells in MDS patients were simultaneously apoptotic or "antonymous." We conclude that MDS are highly proliferative disorders in which the ineffective hematopoiesis is probably the result of excessive apoptosis rather than slow proliferation.

Apoptosis↗
PubMed1996

Novel insights into the biology of myelodysplastic syndromes: excessive apoptosis and the role of cytokines.

The paradox of myelodysplastic syndromes (MDS) which present with pancytopenias despite cellular bone marrows (BM) was investigated by conducting detailed studies of proliferation and apoptosis in 89 MDS patients. Our results demonstrated a rapid rate of both proliferation as well as apoptosis. Levels of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and interleukin-1 beta (IL-1 beta) were measured in the same patients. High levels of TNF-alpha were found to correlate with high levels of apoptosis in 83 MDS patients (P = 0.0045). We propose a dual role for TNF-alpha (or other cytokines) in the pathogenesis of MDS. On the one hand, TNF-alpha induces apoptosis in the maturing cells causing pancytopenia while on the other, it stimulates the proliferation of the primitive progenitors accounting for the hypercellular BM frequently seen in MDS. A new model for MDS is presented. The initial abnormality probably affects a primitive hemopoietic progenitor which acquires a growth advantage leading to monoclonal hemopoiesis, which in turn makes these cells susceptible towards acquiring additional mutations and appearance of cytogenetically marked (or unmarked) clones. Cytokines such as TNF-alpha whose source is presently unknown, then contribute towards the clinical syndrome of pancytopenia and hypercellularity.

Antigens, CD34↗
PubMed1996

A paradigm shift in myelodysplastic syndromes.

A poorly defined transforming event(s) affects the pluripotential bone marrow (BM) stem cell in myelodysplastic syndromes (MDS), conferring a growth advantage upon it which leads eventually to monoclonal hematopoiesis. The progeny of this transformed ancestor undergo recognizable albeit dysplastic maturation. We propose that this picture is further complicated by a variety of cytokines, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF-beta) and interleukin 1beta (IL-1beta) which exert a dual effect on the diseased cells. The immature CD34+ cells are stimulated to proliferate, while their later differentiated daughters are induced to undergo apoptosis accounting for the clinical syndrome of pancytopenia despite hypercellular BMs. Studies directed at measuring the rates of proliferation and apoptosis as well as the levels of TNF-alpha, TGF-beta and IL-1beta confirm this hypothesis and are presented in greater detail. A novel approach towards MDS therapy emerges as a result of this paradigm shift based upon the premise that anti-cytokine therapy would prevent excessive intramedullary apoptosis and result in improved cytopenias as well as cause a slowing down of the diseased precursor cell proliferation resulting in resumption of polyclonal hematopoiesis. Because a number of cytokines function through common lipid second messengers, interruption of this pathway should theoretically cause disruption in the signalling of a cascade of cytokines.

Apoptosis↗
PubMed1995

A multivariate study of non Hodgkin's lymphoma involving proliferation, apoptosis, bcl-2 and the microenvironment.

The study was carried out on 22 patients with non-Hodgkin's lymphoma (NHL) who had received sequential infusions of two thymidine analogues iododeoxyuridine (IUdR) and bromodeoxyuridine (BrdU). Cell cycle kinetic studies seemed to differentiate distinctly between low grade lymphoma (n = 8, LI = 2.6%) compared to that of intermediate grade (n = 9, LI = 13%, p = 0.0001) and high grade NHL (n = 5, LI = 16.3%, p = 0.0062). While the majority of 14 intermediate and high grade lymphomas had a high labeling index there were 3/14 patients with a LI of 5.5%, 5.5% and 4.1% respectively. A decrease in the rate of programmed cell death (PCD) or apoptosis due to the overexpression of bcl-2 has been implicated as the possible pathogenesis for follicular lymphoma. We determined the presence of bcl-2 protein immunohistochemically and apoptosis by in situ end labeling of DNA which detects cells in early stages of PCD not recognized morphologically. Nine NHL patients demonstrated PCD ranging from 1%-40%, while it was undetectable in 13/22 patients. Of these 13 cases, 6 showed the presence of bcl-2 expression. To understand the relationship of the microenvironment to the lymphoma cells, the presence of transforming growth factor beta (TGF-beta) was determined immunohistochemically. TGF-beta was present in all the cases where bcl-2 was present, except one. This study highlights some of the key biological features of NHL cells and their microenvironment.

Apoptosis↗
PubMed1988

Concomitant therapy with infusion of cisplatin and 5-fluorouracil plus radiation in head and neck cancer.

We have combined cisplatin, 5-fluorouracil infusion, and radiation in an every-other-week schedule in a phase I-II study of 44 patients with head and neck cancer to assess toxicity and response. Ten patients were treated palliatively with 2 to 6 cycles of therapy, and 34 were treated curatively with a planned 7 cycles. Of 34 patients treated curatively, all were initially controlled. Three died during treatment (1 myocardial infarction, 1 bowel perforation, and 1 renal failure after amino-glycoside antibiotics). Four patients have had regional recurrences, 7 failed at distant sites (follow-up 2 to 5 yr). Thirty-three percent of 20 patients with complete clinical disappearance of all evidence of their cancer have had a recurrence, as have 38% of 14 (P greater than .1) with some residual abnormalities (partial responders) following treatment. All failures were in the 25 patients with T4 and/or N3 disease. None of the 9 patients with lesser stage IV or stage III disease who were followed for 24 months or more had recurrences. Eighteen patients (53%) survive with a projected 3-year survival of 63% (95% confidence interval 47% to 77%). Nine (27%) have died of disease, 1 (3%) died of a second primary in the head and neck, 3 (9%) of intercurrent disease at 15 to 45 months, and 3 (9%) during treatment. Of the 10 patients treated palliatively, 1 died during treatment with hepatic failure, 6 had complete responses, and 2 had partial responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Treatment of advanced head and neck cancer with concomitant radiation and chemotherapy.

Forty-four patients with predominantly inoperable or recurrent head and neck cancers were treated with combined chemotherapy (CT) and radiation therapy (RT) in a Phase I/II study. CT and RT were combined in a concomitant fashion to take advantage of radiosensitizing properties of the chemotherapeutic agents. Each treatment cycle consisted of cisplatin 60 mg/M2 on day 1, 5-FU infusion at a dose of 800 mg/M2 per day continuously for 5 days and RT at 200 cGy per day, days 1 through 5. The treatment cycle was repeated every 2 weeks for 7 cycles in patients treated curatively and for 2 to 6 cycles in patients treated palliatively due to prior radiation therapy or the presence of metastatic disease. Regional control was achieved in 98% of the patients. Regional control has persisted in 87% of the patients treated curatively with a minimum follow-up of 24 months. Distant failure occurred in 23% of this group. Actuarial survival of 2 years for the curative group is 66%. Concomitant combination of radiation with radiation potentiating chemotherapeutic agents shows promise of increase in local control.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Cisplatin and 5-FU infusion chemotherapy in advanced, recurrent cancer of the head and neck: an Eastern Cooperative Oncology Group Pilot Study.

Thirty-four patients with advanced, recurrent head and neck cancer were treated with cisplatin (100 mg/m2 on Day 1) and continuous-infusion 5-FU (1.0 g/m2/24 hours on Days 1-5) every 3-4 weeks. All but one patient had failed prior radiation therapy or surgery; 27 had failed both. Two patients were not evaluable for response because of death within the first 2 weeks from unrelated heart disease. Among 30 patients with squamous cell carcinoma, five achieved complete response (CR) (17%) and 13 achieved partial response (PR) (43%). Durations of response for patients with a CR and PR were 10.4 and 3.1 months, respectively. Median time to disease progression for all patients was 4.5 months and median survival was 9.1 months. Median survival times for all responders and for complete responders and partial responders were 12.5, 14.2, and 10 months, respectively. One additional patient with an adenocarcinoma failed to respond, while a second with an adenoid cystic carcinoma achieved a PR for 3.4 months. Toxicity was moderate: seven patients experienced Eastern Cooperative Oncology Group grade 3 mucositis, and 11 patients had grade 3-4 hematologic toxicity. There was one treatment-related death due to nephrotoxicity. This study supports other studies that show a relatively high degree of activity of cisplatin and continuous-infusion 5-FU in advanced head and neck cancer.

Adult↗
PubMed1984

Doxorubicin and cisplatin for recurrent or metastatic squamous cell carcinoma of the head and neck.

Thirty-six patients with recurrent or metastatic squamous cell carcinoma of the head and neck were treated with doxorubicin and cisplatin. The overall response rate (complete + partial) was 30%, with a median duration of response of 4 months. Median survival durations for responders and nonresponders were 15 and 4 months, respectively. Nausea, vomiting, and alopecia were common. Neither grade 4 myelosuppression nor irreversible renal failure was observed.

Adult↗
PubMed1981

Treatment of stage D prostatic carcinoma with megestrol acetate.

Nine previously untreated patients with stage D prostatic carcinoma received megestrol acetate 40 mg orally three times daily. Responses included five partial regressions, two stabilizations, and two progressions. Duration of response ranged from 3+ to 33+ months, with a mean of 11.7 months and a median of 12 months. Three of five patients who had failed prior hormonal therapy remained objectively stable while receiving megestrol acetate. No gastrointestinal toxicity, gynecomastia, fluid retention, or thromboembolic complications were observed during treatment. Weight gain of 5 to 51 pounds occurred in seven of 14 patients.

Aged↗
PubMed1976

IgE myeloma presenting with classical myeloma features.

A patient with IgE myeloma, presenting with bone lesions and modest anemia without plasma cell leukemia or hepatosplenomegaly, is described. The findings are compared with those of other patients with this and the more common forms of multiple myeloma.

Aged↗
PubMedDate not supplied

Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes.

Extensive apoptosis or programmed cell death (PCD) of both hematopoietic (erythroid, myeloid, megakaryocytic) and stromal cells in myelodysplastic syndromes (MDS) cancels the high birth-rate resulting in ineffective hematopoiesis and has been demonstrated as the probable basis for peripheral cytopenias in MDS by our group. It is proposed that factors present in the microenvironment are inducing apoptosis in all the cells whether stromal or parenchymal. To investigate this hypothesis further, bone marrow biopsies from 46 MDS patients and eight normal individuals were examined for the presence of three cytokines, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta) and granulocyte macrophage-colony stimulating factor (GM-CSF) and one cellular component, macrophages, by the use of monoclonal antibodies immunohistochemically. Results showed the presence of TNF-alpha and TGF-beta in 41/46 and 40/46 cases of MDS respectively, while only 15 cases showed the presence of GM-CSF. Further a significant direct relationship was found between the degree of TNF-alpha and the incidence of PCD (p= 0.0015). Patients who showed high PCD also had an elevated TNF-alpha level. Thus, the expression of high amounts of TNF-alpha and TGF-beta and low amounts of the viability factor GM-CSF may be responsible for the high incidence of PCD leading to ineffective hematopoiesis in MDS. Future studies will be directed at attempting to reverse the lesion in MDS by using anti-TNF-alpha drugs such as pentoxifylline.

Apoptosis↗