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Biomedical subjects

M Kimmel

Publications and source records attributed to M Kimmel.

At least 73 records · Page 4Linked to original sources
PubMed1989

Intravesical bacillus Calmette-Guerin therapy for in situ transitional cell carcinoma involving the prostatic urethra.

A total of 23 patients presenting with multifocal superficial bladder cancer and concomitant in situ transitional cell carcinoma of the prostatic urethra (mucosal in 19 and ductal in 4) underwent transurethral resection and intravesical bacillus Calmette-Guerin therapy. Median followup was 51.6 months (range 6 to 105 months). Of the 23 patients 13 (48 per cent) had a complete response with a median followup of 43.7 months without recurrence. Progression of some type (local, muscle invasion or metastasis) occurred in 10 patients (44 per cent); none occurred in the prostatic urethra. Median interval free of progression was 55.7 months; 7 of 10 patients required cystectomy for progression or refractory disease in the bladder (prostate negative for transitional cell carcinoma). A trial of complete transurethral resection plus intravesical bacillus Calmette-Guerin is a viable alternative to immediate radical cystectomy for patients with mucosal and/or ductal involvement of the prostatic urethra with in situ transitional cell carcinoma.

Administration, Intravesical↗
PubMed1989

Flow cytometry as a predictor of response and progression in patients with superficial bladder cancer treated with bacillus Calmette-Guerin.

Simultaneous bladder wash flow cytometry, voided urinary cytology and cystoscopic examinations were performed at 3-month intervals during a median of 18 months (range 5.5 to 50 months) in 65 patients receiving intravesical bacillus Calmette-Guerin treatment for superficial bladder cancer. Of the 65 patients treated 36 (56 per cent) had a complete response, 12 (18 per cent) had no response and 17 (26 per cent) had progression. Results of examinations at 6 months suggested that a negative bladder wash flow cytometry (29 of 36 patients, r equals 0.73, p less than 10(-7) is a strong predictor of response to bacillus Calmette-Guerin, comparable with cytological (r equals 0.60, p less than 10(-7) or cystoscopic (r equals 0.38, p less than 0.005) examinations alone or combined with cytology (r equals 0.74, p less than 10(-7)). At 6 months a positive bladder wash flow cytometry (r equals 0.44, p less than 0.0005) is as strong a predictor of disease progression as a positive cystoscopic examination (r equals 0.43, p less than 0.0005). The combination of bladder wash flow cytometry and voided urinary cytology is not superior to positive bladder wash flow cytometry alone. Median estimated interval to progression for these patients treated with bacillus Calmette-Guerin was 38 months. In the subgroup with positive bladder wash flow cytometry at 6 months the median interval to progression was 30 months. With a negative bladder wash flow cytometry at 6 months the probability of survival free of progression at 30 months was 85 per cent (p less than 0.01). Thus, negative bladder wash flow cytometry at 6 months is a strong predictor of response to bacillus Calmette-Guerin and also survival free of progression.

Administration, Intravesical↗
PubMed1988

Mammary angiosarcoma. The prognostic significance of tumor differentiation.

Mammary angiosarcoma appears to be a heterogeneous group of neoplasms morphologically, in which growth pattern or grade is an important prognostic factor. In this report, 63 patients whose slides were seen in consultation and/or who were treated at Memorial Sloan-Kettering Cancer Center (MSKCC) are described. Included are 32 MSKCC patients from an earlier study (with additional follow-up for 15 who are alive) and 31 new cases. Twenty-five (40%) patients had low-grade (Type I) lesions (including the only man in the series), 12 (19%) patients had intermediate-grade (Type II) tumors, and 26 (41%) patients had high-grade (Type III) angiosarcomas. Because prognosis is significantly related to the type of angiosarcoma, the lesion should be thoroughly studied microscopically to establish tumor type. Estimated probabilities of disease-free survival 5 years after initial treatment were as follows: Type I: 76%; Type II: 70%; and Type III: 15%. The median length of disease-free survival also was related to tumor type (Type I: greater than 15 years; Type II: greater than 12 years; and Type III: 15 months). Pretreatment duration of the lesion and primary tumor size were not significantly related to the risk of recurrence or to survival. Total mastectomy is recommended for most mammary angiosarcomas. Adjuvant chemotherapy was used in 31 of 63 (49%) patients and, in this group, recurrences developed in 14 (45%) patients. Among 32 (51%) patients not treated with adjuvant chemotherapy, 18 (56%) had recurrences. Whereas the few long-term survivors with Type III tumors received adjuvant chemotherapy, recurrences developed in most patients with comparable lesions who were given this treatment. Because Type III angiosarcoma has a poor prognosis, such treatment may be appropriate for these patients. We were unable to demonstrate that adjuvant chemotherapy significantly improved prognosis for patients with Type I and Type II tumors, although recurrences tended to be less frequent among treated patients.

Adult↗
PubMed1988

Natural history of adenocarcinoma-large cell carcinoma of the lung: conclusions from screening programs in New York and Baltimore.

A mathematical model of the progression kinetics of lung cancer was described and used to shed light on the natural history of adenocarcinoma and large cell carcinoma of lung from data collected in screening studies of male smokers by the Memorial Sloan-Kettering Cancer Center and The Johns Hopkins Medical Institutions. In both programs, estimates of the mean duration of early-stage adenocarcinoma or large cell carcinoma of lung ranged upward from 4 years, and estimates of the probability of detecting it in early-stage disease ranged downward from .16. The probabilities of curing early-stage disease through surgical treatment were found to be at most .52 and .13 in the New York and Baltimore studies, respectively. These estimates led to the conclusion that expected reduction in mortality from adenocarcinoma and large cell carcinoma of lung as due to annual x-ray screening from age 45 to 80 years is not greater than 18% in New York and 5% in Baltimore.

Adenocarcinoma↗
PubMed1988

Interactions of arterial cells: III. Stathmokinetic analyses of smooth muscle cells cocultured with endothelial cells.

Arterial endothelial cells (EC) or their conditioned medium (ECCM) can alter the proliferation of cocultured arterial smooth muscle cells (SMC). Previously, we have shown, as have others, that EC regulate the growth of cocultured SMC depending on the density of both cell types. To ascertain the rate of cell-cycle traverse in preconfluent arterial SMC cocultured with arterial EC or ECCM (derived from preconfluent EC), we have conducted a series of stathmokinetic experiments using flow cytometry to determine where specific changes may occur in the cell cycle. Results of our experiments indicate for the first time that ECCM stimulates the proliferation of preconfluent SMC by significantly shortening the residence times in the G1 and S phases of the cell cycle. The predominant relative effect occurs within the early G1 (G1A) compartment where pretreatment with ECCM shortens the residence time by approximately 55%. Furthermore, we have observed that preincubation of serum-free ECCM with antiplatelet-derived growth factor (PDGF) antibody abolishes any mitogenic effect on SMC. This suggests that EC secrete PDGF-like molecules which enhance the proliferation rate of preconfluent, cocultured SMC. These findings support the hypothesis that arterial EC may secrete mitogens which stimulate arterial SMC proliferation in the vascular wall.

Animals↗
PubMed1988

T-cell subsets in peripheral blood of patients with newly diagnosed and posttreatment Hodgkin's and non-Hodgkin's lymphomas. Analysis by monoclonal antibody staining and flow cytometry.

T-cell subsets in the peripheral blood of patients with Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHLs) were determined using anti T-cell monoclonal antibodies and flow cytometry. Forty HD patients and 30 NHL patients were evaluated; 76 normal blood donors served as controls. Newly diagnosed (untreated) HD and NHL patients had relatively normal values for percentages of total T-cells, helper cells and suppressor cells; their helper/suppressor ratios were also normal. The total lymphocyte count was normal for pretreatment HD, but lower than normal for NHL. Following treatment, both HD and NHL patients showed significantly decreased helper/suppressor ratios, caused by a significant decrease in the percentage of helper cells in HD patients and a significant increase in the percentage of suppressor cells in the small number of NHL patients studied. A small number of NHL patients, followed without specific treatment (passive follow-up), had relatively normal values for percentages of helper and suppressor cells and total T-cells. For both groups of patients off treatment, it is concluded that the lower helper/suppressor ratios are due to the prolonged effects of treatment (predominantly irradiation).

Adult↗
PubMed1987

The sensitivity of bladder wash flow cytometry, bladder wash cytology, and voided cytology in the detection of bladder carcinoma.

The sensitivity of voided urinary cytology (VUC), bladder wash cytology (BWC), and bladder wash flow cytometry (BWFCM) in detecting cancer was studied in 70 patients with biopsy-proven bladder tumors. There were 11 Grade I papillomas, 14 Grade II TA, 18 Grade II-III TIS, 19 Grade II-III T1, and eight Grade II-III T2 carcinomas. One to five VUCs per patient (mean, 2.63) were obtained within the 24 hours preceding biopsy. At endoscopy a bladder wash specimen was obtained and divided for cytologic and flow cytometric examinations. For all tumor categories combined, the sensitivity for one, two, and three voided cytology examinations per patient was 41%, 41%, and 60%, respectively. The sensitivity of a single BWC was 61%, of a single BWFCM, 83%. Thus, one BWFCM is more sensitive than three VUC (binomial test; P = 0.006); one BWC is more sensitive than two VUC (P = 0.01); and one BWFCM is more sensitive than one BWC (P = 0.003). These findings remain significant when papillomas are excluded from the analysis (P less than or equal to 0.03) and when papillomas and T2 tumors are jointly excluded (P less than or equal to 0.02). Only four of 70 patients (6%) had their cancers detected by VUC and/or BWC rather than BWFCM. In summary, irrigation cytology specimens are more sensitive than voided urinary cytology, and bladder wash flow cytometry is more sensitive than either in diagnosing bladder cancer. Flow cytometry is more sensitive because of the better sampling of bladder irrigation compared with voided urine and because of the measurement technique itself.

Biopsy↗
PubMed1987

The sensitivity of flow cytometry compared with conventional cytology in the detection of superficial bladder carcinoma.

Three groups of patients with superficial bladder carcinoma were studied: 110 patients had carcinoma in situ (TIS), 54 had noninvasive papillary transitional cell carcinoma (TA), and 64 had transitional cell carcinoma infiltrating the lamina propria (T1). One to six conventional cytologic examinations per patient (mean 2.8) were obtained during the 24 hour period before biopsy. For all tumor categories combined, the sensitivity was 49%, 54%, 62%, and 66% for one, two, three, and four cytologic examinations per patient, respectively. Cytologic sensitivity varied according to tumor category; it was greater in the TIS and T1 categories than in the TA category. To compare with the cytologic results, a subset of 103 patients had bladder irrigation performed immediately before the biopsy which was subsequently analyzed by flow cytometry. The sensitivity of a single flow cytometric examination for all tumor categories combined was 78%. As with the cytologic examinations, the sensitivity of flow cytometry varied with tumor category; it was greater in TIS and T1 categories than in the TA category. The sensitivity of one flow cytometric examination was superior (binomial test, P less than or equal to 0.05) to that of one or two cytologic examinations for TA tumors and to that of one, two, or three cytologic examinations for TIS, T1, and all tumor categories combined. Only three of 103 patients had their cancers detected by cytologic examination and not by flow cytometry.

Carcinoma in Situ↗
PubMed1987

Estrogen receptor protein of breast cancer in patients with positive nodes. High recurrence rates in the postmenopausal estrogen receptor-negative group.

In 448 patients with positive axillary lymph nodes who were treated with mastectomy at Memorial Sloan-Kettering Cancer Center, New York, from 1973 to 1978, estrogen receptor (ER) status was associated with survival. With a median follow-up of 75 months, significant differences were noted in the 288 postmenopausal patients; ER-positive patients had better six-year disease-free survival than ER-negative patients (60% vs 45%), as well as better overall survival. These differences were true in subgroups with one to three and four or more involved nodes. The addition of adjuvant systemic therapy had no significant effect on either ER-positive or ER-negative patients. The need for new imaginative systemic programs in the subgroup of ER-negative postmenopausal patients with breast cancer with positive nodes is apparent.

Axilla↗
PubMed1987

Effects of inhibition of RNA or protein synthesis on CHO cell cycle progression.

Chinese hamster ovary (CHO) cells, synchronized by selective detachment at mitosis, were treated with various concentrations of actinomycin D (AMD) or cycloheximide (CHX) either immediately, or 1, 2, or 3 hr after mitosis. Since the minimum duration of G1 phase in these cultures was 3.4 hr, the addition of RNA or protein synthesis inhibitors took place at the beginning, first third, second third, or end (G1-S boundary) of G1 phase. The kinetics of exit from G1 phase, the rate and extent of traverse of S phase, and the reaccumulation of RNA were estimated under each set of growth conditions by flow cytometry of acridine orange-stained cells. A mathematical model was constructed to describe the trajectories of the cell populations with respect to their increase in RNA and DNA content in the absence or presence of the inhibitor. The chronologic synchrony imposed on the CHO cell population began to decay within 3 hr, resulting in stochastic entrance of cells into S phase in the absence of inhibitor. Addition of AMD or CHX at 0, 1, 2, or 3 hr after mitosis, regardless of the inhibitor concentration, did not provide evidence of a critical restriction point in G1 beyond which cells were committed to enter S phase and were no longer sensitive to moderate suppression of RNA or protein synthesis. The observed kinetics of cell entrance into an traverse of S phase were consistent with an inherently heterogeneous response to serum stimulation occurring at or just after cell division.

Animals↗
PubMed1987

Malignant lymphoma of the breast. A study of 53 patients.

Fifty-three patients with non-Hodgkin's lymphoma of the breast were reviewed and classified using four current classifications of lymphoma. All patients were female with a mean age of 57 years. The majority of patients had histiocytic or large-cell lesions and presented as clinical Stage I. The tumors were described clinically as primary in the breast, and mammary parenchyma was found in 79% of the diagnostic biopsy specimens. The other specimens showed lymphoma in mammary adipose tissue. Survival was not influenced by the presence or absence of breast parenchyma in the biopsy. Statistically significant survival differences were found to be related to stage at presentation as well as to tumor grade, using Kiel and Working Formulation categories. Patients with Stage I disease and those with low-grade lesions had a more favorable prognosis. No discernible factors, including stage or histologic findings, appeared to affect the recurrence rate.

Adult↗
PubMed1987

The natural history of lung cancer in a periodically screened population.

A mathematical model of the progression kinetics of lung cancer in a periodically screened population is proposed and data collected by the Memorial Sloan-Kettering Cancer Center in New York are used for parameter estimation. It is assumed that the development of adenocarcinoma of lung is a stochastic process with two stages, early and advanced, characterized by mean times, detection probabilities, and cure probabilities. Confidence regions of these parameters are estimated using a number of novel techniques. It is found, surprisingly, that the mean duration of the early stage is at least 4 years, the detectability less than .2, and the curability less than .5. These estimates imply that annual radiographic screening from age 45 to 80 might decrease mortality from adenocarcinoma of lung by something less than 20%.

Adenocarcinoma↗
PubMed1986

Stathmokinetic analysis of human epidermal cells in vitro.

Proliferation kinetics of cultured human epidermal cells is characterized in quantitative terms. Three distinct subpopulations of keratinocytes, two of which are cycling, have been discriminated by two parameter DNA/RNA flow cytometry. Based on mathematical modelling, the cell cycle parameters of the cycling subpopulations have been assessed from stathmokinetic data collected at different time points after initiation of cultures (7-15 days). The first subpopulation is composed of low-RNA cells which resemble basal keratinocytes of epidermis and which show some characteristics of stem cells; these cells have a mean generation time of approximately 100 hr. The second subpopulation consists of high-RNA cells, resembling stratum spinosum cells of epidermis, which have an average generation time of approximately 40 hr. The third subpopulation consists of non-cycling cells with G0/G1 DNA content, with cytochemical features similar to those of cells in granular layer of epidermis. The results based on modelling can reproduce with acceptable accuracy the actual growth curve of the cultured cell population. Analysis of kinetics and differentiation of human keratinocytes is of interest in view of the recent application of cultured epidermal cell sheets for transplantation onto burn wounds. The results of this study also reveal the existence of regulatory mechanisms associated with proliferation and differentiation in the cultured epidermal cell population.

Acridine Orange↗
PubMed1986

Human keratinocyte culture. Identification and staging of epidermal cell subpopulations.

Stratification of human epidermal cells into multilayered sheets composed of basal and suprabasal layers (resembling the stratum germinativum and stratum spinosum of the epidermis) was studied in a dermal component-free culture system. Although no stratum corneum developed in vitro, this culture system provided a method to study early events in human keratinocyte differentiation. Multiparameter flow cytometric analysis of acridine orange-stained epidermal cells from these cultures revealed three distinct subpopulations differing in cell size, RNA content, and cell cycle kinetics. The first subpopulation was composed of small basal keratinocytes with low RNA content and a long generation time. The second subpopulation consisted of larger keratinocytes, having higher RNA content and a significantly shorter generation time. Finally, the third subpopulation contained the largest cells, which did not divide, and represent the more terminally differentiated keratinocytes. This in vitro approach provides discriminating cytochemical parameters by which the maturity of the epidermal cell sheets can be assessed prior to grafting onto human burn patients.

Burns↗
PubMed1985

Kinetic analysis of drug-induced G2 block in vitro.

The data on cell-cycle effects of two prospective antitumour agents, (+)-1,2,-bis(3,5-dioxopiperazine-1-yl)propane (soluble ICRF; NSC 169780) and 1,4-bis(2'chloroethyl)-1,4-diazabicyclo [2.2.1] heptane diperchlorate (CBH; NSC 57198) were used to determine whether a modified stathmokinetic experiment could predict the effects of continuous, long-term (0-48 hr) drug exposure in an in vitro L1210 murine leukaemia cell system. Generally, continuous drug exposure of exponentially growing cells does not provide sufficient quantitative information concerning cell-cycle-phase-specific mechanisms of drug action. Alternatively, stathmokinetic experiments, which are usually limited to some fraction of one cell doubling time, provide little information about long-term drug effects. By using mathematical models constructed for this purpose, however, stathmokinetic data can predict the overall proportion of cells affected by a drug though failing to discern between various kinds of drug action (e.g. reversible v. irreversible block, blocking v. killing action, etc.), especially when it occurs in G2 phase. In addition, it can be shown that for at least one of the drugs (soluble ICRF) the stathmokinetic experiment fails to predict 'after-effects' of drug treatment which extend into the following cell cycle(s). It also becomes clear that the degradation of exponential growth characteristics of quickly dividing cells during long-term, continuous drug exposure makes prediction of cell-cycle kinetic perturbations uncertain when derived from short-duration stathmokinetic experiments. However, with care, the joint application of 'short term' (e.g. stathmokinesis) and 'long term' (e.g. continuous exposure) techniques allow adequate quantitative insight into drug-perturbed cell-cycle kinetics. The applicability of modelling techniques is discussed: in the present instance it is limited to lower drug concentrations. For higher drug concentrations, effects like increased ploidy, ineffective division, etc., make it impossible in the present study to obtain a clear picture of the kinetics.

Animals↗
PubMed1984

Analysis of a cell cycle model based on unequal division of metabolic constituents to daughter cells during cytokinesis.

We demonstrate that the unequal division of RNA during cytokinesis explains the dispersion of cell generation times in CHO cell cultures. Experimental cytometric results reported previously serve as a basis for a probabilistic model of cytokinesis. Unequal RNA division to daughter cells, together with two simple laws of RNA production, are used as a source of randomness within the cell cycle. The model reproduces the experimental growth of the CHO cell population, including the observed variability in RNA content. The model has stabilizing properties which explain why a cell population with increased RNA content characteristics, a few cell cycles, to the original pattern. Other cell cycle characteristics, like sister-to-sister and mother-to-daughter generation time correlations implied by the model, are close to their experimental analogs. The conceptual basis of the model is general enough to include unequal division of factors other than RNA (cell mass, cell proteins, etc.) as sources of generation time variability. It seems that the observed dispersion of cell generation times, explained previously in the terms of random transitions in some part of the cell cycle (the Smith & Martin A and B state hypothesis), can be reduced to the single random event of unequal division. This supplies a new convenient tool in the investigation of cell cycle kinetics.

Animals↗
PubMed1984

Effects of [3H]UdR on the cell-cycle progression of L1210 cells.

Tritium-labelled uridine [( 3H]UdR) perturbs progression of L1210 cells through the mitotic cycle. The main effect manifests as a slowdown or arrest of a portion of cells in G2 and is already observed 2 hr after addition of 0.5-5.0 microCi/ml of [3H]UdR into cultures. At 2.5-5.0 microCi/ml of [3H]UdR a slowdown of cell progression through S is also apparent. Additionally, there is an increase in the number of cells with DNA values higher than 4C in cultures growing in the presence of [3H]UdR for 8-24 hr. A pulse of [3H]UdR of 2 hr duration labels predominantly (95%) cellular RNA. The first cell-cycle effects (G2 slowdown) are observed when the amount of the incorporated [3H]UdR is such that, on average there are fewer than thirty-six [3H] decays per cell which corresponds to approximately 12-19 rads of radiation. The S-phase slowdown is seen at a dose of incorporated [3H]UdR twice as high as that inducing G2 effects. The specific localization of [3H]UdR in nucleoli, peripheral nucleoplasm and in cytoplasm, as well as differences in the kinetics of the incorporation in relation to phases of the cell cycle are discussed in the light of the differences between the effects of [3H]UdR and [3H]thymidine. Mathematical modelling of the cell-cycle effects of [3H]UdR is provided.

Animals↗