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Biomedical subjects

M Kimmel

Publications and source records attributed to M Kimmel.

At least 55 records · Page 3Linked to original sources
PubMed1991

Retention of the mitochondrial probe rhodamine 123 in normal lymphocytes and leukemic cells in relation to the cell cycle.

The cationic fluorochrome rhodamine 123 (R123) is specifically taken up by mitochondria of live cells where it is retained due to the mitochondrial transmembrane potential. After pulse exposure of human normal quiescent or proliferating lymphocytes, human lymphocytic leukemic MOLT cells, and mice leukemic L1210 cells to 10 micrograms/ml of R123, the dye release was studied using flow cytometry. Two distinct phases of R123 release, each following first-order kinetics, were apparent; the half-time of retention for the rapidly and slowly released fractions of R123 was 0.8-1.1 and 2.8-4.2 h, respectively. Simultaneous supravital cell staining with R123 and Hoechst 33342 made it possible to correlate retention of R123 with cell position in the cell cycle. No significant differences were observed in the rate of R123 release from cells in G1 vs S or vs G2 + M phases of the cycle. The data rule out a possibility that the release of R123 is due to periodic depolarization of the mitochondria in the cell as may be postulated by cell cycle models that assume a transient passage of cells through resting phase following division. The observed similar rates of R123 release regardless of cell type or cell cycle phase suggest that the factors affecting the exchange are similar in normal lymphocytes vs leukemic cells and unrelated to cell proliferation rate or phase of the cell cycle. Two distinct rates of R123 release indicate the presence of two kinds of binding sites differing in affinity to the dye.

Cell Cycle↗
PubMed1991

Cell cycle kinetics with supramitotic control, two cell types, and unequal division: a model of transformed embryonic cells.

We develop a mathematical model of cell cycle kinetics of transformed embryonic cells. The model includes supramitotic regulation, in which decisions regarding growth control are made at a point inside the cell division cycle and their impact extends to the next decision point, located in the next division cycle. Another feature is the presence of two varieties of cells, which switch from one to the other with given transition probabilities. The third factor considered is unequal division of cells, also defined in probabilistic terms. We provide a rigorous description of the model and derivation of its equations and analyze its asymptotic properties by defining and investigating an abstract semigroup of positive linear operators in appropriate state space. The spectral properties of the semigroup yield the balanced exponential growth law for the model. To compare the model to experimental data, we derive basic pedigree statistics, beta curves, and generation time correlations. We present numerical calculations based on measurements available for the embryonic cells. We conclude that to yield the experimentally obtained pedigree statistics, switches from one cell variety to the other must be quite infrequent.

Animals↗
PubMed1991

Nonparametric estimation of the size-metastasis relationship in solid cancers.

This paper is concerned with the relationship between the occurrence of metastases and the size of primary cancers. We consider two probabilistic characterizations of this relationship. First is the distribution function of tumor sizes at the point of metastatic transition; second is the probability that detectable metastases are present when the cancer comes to medical attention. The equation relating these two functions is developed and conditions for their being identical are explored. Since the tumor size at the point of metastasis is not usually observable, estimation of the first distribution requires the use of the EM algorithm. Nonparametric methods of estimating both functions are explored, with attention to the fact that tumors often fail to be measured, particularly those that are known to be metastatic. The methods are applied to the estimation of primary tumor size at the point of distant metastasis in lung cancer (epidermoid and adenocarcinoma) and colorectal cancer and at the point of nodal metastasis in breast cancer. Monte Carlo experiments confirm that the bias inherent in the methodology is acceptably small.

Adenocarcinoma↗
PubMed1990

DNA in situ sensitivity to denaturation in bladder cancer and its correlation with tumor stage.

DNA content and sensitivity of DNA in situ to denaturation by acid were analyzed by flow cytometry of cell nuclei freshly isolated from the bladder tumors of 32 patients and were compared with normal urothelium of 8 subjects. DNA sensitivity to denaturation was assessed in RNase treated cells by acridine orange metachromasia following partial denaturation with hydrochloric acid; the extent of denatured DNA is given as an index (alpha t), representing the ratio of single stranded to total DNA per nucleus. Of the low stage tumors (papillomas, Ta, Tis, T1) 11 of 18 (61%) were aneuploid. Of the high stage tumors (T2 and T3a) 11 of 14 (79%) were aneuploid. DNA in nuclei of normal transitional epithelium was very sensitive to denaturation, as was papilloma, characterized by nuclear alpha t indices of 0.73 +/- 0.01 (SD) and 0.73 +/- 0.04, respectively. Nuclear DNA of noninvasive carcinomas (Ta, Tis) was significantly more resistant to denaturation (alpha t = 0.69), and DNA of invasive carcinomas was most resistant, ranging from alpha t = 0.61 (T1 tumors) to alpha t = 0.59 (T2 tumors) to alpha t = 0.57 (T3 tumors). High stage tumors as a group (T2, T3) had significantly different (lower) alpha t values than low stage tumors (Ta, Tis, T1). In model cell culture systems it is known that a decrease in alpha t index, i.e., greater resistance to denaturability, occurs as cells transit from resting phase into the cell cycle. Whether the alpha t index can be used to estimate resting vesus cycling cells of human tumors is still speculative; changes in DNA denaturability also are known to occur with changes in chromatin structure during cell differentiation and in transformation. However, the empirical relationship between alpha t index and tumor stage, of itself, may prove clinically useful in identifying more advanced and perhaps more aggressive tumors.

Biopsy↗
PubMed1990

Lymphomas in dogs. A morphologic, immunologic, and clinical study.

One hundred seventy-six canine lymphomas were classified morphologically using four of the major human lymphoma classification schemes (Rappaport, Lukes-Collins, Kiel, and the Working Formulation). All 176 dogs received the same chemotherapeutic protocol. Sixty-two of these lymphomas had their immunophenotypes established by examination of cell surface markers by automated cytofluorography. Several different morphologic types of canine lymphoma were identified and these were comparable to morphologic categories in human classification schemes. Follicular and low grade lymphomas were rare. The two most common morphologic types were diffuse large cell (centroblastic) and immunoblastic. The Kiel classification appeared to be the most useful human scheme for classifying the canine lymphomas. Cytofluorographic analysis was generally straightforward, and 60 of the 62 lymphomas were placed into one of three immunophenotypic categories: 27 pan-T(LQ1)+SIg+, 21 pan-T(LQ1)-SIg+, and 12 pan-T(LQ1)+SIg-. Two of the lymphomas could not be characterized immunologically because a pre-existing or reactive non-neoplastic population of lymphocytes made interpretation of single cell suspension analysis difficult. The authors identified correlations between morphology and survival and disease-free remission; dogs with high-grade tumors generally survived the longest and had the longest remissions. No correlations were identified between high concentrations of serum lactate dehydrogenase, age, sex, or stage of disease, and morphology, immunophenotype, remission, or survival times. A significant correlation between clinical illness and survival time was documented. The median age of the dogs was nine years, no significant effect of sex on prevalence was observed, and some breeds were significantly overrepresented. Significant morphologic-immunophenotypic correlations included shorter remission and survival times for T-cell tumors than B-cell tumors, and a highly significant correlation between the pan-T(LQ1)+SIg-"T cell" phenotype and hypercalcemia.

Animals↗
PubMed1990

Occult breast carcinoma presenting with axillary lymph node metastases: a follow-up study of 48 patients.

Breast carcinoma presenting with axillary metastases and no clinically apparent primary tumor in the breast is an uncommon form of stage II disease. Published studies have been characterized by small numbers and/or limited follow-up information. Although these patients are often looked on individually as having advanced disease, several published reports suggest that their prognosis is not exceptionally grave. The present study evaluated the largest series thus far described, consisting of 48 patients with a median follow-up of 5 years. Each presented with an axillary mass which proved to be metastatic adenocarcinoma, consistent with mammary origin when examined histologically. No patient had a palpable breast tumor. Mammography was negative in 28 patients (76%), and suspicious or positive in nine (24%). Nine (35%) of 26 metastases were positive for estrogen (ER) and progesterone (PR) receptors, 10 (38%) were negative for both receptors, and seven (27%) were ER positive/PR negative. Primary treatment was mastectomy and axillary dissection in 38 cases, 21 with adjuvant chemotherapy. A primary tumor was found pathologically in the breast in 36 cases (75%). Among 34 reviewed primary lesions, 27 (79%) were invasive and seven (21%) were histologically "noninvasive." Measured size was 0.1 to 6.5 cm (median, 1.5 cm). The number of involved lymph nodes was one to 65 with 20 cases having one to three positive and 20 having four or more positive. Follow-up ranged from 5 to 267 months (median, 60 months). Overall, 29 patients (60%) remained alive and disease free; two (4%) were disease free, but died of other causes; and the status of two (4%) was not known. Fifteen patients developed recurrent carcinoma, including 12 (25%) who died of disease. When compared with a matched series of stage II patients with equivalent extent of disease who presented with palpable breast tumors, patients with occult lesions had a more favorable prognosis overall, as well as when stratified by tumor size and nodal status, but the differences were not statistically significant. These results probably reflect the fact that the majority of stage II patients with clinically occult breast carcinoma usually have a grossly measurable invasive tumor detected pathologically. Consequently, the actual pathologic stage, which takes tumor size into consideration, determines prognosis rather than the apparent clinical stage described when the patient is first examined.

Adult↗
PubMed1990

The response of patients with superficial bladder cancer to a second course of intravesical bacillus Calmette-Guerin.

Of 347 patients who received an initial 6-week course of intravesical bacillus Calmette-Guerin for superficial transitional cell carcinoma of the bladder 28 (8%) were treated with another course. Subsequent progression of disease (muscle infiltration, metastasis or local progression) occurred in 13 patients (46%). Of the 15 patients (54%) without progression 10 (36%) had a complete response and 5 (33%) had new tumors, and they were rendered free of disease after transurethral resection. The median duration of response to course 1 of bacillus Calmette-Guerin was shorter for patients with disease progression after course 2 than for those with no progression (15 and 27 months, respectively, p equals 0.05). The median followup after course 2 was 31.2 months (range 15.6 to 56.4 months). The median interval between courses 1 and 2 of intravesical bacillus Calmette-Guerin was 21.6 months (range 3.6 to 78.8 months). The interval from course 2 of bacillus Calmette-Guerin to progression correlated with the duration of response to course 1 of treatment (p equals 0.01). It appears that a subsequent treatment with bacillus Calmette-Guerin is most likely to be useful in patients who have a sustained response to the initial treatment.

Administration, Intravesical↗
PubMed1990

Juvenile papillomatosis of the breast. A follow-up study of 41 patients having biopsies before 1979.

Juvenile papillomatosis (JP) is a benign proliferative breast tumor rarely found in women older than 30 years of age that may exhibit considerable histologic atypia. Often these findings would be regarded as precancerous in older patients. Rarely, carcinoma and JP have been coexistent at diagnosis, but little is known about the risk for development of carcinoma after excisional biopsy of JP. To examine this issue, the authors reviewed a series of 41 patients with JP who had biopsies between 1960 and 1978 with a median follow-up of 14 years. Age at diagnosis ranged from 15 to 35 years (median, 19 years), whereas at last follow-up the patients were 22-48 years old (median, 36 years). Overall, 21 (58%) reported a positive family history for breast carcinoma, with mothers and maternal aunts being at highest risk. Six had bilateral JP. Subsequent breast carcinoma was diagnosed in four (10%) of the patients with JP. All of these patients were unusual because they had recurrent and bilateral JP. In two instances the changes were multifocal. Each had a positive family history for breast carcinoma. In this series, none of the patients with nonrecurrent unilateral, unicentric JP has thus far had subsequent mammary carcinoma develop. When counseling the JP patient one should take care not to exaggerate her near term risk for development of carcinoma. The present data suggest that concern should be greatest for women with a positive family history and recurrent bilateral JP.

Adenofibroma↗
PubMed1990

Apocrine mammary carcinoma. A clinicopathologic study of 72 cases.

Apocrine carcinoma (AC) is an uncommon, poorly characterized type of breast tumor. In this review, 55 patients with intraductal (ID) AC and 17 patients with infiltrating (IF) AC were analyzed retrospectively to define the histologic features and clinical course of this neoplasm. Recurrences in the breast occurred in 3 of 20 ID-AC patients treated by biopsy alone, but not in the 2 patients who received local radiation therapy after biopsy. One patient with ID-AC had axillary metastases at the time of treatment by mastectomy and died of disease five years later. The remaining patients with ID-AC treated by mastectomy have remained disease free. One of the three patients with IF-AC treated by biopsy alone died of disease, and one of two patients with IF-AC treated by biopsy and radiotherapy was alive with carcinoma. Twelve patients with IF-AC were treated by mastectomy. Ten of them were recurrence free at the time of last observation. More than one-third of the cases of ID-AC and IF-AC were detected by mammography alone. Survival analysis of IF-AC cases compared with nonapocrine duct carcinoma cases matched for stage revealed no statistical difference in estimated recurrence-free survival or estimated survival probability. AC is a distinct morphologic entity with a natural history similar to that of nonapocrine ductal carcinoma.

Adult↗
PubMed1990

Mathematical models of gene amplification with applications to cellular drug resistance and tumorigenicity.

An increased number of copies of specific genes may offer an advantage to cells when they grow in restrictive conditions such as in the presence of toxic drugs, or in a tumor. Three mathematical models of gene amplification and deamplification are proposed to describe the kinetics of unstable phenotypes of cells with amplified genes. The models differ in details but all assume probabilistic mechanisms of increase and decrease in gene copy number per cell (gene amplification/deamplification). Analysis of the models indicates that a stable distribution of numbers of copies of genes per cell, observed experimentally, exists only if the probability of deamplification exceeds the probability of amplification. The models are fitted to published data on the loss of methotrexate resistance in cultured cell lines, due to the loss of amplified dihydrofolate reductase gene. For two mouse cell lines unstably resistant to methotrexate the probabilities of amplification and deamplification of the dihydrofolate reductase gene on double minute chromosomes are estimated to be approximately 2% and 10%, respectively. These probabilities are much higher than widely presumed. The models explain the gradual disappearance of the resistant phenotype when selective pressure is withdrawn, by postulating that the rate of deamplification exceeds the rate of amplification. Thus it is not necessary to invoke a growth advantage of nonresistant cells which has been the standard explanation. For another analogous process, the loss of double minute chromosomes containing the myc oncogene from SEWA tumor cells, the growth advantage model does seem to be superior to the amplification and deamplification model. In a more theoretical section of the paper, it is demonstrated that gene amplification/deamplification can result in reduction to homozygosity, such as is observed in some tumors. Other applications are discussed.

Animals↗
PubMed1990

Voided urine flow cytometry in screening high-risk patients for the presence of bladder cancer.

Fifty-nine patients with a history of bladder cancer were evaluated with three serially voided urines for flow cytometry and cytology within the 24 hours preceding cystoscopy, bladder wash, and biopsy. Evaluation of the 32 patients with biopsy proven cancer revealed that for one, two, and three voided urine specimens, the sensitivity of flow cytometry in detecting bladder cancer was 29%, 35%, and 41%, respectively, whereas the sensitivity of voided urine cytology was 44%, 53%, and 57%, respectively. Bladder wash flow cytometry had a sensitivity of 76%. Interpretation of the voided urine flow cytometry was based on a control group of 80 volunteers with negative voided urine cytology. The control group demonstrated that a minimum of 1500 analyzable cells was necessary for a reliable histogram. Considering all 59 patients, voided urine flow cytometry, bladder wash flow cytometry, and voided urine cytology were acceptable for analysis in 53%, 93%, and 100% of the specimens, respectively. Voided urine specimens appear less suitable than bladder irrigation specimens for evaluation by flow cytometry. Voided urine flow cytometry is less sensitive in detecting bladder cancer than voided urinary cytology or bladder wash flow cytometry and is not effective for use as a bladder cancer screening test.

Cystoscopy↗
PubMed1990

Non-parametric analysis of platelet lifespan.

A model-independent and elementary method of analysis of platelet survival is proposed. The method is based on the finding that the mean and standard deviation of the platelet lifespan can be expressed in the terms of the slope at time 0 and the area under the empirical platelet survival curve. The method is tested using Monte-Carlo simulations and then applied to a set of clinical data.

Algorithms↗
PubMed1989

DNA in situ sensitivity to denaturation as a marker of human breast tumors.

DNA content and in situ sensitivity to denaturation were analyzed by flow cytometry of individual cell nuclei isolated from 40 breast carcinomas, nine fibroadenomas, and 14 samples of normal breast tissue. The extent of DNA denaturation induced by acid was expressed as alpha t, which represents the fraction of DNA staining metachromatically red with the fluorochrome acridine orange. In all cases of normal breast tissue DNA was very sensitive to denaturation and the frequency distribution of alpha t values was unimodal with over 90% of cells having alpha t above 0.6. All fibroadenomas were diploid; four had unimodal alpha t as in normal tissue and five had a bimodal distribution with an additional peak below 0.6. Twenty-seven adenocarcinomas (67%) had a DNA index above 1.0; of these 24 had bimodal alpha t distributions. Among 13 diploid carcinomas 10 had bimodal alpha t distributions. Statistically significant differences were observed in alpha t distributions of normal versus tumor breast tissue (P less than 0.005). In normal tissue and in all tumors a predominant proportion of cells with S and G2 + M DNA content were characterized by DNA resistant to denaturation (alpha t below 0.6). Of interest, the diploid cells from aneuploid tumors which may represent reactive host cells often displayed bimodal distributions of alpha t. These results may be interpreted in light of earlier studies demonstrating increased resistance of DNA to denaturation in diffuse chromatin of proliferating and/or transcriptionally active cells, and greater sensitivity to denaturation of DNA in condensed chromatin of quiescent cells. Thus, the presence of the second peaks representing cells with low alpha t values in breast tumors may indicate a high proportion of proliferating cells, whereas high alpha t populations may represent quiescent and differentiating (condensed chromatin) or dying (pycnotic nuclei) cells. It is likely that the low alpha t diploid cells detected in aneuploid tumors may represent the reactive (transcriptionally active and/or proliferating) infiltrating host cells (i.e., lymphocytes, monocytes) whose presence may also be of prognostic value. The data suggest that a DNA denaturability assay may be useful to characterize tumor and infiltrating host cell populations.

Acridine Orange↗
PubMed1989

The effect of tumor size and tumor cell DNA content on the survival of patients with stage I adenocarcinoma of the lung.

Tumor size at resection and flow cytometric (FCM) DNA distribution of 93 pathologically confirmed AJC Stage I adenocarcinomas of lung were compared with survival. All lung cancers had been treated by lobectomy and mediastinal lymph node dissection at this Institution, and the pathology of all cases was reviewed. Median tumor size was 2.5 cm. FCM DNA assays were carried out on the formalin-fixed, paraffin-embedded tumor tissue. Seventy-nine (85%) of the tumors were aneuploid and 14 were diploid. There was no significant difference in survival between patients with diploid and aneuploid tumors. The DNA index, proliferation fraction, and fraction of aneuploid cells also had no effect on survival. However, patients with tumors smaller than 3 cm in diameter had a significantly better prognosis than those with larger tumors. Thus, in Stage I adenocarcinoma of lung, tumor size but not cellular DNA content distinguishes subgroups with favorable versus unfavorable prognosis.

Adenocarcinoma↗
PubMed1989

Alveolar soft-part sarcoma. A clinico-pathologic study of half a century.

In the period from 1923 to 1986 our pathologists examined pathologic material from 102 patients with alveolar soft-part sarcoma (ASPS). Followup clinical data is available for 91. Median followup is 7 years (range 1 month to 27 years). Local recurrence was only found if residual disease was left at the time of the original excision. Survival in those patients who presented without metastases was 77% at 2 years, 60% at 5 years, 38% at 10 years and 15% at 20 years (median 6 years). No survival advantage could be demonstrated for patients who received chemo and/or radiotherapy, although numbers are small and staging not uniform. An evaluation by electron microscopy and immunohistochemistry cannot confirm recent claims that ASPS is a muscle tumor. ASPS is an unusual neoplasm; the primary therapeutic option is aggressive surgical excision. Survival even with the development of metastases can be long.

Adolescent↗
PubMed1989

Detection of bladder carcinoma in females by flow cytometry and cytology.

The sensitivity of bladder wash flow cytometry (BWFCM), voided urinary cytology (VUC), and cytology of catheterized urine obtained at the time of cystoscopy (CUC) were reviewed on all women evaluated for bladder cancer at Memorial Sloan-Kettering Cancer Center between June 1985 and December 1986. This comprised sixty-four episodes of pathologically proven bladder cancer in 48 women. Considering positive and suspicious results jointly the sensitivities of BWFCM, CUC and 3 VUC were 75%, 64% and 56%, respectively. If only positive results were considered (i.e., suspicious results considered as negative), the sensitivities of BWFCM, CUC and 3 VUC were 64%, 31% and 32%, respectively. The sensitivities of these tests are less than for a predominantly male population, presumably related to the presence of squamous epithelium and greater frequency of pyuria. However, bladder wash flow cytometry and conventional cytology are still a very valuable addition to cystoscopic examination, and the combination of BWFCM with conventional cytology is more sensitive than either procedure alone.

Adult↗
PubMed1989

Asymptotic behavior of a nonlinear functional-integral equation of cell kinetics with unequal division.

A model of cell cycle kinetics is proposed, which includes unequal division of cells, and a nonlinear dependence of the fraction of cells re-entering proliferation on the total number of cells in the cycle. The model is described by a nonlinear functional-integral equation. It is analyzed using the operator semigroup theory combined with classical differential equations approach. A complete description of the asymptotic behavior of the model is provided for a relatively broad class of nonlinearities. The nonnegative solutions either tend to a stable steady state, or to zero. The simplicity of the model makes it an interesting step in the analysis of dynamics of nonlinear structure populations.

Cell Cycle↗