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Biomedical subjects

M R Melamed

Publications and source records attributed to M R Melamed.

At least 127 records · Page 7Linked to original sources
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

Flow cytometry of prostate cancer: relationship of DNA content to survival.

Between March 1970 and December 1978 there were 366 patients with prostatic cancer treated by 125I seed implants and pelvic lymph node dissection. All had a minimum of 5 years follow-up. One hundred thirty-three patients had metastatic prostatic cancer in lymph nodes (Stage D1) at the time of lymph node dissection and seed implantation. Ninety-one of the 133 patients were judged to have sufficient metastatic prostatic cancer in their nodal tissue (greater than 50% replacement with tumor) to justify flow cytometric cellular DNA measurements on the involved paraffin-embedded nodal tissue. Nine patients were excluded due to uninterpretable DNA histograms leaving 82 patients for analysis. Forty-nine patients had aneuploid and 33 had diploid tumors. There was no statistical bias between the aneuploid and diploid groups due to age (P = 0.970, chi 2 test), time between diagnosis and implantation (P = 0.217, chi 2 test), number of positive nodes (P = 0.669, two-sample t test of means), or tumor grade (P = 0.332, chi 2 test). Median survival time of the aneuploid and diploid groups was 5.0 and 8.8 years, respectively (P = 0.0109, log rank test). Cox regression analysis confirmed the effect of aneuploidy versus diploidy on survival by controlling for other potentially confounding variables (age, time from diagnosis to implantation, number of positive nodes, and grade). Grade as a predictor of survival did not approach statistical significance in this series of relatively small size (P = 0.116). Thirty-eight of the 82 patients had moderately differentiated neoplasms. Nineteen of these were aneuploid and 19 diploid. The median survival was 5.8 and 9.1 years, respectively, for these grade-matched aneuploid and diploid groups (P = 0.039, log rank test). We conclude that flow cytometric DNA measurements on archived paraffin-embedded tumor in nodal metastases appear to be a strong predictor of survival for Stage DI prostatic cancer.

Aneuploidy↗
PubMed1987

Effects of a new amsacrine derivative, N-5-dimethyl-9-(2-methoxy-4-methylsulfonylamino)phenylamino-4- acridinecarboxamide, on cultured mammalian cells.

The effects of N-5-dimethyl-9-(2-methoxy-4-methylsulfonylamino)-phenylamino-4- acridinecarboxamide (CI-921; NSC 343499), a lipophilic and water-soluble derivative of amsacrine (NSC 249992), on cell viability, growth, clonogenicity, and progression through the cell cycle were investigated in suspension cultures of Friend erythroleukemic cells and in in suspension cultures of Friend erythroleukemic cells and in adherent cultures of Chinese hamster ovary cells. CI-921 was less toxic toward stationary than toward exponentially growing Chinese hamster ovary cells; colony formation was inhibited by 50% following a 1-h pulse of 190 versus 80 nM CI-921, respectively. Cell viability was unaffected in Friend erythroleukemic cell cultures at concentrations up to 50 nM, although growth was inhibited by 50% following 24 h of continuous exposure to 9.5 nM or a 1 h pulse of 67.5 nM CI-921. Constant exposure of Friend erythroleukemic cells to 10 nM CI-921 slowed proliferation and resulted in prolongation of cell transit through late S and G2 phases. Higher drug concentrations (50 nM) caused a complete cessation of growth marked by greatly suppressed cell transit through S phase and an irreversible block in G2 phase, about 30 min prior to division. In such cases, unbalanced growth was observed with total RNA and protein content of drug-treated cells increasing by 74 and 34%, respectively. Pulse exposure of cells to CI-921 resulted in transient accumulations of cells in S and/or G2 phase depending upon dose. The cell cycle distribution of stationary cultures treated for 1 h with drug and replated at a low cell density were identical to that of controls. Binding of the drug affected the sensitivity of DNA in situ to acid denaturing conditions which provides additional evidence that CI-921 binds to DNA by intercalation.

Amsacrine↗
PubMed1987

Hyperdiploidy of cultured dermal fibroblasts from patients with aerodigestive squamous carcinoma.

The incidence of hyperdiploidy in monolayer cultures of dermal fibroblasts from 88 patients with squamous carcinoma of the aerodigestive tract was compared with similar cultures from 39 normal subjects using three different techniques; 1) metaphase assay (MA), 2) flow cytometry of stationary cell cultures (FCMs), and 3) flow cytometry of proliferating dividing cell cultures (FCMd). In vitro hyperdiploidy was considered to be present (IVH+): 1) by MA if more than 4% of metaphases were altered, excluding tetraploidy; 2) by FCMs if more than 8% of cells in stationary cultures were hyperdiploid (i.e., DNA index greater than 1), and 3) by FCMd if more than 6% of cells in logarithmic cultures were hypertetraploid (i.e., DNA index greater than 2). There was excellent concordance between the three assays, which assigned cell cultures from 55 of the 88 patients with aerodigestive squamous carcinoma (62%) to the in vitro hyperdiploidy positive (IVH+) category. Cell cultures from all 39 normal individuals were hyperdiploidy negative (IVH-). These data suggest that some substantial proportion of patients with aerodigestive squamous carcinoma may have a genetic predisposition for the disease, which can be identified by these assays. The flow cytometry methods were easier to carry out and may be substituted for the metaphase analyses.

Adolescent↗
PubMed1987

Evidence for genetic predisposition for some nasopharyngeal cancers by in vitro hyperdiploidy in human dermal fibroblasts.

A numerical alteration in chromosome complement in human dermal fibroblast cultures, hyperdiploidy with a normal occurrence of tetraploidy (IVH), has been reported to be associated with some hereditary single tumors including squamous carcinoma of the nasopharynx (NPC). Its incidence was compared in cultures derived from 39 NPC patients and 29 clinically normal subjects without a family cancer history by two different methods (percentage of numerically altered metaphases in chromosome preparations from nonconfluent monolayer Petri dish cultures in logarithmic growth, and by the distribution of DNA content of propidium iodide stained cells from plastic flask cultures in stationary growth phase as assayed by flow cytometry) to ascertain its usefulness in identification of such genetic predisposition. Concordance was observed between the two assays. There was a linear relationship between the percentage of hyperdiploid metaphases assayed in the chromosome preparations and the percentage of cells with a DNA index of greater than 1 as determined by flow cytometry. By metaphase assay, none of the 29 normals showed IVH. OF the 39 carcinoma of the nasopharynx patients studied, 19 had IVH and 20 did not. By flow cytometry there were significant differences in the flow cytometry DNA index (p less than 0.001) of IVH-negative (all normals and 20 carcinoma of the nasopharynx patients) and IVH-positive carcinoma of the nasopharynx patients. The percentage of cells with a DNA index of 2 and greater than 1 could be used to distinguish all IVH-negative from the IVH-positive subjects and, thus, were considered to be the parameters of choice in assaying IVH by flow cytometry. None of the subjects studied showed increased in vitro tetraploidy (IVT), which has been associated with some heritable colon cancer syndromes. Irrespective of family cancer history, approximately one-half of the NPC patients (19 of 39) had IVH, which has been reported to be associated with the in vivo expression of certain heritable tumors including carcinoma of the nasopharynx. The average age of carcinoma of the nasopharynx diagnosis was earlier (mean 52 yr) for the IVH-positive group than for the IVH-negative carcinoma of the nasopharynx group (mean 67 yr).

Adult↗
PubMed1987

Monitoring endoscopic treatment of superficial bladder carcinoma by postoperative urinary cytology.

Transurethral resection was the only modality of treatment in 39 patients with long-standing, recurrent, superficial bladder carcinoma. Postoperative urinary cytology was performed within 3 days of each endoscopy. Tumor recurrence was defined by the presence of a positive biopsy or visible papillary tumors on followup cystoscopic examination. Tumor recurred in 38 patients (97.4 per cent) and 1 patient (2.6 per cent) has remained free of disease 74 months following transient positive postoperative cytology. Among the 38 recurrences 15 (39.5 per cent) were positive, 3 (7.9 per cent) suspicious and 20 (52.6 per cent) negative at the postoperative cytological examination. The interval to recurrence did not differ significantly among the 3 groups. The failure of a negative postoperative cytology study to predict a durable response to treatment by transurethral resection reflects the polychronotopic nature of superficial bladder tumors in this select patient population and suggests the need for adjuvant therapy.

Carcinoma, Transitional Cell↗
PubMed1987

Monitoring intravesical bacillus Calmette-Guerin treatment of superficial bladder carcinoma by postoperative urinary cytology.

We studied 51 patients with superficial bladder carcinoma who had been treated with transurethral resection of all gross tumor followed by intravesical bacillus Calmette-Guerin weekly for 6 weeks. Within 72 hours of either the first or second quarterly cystoscopic surveillance examination after bacillus Calmette-Guerin therapy, a conventional cytology study was obtained. Of these patients 8 (15.7 per cent) had positive, 9 (17.6 per cent) suspicious and 34 (66.7 per cent) negative postoperative cytology studies. Subsequent tumor recurrence was defined as a positive biopsy or visible papillary tumors on cystoscopic examination. All 8 patients with a positive postoperative cytology study had tumor recurrence at a median interval of 4 months. Of the 9 patients with a suspicious study 7 (77.8 per cent) had recurrent tumor at a median interval of 7 months and 2 (22.2 per cent) had no evidence of disease at 16 and 19 months, respectively. Of the 34 patients with a negative postoperative cytology study 13 (38.2 per cent) had tumor recurrence after a median interval of 4 months and 21 (67.8 per cent) had no evidence of disease after a median of 25 months. The tumor recurrence rate in patients with a positive or suspicious postoperative cytology study was significantly greater than that of patients with a negative study (p equals 0.001, Fisher's exact test). Postoperative cytology appears to be a significant prognostic indicator following transurethral resection and intravesical bacillus Calmette-Guerin treatment of superficial bladder carcinoma.

Administration, Intravesical↗
PubMed1987

Flow cytometric analysis of primary adenocarcinoma of the bladder.

The flow cytometric findings of bladder irrigation specimens from 4 patients with histologically confirmed primary adenocarcinoma of the bladder are reported. Cells in specimens from 3 patients showed deoxyribonucleic acid aneuploidy and a simultaneous preoperative urinary cytology study was positive. One patient had normal flow cytometry studies, whereas preoperative cytology results were suspicious. These findings indicate that at least some, perhaps most, primary adenocarcinomas of the bladder have abnormalities of deoxyribonucleic acid content. Flow cytometry should be of value in detecting and monitoring these cases, as it is for epidermoid (urothelial) carcinomas.

Adenocarcinoma↗
PubMed1987

Impact of early detection on the clinical course of lung cancer.

The Memorial Sloan-Kettering Lung Cancer Detection Program is described, and data from this study are reported and analyzed. The program enrolled 10,040 cigarette-smoking men who were screened for at least 5 years by annual chest radiographs; half the men randomly selected also had 4-monthly sputum cytologic examinations. Of the 354 lung cancers that developed in these men during the screening period and a 2-year post-screening period, nearly half were adenocarcinomas and nearly one third were epidermoid (or squamous) carcinomas. Lung cancers detected by screening were more likely to be early stage (53 per cent) and resectable (65 per cent) than were those discovered by other means (for example, symptoms) or in the post-screening period (20 per cent early stage, 32 per cent resectable). Sputum cytology was most effective in detecting squamous carcinomas early; chest radiographs were most effective for detecting adenocarcinoma. However, sputum cytology did not reduce lung cancer mortality among these men who were in a program of annual chest radiographic examinations. Overall 5-year survival for all of the men who developed lung cancer was 35 per cent, compared with the national average of 13 per cent.

Carcinoma↗
PubMed1987

Expression of p21ras in normal and malignant human tissues: lack of association with proliferation and malignancy.

Proteins encoded by cellular ras oncogenes (p21ras) are expressed in a wide variety of malignant tumors, including carcinomas, lymphomas, and neuroectodermal tumors. The function of p21ras in these tumors and the distribution and role of p21ras in corresponding normal tissues are unclear. This immunohistochemical study examined the relationship between p21ras expression and malignant transformation, cellular differentiation, and proliferative activity in vivo. p21ras was found to be widely expressed in normal tissues, but within those tissues expression was often sharply restricted to cells at specific stages of differentiation; terminally differentiated cells generally showed stronger reactivity with antibodies to p21ras than did rapidly proliferating cells. Fetal and adult tissues had corresponding patterns of p21ras expression, and the distribution of p21ras in neoplasms paralleled the pattern in normal tissue from which they were derived. Thus, p21ras seems to play a role in many fully differentiated cell types, and levels of p21ras expression do not correlate with proliferative activity in normal cell or, in contrast to past reports, with the transformed phenotype.

Adult↗
PubMed1987

Detection of DNA abnormalities by flow cytometry in cells from cerebrospinal fluid.

To evaluate the diagnostic utility of flow cytometry (FCM) as compared to cytology, DNA and RNA content of cells were measured in 233 samples of cerebrospinal fluid (CSF) from 147 patients with solid tumors or lymphomas and 17 controls with nonmalignant disorders. All control specimens were normal. Twenty-eight samples were abnormal: 20 showed an aneuploid peak and 8 an increased number of cells with DNA content in the S and G2M phases of the cell cycle. Of these 28, cytologic results were positive in 18, suspicious in 3, and negative in 7. All but one of the suspicious and negative cases had confirmatory laboratory and/or radiographic evidence of leptomeningeal metastasis within one week of FCM examination. Cytologic results were positive in eight samples negative by FCM. Compared with cytology, the sensitivity of FCM was 69% and the specificity 95%. Abnormal DNA content by FCM can be a useful adjunct to cytologic examination.

Adolescent↗
PubMed1987

In vitro evidence for genetic predisposition in some human pancreatic adenocarcinoma.

A numerical alteration in chromosome complement in human dermal fibroblast cultures, hyperdiploidy with a normal occurrence of tetraploidy (IVH) has been reported to be associated with some hereditary single tumors, including pancreatic adenocarcinoma (PaCa). The incidence of IVH was compared in cultures derived from 34 PaCa patients and 39 clinically normal subjects without a family tumor history by three assay systems: (a) percentage of numerically altered metaphases in chromosome preparations (MA); (b) percentage of cells from high-density, stationary cultures with a DNA index (DI) greater than 1 (FCMs); (c) percentage of cells with a DI greater than 2 from cultures of cells undergoing division (FCMd). The last two measurements were obtained by flow cytometric measurement of propidium idodide (PI) stained cells. Concordance was observed between the three assays. There was a linear relationship between the percentage of hyperdiploid metaphases assayed in the chromosome preparation and the percentage of cells with a DI greater than 1 by FCMs and a DI greater than 2 by FCMd. IVH was considered to be present (IVH+) by the MA technique if the percentage of numerically altered metaphases was over 4% exclusive of tetraploids, by the FCMs technique if DI greater than 1 was greater than 10%, and by FCMd if DI greater than 2 was greater than 7%. The assayed group could be divided into two IVH groups on the basis of all three assays, individually or collectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1987

In vitro hyperdiploidy in dermal fibroblasts: evidence for genetic predisposition in aerodigestive tract cancer.

A numerical alteration in chromosome complement in human dermal fibroblast cultures, hyperdiploidy with a normal occurrence of tetraploidy (IVH) has been reported (Danes 1984) to be associated with some heritable single tumors including squamous carcinoma of the nasopharynx (Danes 1986). The incidence of IVH was compared in cultures derived from 65 patients with squamous carcinoma in different regions of the aerodigestive tract (ADT) and 32 clinically normal subjects without a family cancer history by 2 different assays, metaphase assay (MA) and flow cytometry (FCM). By MA, none of the 32 normals showed IVH. Of the 65 ADT patients studied, 35 had IVH and 30 did not. By FCM, there were significant differences in the FCM DNA index (p values less than 0.001) of IVH- (all normals and 30 ADT patients) and IVH+ ADT patients. The per cent of cells with a DI of 2 and greater than 1 could be used to distinguish all IVH- from the IVH+ subjects and were thus considered to be the parameters of choice in assaying IVH by FCM. None of the subjects studied showed increased in vitro tetraploidy (IVT) which has been associated with some heritable colon cancer syndromes. Irrespective of family cancer history, approximately half (35/65) of the ADT patients had IVH which has been shown to be associated with the in vivo expression of certain heritable tumors. The average age of squamous carcinoma diagnosis was earlier (mean 50 yrs) for the IVH+ group than for the IVH- ADT group (mean 72 yrs).

Adolescent↗
PubMed1987

Cytokinetic effects of bifunctional antitumor intercalator ditercalinium on Friend erythroleukemia cells.

Ditercalinium (NSC 335153) is a novel 7H-pyridocarbazole dimer in which the two monomers are joined by a rigid bis(ethylpiperidinyl)-linking chain producing a molecule capable of bisintercalation into DNA with extremely high affinity. The effect of ditercalinium on cell proliferation and its interaction with DNA in situ has been investigated in the Friend leukemia cell system. Ditercalinium caused an inhibition of cell growth at 0.5 microM and cell death at 2.5 microM. However, both the cytokinetic and cytotoxic effects became evident only after 1-2 days of continuous drug exposure. In contrast, monointercalators generally affect cell growth within several hours of administration. Furthermore, whereas most intercalators arrest cells in G2 phase, ditercalinium demonstrated no cell cycle phase specificity. In fact, a stathmokinetic experiment, in which vinblastine was used to prevent cell division in exponentially growing Friend leukemia cell cultures, demonstrated that ditercalinium effectively "froze" cells in position throughout the cell cycle, in a dose-dependent fashion. By determining the sensitivity of DNA in situ in fixed Friend leukemia cells to acid-induced denaturation, it was apparent that ditercalinium, rather than stabilizing DNA as do monointercalators, increased the sensitivity of DNA in situ to denaturation induced by acid. It appears, therefore, that the cytokinetic effects and interaction with chromatin of an agent that has the ability to bisintercalate into DNA are qualitatively different from those induced by classical monointercalating drugs.

Animals↗
PubMed1987

Immunoanatomic distribution of cytostructural and tissue-associated antigens in the human urinary tract.

The main objective of the present study is to define the expression and/or modulation of antigenic phenotypes in cells of the normal human kidney and urothelium according to cell type. Fourteen antibodies detecting differentiation and structural antigens expressed in the human urinary tract have been used to define the immunoanatomic distribution of these antigenic systems. They include urinary tract antigens (Tamm-Horsfall glycoprotein and prostate-specific antigen), tissue-associated antigens (epithelial membrane antigen, Factor VIII antigen, and Protein S-100), and cytoskeletal antigens of the intermediate filament classes (cytokeratins, vimentin, desmin, glial fibrillary acidic protein, and neurofilaments. Immunofluorescence and immunoperoxidase analyses performed on normal human fetal and adult tissue sections have demonstrated that these antigens are expressed by different cell types and domains of the nephron. Studies correlating normal fetal and adult tissues reveal that some of the antigens appear at distinct stages of maturation, representing early and late antigenic expression events. These antibodies offer a wide range of potential applications that include studies of embryogenesis of the human urinary tract and immunopathologic analyses of neoplastic and nonneoplastic diseases of the human kidney and urothelium.

Adult↗
PubMed1986

Monitoring intravesical bacillus Calmette-Guerin treatment of superficial bladder carcinoma by serial flow cytometry.

Simultaneous urinary flow cytometry, cytologic, and cystoscopic examinations were performed at 3-month intervals for a minimum of 1 year on 29 patients receiving intravesical bacillus Calmette-Guerin (BCG) treatment of superficial bladder carcinoma. Flow cytometry (FCM) and cytology were concordant in 57 of 103 examinations; both FCM and cytology were positive in 38 instances, and carcinoma was confirmed by biopsy in 35 (92.1%). In 16 instances FCM and cytology were negative, but carcinoma was present on biopsy in 5 (31.3%). Three examinations were suspicious by both techniques. The 46 determinations with discordant FCM and cytology were subdivided into pathologically confirmed recurrences (25 instances) and no evidence of pathologic and/or cystoscopic disease (21 instances). In the 25 instances of recurrences, FCM was positive in 18 (72.0%), suspicious in 3 (12.0%), and negative in 4 (16.0%), while cytology was positive in 3 (12.0%), suspicious in 9 (36.0%), and negative in 13 (52.0%). Most patients had a severe BCG-induced inflammatory response that caused an elevation of the hyperdiploid population, believed secondary to epithelial regeneration and proliferation. In the 21 instances without detectable recurrence, hyperploidy led to a relatively high proportion of positive (15) and suspicious (4) results by FCM, but only eight had distinct aneuploid populations. It is possible that this latter group, at least, is harboring occult carcinoma. Conventional cytology in the nonrecurrent group was positive in 1 (4.8%), suspicious in 7 (33.3%), and negative in 13 (61.9%). In those instances when tumor was confirmed by biopsy, the false-negative rate for FCM was 19.7%; the false-negative rate for cytology was 40.9%. Thus, FCM appears to be more sensitive but less specific than conventional cytology, having a lower false-negative but a higher false-positive rate. Although serial FCM provides an objective quantitative measure of aneuploid stemlines and hyperdiploid populations in bladder irrigation specimens and can be helpful in following intravesical BCG therapy for superficial bladder carcinoma, it should still be used with conventional cytology. The greatest difficulty with FCM at present, as with conventional cytology, is in cases of marked inflammation. The results reported here were obtained under the most stringent conditions and represent the minimum level of accuracy. Potential improvements in the technique, with the addition of immunologic or other markers, hold hope of further increasing the accuracy of FCM.

Aged↗
PubMed1986

Immunohistologic expression of blood-group antigens in normal human gastrointestinal tract and colonic carcinoma.

A panel of 7 mouse monoclonal antibodies and the lectin from Ulex europeus, detecting blood-group-related antigens of the ABH and Lewis systems, have been used to define the distribution of these antigenic structures within the human gastrointestinal tract, and to characterize their expression and modulation in colorectal carcinomas. The reagents employed detect the following blood-group specificities: A (all variants), B, H (type 2), Lewisa, Lewisb, X (Lewisx), Y (Lewisy) and type 1 precursor chain. Immunohistochemical studies demonstrate that these antigens are differentially expressed in various cell types and developmental stages of the human gastrointestinal tract. ABH expression undergoes developmental modulation in the human colorectal tract from positive to negative during embryogenesis, and is lost in adult cells. Colorectal tumors exhibit neosynthesis of ABH specificities that appear in tumor cells, and accumulation of the precursor antigens. They also show increased expression of Lewis antigens, especially Y determinant, which has a restricted pattern of distribution in normal tissues and is not found in normal colonic mucosa. Enhancement of the Lewis antigens is observed in all colorectal tumors analyzed, regardless of blood-group type and secretory status of the individuals studied. Tumor modulation of these antigens may be related to activation of suppressed genes and enhancement of fucosyltransferases.

ABO Blood-Group System↗