Doxorubicin (DOX) and VP16 are DNA topoisomerase II inhibitors yet only DOX induces an irreversible cardiotoxicity, likely through DOX-induced oxidative stress. Egr-1 is overexpressed after many stimuli that increase oxidative stress in vitro and after DOX-injection into adult mice in vivo. To investigate Egr-1 function in the heart, we compared the molecular and histological responses of wild type (+/+) and Egr-1 deficient (-/-) female mice to saline, DOX, VP16, the cardioprotectant dexrazoxane (DZR), or DOX+DZR injection. DOX, and to a lesser extent VP16, induced characteristic increases in cardiac muscle and non-muscle genes typical of cardiac damage in +/+ mice, whereas only beta-MHC and Sp1 were increased in -/- mice. DZR-alone treated +/+ mice showed increased cardiomyocyte transnuclear width without a change to the heart to body weight (HW/BW) ratio. However, DZR-alone treated -/- mice had an increased HW/BW, increased cardiomyocyte transnuclear width, and gene expression changes similar to DOX-injected +/+ mice. DZR pre-injection alleviated DOX-induced gene changes in +/+ mice; in DZR+DOX injected -/- mice the increases in cardiac and non-muscle gene expression were equal to, or exceeded that, detected after DOX-alone or DZR-alone injections. We conclude that Egr-1 is required for DOX-induced molecular changes and for DZR-mediated cardioprotection.

Whether old uteri that have undergone involution do so by an apoptotic mechanism was examined by the presence of known biochemical and morphological markers for programmed cell death. Terminin, a protein identified by an unique monoclonal antibody, has three forms, Tp-90, Tp-60, and Tp-30: Tp-90 (the 90 kDa form) is only present in growing and quiescent non-growing cells; Tp-60 (the 60 kDa form) is found in senescent cells; and finally, Tp-30 (the 30 kDa form) is found in cells committed to apoptotic death. Biochemical analysis of a protein, Tp30, previously identified as a marker for the commitment to programmed cell death, was performed with both young (5-month-old) and old (24-month-old) C57BL/6J mouse uteri. In addition to biochemical analysis of Tp30 presence in uterine tissue, propidium iodide (PI) staining and DNA framentation by nick-end labelling with fluorescence-conjugated UTP were used to characterize apoptosis-related changes in the chromatin organization of the nucleus. Results indicate that within the old uterus Tp-30 is indeed detected in the tissue extracts and was the major terminin band, while Tp-90 and Tp-60 were the major bands observed in extracts of the younger mouse uterus. The presence of Tp30 in the older uterine tissue suggests that the tissue regression which has occurred in the uterus of older mice may be apoptotic in nature. This suggestion is further supported by the demonstration of increases in the number of cells showing apoptotic morphology, i.e. positive staining with UTP reflecting the presence of nuclei with nicked DNA, localized exclusively in the uterine stroma of older females. The presence of DNA fragmentation, as reflected by UTP staining, was virtually absent from the young uteri. These data suggest that apoptosis may be a part of the cellular mechanism contributing to the regression of uterine tissue in the older female during involution, appearing as an age-dependent event.

A 75-year-old woman presented with a ganglion-like nodule on the dorsal aspect of the right foot. A 2.5 x 1.5 cm, saccular and malleable tumor, that was in continuity with the dorsal venous arch, was completely resected. It was characterized by a diffuse intramural and circumferential, low grade, malignant, smooth muscle proliferation with an aneurysmal-like luminal space. No endoluminal or periadventitial invasive neoplastic component was present. The patient had no evidence of disease at 58-month follow-up. This is the first reported case of venous leiomyosarcoma in the foot. Furthermore, the intramural confinement of neoplastic growth is a unique observation.

Statin, a non-proliferation-specific nuclear antigen, was used here to assess the colonic crypt kinetics of the mucosa bordering a human colon cancer. Mucosal strips adjacent to a colon cancer obtained from operative specimens were immediately cut into five one cm segments and stored in liquid nitrogen. An immunohistological technique using the statin antibody as a nuclear marker was used to determine the labelling indices of the non-cycling compartment at the varying distances. Optical density measurements of the nuclear reaction product served to objectively identify the statin-positive nucleus. The results indicate that there is a statistically significant reduction (P < 0.0001) in the statin-positive labelling index in the entire crypt length for a distance of three cms. The division of the entire crypt into four levels (A, B, C and D) demonstrates that this effect is principally due to the upward extension of the statin-negative cell mass into levels B and C with a corresponding decrease in the labelling index of the statin-positive nuclei in these levels. The in vivo expression of nuclear statin demonstrates its usefulness in accurately determining the size of the non-proliferative compartment in the human colonic crypt adjacent to a colon cancer.

The purpose of this study was to determine the temporal relationships, in the rat prostate following castration, the expressions of terminin, a cytoplasmic marker for senescence, and, statin, a nuclear marker for cell quiescence and senescence. The presence of these two proteins was determined at 0, 1, 2, 4, 8, 24 and 48 hours in the ventral lobe of the prostate following castration. Immunofluorescence techniques for double labelling were used and assessed with confocal microscopy. At 0 hour the mean % labelling index (LI) for terminin was 0% and 98% for statin. One hour following castration a complete reversal of expression of these two markers occurred indicating that the terminin marker is expressed at the start of programmed cell death or apoptosis. The mean % LI for terminin at 1, 2, 4, 8, 24 and 48 hours following castration were 54, 82, 63, 39, 44 and 41% respectively. The mean % labelling index of statin remained at zero during these time intervals. It is concluded that following castration, the prostatic ventral lobe exits from the quiescent phase to reenter cell cycle traverse. This is coupled by the loss of statin and the expression of the cytoplasmic marker terminin at the start of programmed cell death prior to the appearance of any histologic features of apoptosis.

The purpose of this study was to analyze the expression of a mutant (MUT) p53 oncogene protein in the mucosal crypts adjacent to a human colon cancer. Five 1-cm mucosal segments were taken from the surgical specimens over a 5-cm distance from the tumor. Immunohistochemistry was performed using a monoclonal antibody (Ab3) to the MUT p53 and examination by light microscopy. The mean % labelling index (LI) of 10 crypts/cm segment was determined by image analysis. The LI for the entire crypt length for the first cm segment was 33.51 +/- 4.2 and for the second cm segment was 29.26 +/- 5.4 (p < 0.02). Due to the unequal distribution of the label within the crypt length, it was divided into halves so that the LI of these levels could be determined. The LI for the upper and lower crypt levels for the first cm segment were 28.67 +/- 3.2 and 78.23 +/- 4.6 (p < 0.01); for the second segment, the LI were 22.0 +/- 5.1 and 68.66 +/- 4.7 (p < 0.01). No expression of MUT p53 nuclear protein was noted distally at 3-5 cm. The localization of MUT p53 protein product to the crypt stem cell nucleus supports the contention that a malignant field change exists in the transitional mucosa adjacent to a human colon cancer.

Surgical specimens of 29 human thyroid masses, both benign and malignant, were examined by means of a novel monoclonal antibody immunoreactive to statin, which is expressed only in quiescent G0 cells. The nuclei of normal thyroid follicle tissue together with nodular goitres and follicular adenomata had similar labelling indices of 96 +/- 2.67, 95 +/- 2.43 and 94 +/- 1.98 respectively. By contrast the labelling indices of papillary and undifferentiated thyroid malignancies were 82 +/- 3.05 and 15.2, respectively. These results indicate that normal thyroid tissues as well as benign thyroid tumors have similar non-proliferative activities. The differentiated papillary cancers have a smaller non-cycling compartment, the smallest being present in the most biologically aggressive undifferentiated thyroid cancer. The immunohistological evaluation of statin in the nuclei of human thyroid malignancies correlates with their biological behaviour in an inverse relationship.

American Society of Colon and Rectal Surgeons 91st Annual Convention Podium and Poster abstracts: PDF Only

Background. The appropriateness of resection in patients from whom polyps with invasive adenocarcinoma were excised has been questioned. Methods. To determine the results of this policy, the authors reviewed the outcome of 42 patients from whom 44 such polyps were removed. Each polyp was categorized for the level of invasion according to the classification of Haggitt. Results. Level 1 invasion was found in 27%; level 2, in 9%; level 3, in 11%; level 4, in 39%; and uncertain, in 14%. The histologic grade was well differentiated in 48% of patients and moderately differentiated in 52%. No polyps contained poorly differentiated adenocarcinoma; lymphatic and vascular invasion were not encountered. Excision was judged complete in 23 patients; 11 underwent resection, and in none was residual adenocarcinoma identified. In 14 patients, margins could not be evaluated; of 12 patients who underwent resection, residual adenocarcinoma was found in 1. Of the seven patients with positive margins who underwent resection, residual adenocarcinoma was found in only two. In the resected specimens in which residual carcinoma was encountered, all original lesions were designated level 4. None of the patients treated by polypectomy alone has experienced a recurrence at a mean follow-up time of 66 months (range, 12-152 months). Conclusions. The authors conclude that only patients with level 4 invasion require resection.

This study was designed to examine the state of proliferation in the rat thyrocyte following the administration of thyroid stimulating hormone (TSH). An immunohistochemical technique involving the use of a monoclonal antibody to statin, a nonproliferation‐specific nuclear antigen, was developed to measure the subpopulation of cells that have ceased to divide. Following the random assignment of young male Sprague‐Dawley rats into various groups, the rats in the control group received a single intraperitoneal (i‐p) injection of normal saline, whereas the experimental groups received single i‐p injections of TSH at doses of 0.25, 0.50, and 1.0 IU, respectively. All rats were subsequently sacrificed in groups of three at 1, 2, 4, and 24 hours. The statin antibody label was readily identified within the follicle cell nucleus. Results revealed a statistically significant transient decrease in the mean percent statin‐positive nuclei in the TSH‐treated groups. The time‐ and dose‐dependent effect of TSH was maximal at 2 hours and no longer discernible at 24 hours. A second experiment involving the chronic administration of TSH (i‐p 0.25 IU twice daily) resulted in a cumulative response with a statistically significant progressive decrease in the mean percent of statin‐positive nuclei at 5 and 10 days, returning to near normal values 5 days following the cessation of treatment. Determination of the nuclear optical density of the statin reaction product by image analysis techniques revealed that a single injection of TSH resulted in a rapid disappearance of the statin nuclear protein. This result suggests that the disappearance of statin in the nucleus appears to reflect the event of cells leaving the nondividing quiescent state to resume the cell cycle traverse following the administration of TSH. The disappearance of statin appears as an early nuclear event that parallels the earliest known cytoplasmic pinocytotic response to TSH in the rat thyroid follicle cell.

Haggitt's classification is a useful guide in the management of patients with large bowel polyps which contain invasive adenocarcinoma in that patients with levels 1 to 3 require no operation. Nuclear morphometry has been shown to be a useful prognostic discriminant for patients with invasive carcinoma of the large bowel. The nuclear shape factor of 44 polyps with invasive carcinoma was studied to determine whether this parameter was of value to define those patients with Haggitt level 4 who should have a resection. The shape factor of 50 interphase nuclei was obtained through the use of image analysis by tracing the nuclear profiles as digitized on a video screen. The nuclear shape factor was defined as the degree of circularity of the nucleus, a perfect circle recorded as 1.0. Our previous experience showed a nuclear shape factor greater than 0.84 was associated with a poor outcome. The overall mean shape factor was 0.71 (0.59-0.85). There was a tendency for the patients with residual disease to have values in the upper range. Our findings suggest that nuclear morphometry fails to add any predictive information in this clinical situation.

We present a case of pagetoid carcinomatous involvement of the penile urethra and periurethral glands following cystoprostatectomy for high-grade transitional cell carcinoma of the urinary bladder. Previously reported cases with involvement of the urethra are reviewed. This condition is believed to be a rare variant of transitional cell carcinoma in situ.

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R.31; Sugihara, K.32; Hojo, K.32; Moriya, Y.32; Hasegawa, H.32; Krueger, B.25; Warren, W.25; Faber, L. P.25; Abel, M. E.5; Chiu, Y. S. Y.5; Russell, T. R.5; Volpe, P. A.5; Frazee, R. C.33; Roberts, J.33; Symmonds, S.33; Snyder, S.33; Hendricks, J.33; Smith, R.33; Merchant, N.34,35; Hashmi, H.34; Scalea, T.34; Whelan, R.34; Longo, W. E.3,36; Gusberg, B. J.36; Ballantyne, G. H.36; Davidson, T.37,38; Allen-Mersh, T. G.37,38; Gazzard, B.37; Miles, A. J. G.37; Wastell, C.37; Viponde, M.37; Stotter, A.37; Miller, R. F.37; Fieldman, N.37; Slack, W. W.37; Tjandra, J.3; Savoca, P. E.36; Flannery, J. T.36; Modlin, I. M.36; Tsukada, K.3; Tazawa, K.3; Lavery, E. C.3; Voeller, G. R.39; Bunch, G.39; Britt, L. G.39; Neto, J. A. Reis40; Quilici, F. A.40; Cordeiro, F.40; Reis, J. A. Jr40; Wojcik, J. B.41; Banerjee, S. R.41; Walters, D. L.41; Cherry, D. A.41; Bleday, R.9; Pena, J. P.9; Buls, J. G.9; Pascual, R.42; Tripodi, G.42; Padmanabhan, A.42; Schouter, W. R.43; Blankensteijn, J. 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M.74; Lavery, I.74; Oakley, J.74; Church, J.74; Fazio, V.74; Asbun, H. J.75; Castellanos, H.75; Asbun, J.76; Franko, E. R.77; Ivatury, R. R.77; Schwalb, D.77; Saad, R.3; Schroeder, T.3; Reis, J. A. Jr.40; Dziki, A. J.78; Duncan, M. D.78; Harmon, J. W.78; Saini, N.78; Malthaner, R. A.78; Fernicola, M. T.78; Hakki, F. Z.78; Trad, K. S.78; Ugarte, R. M.78; Ryan, P.79; Chang, H. R.80; Chavoshan, B.80; Barsoum, G.1; Bonardi, R.81; Scaramelo, A.81; Possebon, A.81; Peres, C.81; Röhrig, C.81; Kappas, A. M.1; Ortiz, J.1; Fan, H. A.31; Milsom, J.31; Lechner, P.62; Lind, P.62; Cesnik, H.62; Venkatesh, K. S.82; Larson, D. M.82; Morrison, D. N.82; Ramanujam, P. J.82; Rubbini, M.83; Mascoli, F.83; Mari, C.83; Bresadola, V.83; Donini, I.83 Author Information

We undertook this study to determine the effect of rumenectomy (a known cause of duodenal crypt cell hyperplasia) on the epithelial growth kinetics of the crypt-villus axis in rat duodenum. Ten rats were randomly assigned to control (gastrotomy) and experimental (rumenectomy) groups. After 14 days rats were sacrificed and representative sections were stained with the monoclonal antibody to statin, a non-proliferation-specific protein, by the immunoperoxidase procedure. In the control group, the mean percentages of statin-positive cells in the proximal duodenum, distal duodenum, proximal jejunum, and distal jejunum were 79 +/- 8.5, 79.5 +/- 5.7, 85 +/- 1.4, and 83.5 +/- 0.7, respectively. In the rumenectomy group, statin-positive nuclei were found in the region of the villous apices only, and the corresponding values for the above four areas were 26.2 +/- 4.9, 24.5 +/- 3.5, 31.7 +/- 4.5, and 80.5 +/- 2.1. Except for distal jejunum, the differences in statin expression in the control and experimental groups were significant (p less than 0.001). Rumenectomy leads to the disappearance of statin from the villous column cells of the duodenum and proximal small bowel. The lack of expression of statin in the rumenectomy group documents the potential usefulness of this measure in future studies in neoplasia were understanding of the proliferative status is of crucial importance.

A case of parathyroid cyst is reported in which the diagnosis was suggested when watery, clear fluid was aspirated from a mass found in the anterior region of the neck of a 34-year-old woman on routine medical examination. The diagnosis was confirmed by measurement of the parathormone content in the cyst fluid and by histologic examination of the cyst wall. Although rare, parathyroid cyst should be considered in the differential diagnosis of cysts in the anterior compartment of the neck. Surgery has been the usual treatment of such cysts, but several reports have been published in which repeated aspiration resulted in the disappearance of the cyst. If conservative treatment of a parathyroid cyst is unsuccessful, the cyst should be removed surgically.

Various techniques have been used to enhance carcinogenesis in experimental animals. This study examines the effects of the excision of the forestomach (rumen), a squamous epithelial pouch of the rat, on the incidence and distribution of intestinal neoplasms induced by 1,2-dimethylhydrazine (DMH). Thirty-four male Sprague-Dawley rats were randomly assigned to control and experimental groups. The experimental group was subjected to an excision of the rumen while the control group underwent a gastro-rumenotomy and closure. Following a two week recovery period, each animal was weighed and injected with DMH (20 mgm/kg body wt) on a weekly basis for 22 weeks. At 24 weeks, the 32 surviving rats were sacrificed and the number, location, and histology of the neoplasms in the intestinal tract of each rat were noted. Rumenectomy resulted in a statistically increased incidence of neoplasms in the proximal small bowel (mean of 1.3 +/- 0.01 neoplasms/rat) when compared with the control group (mean of 0.1 +/- 0.2 neoplasms/rat) (p less than 0.001); but did not influence the incidence, distribution, or histology of colonic neoplasms between control and experimental animals. All neoplasms of the proximal small bowel when examined histologically were classified as invasive adenocarcinomas. The colon contained adenomata and carcinoma in situ, as well as adenocarcinomas. It is therefore concluded that excision of the rumen of the rat stomach selectively promotes malignant formation in the proximal small bowel following repeated injections of DMH.

Insulin binding and down-regulation were studied in primary cultures of human and rat hepatocytes. Equilibrium binding characteristics were similar in the two species, with a curvilinear Scatchard plot compatible with binding sites of high and low apparent affinities. The dose-response curve for insulin stimulation of glycogen synthesis coincided with the dose-occupancy curve of the low affinity sites; a maximal biological effect was reached at 50% occupancy. Exposure of rat hepatocytes to 2 X 10(-9) M insulin for 24 h produced a 48% decrease in binding capacity due to decreases in both types of binding sites and a 50% decrease in maximal insulin stimulation of glycogen synthesis. After exposure to the same insulin concentration human cells had an 83% decrease in maximum binding capacity, due exclusively to a complete loss of low affinity sites, and a total suppression of insulin stimulation of glycogen synthesis. In both species there was a biphasic relation between degradation and binding: over the range of insulin concentration producing binding mainly to high affinity sites degradation increased slowly as binding increased; with higher insulin concentrations and saturation of high affinity sites degradation increased rapidly as binding to low affinity sites increased. At equal levels of binding, down-regulated cells degraded insulin more rapidly than normal cells. It is concluded that: 1) insulin bound to sites of low apparent affinity is responsible for the hormone's glycogenic effect, 2) down-regulation of human hepatocytes virtually eliminates such binding and the glycogenic response and also increases the rate of degradation of insulin in relation to the amount bound to high affinity sites, 3) human cells are more sensitive than rat cells to down-regulation. It is suggested that in human cells the major effects of exposure to insulin are an inhibition of insulin internalization and an increase in the rate of degradation of that insulin which is internalized; in rat cells the major effects are a decrease in cell surface binding and an increased rate of degradation of internalized insulin.