Morphometric and biochemical peculiarities of fatty tissue in patients with cancer of the breast and lung

Subcutaneous adipose tissue was examined in 77 patients with breast cancer, 61 patients with lung cancer and in a control group of 23 male and 27 female with non-tumor pathology; the weight and age of controls matched those of cancer patients. The obesity in breast cancer patients was of the hypertrophic type, and of combined type (hypertrophic-hyperplastic) in patients who were more than 50% overweight. The increased level of adipose tissue in lung cancer patients was mostly due to the larger size of adipocytes. The concentration of unsaturated fatty acids in adipose tissue in breast cancer patients was in direct correlation with the level of this tissue and adipocyte size, while, in lung cancer group, this correlation was reversed. There was no inverse correlation between the size and c-AMP level of adipocytes in both cancer groups. Resistance to the inhibitory effect of glucose on lipolysis occurring in adipose tissue was more frequent in cancer patients than in controls. Antilipolytic effect of insulin in subcutaneous adipose tissue of breast cancer patients was less pronounced than in lung cancer group. Liposynthetic activity in adipose tissue was identical in all study groups. Lipolytic activity in adipose tissue was enhanced in both cancer groups, but in the breast cancer group it was in direct correlation with overweight, while in lung cancer patients--with the degree of tumor progression.     

Is the apparent rise in cancer mortality in the elderly real? analysis of changes in certification and coding of cause of death in England and Wales, 1970–1990

The effect of changes in recording and coding of cause of death on trends in cancer mortality in England and Wales in persons aged 45 and over during 1970–1990 is reviewed. During this period, all-cancer mortality rates increased only at ages over 75 in males and over 55 in females. Rises in cancer mortality were largely due to increases in cancer of lung, prostate and unspecified site in men, and of lung, breast and unspecified site in women. Death coding and certification artefacts were much larger in older persons. In those aged 75–84, a change in the position of recording cancer on the death certificate could potentially account for 46% of the recorded increase in prostate-cancer mortality and 28% of the increase in breast-cancer mortality. The decrease in recorded mortality from ill-defined terminal events was far greater than the increase in cancer mortality in this age group. The rise in all-cancer mortality in the elderly was partly due to an increase in lung-cancer mortality, and data artefacts explained a large proportion of the increase in the other common specified cancers in those aged 75–84. The use of routine mortality statistics to chart progress against cancer lacks validity at older ages because of imprecision in certification of cause of death.     

Urethral involvement in female patients with bladder cancer. A study of 22 cystectomy specimens

The cystectomy specimens of 22 female patients with various types of bladder cancer were studied for evidence of urethral involvement. The bladder showed high-grade invasive transitional cell carcinoma in 18 patients, in 14 cases in association with flat carcinoma in situ (multifocal in 11 cases and unifocal in three). Three patients had multifocal carcinoma in situ of the bladder without evidence of invasion, and one patient had multifocal high-grade noninvasive papillary carcinoma. Urethral carcinoma in situ was observed in four of 14 patients (29%) with multifocal carcinoma in situ of the bladder, in three cases extending into the periurethral glands. This frequent concurrence of carcinoma in situ of the bladder with urethral and periurethral gland involvement, analogous to the carcinomatous involvement of the prostatic urethra and ducts in male patients, warrants caution in the intravesical therapy of female patients with superficial bladder cancer. The urethra showed invasive carcinoma in three of 18 patients (17%) with invasive bladder cancer (stromal invasion in two cases and vascular invasion in one). This finding reconfirms the use of routine urethrectomy in conjunction with cystectomy in female patients with invasive bladder cancer. An incidental finding was the presence of condylomatous changes in the urethra in five cases (23%).     

Analysis of Clonal Evolution in a Tumor Consisting of pSV2neo-transfected Mouse Fibrosarcoma Clones

The process of clonal evolution was analyzed in a line of methylcholanthrene-induced mouse fibrosarcomas. The tumor cells were transfected with pSV2neo gene and 22 clones were randomly isolated. Genetically tagged clones were mixed and inoculated into syngeneic mice. Southern blot analysis revealed that one of the clones, no. 11, dominated both in tumors in situ and in lung metastatic nodules. No. 11 clone and other clones were similar in growth rates in vitro and in vivo , in spontaneous and experimental metastatic abilities, in immunogenicity, and in the capacity of intercellular communication in vitro . Although no. 11 clone overgrew other clones in vivo , this was not the case when clones were mixed and maintained in vitro . We conclude that clonal interactions in vivo may be responsible for the dominance of no. 11 clone in the tumor. It is likely that the preferential metastasis of no. 11 clone to the lung may be a simple reflection of the proliferative advantage of the dominant clone in the tumor in situ .     

Cancer in East African Indians

An analysis of 586 cases of cancer occurring in Indians resident in East Africa is presented and compared with proportional rates found in Indians in India and Durban. The proportion of carcinoma of the breast is much higher in East Africa than in India or South Africa, particularly among Muslim women. The high rate of gastric and bronchial neoplasms seen in Durban is not found in East Africa. Indians in East Africa and Durban both show a markedly lower proportion of buccal neoplasms than that which pertains in India. Reasons for these variations are discussed, most of which are explicable in terms of differences in the environment.     

Melanoma in Western Australia 1975-76 to 1980-81: trends in demographic and pathological characteristics

Trends in incidence rates of cutaneous malignant melanoma in Western Australia from 1975-76 to 1980-1981 have been examined with reference to age, sex, body site, presence or absence of dermal invasion, tumour thickness, histological type, socioeconomic status and occupation. The incidence rates of all melanomas increased from 22.1 to 31.5 per 100,000 person-years in males and from 23.6 to 28.6 in females. In males, the relative annual increase in the incidence of invasive melanoma was 2.2%, and in females it was 5.6%. In-situ melanomas had larger relative increases in incidence (28% per annum in males and 10% in females) and the thickness of invasive lesions decreased between 1975-76 and 1980-81. The relative increase in incidence of invasive melanomas was greatest on the body sites with the highest rates initially--the trunk in males and the lower limbs in females. There was an increase in the proportion of invasive lesions classified as superficial spreading melanoma. The increase in incidence of in situ melanomas was largely restricted to the head and neck in older men of high socioeconomic status resident in Perth. This trend in in-situ melanoma was mainly due to an increase in the recorded incidence of Hutchinson's melanotic freckle. It may have been, in part, an artefact due to increased recognition of Hutchinson's melanotic freckle in this sub-group of the population.     

Effect of preoperative chemotherapy by intraarterial infusion of cisplatin (cis-dichlorodiammineplatin) on primary osteosarcomas

Preoperative chemotherapy was conducted in seven cases of osteosarcoma by twice administering intraarterial infusions of cisplatin (100 mg/m2/day) and the effects were studied through evaluations of clinical symptoms, plane radiograms, angiographic findings, serum alkaline phosphatase levels determined prior to and after the intraarterial infusion, and the rate of necrosis of tumor cells in the resected material. Results of treatment were as follows: disappearance of pain in two cases; reduction of pain in five cases; reduction in tumor size in three cases; and an increase in tumor size in one case. Radiograms obtained after treatment showed a reduction of tumor shadow at the extraskeletal site in one case; no change in five cases; an increase in one case, a clearly defined lesion border in one case; and no change in six cases. The radiograms showed no significant change in many cases, but this is perhaps because the radiograms were taken only four weeks after the start of treatment. Angiograms obtained after the preoperative chemotherapy revealed the disappearance of neovascularity in neoplasms in three cases, reduction in two cases, and no change in two cases. Reductions in the rates of serum alkaline phosphatase levels were in the range of 8.3 to 93% (average, 47.8%); the rates of necrosis of the tumor cells in the resected materials were ranged from 53 to 95% (average, 82.1%). The present chemotherapy resulted in formation of a fibrous connective tissue in the reactive zone and in increase in thickness of its pseudo-capsule. From this, it may be said that, if a tumor is to be resected in the area a few of more centimeters distant from the newly formed tissue, the surgery can be conducted within a wide curative margin, or a safer surgical margin. Results obtained from an overall evaluation of the effects showed the chemotherapy to be markedly effective in one case, effective in four cases, slightly effective in one case, and to have no effect in one case. For making life prognostic evaluations, more case data and longer-range follow-up observations will be needed.     

Malignant neoplasms in pregnancy--report of 28 cases treated in our hospital

We report 28 cases of malignant disease in pregnant women. They were divided into 14 cases of intrapelvic tumors and 14 of extrapelvic tumors. The intrapelvic tumors were cervix cancer in nine and ovarian cancer in five, while the extrapelvic tumors were brain tumors in three, maxillary cancer in one, tongue cancer in one, pharyngeal cancer in one, breast cancer in one, gastric cancer in two, osteosarcoma in one Hodgkin's lymphoma in one, and leukemias in three. The prognoses of the patients with intrapelvic tumors were relatively good. But those of extrapelvic diseases were poor.     

Effect of hydralazine on the blood flow in tumors and normal tissues in rats

The effects of hydralazine on the blood flow in various normal tissues and R3230 Ac adenocarcinomas grown in different sites in rats were studied. Tumors were induced in the kidney, liver, and flank (s.c.) by injection of small pieces of tumors. Tumors were also induced in small intestine, cecum, and mesentery by intraperitoneal injection of finely minced tumor tissue. The blood flow and cardiac output were measured by radioactive microsphere method. An intra-arterial injection of hydralazine at 2.5-10.0 mg/kg significantly reduced the blood flow in most normal tissues, whereas it markedly increased the blood flow in muscle. The blood flow in the brain and testes remained unchanged. The blood flow in the tumors varied depending on the tumor site and was markedly smaller than the blood flow in the host normal tissues in which the tumors grew. The blood flow in tumors decreased significantly upon injection of hydralazine except in the tumors grown in the liver, where the blood flow remained unchanged. The hydralazine injection slightly increased cardiac output and markedly decreased blood pressure. It appeared that the decreases in blood flow by hydralazine in the tumors and most normal tissues were caused mainly by diversion of blood to muscle, resulting in a marked increase in the muscle blood flow without a similar concomitant increase in cardiac output. The results obtained in the present study indicate that hydralazine may be useful for improving the efficacy of hyperthermia or for enhancing the toxicity of hypoxic cell specific bioreductive drugs in treating the tumors grown in skeletal muscle. However, the significant decline in blood flow in most normal tissues may pose potential problems in the use of hydralazine to enhance the effect of hyperthermia or bioreductive drugs on tumors grown in normal tissues other than muscle.     

Histochemical characterization of focal hepatic lesions induced by single diethylnitrosamine treatment in infant mice

Focal hepatocellular lesions, induced in our infant mouse system (15-day-old B6C3F1 mice) by a single carcinogenic dose of diethylnitrosamine (2.5 or 5.0 micrograms/g body weight), were characterized histochemically using toluidine blue, periodic acid-Schiff, glycogen phosphorylase, glycogen synthetase, glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase, ATPase, gamma-glutamyl transpeptidase, and acid phosphatase. Animals were killed 5, 12, 18, and 24 weeks following diethylnitrosamine treatment. The first focal lesions were observed in mice killed at 12 weeks. All foci showed patchy cytoplasmic basophilia and a slight decrease in the glycogen content. The early foci (12 weeks) showed no change in the levels of glycogen phosphorylase and glycogen synthetase, a strong reduction of glucose-6-phosphatase, and a high increase in glucose-6-phosphate dehydrogenase. In addition, 56% of foci in males and 86% of foci in females showed a slight rise in glyceraldehyde-3-phosphate dehydrogenase, and 12% of foci in males and 17% of foci in females had a lower acid phosphatase. The level of cytoplasmic ATPase was slightly decreased in 22% of foci. By 24 weeks, a decrease in the activity of cytoplasmic ATPase was observed in 84 and 100% of foci in males and females, respectively. The increase in the membrane ATPase was observed in 65% of foci in males and 7% of foci in females. By that time, the decrease in acid phosphatase was observed in 78% of foci in males and 37% of foci in females. The gamma-glutamyl transpeptidase failed to show any increase in its activity, indicating that this enzyme was not a "marker" of the hepatocellular lesions developing under the experimental conditions. Strong decrease in glucose-6-phosphatase in association with a manifest increase in glucose-6-phosphate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase activities indicated a shift from gluconeogenesis to glycolysis. Since this metabolic shift occurred concurrently with an increase in the labeling indices and focal size, it appears that these changes act in concert, representing expression of the acquired functional and replicating potential of the focal cell population.     

Toxicity and mutagenicity of a mixture of 25 chemicals found in contaminated groundwater

A defined mixture of 25 chemicals that are often found in contaminated groundwater was prepared as an aqueous solution and studied for mutagenicity in bacteria, for prophage induction in bacteria, for palatability and effect on weight-gain in rats and mice, and for cytogenetic effects in bone marrow cells of rats and mice. The bacterial mutation and prophage induction tests were negative. Exposure to the mixture in drinking water for two weeks resulted in a concentration-related decrease in water consumption in male and female rats and mice. Concentration-related decreases in weight gain were observed in male and female mice; in rats, only the high-dose groups showed decreased weight gains. A small but significant increase in sister chromatid exchanges was seen in male mice and a similar weak effect on micronucleated polychromatic erythrocytes (PCE) in the bone marrow of males and females. Also in bone marrow of male and female mice, an increase in mitotic index and a decrease in average cell generation time was observed. The %PCE in bone marrow was decreased in female mice only, while the %PCE in peripheral blood was increased in both sexes. In rats, the only effects observed in the cytogenetic studies were increased PCE frequencies in the peripheral blood of males and in the bone marrow of males and females. These results indicate that the 25-chemical mixture studied is not genotoxic in bacteria and that a concentration-dependent effect on its palatability to rodents leads to reduced water consumption, food consumption and weight gain. Although the bone marrow effects may be associated with disruptions of normal erythropoiesis that, in turn, alter the cytogenetic end-points reported, elevations of SCE and MN-PCE in mice suggest the 25-chemical mixture, under the conditions of administration, leads to cytogenetic damage in the bone marrow. Such damage may indicate a potential health hazard.     

Genomic alterations in preneoplastic lesions

The genomic alterations in preneoplastic lesions are summarized in this review. 3p and 9p in the lung, 9p in the bladder, 8p in the prostata, 19q and 1p in oligodendroglioma, and 22q in meningioma were reported to be deleted. Somatic mutation of p53 was found in preneoplastic lesions of the esophagus, stomach, colon, thyroid, and astrocytoma. Adenoma-carcinoma sequence (Apc, ras, p53 gene alterations) in colon, LKB1 gene in Peutz-Jeghers syndrome, Smad4 in juvenile polyposis, hMSH2, hMLH1, PMS1, PMS2 genes in HNPCC, VHL gene in kidney, WT1 in Wilms tumor, RB gene in retinoblastoma, and ret gene in MEN were reportedly altered in preneoplastic lesions involved in hereditary tumors. Cervical dysplasia and papilloma of the head and neck infected by human papilloma virus and liver infected by B-type hepatitis virus are also precancerous. Genomic instability, APC gene alteration, point mutation of K-ras in preneoplastic lesions of stomach and K-ras and p16 alterations in metaplasia of pancreas were also found. Advances in research on genomic alterations in preneoplastic lesions will contribute to prevention and early detection of cancer.     

Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression

BACKGROUND: The recently identified RASSF1 locus is located within a 120-kilobase region of chromosome 3p21.3 that frequently undergoes allele loss in lung and breast cancers. We explored the hypothesis that RASSF1 encodes a tumor suppressor gene for lung and breast cancers. METHODS: We assessed expression of two RASSF1 gene products, RASSF1A and RASSF1C, and the methylation status of their respective promoters in 27 non-small-cell lung cancer (NSCLC) cell lines, in 107 resected NSCLCs, in 47 small-cell lung cancer (SCLC) cell lines, in 22 breast cancer cell lines, in 39 resected breast cancers, in 104 nonmalignant lung samples, and in three breast and lung epithelial cultures. We also transfected a lung cancer cell line that lacks RASSF1A expression with vectors containing RASSF1A complementary DNA to determine whether exogenous expression of RASSF1A would affect in vitro growth and in vivo tumorigenicity of this cell line. All statistical tests were two-sided. RESULTS: RASSF1A messenger RNA was expressed in nonmalignant epithelial cultures but not in 100% of the SCLC, in 65% of the NSCLC, or in 60% of the breast cancer lines. By contrast, RASSF1C was expressed in all nonmalignant cell cultures and in nearly all cancer cell lines. RASSF1A promoter hypermethylation was detected in 100% of SCLC, in 63% of NSCLC, in 64% of breast cancer lines, in 30% of primary NSCLCs, and in 49% of primary breast tumors but in none of the nonmalignant lung tissues. RASSF1A promoter hypermethylation in resected NSCLCs was associated with impaired patient survival (P =.046). Exogenous expression of RASSF1A in a cell line lacking expression decreased in vitro colony formation and in vivo tumorigenicity. CONCLUSION: RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung and breast cancers through hypermethylation of its promoter region.     

Carcinoma in situ of the breast.

A series of 87 cases of carcinoma in situ of the breast was reviewed. IN 49 CASes in which lobular carcinoma in situ was shown on biopsy, three patients were found to have invasive carcinoma in the subsequently done mastectomy. All three of these cases were in a group of 14 patients shown in have bilateral lobular carcinoma in situ on biopsy. In a group of 38 patients with intraductal carcinoma on biopsy, seven were found to have invasive carcinoma in the mastectomy that was subsequently done. Lymph node metastases were found in one patient in the lobular group and four patients in the intraductal group. Three patients in the intraductal group died of cancer. None in the lobular group has died of cancer.     

Chronic paronychia, and oral and vaginal candidal carriage

In 60 patients with chronic paronychia, Candida was found in the paronychia in 39 patients (C. albicans in 30 of them), in the vagina in 8 patients (C. albicans in 7 of them) and in the mouths in 47 patients (C. albicans in 40 of them). In the mouths of a control group of 60 female patients of comparable age, Candida was found in only 30 (C. albicans in 24). The incidence of Candida in the mouth was not affected by the presence of "predisposing factors" nor was there any difference in candidal carriage rate in paronychia and mouths of subjects in the fertile period and those in the menopause. C. albicans was present in the vagina in the fertile period only.
The incidence of chronic paronychia was less in the 5^th decade than in either the 4^th or 6^th decades.     

Analysis of clonal evolution in a tumor consisting of pSV2neo-transfected mouse fibrosarcoma clones

The process of clonal evolution was analyzed in a line of methylcholanthrene-induced mouse fibrosarcomas. The tumor cells were transfected with pSV2neo gene and 22 clones were randomly isolated. Genetically tagged clones were mixed and inoculated into syngeneic mice. Southern blot analysis revealed that one of the clones, no. 11, dominated both in tumors in situ and in lung metastatic nodules. No. 11 clone and other clones were similar in growth rates in vitro and in vivo, in spontaneous and experimental metastatic abilities, in immunogenicity, and in the capacity of intercellular communication in vitro. Although no. 11 clone overgrew other clones in vivo, this was not the case when clones were mixed and maintained in vitro. We conclude that clonal interactions in vivo may be responsible for the dominance of no. 11 clone in the tumor. It is likely that the preferential metastasis of no. 11 clone to the lung may be a simple reflection of the proliferative advantage of the dominant clone in the tumor in situ.     

Squamous cell carcinomas of the head and neck in Norway, 1953-92: an epidemiologic study of a low-risk population

Trends in incidence, five-year relative survival, and mortality among patients in Norway with squamous cell carcinoma of the oral sites, oro-/hypopharynx, and larynx were studied for the period 1953-92. Throughout the first part of the study period, age-adjusted incidence rates (AAIR) of oral cancer remained stable in both genders. Since the end of the 1960s, AAIRs increased by 13 percent per five-year period in males and 12 percent in females. The figures suggest increased male incidence rates of oral cancer in younger age groups. During the same period, AAIRs of cancers of the oro-/hypopharynx in males increased by 19 percent per five-year period. The AAIRs of laryngeal cancer increased steadily from 1953-92 among both males and females by 17 percent and 21 percent per five-year period, respectively. For all sites, changes in AAIRs for males were greater in rural than in urban areas. No improvement in detection of disease at a localized stage was observed for either gender. There are indications of improvements in the five-year relative survival rates for oral and pharyngeal cancer in both genders. For all sites, relative survival was better in younger than in older patients. Only in the case of pharyngeal cancer in males was an increase in disease-specific mortality rates positive for a time trend.     

NTP technical report on toxicity studies of urethane in drinking water and urethane in 5% ethanol administered to F344/N rats and B6C3F1 mice

Urethane, a byproduct of fermentation found in alcoholic beverages, is carcinogenic in rodents and is classified by the International Agency for Research on Cancer as a possible human carcinogen. The United States Food and Drug Administration nominated urethane for study because of the widespread exposure of humans through the consumption of fermented foods and beverages and because of a lack of adequate dose-response data about the carcinogenicity of urethane with and without the coadministration of ethanol. Comparative studies of urethane in drinking water and in 5% ethanol were conducted to investigate possible effects of ethanol on urethane toxicity. Toxicokinetic studies of urethane in drinking water and in 5% ethanol and genetic toxicity studies of urethane in vivo and in vitro were also conducted. Groups of 10 male and 10 female F344/N rats and B6C3F1 mice, 6 weeks of age, received 0, 110, 330, 1,100, 3,300, or 10,000 ppm urethane in drinking water or in 5% ethanol for 13 weeks. Toxicokinetic evaluations were performed for urethane in the plasma of male mice after 13 weeks of administration in drinking water or 5% ethanol. The mutagenicity of urethane in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 with and without S9 was tested at doses up to 16,666 micrograms/plate; urethane was also tested for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells and sex-linked recessive lethal mutations and chromosomal reciprocal translocations in Drosophila melanogaster. The frequency of micronucleated erythrocytes induced in peripheral blood and bone marrow cells of mice by urethane in drinking water and in 5% ethanol was also evaluated. In rats that received urethane in drinking water, seven males and four females administered 10,000 ppm and one female administered 3,300 ppm died before the end of the study; body weight gains were reduced at these concentrations. Two males and all females given 10,000 ppm urethane in 5% ethanol died during the study, and the body weight gains of males and females that received 3,300 ppm were lower than those of the controls. Relative right kidney, liver, and lung weights of males and females and relative right testis weights of males administered 1,100 ppm or greater were generally higher than those of the controls in each study. Leukopenia and lymphopenia were observed in rats receiving urethane in either drinking water or ethanol and occurred in males receiving 330 ppm or greater and females receiving 110 ppm or greater. Other differences in hematology and clinical chemistry variables were not considered to be biologically significant. Lymphoid depletion of the spleen, lymph nodes, and thymus was observed in male and female rats receiving 1,100, 3,300, or 10,000 ppm urethane in drinking water. Cellular depletion of the bone marrow occurred in males and females in the 10,000 ppm groups. Hepatocellular fatty changes and clear cell foci of alteration were noted in the liver of males and females that received 3,300 or 10,000 ppm. The incidences of nephropathy were significantly increased in female rats that received 1,100 ppm or greater; the severity of this lesion in exposed males and females was greater than that in the controls. Females that received 330 ppm or greater had higher incidences of cardiomyopathy than the controls; the severity of this lesion was greater in males in the 10,000 ppm group and females in the 3,300 and 10,000 ppm groups than in the controls. In rats that received urethane in 5% ethanol, lymphoid depletion occurred in males and females in the 3,300 and 10,000 ppm groups. Cellular depletion of the bone marrow was observed in males and females in the 10,000 ppm groups. Only males in the 10,000 ppm group had hepatocellular fatty change (8/10) and clear cell foci (1/10); the incidence and severity of nephropathy in males and females and cardiomyopathy in males were similar to those in rats administered urethane in drinking water; however, no cardiomyopathy was observed in females receiving urethane in ethanol. The estrous cycle length of females receiving urethane in ethanol appeared to be longer than that of females receiving urethane in drinking water. Because cycle length was longer in the 10,000 ppm groups than in the controls in both the drinking water and ethanol vehicle studies, this difference may represent an exacerbation of the toxicity of urethane. A longer estrous cycle may be a sign of reproductive impairment and correlates with a decrease in female fecundity. All mice administered 10,000 ppm urethane in either vehicle died. All mice that received 3,300 ppm urethane in drinking water died, while only one male and four females receiving 3,300 ppm urethane in 5% ethanol died. Body weight gains of males and females in all 1,100 ppm groups were less than those of the respective controls, but the weight gains of mice receiving 1,100 ppm urethane in 5% ethanol were greater than those of mice receiving urethane in drinking water. The mean body weights of the lower exposure groups were similar to those of the respective controls, and there were no other differences between the body weights of mice receiving urethane in drinking water and those receiving urethane in 5% ethanol. Fluid consumption, and therefore total urethane intake, appeared lower in mice receiving the 5% ethanol vehicle than in those receiving the water vehicle. The relative right kidney, liver, and lung weights of males and females administered urethane in drinking water or ethanol were generally greater than those of the controls. Clearance of urethane from the plasma of male mice was complete within 2 hours after urethane was administered in water, but urethane was not cleared 12 hours after administration in 5% ethanol. At the end of 13 weeks of urethane administration, the plasma urethane elimination half-life was 0.8 hours; the kinetics were similar for concentrations of 110, 330, and 1,100 ppm urethane in water and in ethanol. However, at each exposure level, the plasma urethane concentration was four times greater for urethane administered in 5% ethanol than for urethane administered in drinking water, indicating a possible inhibition of urethane metabolism by ethanol. Kinetic measurements for elimination by female mice could not be obtained from the data collected. In mice administered urethane in drinking water, lung inflammation occurred in males and females that received 1,100 ppm or greater. Alveolar epithelial hyperplasia occurred in the lungs of males in the 330 and 1,100 ppm groups and females in the 1,100 ppm group; one male mouse in the 330 ppm group had an alveolar/bronchiolar adenoma (see the following summary table). Mice receiving urethane in 5% ethanol had lower incidences and severity of lung inflammation but generally greater incidences and severity of alveolar epithelial hyperplasia than mice receiving the same concentrations of urethane in drinking water. Alveolar/bronchiolar adenomas occurred in four males and one female administered urethane in ethanol. [table: see text] Nephropathy was observed in males and females that received urethane in either vehicle, and the lesions in female mice were more severe than those in male mice; ethanol did not appear to increase the incidence or severity of nephropathy. Cardiomyopathy occurred in males and females that received 1,100 or 3,300 ppm urethane in drinking water and in females that received 3,300 ppm urethane in ethanol. Lymphoid depletion occurred in mice that received 3,300 or 10,000 ppm urethane; 5% ethanol did not appear to enhance these effects. However, urethane in 5% ethanol induced ovarian atrophy; the incidence of this lesion was lower in females receiving urethane in drinking water. A concentration of 1,100 ppm urethane in either drinking water or ethanol effectively stopped estrous cycling. Urethane is clearly genotoxic in vitro and in vivo. In vitro, urethane induced mutations in Salmonella typhimurium strain TA1535 in the presence of liver S9 enzymes. Sister chromatid exchanges were induced in cultured Chinese hamster ovary (CHO) cells with and without S9. However, no induction of chromosomal aberrations was observed in CHO cells treated with urethane, with or without S9. In vivo, urethane induced sex-linked recessive lethal mutations and reciprocal translocations in germ cells of adult male Drosophila melanogaster fed urethane. Significantly increased frequencies of micronucleated erythrocytes were observed in peripheral blood obtained from male and female mice after 45 days of exposure and in bone marrow and peripheral blood obtained after 13 weeks of exposure to urethane in drinking water. There appeared to be no significant difference in the magnitude of the response in the peripheral blood micronucleus test between mice administered urethane in drinking water and mice administered urethane in 5% ethanol. In summary, concentrations of 1,100 ppm urethane or greater in drinking water caused lymphoid and bone marrow cell depletion and hepatocellular lesions and increased the severity of nephropathy and cardiomyopathy in male and female rats. The lethal effects of 10,000 ppm urethane were slightly exacerbated by 5% ethanol in female rats. Urethane administered in drinking water induced lung inflammation, alveolar and bronchiolar hyperplasia, alveolar/bronchiolar adenomas, nephropathy, cardiomyopathy, lymphoid and bone marrow cell depletion, seminiferous tubule degeneration, and ovarian atrophy and follicular degeneration in mice. In female mice, 5% ethanol appeared to exacerbate ovarian atrophy. Mice administered urethane in 5% ethanol consumed less fluid, and therefore less urethane, than mice receiving urethane in drinking water. Coadministration of urethane and ethanol inhibited the clearance of urethane from plasma. (ABSTRACT TRUNCATED)     

Restoration of plakoglobin expression in bladder carcinoma cell lines suppresses cell migration and tumorigenic potential

The reduction or loss of plakoglobin expression in late-stage bladder cancer has been correlated with poor survival where upregulation of this catenin member by histone deacetylase inhibitors has been shown to accompany tumour suppression in an in vivo model. In this study, we directly addressed the question of the role of plakoglobin in bladder tumorigenesis following restoration, or knockdown of expression in bladder carcinoma cell lines. Restoration of plakoglobin expression resulted in a reduction in migration and suppression of tumorigenic potential in vivo. Immunocytochemistry revealed cytoplasmic and membranous localisation of plakoglobin in transfectants with < 1% of cells displaying detectable nuclear localisation of plakoglobin. siRNA knockdown experiments targeting plakoglobin, revealed enhanced migration in all cell lines in the presence and absence of E-cadherin expression. In bladder cell lines expressing low levels of plakoglobin and desmoglein-2, elevated levels of desmoglein-2 were detected following restoration of plakoglobin expression in transfected cell lines. Analysis of wnt signalling revealed no activation event associated with plakoglobin expression in the bladder model. These results show that plakoglobin acts as a tumour suppressor gene in bladder carcinoma cells and the silencing of plakoglobin gene expression in late-stage bladder cancer is a primary event in tumour progression.     

某三甲医院“癌痛规范治疗”项目实施前后麻醉性镇痛药使用情况分析

目的:调查我院癌痛规范化治疗（good pain management，GPM）示范病房项目对我院癌痛患者麻醉性镇痛药物规范化使用的促进情况。方法:收集我院GPM项目开展前（2012年）、GPM项目开展后（2016年），GPM科室（肿瘤科）和非GPM科室（其他科室）门诊及住院癌痛患者麻醉性镇痛药处方数据。结果:GPM科室门诊口服阿片类控缓释剂型比例由2012年的18%上升到2016年91%，明显高于非GPM科室的76%；门诊长疗程处方比例由2012年58%上升到2016年79%，也显著高于非GPM科室的49%。GPM科室病房口服控缓释阿片类药品比例由68.96%提高到90.35%，亦高于非GPM科室的62.62%。GPM科室没有使用杜冷丁控制癌痛。结论:GPM项目实施4年后，GPM科室在癌痛规范化治疗方面有明显进步。与非GPM科室相比，GPM科室癌痛治疗更为积极主动、规范合理。GPM项目促进癌痛规范化用药成效显著。