Body mass index and colorectal cancer prognosis: a systematic review and meta-analysis.

Colorectal cancer is one of the most common cancers worldwide. However, it is unclear what influence body mass index (BMI) has on colorectal cancer prognosis. We conducted a systematic review and meta-analysis of observational studies to examine the association of BMI with colorectal cancer outcomes. We searched MEDLINE and EMBASE databases from inception to February 2015 and references of identified articles. We selected observational studies that reported all-cause mortality, colorectal cancer-specific mortality, recurrence and disease-free survival according to BMI category. Random-effects meta-analyses were conducted to combine estimates. We included 18 observational studies. Obese patients had an increased risk of all-cause mortality [relative risk (RR) 1.14; 95 % confidence interval (CI) 1.07-1.21], cancer-specific mortality (RR 1.14; 95 % CI 1.05-1.24), recurrence (RR 1.07; 95 % CI 1.02-1.13) and worse disease-free survival (RR 1.07; 95 % CI 1.01-1.13). Underweight patients also had an increased risk of all-cause mortality (RR 1.43; 95 % CI 1.26-1.62), cancer-specific mortality (RR 1.50; 95 % CI 1.20-1.87), recurrence (RR 1.13; 95 % CI 1.05-1.21) and worse disease-free survival (RR 1.27; 95 % CI 1.13-1.43). Overweight patients had no increased risk for any of the outcomes studied. Both obese and underweight patients with colorectal cancer have an increased risk of all-cause mortality, cancer-specific mortality, disease recurrence and worse disease-free survival compared to normal weight patients.

Combination of oral non-absorbable and intravenous antibiotics versus intravenous antibiotics alone in the prevention of surgical site infections after colorectal surgery: a meta-analysis of randomized controlled trials.

BACKGROUND: Oral non-absorbable antibiotics work by decreasing intraluminal bacterial content after mechanical bowel preparation. The advantage of adding oral non-absorbable antibiotics to intravenous antibiotics to decrease surgical site infection (SSI) after colorectal surgery is not well known. We conducted a meta-analysis of randomized controlled trials (RCT) comparing the effectiveness of combined oral non-absorbable and intravenous antibiotics versus intravenous antibiotics alone in reducing the incidence of SSI following colorectal surgery. METHOD: We included RCT comparing a combination of oral non-absorbable antibiotics and intravenous antibiotics to intravenous antibiotics alone in order to prevent SSI after colorectal surgery. Outcomes assessed included postoperative infectious complications, such as surgical wound infections (SWI) defined as a combination of superficial and deep SSI, organ-space infections and anastomotic dehiscence. RESULTS: Sixteen RCT published between 1979 and 2007 were included in the meta-analysis. The overall analyses indicated that patients randomly assigned to an oral non-absorbable antibiotic in addition to an intravenous antibiotic had a reduced risk of SWI (RR: 0.57 [95% CI: 0.43-0.76], p = 0.0002) compared with participants receiving only intravenous antibiotics. The use of oral non-absorbable antibiotics in addition to intravenous antibiotics had no significant effect on organ-space infections (RR: 0.71 [95% CI: 0.43-1.16], p = 0.2) or the risk of anastomotic leak (RR: 0.63 [95% CI: 0.28-1.41], p = 0.3). CONCLUSION: Our meta-analysis shows that a combination of oral non-absorbable antibiotics and intravenous antibiotics significantly lowers the incidence of SWI compared with intravenous antibiotics alone. In light of our results, the use of oral non-absorbable antibiotics in colorectal surgery should be encouraged.

Altered mammary responsiveness to estradiol and progesterone in mice exposed neonatally to diethylstilbestrol.

Mammary glands from ovariectomised neonatally diethylstilbestrol (DES)-exposed (0.1 microgram daily for the first 5 days of life) mice seem morphologically indistinguishable from those of ovariectomised controls. However, administration of exogenous hormones reveals a differential response. In DES-exposed mice, estrogen implantation resulted in greater incidence of dilated ducts along with greater incidence of dilated ducts along with greater incidence and severity of terminal ductal hyperplasia and greater severity of cystic alveolar adenosis; combined estrogen and progestin treatment resulted in greater severity of terminal duct hyperplasia and less alveolar formation, and progestin treatment resulted in lower incidence and degree of lateral budding. Thus, mammary sensitivity to sex steroids is altered by early exposure of mice to DES.

Sensitivity of the vagina and uterus of mice neonatally exposed to estrogen or androgen to postnatal treatment with estrogen or androgen.

Newborn female BALB/cCrgl mice receiving 5 micrograms of testosterone or 0.01 micrograms of diethylstilbestrol daily for the first 5 days of life were examined at various times after secondary exposure to testosterone and 17 beta-estradiol, respectively. Neonatal administration of testosterone induced squamous stratification associated with constant cornification of the vaginal epithelium in intact mice. Later exposure to testosterone suppressed cornification, resulting in superficial epithelial mucification in almost all mice by 4 months of age. However, at 6 months of age, the incidence of mucification dropped to 58%. Cervicovaginal lesions developed in the groups of mice given neonatal testosterone in combination with later testosterone and sacrificed at 4 and 6 months of age. Continuous vaginal stratification was found in 14% of ovariectomized, neonatally diethylstilbestrol-treated mice at 13 months of age. The incidence of this ovary-independent change increased to 40% at 24 months of age. Postnatal estrogen replacement significantly increased the incidence of squamous stratification in these mice. Neonatal diethylstilbestrol treatment alone induced cervicovaginal lesions in 4.5% of ovariectomized mice at 13 months of age; secondary 17 beta-estradiol exposure significantly enhanced the development of lesions to 44%. However, at 24 months of age, there was no difference in the incidence of lesions in ovariectomized, neonatally treated mice with or without the secondary 17 beta-estradiol treatment. These results suggest that the effects of neonatal exposure to a relatively low dose of estrogen, androgen, or related substance may become obvious later in life as a result of later exposure to hormones.

Reproductive abnormalities in female mice exposed neonatally to various doses of coumestrol.

Female C57BL/Crgl mice were neonatally exposed to various doses of coumestrol to determine the threshold doses required for the occurrence of reproductive tract abnormalities. Newborn mice received daily subcutaneous injections of 10(-3), 10(-2), 8 X 10(-2), 10(-1), 1, 5, 25, 50, and 100 micrograms coumestrol in 0.005 ml dimethyl sulfoxide (DMSO) or DMSO alone, or received no treatment for the first 5 d of life. Some of the animals were ovariectomized at 40 d of age. Mice were killed at 20-22 mo of age. All neonatal doses of coumestrol advanced vaginal opening before that of controls. At 2 and 20-22 mo of age, doses greater than or equal to 25 micrograms consistently resulted in ovary-independent persistent vaginal cornification as judged by vaginal smears. Intact untreated and DMSO-treated control mice exhibited aging changes in the genital tract, some cervical adenosis and early cervicovaginal pegs and downgrowths, uterine cystic glandular hyperplasia, corpora lutea, and scattered areas of ovarian ceroid deposition. Intact mice receiving neonatal coumestrol exhibited cervicovaginal pegs and downgrowths (at all doses with the exception of 25 and 50 micrograms), cervical adenosis (at doses greater than or equal to 8 X 10(-2) micrograms), uterine squamous metaplasia (significant at doses greater than or equal to 50 micrograms), and a decrease in uterine cystic glandular hyperplasia (significant at doses greater than or equal to 25 micrograms). The levels of 10(-1), 5, and 100 micrograms neonatal coumestrol daily resulted in hemorrhagic follicles. An increase in ovarian ceroid deposition (significant at doses greater than or equal to 5 micrograms) was observed. At 40 d and 20-22 mo of age, corpora lutea were consistently absent from the 100-micrograms-treated animals. Most of the ovariectomized untreated and DMSO-treated control animals showed typical castrate-like morphology of the genital tract, with the majority of the control mice exhibiting uterine cystic glandular hyperplasia. Ovariectomized mice receiving coumestrol neonatally exhibited various degrees of cervicovaginal alterations: pegs and downgrowths (significant at all doses with the exception of 10(-1) micrograms), endometrial collagen deposition (significant at greater than or equal to 25 micrograms), and reduced or absent uterine glands (significant at 10(-3), and 10(-11), and at all doses greater than or equal to 5 micrograms).

Steroid binding alterations in tissue compartments of the vagina of control and neonatally diethylstilbestrol-treated adult mice.

Steroid binding in both the vaginal epithelium and the vaginal fibromuscular wall (FMW) was compared in control and neonatally estrogen-treated mice. Neonatal treatment with a low dose of the estrogen diethylstilbestrol (DES) had no significant effect on adult estrogen binding within the assayed vaginal compartments; however, this treatment caused a 2-fold increase in the level of cytosolic progestin binding in the vaginal FMW over that in vehicle-treated mice. This low neonatal dose did not affect the level of progestin binding in the vaginal epithelium. In contrast, neonatal treatment with a larger dose of DES caused marked increases in cytosolic progestin binding, decreases in cytosolic estrogen binding, and increases in nuclear estrogen binding within the FMW. Furthermore, as a result of the changes in specific binding induced by the neonatal DES treatment, the degree of the estrogen binding within in each tissue shifted from a predominantly cytosolic site to a nuclear one.

Long-term genital tract changes in female mice treated neonatally with coumestrol.

The neonatal mouse model has proven to be an effective system to examine long-term reproductive tract abnormalities resulting from early exposure to estrogens. Newborn C57BL/Crgl mice received 8 x 10(-2) micrograms diethylstilbestrol (DES) or 100 micrograms coumestrol (a plant estrogen) in 0.005 mL dimethyl sulfoxide (DMSO) or DMSO alone or received no treatment for the first 5 days of life. Half of the animals were ovariectomized at 40 days of age. Vaginal lavages were examined for 15 consecutive days before termination at 13 months of age, at which time genital tracts and mammary glands were removed for histological examination. Diethylstilbestrol- and coumestrol-treated animals exhibited ovary-independent persistent vaginal cornification as well as cervico-vaginal pegs and downgrowths, uterine squamous metaplasia, and an enhancement of age-related changes in the ovary including hemorrhagic follicles. In general, neonatal exposure to the naturally occurring plant estrogen, coumestrol, has long-term effects similar to those seen following exposure to natural and synthetic estrogens.

Reproductive alterations in female C57BL/Crgl mice exposed neonatally to zearalenone, an estrogenic mycotoxin.

Newborn female mice were injected daily for 5 days with 1 microgram zearalenone (Z, a weakly estrogenic mycotoxin present in cereal grains), resulting in ovary-dependent reproductive tract alterations at 8 months of age. Corpora lutea were absent from 25 of 34 (74%) Z-treated mice, indicating ovarian dysfunction. Fifty-six percent of Z-treated mice had dense collagen deposition in the uterine stroma and lacked uterine glands. Squamous metaplasia of the uterine luminal epithelium was found in 59% of Z-treated mice, and altered vaginal epithelium was found in 32% (2 mice had dysplastic lesions). Ovariectomized Z-treated mice were indistinguishable from ovariectomized controls.

Influence of neonatal diethylstilbestrol treatment on androgen and estrogen receptor levels in the mouse anterior prostate, ventral prostate and seminal vesicle.

Perinatal exposure to the synthetic estrogen, diethylstilbestrol (DES), affects the structure of both male and female reproductive systems. Changes may also occur in the levels of steroid hormone receptors. Cytosolic and nuclear androgen and estrogen receptor levels (expressed per mg DNA) from the sex accessory glands of male BALB/c mice exposed neonatally to DES were analyzed by exchange assays. Neonatal DES exposure caused significant decreases in: (1) cytosolic androgen and cytosolic and nuclear estrogen receptor levels in the anterior prostate and (2) cytosolic estrogen receptor levels in the ventral prostate. A significant increase was seen in the cytosolic estrogen receptor levels in the seminal vesicle. Significant decreases in cytosolic protein levels occurred in all DES-exposed glands.

Effects of testosterone on morphology and on progestin and estrogen receptor levels in the mouse uterus and mammary gland.

The effects of androgen on the morphology and levels of cytosolic estrogen and progestin receptors (ER and PR) were studied in the mouse uterus and mammary gland. Testosterone neonatally and/or continuously in the adult lowers ER and PR levels particularly at early ages (40-60 days of age) in both the uterus and mammary gland. At older ages, less prominent changes in ER and PR levels are observed. Neonatal androgen treatment appears to exert both direct effects on the uterus and mammary gland and indirect effects (via the hypothalamo-hypophysio-ovarian axis). At all ages, neonatal testosterone in combination with continuous adult testosterone consistently depressed PR levels in both uterus and mammary gland, indicating that testosterone is a negative modulator of PR in these tissues.

Vaginal abnormalities in ovariectomized BALB/cCrgl mice after neonatal exposure to different doses of diethylstilbestrol.

Newborn BALB/cCrgl female mice received five daily injections of various doses of diethylstilbestrol (DES), 0.0001-10 micrograms. Mice were killed at 6 days of age or at 4 months after ovariectomy at 40-42 days. Subepithelial nodules of polygonal cells in the upper (Mullerian) vagina during early postnatal life were associated with the later occurrence of ovary-independent persistent stratification with or without cornification in mice treated neonatally with 0.1-10 micrograms DES and thus are a possible predictor of this phenomenon. The thresholds for the induction of ovary-independent epithelial pegs, downgrowths and adenosis (glandular formations) were 0.1 microgram and 0.5 microgram DES/day, respectively.

Neonatal administration of prolactin antiserum alters the developmental pattern of T- and B-lymphocytes in the thymus and spleen of BALB/c female mice.

We have evaluated the effect of neonatal administration of mouse prolactin (PRL) antiserum on the developmental expression of T- and B-lymphocytes in the thymus and spleen of female BALB/c mice. Newborn female mice were injected subcutaneously with a 50-microliters aliquot of PRL antiserum or normal rabbit serum on days 1, 2, and 3. On neonatal day 5, the PRL antiserum-treated group had a significantly (P less than 0.05) increased population of cells in the thymus and the spleen that were positive for Thy-1.2 and for L3T4. Increases in Thy-1.2- and L3T4-positive cells in the thymus were detectable also on days 8 and 14 in mice that received the PRL antiserum and in mice injected with bromocriptine, a dopamine agonist that inhibits PRL release from the anterior pituitary. On neonatal days 21, 28, and 32, there were no significant differences in the percentage of cells positive for Thy-1.2, Ly-2 (formerly Lyt-2), or L3T4 antigens in the thymus. However, there were significant increases in the percentage of Thy-1.2- and L3T4-positive spleen cells in the bromocriptine-treated group at all times monitored and in the PRL antiserum-treated group except on day 14. In addition, the percentage of splenocytes that were positive for IgG was significantly increased in the PRL antiserum-treatment group on days 8-28, although not on neonatal day 32. Of tissues known to contain PRL receptors, neonatal administration of PRL antiserum or bromocriptine resulted in a significant alteration in the wet weight of spleen and liver, with no significant effect in thymus, heart, and kidney. Pituitary implants also resulted in a significant increase in both concanavalin A- and lipopolysaccharide-stimulated thymidine incorporation into murine splenic lymphocytes prepared from 45-day-old female mice. These data extend the role of PRL as an immunomodulator of adult lymphocyte function to a role in the developmental expression of T- and B-lymphocyte populations in the thymus and spleen of mice.

Long-term alterations in histology and steroid receptor levels of the genital tract and mammary gland following neonatal exposure of female BALB/cCrgl mice to various doses of diethylstilbestrol.

The relation of the dosage of diethylstilbestrol (DES) administered neonatally to the incidence and severity of genital tract and mammary gland lesions and to the levels of sex hormone receptors was examined using a mouse model for human intrauterine DES exposure. Female BALB/cCrgl mice received various doses of DES (ranging from 5 X 10(-1)-10(-5) micrograms daily for the first 5 days of life) or the sesame oil vehicle alone. In the vagina, at all ages examined (1, 2, 6, and 12 months) cytosolic estrogen receptors are consistently decreased after high doses of neonatal DES (10(-1) and 1 microgram). In contrast, at the same ages, vaginal cytosolic progestin receptors increase after identical doses. In the uterus, the 1-microgram dose of neonatal DES also consistently decreases cytosolic estrogen receptors while increasing cytosolic progestin receptors at 1, 2, and 6 months of age. Histologically, neonatal doses of 5 X 10(-2) micrograms DES result in vaginal lesions at 2 months. With age, this threshold level decreases, implying interaction with an altered hormonal milieu. The uterus shows a sensitivity similar to that of the vagina in regard to the histopathological effects of neonatal DES. The ovary and mammary glands are 10- to 100-fold more sensitive to neonatal DES exposure.

Frequent occurrence of polyovular follicles in ovaries of mice exposed neonatally to diethylstilbestrol.

The occurrence of polyovular follicles (PF) was examined at 10-34 days of age in the ovaries of BALB/cCrgl female mice given five daily injections of 0.1 microgram diethylstilbestrol (DES), 2 micrograms DES, 100 micrograms progesterone (P), 137 micrograms 17 alpha-hydroxyprogesterone caproate (HPC), 20 micrograms testosterone (T), 20 micrograms 5 alpha-dihydrotestosterone (5 alpha-DHT), or oil vehicle alone starting on the day of birth, and of C57BL/Tw females given five neonatal injections of 1 microgram DES, 20 micrograms 17 beta-estradiol (E2), 50 micrograms 5 alpha-DHT, 50 micrograms 5 beta-DHT, or the vehicle alone. Ovaries of 30-day-old C57BL mice given five daily injections of 1 microgram DES starting at 3-25 days of age were also examined. PF incidence (% of PF per ovary) and PF frequency (% of mice with PF) were significantly greater in BALB/c mice receiving injections of DES, P, HPC, and T than in the controls. In DES-treated mice at 34 days, PF incidence (2-13 oocytes/follicle) was 120-340 times higher than in the controls. BALB/c mice treated with T, P, and HPC showed PF incidence (two to four oocytes/follicle) three- to six-fold higher than in the controls. In 30-day-old C57BL mice treated with T, E2, and DES, PF incidence also increased by two- to 50-fold. 5 alpha-DHT and 5 beta-DHT failed to increase PF incidence. PF incidence was significantly increased only when neonatal DES treatment was begun on days 0 to 3, but was reduced when started at days 10-25.(ABSTRACT TRUNCATED AT 250 WORDS)

Induction of abnormal epithelial changes by estrogen in neonatal mouse vaginal transplants.

Adenosis occurred in transplanted C57BL and BALB/c mice Müllerian-derived reproductive tract regions, cervix, and/or fornix (FX), and middle vagina but never in the urogenital sinus-derived portion of the vagina, after a 1-mo exposure to endogenous ovarian hormones or exogenous estradiol (E2). Grafts in ovariectomized hosts did not exhibit adenosis, confirming its dependence on estrogen. C57BL FX and midvaginal transplants from 1-, 3-, and 5-day-old donors but not from 7- or 10-day-old donors developed adenosis, indicating a critical period before day 6. Prolonged E2 exposure (to 2 mo) decreased the adenosis incidence observed in the C57BL FX group but not in midvaginal transplants. Progesterone added during the second half of transplantation to continuing exogenous E2 prevented this reduction in the FX group; however, adenosis incidence in the similarly treated middle vagina group was less than that observed after 1 or 2 mo of E2 treatment alone. Progesterone present throughout the 2-mo transplantation period did not significantly affect adenosis incidence induced by 2-mo exposure of midvaginal or FX grafts to E2 alone. Changes suggestive of squamous cell carcinoma were found in a few BALB/c midvaginal grafts after E2 exposure for 1 mo and in some C57BL midvaginal and FX grafts after E2 and progesterone exposure for 2 mo.

Estrogen and progestin receptors in mouse vaginal epithelium and fibromuscular wall.

Both sodium molybdate and Percoll density gradient stabilize the hormone-binding capacities of the estrogen and progestin receptors and individually increase the recovery of these receptors in prepared cytosols of the separated mouse vaginal epithelium and fibromuscular wall. Their effects are additive. The concentrations of estrogen receptors are similar in the epithelial and fibromuscular compartments, whereas progestin receptor concentrations are higher in the epithelium.

Long-term responses of the mouse uterus to neonatal diethylstilbestrol treatment and to later sex hormone exposure.

The effects of ovariectomy at 1 month of age and continuous 17 beta-estradiol (E2) and/or progesterone (P) replacement on the uterus of BALB/cCrgl mice neonatally treated with diethylstilbestrol [(DES) CAS: 56-53-1; alpha-alpha'-diethyl-4,4'-stilbenediol] or sesame oil were recorded after 1, 4, 7, and 10 months of treatment. DES-exposed uteri were found to be hypoplastic, less responsive to the growth-promoting effects of E2, and more likely to develop smooth muscle abnormalities after continuous hormonal treatment than similarly treated control uteri. Neonatal DES treatment led to leukocytic infiltration, disruption in the organization of the inner circular smooth muscle layer, and development of a population of epithelial cells believed to respond to later E2 treatment by proliferation and stratification (squamous metaplasia). Qualitative and quantitative responses to continuous P treatment and the development of cystic glandular hyperplasia and adenomyosis were found to be unaltered by neonatal DES administration. The relevance of these results to the problems of uterine abnormalities observed in women exposed to DES in utero is discussed.

Effects of long-term implantation of vaginal concretions on the cervicovaginal epithelium of mice.

In two experiments, neonatal female BALB/cCrgl or BALB/cfC3HCrgl mice were given subcutaneous injections of 5 micrograms 17 beta-estradiol or sesame oil for the first 3 days of life and were ovariectomized at 60 days of age, at which time vaginal concretions (Experiments I and II) or silica (Experiment II) were implanted intravaginally. Mice were examined at 12 months of age. Three abnormal cervicovaginal epithelial responses were noted: persistent vaginal stratification/cornification (PVS); prominent vaginal squamocolumnar junction (SCJ); epithelial pegs, downgrowths, or lesions (dysplasias). PVS, not present in unimplanted controls, occurs in at least half of the members of the neonatally estrogen-treated groups; implants of concretions or silica did not increase its incidence significantly. Although SCJ was observed in implanted but not in unimplanted controls, its incidence was significantly higher in neonatally estrogen-treated mice than in either control group. The elevated incidence in neonatally estrogen-treated mice was not increased further by implantation of concretions or silica. In neonatally estrogenized mice, the subsequent implantation of a concretion significantly increased the incidence of cervicovaginal abnormalities. Increased PVS and SCJ are teratological consequences of neonatal exposure to a small amount of estrogen; on the other hand, increased dysplasias may, in part, be responses of the estrogenized vaginal epithelium to the concretions.

Cervicovaginal abnormalities in BALB/c mice treated neonatally with sex hormones.

Newborn female BALB/cCrgl mice received hormone treatments (daily for 5 days): 10(-1) micrograms diethylstilbestrol (DES), 2 X 10(-1) micrograms DES, 2 micrograms DES, 100 micrograms progesterone (P), 137 micrograms 17 alpha-hydroxyprogesterone caproate, 10(-1) micrograms DES + 100 micrograms P, 2 micrograms DES + 100 micrograms P, 5 micrograms testosterone (T), 20 micrograms T, 20 micrograms 5 alpha-dihydrotestosterone (DHT), or sesame oil and were examined at 25 days, 35 days, or from 10 to 30 days of age. Three major cervicovaginal abnormalities were noted: adenosis (heterotopic columnar epithelium) in the fornices; altered common cervical canal (aberrantly simplified cervical lumen), and twin fornix (lateral branching of either or both fornices). Only DES, administered alone or in conjunction with P, resulted in adenosis and altered common cervical canal. At 25 days, all mice given 2 X 10(-1) micrograms DES showed adenosis. At 35 days, 75% of mice given 10(-1) micrograms or 2 micrograms DES showed adenosis. Adenosis incidence following 10(-1) micrograms DES was decreased by concomitant P. Altered common cervical canal was present in more than 90% of mice treated with DES alone at both 25 and 35 days; concomitant P lowered the incidence in mice receiving 10(-1) micrograms DES. Neonatal exposure to endogenous prolactin from a pituitary transplant did not modify the response. Twin fornix was not evident 10 days after neonatal androgen treatment. The frequency increased significantly by day 15 of treatment, reaching 100% by day 20; incidence then declined to 86% and 63% on days 25 and 30 after treatment, respectively. Thus, neonatal sex hormone administration results in various cervicovaginal changes, some transient, decreasing with age in young mice.

Prevention by progesterone of cervicovaginal lesions in neonatally estrogenized BALB/c mice.

Instillation of progesterone into the vaginal lumen of BALB/c mice treated neonatally with 25 micrograms 17 beta-estradiol resulted in a significant decrease in vaginal concretions (P less than 0.025), vaginal cornification (P less than 0.025) and vaginal lesions (P less than 0.05).