Uterine carcinosarcomas and grade 3 endometrioid cancers: evidence for distinct tumor behavior

OBJECTIVE: To compare the clinical behavior and outcome of uterine carcinosarcomas and grade 3 endometrioid carcinomas. METHODS: Data on patients with grade 3 endometrioid adenocarcinomas and uterine carcinosarcomas, from 1988 to 2004, was obtained from the Surveillance, Epidemiology, and End Results database. Mortality was analyzed using Cox proportional hazards models. Survival analysis was performed with the Kaplan-Meier method and log rank test. RESULTS: The cohort included 8,986 women with 5,024 (56%) grade 3 endometrioid carcinomas and 3,962 (44%) uterine carcinosarcomas. Women with uterine carcinosarcomas were older (aged 70 years compared with 66 years; P<.001) and more often nonwhite (23% compared with 15%; P<.001). These women presented with more advanced disease (stage III/IV 41% compared with 31%; P<.001). Multivariable analysis demonstrated that uterine carcinosarcoma histology, advanced age, nonwhite race, and advanced stage were independent predictors of poor survival. Cancer-specific mortality was 45% lower in women with grade 3 endometrioid carcinomas (hazard ratio 0.55; 95% confidence interval [CI] 0.5-0.6). The 5-year cancer-specific survival was lower for women with uterine carcinosarcoma for each disease stage. Survival for stage IC was 38% (95% CI 33-45%) for uterine carcinosarcoma compared with 68% (95% CI 63-73%) for grade 3 endometrioid carcinoma. For stage III, survival was 22% (95% CI 19-26%) for uterine carcinosarcoma compared with 45% (95% CI 41-49%) for grade 3 endometrioid carcinoma. CONCLUSION: Carcinosarcomas present at more advanced stage and have worse survival than grade 3 endometrioid carcinomas. Carcinosarcomas may represent a distinct biologic entity. LEVEL OF EVIDENCE: II.     

Sodium pancratistatin 3,4-o-cyclic phosphate, a water-soluble synthetic derivative of pancratistatin, is highly effective in a human colon tumor model

Sodium pancratistatin 3,4- O-cyclic phosphate ( 2) is a novel water-soluble synthetic derivative of pancratistatin ( 1), a natural alkaloid constituent of Amaryllidaceae plants, that exhibits good cytostatic and antineoplastic activity but is highly insoluble. Unlike most other natural alkaloids it does not act by binding to tubulin, and its mechanism of action has yet to be fully elucidated. Here the efficacy of 2 in a human colon adenocarcinoma model, DLD-1, and some understanding of its mode of action are investigated. Agreeing with previous studies, low cytotoxicity in vitro was seen for 2 with IC 50's of 253 and 19.7 microM for 1 and 96 h exposures, respectively. However in vivo the compound caused statistically significant tumor growth delays ( p < 0.01) at its maximum tolerated dose, and significant vascular shutdown and tumor necrosis were observed. Like 1, the compound appeared to have an unconventional mechanism of action with no effect on microtubule structure, yet causing a G 2/M block, while it was seen to disrupt mitochondrial function. The mechanism of action of 1 and 2 appears to be similar. Thus compound 2, being considerably more soluble than 1, has good potential as an anticancer agent, and further investigation is warranted.     

The transitional phase of ductus venosus reversed flow in severely premature IUGR fetuses

The guiding hypothesis for this work is that in severe intrauterine growth-restricted (IUGR) fetuses, the time from ductus venosus (DV) reversed flow (RF) appearance to intrauterine fetal demise (IUFD) or nonreassuring fetal testing is variable. As such, there must be a transitional phase between the presence of end-diastolic forward flow (FF) and absent or reversed end-diastolic flow (A/REDF). Ductus venosus Doppler was serially studied in 19 IUGR fetuses (estimated fetal weight < 10th percentile and umbilical artery pulsatility index > 95th percentile) from diagnosis until demise or delivery occurring for nonreassuring fetal testing. Ductus venosus waveforms were assessed qualitatively: forward flow versus absent or reversed flow in diastole. Two sets of at least 30 consecutive ductus venosus waveforms were obtained at each examination. If the waveforms differed between the two sets, they were defined as alternating. Cord arterial pH and base excess (BE) were obtained at birth. In 14 cases, DVRF occurred intermittently between periods of FF during the same clinical visit. Intermittent DVRF was present from 2 to 57 days (median, 13 days) and became continuous from 1 to 23 days (median, 7 days) before the occurrence of delivery for nonreassuring fetal testing or fetal demise. One fetus had an abnormal arterial pH (< 7.0) and one had an abnormal BE (< -12). These data show that (1) there is a transitional phase in which DV alternates FF and A/RF before RF becomes persistent; (2) the time from the appearance of DVRF to delivery or IUFD is variable, and (3) not all very preterm IUGR fetuses with continuous DVRF are acidemic. Because of these findings, the decision of delivery regarding early severe IUGR fetuses should be individualized, and the DVRF Doppler information has to be integrated with other antenatal fetal parameters.     

Effectiveness of fetal fibronectin testing compared with digital cervical assessment of women with preterm contractions

The purpose of this study is to determine the effectiveness of fetal fibronectin (FFN) compared to assessment of cervical dilation (CD) in clinical management of women with symptomatic preterm labor (PTL). Pregnant women presenting to Thomas Jefferson University Hospital between May 1, 2001 and November 30, 2002 with symptomatic PTL underwent FFN sampling and had a complete clinical evaluation including a pelvic bimanual examination. Inclusion criteria were singleton pregnancy, gestational age (GA) between 24 (0) and 33 (6) weeks, CD < 3 cm, and intact amniotic membranes. FFN samples were sent out and results were available within 4-12 hours. Clinical management including tocolysis, antenatal steroids, and hospitalization was determined based on digital CD assessment and FFN status. A dilated cervix was defined as CD > 1 cm. Ninety-three patients were included. Spontaneous preterm delivery (SPTD) at < 37 weeks occurred in 20 of 93 (21.5%) patients. Medical therapy use was significantly higher in patients with dilated cervix than in those with a closed cervix (all P values < 0.05). Tocolysis and steroid use in FFN-negative patients and FFN-positive patients were not significantly different. Furthermore, tocolytic use was higher in FFN-negative patients than in women with positive FFN (50% versus 42.1%; P = 0.53). Use of antenatal steroids was similar in patients with CD >/= 1 cm and a positive FFN (54.5% versus 47.4%; P = 0.92). Compared with FFN-negative patients, women with closed cervix were less likely to undergo interventions. In symptomatic PTL patients, CD determined clinical management more than FFN status. Overall, the use of FFN was not effective in decreasing "unnecessary" clinical interventions.     

Emergent effects of global change on consumption depend on consumers and their resources in marine systems

A better understanding of how environmental change will affect species interactions would significantly aid efforts to scale up predictions of near-future responses to global change from individuals to ecosystems. To address this need, we used meta-analysis to quantify the individual and combined effects of ocean acidification (OA) and warming on consumption rates of predators and herbivores in marine ecosystems. Although the primary studies demonstrated that these environmental variables can have direct effects on consumers, our analyses highlight high variability in consumption rates in response to OA and warming. This variability likely reflects differences in local adaptation among species, as well as important methodological differences. For example, our results suggest that exposure of consumers to OA reduces consumption rates on average, yet consumption rates actually increase when both consumers and their resource(s) are concurrently exposed to the same conditions. We hypothesize that this disparity is due to increased vulnerability of prey or resource(s) in conditions of OA that offset declines in consumption. This hypothesis is supported by an analysis demonstrating clear declines in prey survival in studies that exposed only prey to future OA conditions. Our results illustrate how simultaneous OA and warming produce complex outcomes when species interact. Researchers should further explore other potential sources of variation in response, as well as the prey-driven component of any changes in consumption and the potential for interactive effects of OA and warming.

Numerous studies have demonstrated direct effects of ocean acidification (OA) and warming on organismal physiology and performance (1, 2), yet forecasting the emergent ecological effects of environmental change on communities remains a challenge due to the complexity of interactions between species (3–5) and stressors (1, 2, 6–8) in functioning ecosystems. Species interactions have the potential to drive shifts in communities (5, 9–11) or buffer them (5, 12, 13) from environmental change. For example, environmentally mediated increases in growth of some algal species can lead to ecosystem shifts if they outcompete or overgrow other species (14). However, environmentally mediated increases in consumption rates of key herbivores have the potential to limit this overgrowth of algae and the associated community shift (13). Indeed, authors of several of the studies that have revealed potential emergent effects of OA (14–16) or warming (17, 18) on entire marine communities attributed the observed responses at least in part to changes in species interactions. In addition, pronounced shifts in species assemblages and ecosystems during natural, large-scale warming events are often linked to modified species interactions (19, 20). Establishing general patterns of environmental control on species interactions has thus been proposed as a promising avenue for scaling up the effects of environmental change from individuals to ecosystems (9, 21–24).Environmentally mediated changes in trophic interactions may be especially important in determining the effects of global change on ecosystems, due to their potential to have cascading effects on community structure (25, 26). OA (27, 28) and warming (29–31) are generally predicted to alter consumers’ energetic demands, although the effects on consumption will depend on the shape of the performance curves, how close current environmental temperatures are to their performance optima, the magnitude of the environmental change, and their energy allocation strategies (25). The effects of OA on consumption are more likely to vary among taxa with different traits than the effects of warming, which universally affects metabolism. For example, the effects of OA can vary with the degree of calcification or the level of mobility of a given species (1, 2). However, the ability of consumers in nature to sufficiently compensate for changes in energetic demands associated with either OA or warming through altered consumption will also depend on their prey or resources (32–34). For example, an increase in a consumer’s energetic demand could be met through increased ingestion of a given resource. Shifts in the escape response, production of physical or chemical deterrents, or the size or biomass of the resource species driven by environmental change, however, can mediate the outcome (4). Thus, deciphering the environmental controls on trophic interactions requires analysis of both the consumer- and resource-driven components of predation and herbivory in future conditions.In most studies that assess the effects of OA, warming, or both on the consumption rates of marine species, researchers use controlled laboratory experiments that are amenable to meta-analysis. In these experiments, a consumer or resource is most often exposed to current and future environmental conditions for a period of days to months. Thus, the effects measured are primarily plastic and represent an organism’s ability to acclimate physiologically or behaviorally. Often, the consumer is held in treatment conditions and given prey or a resource that has not been acclimated to the experimental conditions (defined here as consumer-only experiments). In contrast, more complex studies (e.g., multispecies mesocosms or studies focused on species interactions or community-level responses) tend to include both the consumer and its resource(s) in the experimental conditions. While the responses in these experiments still represent the physiological or behavioral acclimation of the species involved, these multispecies experiments capture potential emergent effects of environmental change on species interactions that result from the direct effects on both the consumer and the resource. Prior meta-analyses have shown that there can be important variation in the temperature sensitivity of different ecological rates, such as attack rates and escape rates that can influence the emergent effects based on variation in sensitivity among trophic roles (30). Similarly, OA has been shown to affect both predator and prey detection and behavior (35–37), as well as algal traits that could affect herbivory, such as nutritional status or chemical deterrents (37). Most rare are those studies that expose only prey or resources to experimental conditions and then test their vulnerability to predation using a predator or herbivore that is not acclimated to the experimental conditions being tested. In contrast to the consumer-only experiments, these “resource-only” experiments capture how environmental change may affect the vulnerability or palatability of species that serve as resources.Experiments also vary in the complexity of environmental manipulation. Although OA and warming are happening in concert in nature, many early studies focused on the biological effects of OA or warming in isolation. As global change biology has progressed, the focus has shifted toward multifactor studies that incorporate both OA and warming in combination (e.g., factorial experiments). These studies are critically important for forecasting emergent effects, as the combined effects of OA and warming may not be additive (1, 2). This may be especially important if OA and warming have different modes of action on marine organisms (38). Synergisms, in which the effects of OA and warming exacerbate one another, have gained the most attention because of their potential to cause dramatic ecological shifts. However, even with different modes of action, one environmental-change factor may primarily drive an organism’s overall response, leading to unexpected outcomes.We conducted a systematic review (SI Appendix, Fig. S1 and Dataset S1) to assemble a database of published studies (Dataset S2) and conduct a meta-analysis quantifying the individual and combined effects of OA and warming on consumption rates, testing for variation between predator–prey and herbivore–resource interactions. We also tested for variance in the individual and combined effects of each environmental variable on different trophic roles (i.e., studies that exposed only consumers or only resources to treatment conditions prior to measuring consumption) to provide insight on their relative importance in the overall response of predation and herbivory rates in future conditions. We then tested whether taxonomic groups or life stages of interacting organisms explain any remaining variance among underlying studies to aid interpretation and identify gaps in our knowledge that need to be addressed to move the field forward. We also quantified the effects of OA and warming on prey survival in resource-only experiments, as well as the effects on consumer preference of prey or resources raised in ambient or future conditions. Finally, to quantitatively address the potential for nonadditive effects of the combined exposure to OA and warming, we calculated the individual and interactive effects of OA and warming on consumption rates for the subset of studies that factorially manipulated both variables.