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ClinicalTrials.gov, NCT01760954 and NCT02143713.

Study question: Can asoprisnil, a selective progesterone receptor modulator, provide clinically meaningful improvements in heavy menstrual bleeding (HMB) associated with uterine fibroids with an acceptable safety profile? Summary answer: Uninterrupted treatment with asoprisnil for 12 months effectively controlled HMB and reduced fibroid and uterine volume with few adverse events. What is known already: In a 3-month study, asoprisnil (5, 10, and 25 mg) suppressed uterine bleeding, reduced fibroid and uterine volume, and improved hematological parameters in a dosedependent manner. Study design, size, duration: In two phase 3, double-blind, randomized, placebo-controlled, multicenter studies, women received oral asoprisnil 10 mg, asoprisnil 25 mg, or placebo (2:2:1) once daily for up to 12 months. Participants/materials, setting, methods: Premenopausal women ≥18 years of age in North America with HMB associated with uterine fibroids were included (N=907). The primary efficacy endpoint was the percentage of women who met all 3 predefined criteria at 12 months, or final month for subjects who prematurely discontinued: (1) ≥50% reduction in monthly blood loss (MBL) by menstrual pictogram, (2) hemoglobin concentration ≥11 g/dL or an increase of ≥1 g/dL, and (3) no interventional therapy for uterine fibroids. Secondary efficacy endpoints included changes in other menstrual bleeding parameters, volume of the largest fibroids, uterine volume, and health-related quality of life (HRQL). Main results and the role of chance: In all, 90% and 93% of women in the asoprisnil 10 mg and 25 mg groups, respectively, and 35% of women in the placebo group met the primary endpoint (P<0.001). Similar results were observed at month 6 (P<0.001). The percentage of

Intestinal tumors from mice and humans can have a polyclonal origin. Statistical analyses indicate that the best explanation for this source of intratumoral heterogeneity is the presence of interactions among multiple progenitors. We sought to better understand the nature of these interactions. An initial progenitor could recruit others by facilitating the transformation of one or more neighboring cells. Alternatively, two progenitors that are independently initiated could simply cooperate to form a single tumor. These possibilities were tested by analyzing tumors from aggregation chimeras that were generated by fusing together embryos with unequal predispositions to tumor development. Strikingly, numerous polyclonal tumors were observed even when one genetic component was highly, if not completely, resistant to spontaneous tumorigenesis in the intestine. Moreover, the observed number of polyclonal tumors could be explained by the facilitated transformation of a single neighbor within 144 μm of an initial progenitor. These findings strongly support recruitment instead of cooperation. Thus, it is conceivable that these interactions are necessary for tumors to thrive, so blocking them might be a highly effective method for preventing the formation of tumors in the intestine and other tissues.colon cancer | spatial statistics | clonal interactions | mouse model T umors are often heterogeneous with respect to several distinguishable properties, including differentiation state, proliferation rate, metastatic potential, and therapeutic response. Two models to explain intratumoral heterogeneity have been proposed. The clonal evolution model asserts that different subclones arise from a single progenitor as a consequence of molecular changes followed by selection for dissimilar microenvironments within a tumor (1). By contrast, the cancer stem cell model contends that a small population of stem cells originating from a single progenitor is responsible for tumor maintenance but the progeny can differentiate in several diverse ways (1). A key assumption in both models is that tumors are derived from a single progenitor.Evidence is steadily accruing that intestinal tumors are often polyclonal rather than monoclonal (2). Merritt et al. (3) demonstrated that hereditary tumors in the mouse intestine are often derived from multiple progenitors. In this study, aggregation chimeras were generated by fusing embryos carrying the Min allele of the Adenomatous polyposis coli gene (Apc Min/+ ) to embryos carrying Min and the Rosa26 lineage marker (Apc Min/+ R26 + ). Clonal structure was assessed in histologic sections of tumors stained for the lineage marker. A significant number (8%) of early adenomas were heterotypic, being composed of cells from the two different embryos. Using a similar approach, Thliveris et al. (4) demonstrated that carcinogen-induced tumors in mice are also derived from multiple progenitors. In both studies, the intestines consisted of small blue and white patches. This chimeric pattern increases the power to ...

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