Does the presence of single compared to multiple endometrial polyps alter the risk of cancer in post-menopausal women?

OBJECTIVE: To evaluate the relative rates of malignancy in women with single and multiple polyps presenting to a UK Cancer Centre with postmenopausal bleeding (PMB). STUDY DESIGN: A retrospective review of patients treated at Royal Derby Hospital (RDH) for PMB who underwent outpatient hysteroscopy based on ultrasonographic suspicion of endometrial polyps between May 2014 to December 2019. The main outcome measure was the rates of precancerous and malignant histology for single or multiple polyps. The secondary outcomes assessed the influence of risk factors on the rates of malignancy within the single and multiple polyps groups. RESULTS: The study population was 851 women of which 533 were in the single polyp group and 318 in the multiple polyps group. The multiple polyps group (mean age 65.2 years) was older compared to the single polyp group (mean age 62.1 years), P = 0.0001. Elevated rates of cancer was driven most significantly by endometrioid cancer in the multiple polyps compared to single polyp group, with rates of 50/314 (16 %) and 28/512 (5.5 %) respectively, P=< 0.00001. For rarer histologies there was no significant difference between the proportion of serous, carcinosarcomas and clear cell cancers between those with single compared to multiple polyps (P > 0.05). Significantly more endometrial hyperplasia with atypia (AEH) was found in the multiple polyps compared to single polyp group, with rates of 18/314 (5.7 %) and 15/512 (2.9 %) respectively, P = 0.046. CONCLUSION: Our study found increased rates of endometrioid cancer and its precursor, AEH within the multiple polyps compared to the single polyps groups. Future risk predicting algorithms should consider incorporating single and multiple polyps as part of their risk model.

Structure-activity relationship of the aminomethylcyclines and the discovery of omadacycline.

A series of novel tetracycline derivatives were synthesized with the goal of creating new antibiotics that would be unaffected by the known tetracycline resistance mechanisms. New C-9-position derivatives of minocycline (the aminomethylcyclines [AMCs]) were tested for in vitro activity against Gram-positive strains containing known tetracycline resistance mechanisms of ribosomal protection (Tet M in Staphylococcus aureus, Enterococcus faecalis, and Streptococcus pneumoniae) and efflux (Tet K in S. aureus and Tet L in E. faecalis). A number of aminomethylcyclines with potent in vitro activity (MIC range of ≤0.06 to 2.0 µg/ml) were identified. These novel tetracyclines were more active against one or more of the resistant strains than the reference antibiotics tested (MIC range, 16 to 64 µg/ml). The AMC derivatives were active against bacteria resistant to tetracycline by both efflux and ribosomal protection mechanisms. This study identified the AMCs as a novel class of antibiotics evolved from tetracycline that exhibit potent activity in vitro against tetracycline-resistant Gram-positive bacteria, including pathogenic strains of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). One derivative, 9-neopentylaminomethylminocycline (generic name omadacycline), was identified and is currently in human trials for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP).

In vitro and in vivo antimalarial efficacies of optimized tetracyclines.

With increasing resistance to existing antimalarials, there is an urgent need to discover new drugs at affordable prices for countries in which malaria is endemic. One approach to the development of new antimalarial drugs is to improve upon existing antimalarial agents, such as the tetracyclines. Tetracyclines exhibit potent, albeit relatively slow, action against malaria parasites, and doxycycline is used for both treatment (with other agents) and prevention of malaria. We synthesized 18 novel 7-position modified tetracycline derivatives and screened them for activity against cultured malaria parasites. Compounds with potent in vitro activity and other favorable drug properties were further tested in a rodent malaria model. Ten compounds inhibited the development of cultured Plasmodium falciparum with a 50% inhibitory concentration (IC50) after 96 h of incubation of <30 nM, demonstrating activity markedly superior to that of doxycycline (IC50 at 96 h of 320 nM). Most compounds showed little mammalian cell cytotoxicity and no evidence of in vitro phototoxicity. In a murine Plasmodium berghei model, 13 compounds demonstrated improved activity relative to that of doxycycline. In summary, 7-position modified tetracyclines offer improved activity against malaria parasites compared to doxycycline. Optimized compounds may allow lower doses for treatment and chemoprophylaxis. If safety margins are adequate, dosing in children, the group at greatest risk for malaria in countries in which it is endemic, may be feasible.