Abemaciclib Combined With Endocrine Therapy for the Adjuvant Treatment of HR+, HER2-, Node-Positive, High-Risk, Early Breast Cancer (monarchE).

PURPOSE: Many patients with HR+, HER2- early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2- advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting. METHODS: This open-label, phase III study included patients with HR+, HER2-, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse-free survival, overall survival, and safety. RESULTS: At a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone (P = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib. CONCLUSION: Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2- node-positive EBC at high risk of early recurrence.

Parasitological and morphological study of Schistosoma mansoni and diabetes mellitus in mice.

Schistosomes are blood-dwelling flukes which are highly dependent on the host metabolism. The aim of this study was to investigate possible relationship between streptozotocin-induced diabetes and the outcome of acute murine schistosomiasis mansoni. Male and female SW mice were treated by a single intraperitoneally injected dose of streptozotocin (180 mg/kg). Seven days after induction, both control and diabetic animals were infected with 70 Schistosoma mansoni cercariae (BH strain). Diabetics and their controls were weighed 45 days after birth and for the last time prior to killing. Susceptibility to infection was evaluated twice a week by quantifying fecal egg excretion 7-9 weeks post-infection by the Kato-Katz' thick smear method. Mice were euthanized the day after the last fecal examination was performed. Adult worms were recovered from the portal system and mesenteric veins, whereas liver and intestine were removed for enumeration of egg load. No differences in worm length or in measurements of the reproductive organs, tegument, and suckers were detected. Also oviposition was unaffected as the total number of eggs per female worm from the liver, the small and the large intestine was the same in both groups. An oogram evaluation revealed a lower percentage of mature (23.0% vs. 40.7%) and a higher percentage of immature (69.1% vs. 51.7%) eggs in the small intestine of the diabetic mice. We suggest that principally a hampered egg passage through the intestine tissue caused this reduction and that probably both the eggs and the impaired host response play a role.

Development of Schistosoma mansoni worms in mice analyzed by bright field and confocal microscopy

The blood flukes of mammals (Digenea: Schistosomatidae) are among trematodes unique whose adult worms have separeted sexes which are dissimilar in appearance. The developmental features, growth and organogenesis of Schistosoma mansoni were studied in Swiss Webster mice by a digital system for image analysis and confocal microscopy. Data so far obtained showed two phases with significative morphological changes at 3-4 weeks post-infection, and a gradual similar development onwards in the reproductive system and tegument. Our male-dependent phase demonstrated that mating occurs before sexual maturing. At week three, the majority of male worms (59 percent) had formed the gynaecophoric canal although testicular lobes and tegumental tubercles were absent. By this time, 33 percent females had an incipient ovary (without cellular differentiation). At week four, 77.2 percent males presented testicular lobes with few germinative cells while 26 percent had developing tegumental tubercles. The immature ovary was observed in 69 percent females. Suckers followed different pattern of growth between male and females. The size of oral and ventral suckers from six-week-old male worms grew abruptly (3.0 fold) more than that of three-week-old. In female worms, maximum growth was attained at week four, reducing in size thereafter. From sixth week onwards, all specimens showed the fully developed reproductive system. Probably, these features are morphological traits which schistosome has experienced from hermaphrodite to dioecy.

Development of Schistosoma mansoni worms in mice analyzed by bright field and confocal microscopy.

The blood flukes of mammals (Digenea: Schistosomatidae) are among trematodes unique whose adult worms have separated sexes which are dissimilar in appearance. The developmental features, growth and organogenesis of Schistosoma mansoni were studied in Swiss Webster mice by a digital system for image analysis and confocal microscopy. Data so far obtained showed two phases with significative morphological changes at 3-4 weeks post-infection, and a gradual similar development onwards in the reproductive system and tegument. Our male-dependent phase demonstrated that mating occurs before sexual maturing. At week three, the majority of male worms (59%) had formed the gynaecophoric canal although testicular lobes and tegumental tubercles were absent. By this time, 33% females had an incipient ovary (without cellular differentiation). At week four, 77.2% males presented testicular lobes with few germinative cells while 26% had developing tegumental tubercles. The immature ovary was observed in 69% females. Suckers followed different pattern of growth between male and females. The size of oral and ventral suckers from six-week-old male worms grew abruptly (3.0 fold) more than that of three-week-old. In female worms, maximum growth was attained at week four, reducing in size thereafter. From sixth week onwards, all specimens showed the fully developed reproductive system. Probably, these features are morphological traits which schistosome has experienced from hermaphrodite to dioecy.

A new description of the reproductive system of Schistosoma mansoni (Trematoda: Schistosomatidae) analyzed by confocal laser scanning microscopy.

Classical schemes of the adult Schistosoma mansoni reproductive system have been described. In our study, whole adult worms derived from unisexual or mixed infections and stained with carmine chlorine were virtually and tomographically analyzed under confocal laser scanning microscopy. We found that: (1) there were morphological differences in the ovary, vitteline glands and testicular lobes between specimens derived from unisexual or mixed infections; (2) there was always a single lobed ovary (three or four lobes), presenting differentiation from the anterior to the posterior lobes, where the most mature oocytes were located; (3) the proximal segment of oviduct was connected to an ampullary dilatation, full of tailed spermatozoa, characterizing a seminal receptacle; (4) there was no long vitelline duct, but a short one that begins at the end of the proximal region of the vitelline gland; (5) long cells of Mehlis' gland placed radially around the ootype were not observed. Otherwise, the ootype was only lined by thick cuboidal epithelial cells with plaited bases and nuclei with flabby chromatin, making a clear distinction from the uterine epithelium. This morphological feature suggests that each cell represents a gland. (6) In coupled males, the specimens located inside the gynaecophoric canal had smaller testicular lobes, suckers, and body length and width when compared to their partners. Our results show that the reproductive system does not follow a unique pattern within flatworms. Due to its better resolution, confocal laser scanning microscopy, using a reflected mode with tomographic sections, allows new interpretations, modifying the adopted and current descriptions of the internal morphological structures of S. mansoni adult worms.

Caracterização de cepas de Schistosoma mansoni por morfometria de vermes adultos provenientes de infecção unissexual / Characterization of Schistosoma mansoni strains by morphometry of adult worms derived from single-sex infection

Camundongos foram infectados com cercárias, de um único sexo, de cepas simpátricas do Schistosoma mansoni. Nos vermes adultos, foram encontradas diferenças significativas (p<0,05) nas ventosas, lobos testiculares, ovário e espessura do tegumento. O experimento demonstra que a morfometria de vermes isolados de infecção unissexual também é uma ferramenta na identificação de cepas do Schistosoma mansoni.

Estudo parasitológico e histopatológico da infecção esquistossomótica em camundongos albinos com diabetes mellitus induzida por estreptozotocina / Parasitologic and hispatologic study of esquistossomotic infection in albinos mice with induced diabetes mellitus by streptozotocin

A associação entre esquistossomose mansônica e diabetes mellitus foi estudada em camundongos albinos na fase aguda da infecção esquistossomótica. A droga esreptozotocina (STZ) foi usada para induzir diabetes antes ou depois de 45 dias de infecção...a A análise da morfologia do verme por mnicroscopia de campo claro e de varredura laser confocal (CLSM), mostrou uma grande diminuição das células em um ou diversos lobos testiculares, e vários ovários se encontravam atrofiados enquanto as glândulas vitelínicas não foram afetadas. Ao invés de hiperglicemia, a causadora da degeneração foi STZ pois os vermes dos camundongos injetados com uma dose não diabetogênica ou com nicotinamida para prevenir a diabetes, mostraram as mesmas alterações. Também nenhuma mudança morfológica ou morfométrica foi vista em vermes de camundongos diabéticos que haviam recebido STZ antes da infecção. Apenas uma fêmea continha um pequeno folículo anterior ao ovário, que foi comparado morfologicamente aos lobos supranumerários os quais foram, ocasionalmente, encontrados em machos de outros estudos. O ovário adicional não foi considerado com um lobo testicular mas, cerca de metade dos lobos supranumerários continha oócitos completamente maduros.A infecção dos camundongos diabéticos resultou em uma quantidade ligeiramente menor de vermes nas veias porta e mesentéricas porém não foram alteradas a oviposição das fêmeas e a distribuição dos ovos entre o fígado e o intestino. A contagem de ovos fecais foi cerca de 4 vezes mais baixa nos animais hiperglicêmicos e cerca de 3 vezes quando calculados por verme fêmea. Os granulomas hepáticos dos camundongos diabéticos tiveram em geral uma quantidade menos acentuada de células inflamatórias; eram menores e continham menos fibras de colágeno. Concluimos que STZ altera a morfologia dos ovários e lobos testiculares de S. mansoni in vivo e afeta a viabilidade dos ovos. Isto suere que STZ afeta a oogênes e a espermatogênese e pode causar a esterilização dos esquistossomas. A diabetes mellitus, definida pelo estado hiperglicêmico dos camundongos foi responsável pela menor excreção fecal dos ovos, a qual foi causada ou por uma deficiência na maturação dos ovos ou por mudanças na resposta inflamatória. Portanto, STZ tem um efeito direto sobre Schistosoma mansoni e pode, ao causar diabetes no hospedeiro, atingir a biologia do helminto e a resposta do hospedeiro.

[Characterization of Schistosoma mansoni strains by morphometry of adult worms derived from single-sex infection]. / Caracterização de cepas de Schistosoma mansoni por morfometria de vermes adultos provenientes de infecção unissexual.

Mice were infected with only one sex cercaria derived from sympatric strains of Schistosoma mansoni. Adult worms presented significative differences (p < 0.05) regarding suckers, testicular lobes, ovary and thickness of the tegument. Data show that morphometric study of unisexual infection worms can be also used for characterization of Schistosoma mansoni strains.

Natural Schistosoma mansoni infection in Nectomys squamipes: histopathological and morphometric analysis in comparison to experimentally infected N. squamipes and C3H/He mice.

Histopathologic and morphometric (area, perimeter, major and minor diameters) analysis of hepatic granulomas isolated from twelve naturally infected Nectomys squamipes were compared to four experimentally infected ones and six C3H/He mice. Liver paraffin sections were stained for cells and extracellular matrix. Both groups of N. squamipes presented peculiar granulomas consisting predominantly of large macrophages, full of schistosome pigment, characterizing an exudative-macrophage granuloma type, smaller than the equivalent granuloma type in mouse. Naturally infected animals exhibited granulomas in different stages of development, including large number of involutional types. Morphometric analysis showed that all measurements were smaller in naturally infected animals than in other groups. The results demonstrated that both N. squamipes groups reproduced, with small variations, the hepatic granuloma aspects already described in cricetidium (Calomys callosus), showing a genetic tendency to set up strong macrophage responses and small granulomas. Unexpectedly, natural infection did not engender distinguished histopathological characteristics distinct from those derived from experimental single infection, showing changes predominantly secondary to the duration of infection. It appears that the variability of the inocula (and the number of infections?) interfere more with the quantity than with the quality of the pathological changes, denoting some morpho-functional determinism in the response to schistosomal infection dependent on the animal species.

Natural Schistosoma mansoni infection in Nectomys squamipes: histopathological and morphometric analysis in comparison to experimentally infected N. squamipes and C3H/He mice

Histopathologic and morphometric (area, perimeter, major and minor diameters) analysis of hepatic granulomas isolated from twelve naturally infected Nectomys squamipes were compared to four experimentally infected ones and six C3H/He mice. Liver paraffin sections were stained for cells and extracellular matrix. Both groups of N. squamipes presented peculiar granulomas consisting predominantly of large macrophages, full of schistosome pigment, characterizing an exudative-macrophage granuloma type, smaller than the equivalent granuloma type in mouse. Naturally infected animals exhibited granulomas in different stages of development, including large number of involutional types. Morphometric analysis showed that all measurements were smaller in naturally infected animals than in other groups. The results demonstrated that both N. squamipes groups reproduced, with small variations, the hepatic granuloma aspects already described in cricetidium (Calomys callosus), showing a genetic tendency to set up strong macrophage responses and small granulomas. Unexpectedly, natural infection did not engender distinguished histopathological characteristics distinct from those derived from experimental single infection, showing changes predominantly secondary to the duration of infection. It appears that the variability of the inocula (and the number of infections?) interfere more with the quantity than with the quality of the pathological changes, denoting some morpho-functional determinism in the response to schistosomal infection dependent on the animal species

Lower faecal egg excretion in chemically-induced diabetic mice infected with Schistosoma mansoni due to impaired egg maturation

The effect of streptozotocin-induced diabetes mellitus was studied in mice infected with Schistosoma mansoni. Faecal egg excretion was lower in diabetic mice but worm load and total amount of eggs in the intestine tissue were equal to the control group. Evaluation of an oogram showed a great number of immature dead eggs and a low number of mature eggs in diabetic mice. It was therefore concluded that faecal egg excretion was lower in diabetic mice due to impaired egg maturation