Triple-Negative Breast Cancer: A Review of Current Curative Intent Therapies

Breast cancer is the most commonly diagnosed malignancy in women, with triple-negative breast cancer (TNBC) accounting for 10–20% of cases. Historically, fewer treatment options have existed for this subtype of breast cancer, with cytotoxic chemotherapy playing a predominant role. This article aims to review the current treatment paradigm for curative-intent TNBC, while also reviewing potential future developments in this landscape. In addition to chemotherapy, recent advances in the understanding of the molecular biology of TNBC have led to promising new studies of targeted and immune checkpoint inhibitor therapies in the curative-intent setting. The appropriate selection of TNBC patient subgroups with a higher likelihood of benefit from treatment is critical to identify the best treatment approach.     

Thrombophilic mutations in pre-eclampsia and pregnancy-induced hypertension

AIM: The aim of the present study was to determine the existence or prevalence of thrombophilic markers such as Factor V Leiden, prothrombin G20210A, protein S, protein C, activated protein C and anti-thrombin in pre-eclampsia and pregnancy-induced hypertensive patients. METHODS: Blood samples were collected from a total number of 124 women at the maternity unit, University of Malaya Medical Center. These included 49 patients with pre-eclampsia, 63 patients with pregnancy-induced hypertension and 12 normal pregnant women. DNA was extracted from the blood samples. Factor V Leiden (Taq I) and prothrombin G20210A (Hind III) genotyping was done on polymerase chain reaction-restriction fragment length polymorphism. Anti-thrombin activity and the concentrations of protein C, protein S and activated protein C were measured using the IL Coagulation System (Hemosil). RESULTS: Of the 124 subjects, one pre-eclampsia patient was homozygous for Factor V Leiden mutation but prothrombin G20210A mutation was not present in any of the subjects. The subject with Factor V Leiden mutation also had a low activated protein C resistance and a low protein S concentration. CONCLUSIONS: Factor V Leiden mutation is present in the Asian population and may very well serve as one of the genetic factors responsible for pre-eclampsia and other adverse pregnancy outcomes.     

Concurrent oxytocin with dinoprostone pessary versus dinoprostone pessary in labour induction of nulliparas with an unfavourable cervix: a randomised placebo-controlled trial

Objective  To compare concurrent oxytocin with dinoprostone pessary versus dinoprostone pessary in labour induction for nulliparas with an unfavourable cervix.
Design  A randomised double-blind study.
Setting  University Malaya Medical Centre, Malaysia.
Population  Nulliparas at term with intact membranes, Bishop score ≤ 6 and admitted for labour induction.
Methods  All women received 3 mg dinoprostone pessary for labour induction. Those randomised to the oxytocin arm received oxytocin infusion started at 1 mu/minute and doubled every 30 minutes to a maximum 16 mu/minute. Women assigned to placebo received identical volume of saline infusion. After 6 hours, infusion was stopped and vaginal reassessment performed to guide further management.
Main outcome measures  Primary outcome was vaginal delivery within 24 hours.
Results  Concurrent oxytocin infusion with dinoprostone pessary did not significantly increase vaginal delivery rate within 24 hours (48.6 versus 35.9%; P = 0.07, relative risk [RR] 1.4 [95% CI 1.0–1.9]). It reduced the requirement for repeat dinoprostone (37.1 versus 61.2%; P = 0.001, RR 0.61 [95% CI 0.45–0.81]) and improved maternal satisfaction with the birth process (median score of 3 versus 5 on a 10-point visual analogue scale, P = 0.007). Caesarean rates were not different (41.9 versus 44.7%, P = 0.52).
Conclusions  Labour induction with concurrent oxytocin infusion and vaginal dinoprostone could be considered for nulliparas with an unfavourable cervix. Larger studies are needed.     

The prevalence of fimbrial pathology in patients with early stages of endometriosis

STUDY OBJECTIVE: The presence of fimbrial pathology in advanced endometriosis is clearly understood. However, little is known about the prevalence of fimbrial pathology in early stages of endometriosis. The purpose of this study is to determine the prevalence of fimbrial pathology in patients with infertility with early stages of endometriosis. DESIGN: Historical cohort study (Canadian Task Force classification II/III). SETTING: Tertiary referral center. PATIENTS: The study group (Group 1) consisted of 315 infertile women who were found to have stage I or stage II endometriosis, and the control group (Group 2) consisted of 152 infertile women without endometriosis (Group 2). INTERVENTION: Laparoscopic evaluation for the presence and type of fimbrial pathology. MEASUREMENTS AND MAIN RESULTS: The prevalence of fimbrial pathology was significantly higher in infertile patients with early stages of endometriosis (50.2%) compared with infertile patients with no endometriosis (17.8%, p <.0001). CONCLUSION: These preliminary data suggest the presence of fimbrial pathology in many patients with early stages of endometriosis. Such pathology may act as a mechanical factor interfering with the ovum pick-up mechanism.     

Antibodies to certain arboviruses in humans from a flooded village in Egypt

A study was carried out on 180 sera collected from inhabitants of a seepage flooded village (Begiram) in a Nile Delta governorate in Egypt. The aim of the study was to monitor the prevalence of certain arboviruses; some of them are known to be endemic in Egypt. Sera were screened by ELISA except for the HTN by IF, and the results indicated that WN and SFS exhibited the highest prevalence 45.5% followed by SFN (21%). These 3 viruses are known to be endemic in Egypt. The high prevalence of W.N. and S.F.S viruses in Begiram village in comparison to lower rates detected in sera from nearby Sharkqiya governorate collected almost at the same time may reflect the adverse effect of the environmental change in the flooded village. RNF virus which caused a major epidemic in Egypt in 1977 and continued to be circulating until 1980, its antibodies were detected only in those above 20 years of age with a prevalence rate of 5%. Antibodies against two tick borne viruses viz QRF and CCHF were also detected with low prevalence rate 2.75% and 1.1% respectively; also antibodies to the rodent-borne HTN virus were detected with prevalence rate 1.1%. Antibodies to mosquito borne SIN and BAT viruses were not detected in the tested sera.     

Adult extracardiac rhabdomyomas presenting as a slowly growing neck mass

Rhabdomyomas are rare benign tumors arising from skeletal muscle cells, most common cardiac in origin and usually seen in pediatric age group, often associated with neurophakomatosis like tuberous sclerosis. Extracardiac tumors are rare and are classified based on histology into adult, fetal and genital forms. The adult form of extracardiac rhabdomyoma are seen in the head and neck region in vast majority of cases. These can occur within the pharyngeal or laryngeal compartments along with other neck spaces and the orbits. In this case report, we describe the findings of adult extracardiac rhabdomyoma and discuss the striking similarity with lymphomas on imaging.     

An approach for evaluating the effects of dietary fiber polysaccharides on the human gut microbiome and plasma proteome

Increases in snack consumption associated with Westernized lifestyles provide an opportunity to introduce nutritious foods into poor diets. We describe two 10-wk-long open label, single group assignment human studies that measured the effects of two snack prototypes containing fiber preparations from two sustainable and scalable sources; the byproducts remaining after isolation of protein from the endosperm of peas and the vesicular pulp remaining after processing oranges for the manufacture of juices. The normal diets of study participants were supplemented with either a pea- or orange fiber-containing snack. We focused our analysis on quantifying the abundances of genes encoding carbohydrate-active enzymes (CAZymes) (glycoside hydrolases and polysaccharide lyases) in the fecal microbiome, mass spectrometric measurements of glycan structures (glycosidic linkages) in feces, plus aptamer-based assessment of levels of 1,300 plasma proteins reflecting a broad range of physiological functions. Computational methods for feature selection identified treatment-discriminatory changes in CAZyme genes that correlated with alterations in levels of fiber-associated glycosidic linkages; these changes in turn correlated with levels of plasma proteins representing diverse biological functions, including transforming growth factor type β/bone morphogenetic protein-mediated fibrosis, vascular endothelial growth factor-related angiogenesis, P38/MAPK-associated immune cell signaling, and obesity-associated hormonal regulators. The approach used represents a way to connect changes in consumer microbiomes produced by specific fiber types with host responses in the context of varying background diets.

Advances in our understanding of the role of the gut microbiome in regulating many aspects of human physiology hold the promise of evolving our view of human nutrition by establishing mechanistic connections between the foods we consume and how they affect health status. One manifestation of this effort is a series of studies, performed on well-phenotyped cohorts, that seek to relate features of gut microbial community composition (organisms, genes), dietary practices, and pre- and postprandial cardiometabolic responses to test meals (1–4). A key question raised by these initiatives relates to the nature of the “bioactive” components of foods. Specifically, what are the nutrients utilized by various gut community members or microbiome-encoded metabolic pathways? What products are produced by biotransformation of these nutrients? How are these products linked to specific host physiologic (or pathophysiologic) processes?Plant-derived dietary fibers represent a “poster child” for these efforts and illustrate the formidable challenges faced. The health benefits of dietary fibers are widely known, as is their inadequate representation in Western diets. However, natural fibers are structurally complex and highly diverse. They contain numerous, typically undefined polysaccharide structures and largely unspecified protein, lipid, and small molecule constituents. Their composition varies as a function of their origin (food staple and cultivar), the different methods employed to recover them from these sources, as well as the different techniques used to incorporate them into processed foods with acceptable organoleptic properties (5). Moreover, analyzing the host effects of metabolism of different fibers is confounded by the fact that there is substantial intra- and interpersonal variation in microbiome configuration (6, 7).Snacking is becoming an ever more dominant feature of daily life worldwide and thus provides an opportunity to introduce nutritious ingredients, such as fibers, into diets. However, obtaining structure-activity relationships for specific fiber types and their corresponding targets in the gut community is foundational for designing snack foods that evoke and/or reinforce microbiome responses that are beneficial to the host.Degradation of dietary polysaccharides is a function primarily performed by bacterial carbohydrate-active enzymes (CAZymes). The gut microbiome harbors tens of thousands of CAZyme genes belonging to at least 136 glycoside hydrolase (GH) and 29 polysaccharide lyase (PL) families [extrapolated and updated from El Kaoutari et al. (8)]. In contrast, the human genome only contains 98 GH and no PL genes (9), of which <20% contribute to the processing of dietary glycans.In the current study, we test the effects of dietary supplementation with two snack food prototypes, one containing pea fiber and the other orange fiber, in two pilot studies of overweight and obese individuals consuming their normal, unrestricted diets. Our strategy was to focus on fiber-associated changes in the abundances of microbial GH and PL genes to determine whether responses to the pea or orange fiber prototypes in the gut microbiome and host are decipherable against a background of varying dietary practices and starting microbiome configurations. Higher order singular value decomposition (10) was utilized as a feature selection tool to identify treatment-discriminating changes in GH and PL gene representation. Mass spectrometric assays of the levels of fecal glycan structures (glycosidic linkages) were subsequently performed and the results were correlated with changes in the abundances of treatment-discriminating GH and PL genes with known or predicted substrate specificities. Our analysis concluded by measuring changes in levels of 1,305 plasma proteins in each study participant as a function of fiber treatment and applying computational tools to identify links between these microbiome and plasma proteome changes in response to fiber consumption. Our results provide an approach, using pilot human studies, for selecting specific fiber preparations, plus informative microbiome and host biomarkers, that can be advanced to proof-of-concept clinical trials which assess their capacity for precise manipulation of microbiome and host features.