Breast cancer polygenic risk scores in the clinical cancer genetic counseling setting: Current practices and impact on patient management.

Multivariate risk models are commonly used in clinical practice to estimate a woman's lifetime risk for breast cancer and assist in implementation of appropriate screening and risk reduction strategies. More recently, breast cancer polygenic risk scores (PRS) have been derived and integrated into these models to further improve risk estimation. While breast cancer PRS have been offered by two clinical diagnostic laboratories since 2017, little is known about the extent to which genetic counselors are ordering breast cancer PRS or incorporating the results into patient management. This study surveyed U.S. cancer genetic counselors from October 2019 to January 2020 to identify and understand their current practices with breast cancer PRS, to determine the impact of breast cancer PRS on patient management, and to anticipate future genetic counselor practices with breast cancer PRS. Fewer than half of respondents (43%, 51/120) had ordered breast cancer PRS and approximately one-third (35%, 16/46) reported that the PRS had changed their medical management recommendations. The majority of cancer genetic counselors had not ordered PRS, most commonly due to (a) lack of clinical guidelines (90%, 60/67), (b) insufficient evidence of clinical utility (88%, 59/67), and (c) lack of availability for patients of non-European ancestry (70%, 47/67). Of genetic counselors who had not ordered breast cancer PRS, only 10% (7/68) did not believe they would order PRS in the future. This is the first study to characterize genetic counselors' experiences with breast cancer PRS. Results from this study indicate that although breast cancer PRS have been clinically available for patients for several years, most cancer genetic counselors are not yet convinced they are ready to be incorporated into patient care.

Cost-effectiveness of treatments for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding affects up to one third of women in the United States, resulting in a reduced quality of life and significant cost to the health care system. Multiple treatment options exist, offering different potential for symptom control at highly variable initial costs, but the relative value of these treatment options is unknown. OBJECTIVE: The objective of the study was to evaluate the relative cost-effectiveness of 4 treatment options for heavy menstrual bleeding: hysterectomy, resectoscopic endometrial ablation, nonresectoscopic endometrial ablation, and the levonorgestrel-releasing intrauterine system. STUDY DESIGN: We formulated a decision tree evaluating private payer costs and quality-adjusted life years over a 5 year time horizon for premenopausal women with heavy menstrual bleeding and no suspected malignancy. For each treatment option, we used probabilities derived from literature review to estimate frequencies of minor complications, major complications, and treatment failure resulting in the need for additional treatments. Treatments were compared in terms of total average costs, quality-adjusted life years, and incremental cost-effectiveness ratios. Probabilistic sensitivity analysis was conducted to understand the range of possible outcomes if model inputs were varied. RESULTS: The levonorgestrel-releasing intrauterine system had superior quality-of-life outcomes to hysterectomy with lower costs. In a probabilistic sensitivity analysis, levonorgestrel-releasing intrauterine system was cost-effective compared with hysterectomy in the majority of scenarios (90%). Both resectoscopic and nonresectoscopic endometrial ablation were associated with reduced costs compared with hysterectomy but resulted in a lower average quality of life. According to standard willingness-to-pay thresholds, resectoscopic endometrial ablation was considered cost effective compared with hysterectomy in 44% of scenarios, and nonresectoscopic endometrial ablation was considered cost effective compared with hysterectomy in 53% of scenarios. CONCLUSION: Comparing all trade-offs associated with 4 possible treatments of heavy menstrual bleeding, the levonorgestrel-releasing intrauterine system was superior to both hysterectomy and endometrial ablation in terms of cost and quality of life. Hysterectomy is associated with a superior quality of life and fewer complications than either type of ablation but at a higher cost. For women who are unwilling or unable to choose the levonorgestrel-releasing intrauterine system as a first-course treatment for heavy menstrual bleeding, consideration of cost, procedure-specific complications, and patient preferences can guide the decision between hysterectomy and ablation.

Dermatomyositis: a debilitating paraneoplastic phenomenon following a diagnosis of localised squamous cell carcinoma of the cervix.

This case report describes the management of a patient, recently diagnosed with Stage IIIC cervical cancer, presenting with significant proximal muscle weakness, dysphagia and cutaneous changes over the hands, knees and outer thighs bilaterally. Following multiple investigations, this clinical presentation was proven to be dermatomyositis as a paraneoplastic phenomenon, a rare diagnosis with cervical cancer.Improvement of the presenting symptoms followed commencement of radical chemoradiation to the primary tumour plus administration of high dose steroids and intravenous immunoglobulins.As demonstrated in this case, and accompanying literature review, dermatomyositis is a rare complication of cervical cancer but should be considered as urgent treatment of the underlying malignancy is imperative. Involving members of the multidisciplinary team, including dieticians and physiotherapists, is of utmost importance to optimise the patient's recovery from such a debilitating diagnosis.

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.

We describe the identification and characterization of a series of covalent inhibitors of the C-terminal kinase domain (CTKD) of MSK1. The initial hit was identified via a high-throughput screening and represents a rare example of a covalent inhibitor which acts via an SNAr reaction of a 2,5-dichloropyrimidine with a cysteine residue (Cys440). The covalent mechanism of action was supported by in vitro biochemical experiments and was confirmed by mass spectrometry. Ultimately, the displacement of the 2-chloro moiety was confirmed by crystallization of an inhibitor with the CTKD. We also disclose the crystal structures of three compounds from this series bound to the CTKD of MSK1, in addition to the crystal structures of two unrelated RSK2 covalent inhibitors bound to the CTKD of MSK1.

The allosteric modulation of complement C5 by knob domain peptides.

Bovines have evolved a subset of antibodies with ultra-long heavy chain complementarity determining regions that harbour cysteine-rich knob domains. To produce high-affinity peptides, we previously isolated autonomous 3-6 kDa knob domains from bovine antibodies. Here, we show that binding of four knob domain peptides elicits a range of effects on the clinically validated drug target complement C5. Allosteric mechanisms predominated, with one peptide selectively inhibiting C5 cleavage by the alternative pathway C5 convertase, revealing a targetable mechanistic difference between the classical and alternative pathway C5 convertases. Taking a hybrid biophysical approach, we present C5-knob domain co-crystal structures and, by solution methods, observed allosteric effects propagating >50 Å from the binding sites. This study expands the therapeutic scope of C5, presents new inhibitors, and introduces knob domains as new, low molecular weight antibody fragments, with therapeutic potential.

Antibodies are proteins produced by the immune system that can selectively bind to other molecules and modify their behaviour. Cows are highly equipped at fighting-off disease-causing microbes due to the unique shape of some of their antibodies. Unlike other jawed vertebrates, cows' antibodies contain an ultra-long loop region that contains a 'knob domain' which sticks out from the rest of the antibody. Recent research has shown that when detached, the knob domain behaves like an antibody fragment, and can independently bind to a range of different proteins. Antibody fragments are commonly developed in the laboratory to target proteins associated with certain diseases, such as arthritis and cancer. But it was unclear whether the knob domains from cows' antibodies could also have therapeutic potential. To investigate this, Macpherson et al. studied how knob domains attach to complement C5, a protein in the inflammatory pathway which is a drug target for various diseases, including severe COVID-19. The experiments identified various knob domains that bind to complement C5 and inhibits its activity by altering its structure or movement. Further tests studying the structure of these interactions, led to the discovery of a common mechanism by which inhibitors can modify the behaviour of this inflammatory protein. Complement C5 is involved in numerous molecular pathways in the immune system, which means many of the drugs developed to inhibit its activity can also leave patients vulnerable to infection. However, one of the knob domains identified by Macpherson et al. was found to reduce the activity of complement C5 in some pathways, whilst leaving other pathways intact. This could potentially reduce the risk of bacterial infections which sometimes arise following treatment with these types of inhibitors. These findings highlight a new approach for developing drug inhibitors for complement C5. Furthermore, the ability of knob domains to bind to multiple sites of complement C5 suggests that this fragment could be used to target proteins associated with other diseases.

Comparison of the levonorgestrel-releasing intrauterine system, hysterectomy, and endometrial ablation for heavy menstrual bleeding in a decision analysis model.

BACKGROUND: A better understanding of the relative risks and benefits of common treatment options for abnormal uterine bleeding (AUB) can help providers and patients to make balanced, evidence-based decisions. OBJECTIVES: To provide comparative estimates of clinical outcomes after placement of levonorgestrel-releasing intrauterine system (LNG-IUS), ablation, or hysterectomy for AUB. SEARCH STRATEGY: A PubMED search was done using combinations of search terms related to abnormal uterine bleeding, LNG-IUS, hysterectomy, endometrial ablation, cost-benefit analysis, cost-effectiveness, and quality-adjusted life years. SELECTION CRITERIA: Full articles published in 2006-2016 available in English comparing at least two treatment modalities of interest among women of reproductive age with AUB were included. DATA COLLECTION AND ANALYSIS: A decision tree was generated to compare clinical outcomes in a hypothetical cohort of 100 000 premenopausal women with nonmalignant AUB. We evaluated complications, mortality, and treatment outcomes over a 5-year period, calculated cumulative quality-adjusted life years (QALYs), and conducted probabilistic sensitivity analysis. MAIN RESULTS: Levonorgestrel-releasing intrauterine system had the highest number of QALYs (406 920), followed by hysterectomy (403 466), non-resectoscopic ablation (399 244), and resectoscopic ablation (395 827). Ablation had more treatment failures and complications than LNG-IUS and hysterectomy. Findings were robust in probabilistic sensitivity analysis. CONCLUSIONS: Levonorgestrel-releasing intrauterine system and hysterectomy outperformed endometrial ablation for treatment of AUB.