ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-Induced Peripheral Neuropathy in Black Women With Early-Stage Breast Cancer.

PURPOSE: Black women experience higher rates of taxane-induced peripheral neuropathy (TIPN) compared with White women when receiving adjuvant once weekly paclitaxel for early-stage breast cancer, leading to more dose reductions and higher recurrence rates. EAZ171 aimed to prospectively validate germline predictors of TIPN and compare rates of TIPN and dose reductions in Black women receiving (neo)adjuvant once weekly paclitaxel and once every 3 weeks docetaxel for early-stage breast cancer. METHODS: Women with early-stage breast cancer who self-identified as Black and had intended to receive (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel were eligible, with planned accrual to 120 patients in each arm. Genotyping was performed to determine germline neuropathy risk. Grade 2-4 TIPN by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was compared between high- versus low-risk genotypes and between once weekly paclitaxel versus once every 3 weeks docetaxel within 1 year. Patient-rated TIPN and patient-reported outcomes were compared using patient-reported outcome (PRO)-CTCAE and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity. RESULTS: Two hundred and forty of 249 enrolled patients had genotype data, and 91 of 117 (77.8%) receiving once weekly paclitaxel and 87 of 118 (73.7%) receiving once every 3 weeks docetaxel were classified as high-risk. Physician-reported grade 2-4 TIPN was not significantly different in high- versus low-risk genotype groups with once weekly paclitaxel (47% v 35%; P = .27) or with once every 3 weeks docetaxel (28% v 19%; P = .47). Grade 2-4 TIPN was significantly higher in the once weekly paclitaxel versus once every 3 weeks docetaxel arm by both physician-rated CTCAE (45% v 29%; P = .02) and PRO-CTCAE (40% v 24%; P = .03). Patients receiving once weekly paclitaxel required more dose reductions because of TIPN (28% v 9%; P < .001) or any cause (39% v 25%; P = .02). CONCLUSION: Germline variation did not predict risk of TIPN in Black women receiving (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel. Once weekly paclitaxel was associated with significantly more grade 2-4 TIPN and required more dose reductions than once every 3 weeks docetaxel.

Challenges Experienced by Black Women with Breast Cancer During Active Treatment: Relationship to Treatment Adherence.

BACKGROUND: Although rates of death from breast cancer have declined in the USA for both Black and White women since 1990, mortality rates for Black women remain strikingly higher - 40% higher compared to White women (American Cancer Society 1). The barriers and challenges that may be triggering unfavorable treatment-related outcomes and diminished treatment adherence among Black women are not well understood. METHODS: We recruited 25 Black women with breast cancer who were to receive surgery and chemotherapy and/or radiation therapy. Through weekly electronic surveys, we assessed types and severity of challenges across various life domains. Because the participants rarely missed treatments or appointments, we examined the impact of severity of weekly challenges on thoughts of skipping treatment or appointment with their cancer care team using a mixed-effects location scale model. RESULTS: Both a higher average severity of challenges and a higher deviation of severity reported across weeks were associated with increased thoughts on skipping treatment or appointment. The correlation between the random location and scale effects was positive; thus, those women that reported more thoughts on skipping a dose of medicine or appointment were also more unpredictable with respect to the severity of challenges reported. CONCLUSIONS: Black women with breast cancer are impacted by familial, social, work-related, and medical care factors, and these may in turn affect adherence to treatment. Providers are encouraged to actively screen and communicate with patients regarding life challenges and to build networks of support within the medical care team and social community that can help patients successfully complete treatment as planned.

Got PIDD1? Natural killer cells clear polyploid cells to ensure a balanced genome.

Removal of polyploid cells is essential to preventing cancer and restricting tumor growth. A new study published in The EMBO Journal shows assembly of the NEMO-PIDDosome on extra centrioles. Activation of this protein complex leads to NF-κB activation that, in turn, induces NK cell-mediated cell clearance.

Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.

Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm ( NPM1c+ ). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a pro-apoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm, and DNA damage-induced apoptosis is caspase-2-dependent in NPM1c+ AML but not in NPM1wt cells. Strikingly, in NPM1c+ cells, loss of caspase-2 results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment in the AKT/mTORC1 and Wnt signaling pathways. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells with and without caspase-2. Together, these results show that caspase-2 is essential for proliferation and self-renewal of AML cells that have mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function and may even be a druggable target to treat NPM1c+ AML and prevent relapse.

Racial disparities in cascade testing for cancer predisposition genes.

We sought to determine whether there are racial disparities in cascade testing rates and whether providing testing at no-charge impacts rates in Black and White at-risk-relatives (ARR). Probands with a pathogenic/likely pathogenic germline variant in a cancer predisposition gene were identified up to one year before and up to one year after cascade testing became no-charge in 2017. Cascade testing rates were measured as the proportion of probands who had at least one ARR obtain genetic testing through one commercial laboratory. Rates were compared between self-reported Black and White probands using logistic regression. Interaction between race and cost (pre/post policy) was tested. Significantly fewer Black probands than White probands had at least one ARR undergo cascade genetic testing (11.9% versus 21.7%, OR 0.49, 95% CI 0.39-0.61, p < 0.0001). This was seen both before (OR 0.38, 95% CI 0.24-0.61, p < 0.001) and after (OR 0.53, 95% CI 0.41-0.68, p < 0.001) the no-charge testing policy. Rates of an ARR undergoing cascade testing were low overall, and significantly lower in Black versus White probands. The magnitude of difference in cascade testing rates between Blacks and Whites did not significantly change with no-charge testing. Barriers to cascade testing in all populations should be explored in order to maximize the benefits of genetic testing for both treatment and prevention of cancer.

"How is it going to help?": Exploring Black breast cancer patients' questions about biomarker testing to predict chemotherapy-induced peripheral neuropathy.

Objective: Many Black breast cancer patients experience chemotherapy-induced peripheral neuropathy (CIPN). Our study assessed Black breast cancer patients' questions about a biomarker test that can predict likelihood of CIPN. Methods: Nineteen Black women who were previous/current breast cancer patients participated in focus groups. Researchers briefly explained CIPN and the biomarker test, and then participants were asked what questions they would have about the test and its use in treatment decisions. These participant-voiced questions composed the data for this study and were analyzed using thematic analysis. Results: Participants' questions centered on six themes: reasons for the test, effect on timeline of breast cancer treatment, testing procedure, limits of test (including accuracy), research done to develop this test (including research participants), and concerns about personal information connected to the test (including DNA). Conclusion: This study provides an exploratory look at questions that Black breast cancer patients may have about toxicity biomarker testing use in breast cancer treatment decisions. Innovation: These findings provide a starting point for developing patient-centered approaches for integrating this precision medicine tool into clinical care. The methodological choice to generate participants' questions (rather than answers to a question) led to robust, actionable data.

Elevated insulin-like growth factor-1 in patients without clinical evidence of acromegaly.

OBJECTIVES: To (1) identify the frequency of IGF-1 elevation in a cohort of patients without clinically suspected GH excess, in a state-based reference laboratory over a 24-month period, and (2) to examine potential differences in comorbidities and relevant medications between people with an elevated IGF-1 compared to a matched control group. DESIGN: All IGF-1 measurements at Pathology Queensland between 1/12/2018-1/12/2020 were identified. The medical records of those with IGF-1 ≥1.1x the upper limit of the reference range were appraised to determine: (1) documentation of acromegalic features, (2) relevant comorbidities and medication use, and (3) further investigations to exclude pathological GH excess. PATIENTS AND MEASUREMENTS: There were 2759 IGF-1 samples measured in 1963 people ≥18 years, over the specified period. Of these, 204 had IGF-1 ≥1.1x the upper limit of the age-matched reference range; 102 cases (61M, 41F) met inclusion criteria, and were matched to 102 controls with a normal IGF-1 based on age, sex, gonadal status and pituitary anatomy on MRI. RESULTS: There were significant differences in the frequency of dopamine agonist use (19/102 cases vs. 6/102 controls, OR = 3.66, 95% confidence interval [CI]: 1.45-9.29, p = .009) and chronic kidney disease (CKD) (14/102 cases vs. 4/102 controls, OR = 3.90, 95% CI: 1.28-11.14, p = .024). CONCLUSIONS: Out of 1963 patients having IGF-1 measured, 102 (5.2%) had an elevated IGF-1 where there was no known acromegaly, GH replacement or endogenous glucocorticoid excess. Intraindividual biological variability, assay imprecision and physiological factors are known contributors to falsely elevated IGF-1, dopamine agonist therapy and CKD should also be considered.

The role of the nucleolus in regulating the cell cycle and the DNA damage response.

The nucleolus has long been perceived as the site for ribosome biogenesis, but numerous studies suggest that the nucleolus carefully sequesters crucial proteins involved in multiple cellular functions. Among these, the role of nucleolus in cell cycle regulation is the most evident. The nucleolus is the first responder of growth-related signals to mediate normal cell cycle progression. The nucleolus also senses different cellular stress insults by activating diverse pathways that arrest the cell cycle, promote DNA repair, or initiate apoptosis. Here, we review the emerging concepts on how the ribosomal and nonribosomal nucleolar proteins mediate such cellular effects.

Congenital Tuberculosis After In Vitro Fertilization: A Case for Tuberculosis Screening of Women Evaluated for Infertility.

We report a case of multidrug-resistant congenital tuberculosis (TB) in an infant conceived by in vitro fertilization and review 22 additional infant-mother pairs in the literature. Females evaluated for infertility should be screened for TB risk, and those at risk require a TB-specific diagnostic evaluation before receiving assisted reproductive treatment.

The NLRP3 inflammasome fires up heme-induced inflammation in hemolytic conditions.

Overactive inflammatory responses are central to the pathophysiology of many hemolytic conditions including sickle cell disease. Excessive hemolysis leads to elevated serum levels of heme due to saturation of heme scavenging mechanisms. Extracellular heme has been shown to activate the NLRP3 inflammasome, leading to activation of caspase-1 and release of pro-inflammatory cytokines IL-1ß and IL-18. Heme also activates the non-canonical inflammasome pathway, which may contribute to NLRP3 inflammasome formation and leads to pyroptosis, a type of inflammatory cell death. Some clinical studies indicate there is a benefit to blocking the NLRP3 inflammasome pathway in patients with sickle cell disease and other hemolytic conditions. However, a thorough understanding of the mechanisms of heme-induced inflammasome activation is needed to fully leverage this pathway for clinical benefit. This review will explore the mechanisms of heme-induced NLRP3 inflammasome activation and the role of this pathway in hemolytic conditions including sickle cell disease.

Lethal and Non-Lethal Functions of Caspases in the DNA Damage Response.

Members of the caspase family are well known for their roles in the initiation and execution of cell death. Due to their function in the removal of damaged cells that could otherwise become malignant, caspases are important players in the DNA damage response (DDR), a network of pathways that prevent genomic instability. However, emerging evidence of caspases positively or negatively impacting the accumulation of DNA damage in the absence of cell death demonstrates that caspases play a role in the DDR that is independent of their role in apoptosis. This review highlights the apoptotic and non-apoptotic roles of caspases in the DDR and how they can impact genomic stability and cancer treatment.

Factor-guided diagnosis of coagulopathy associated with coumarin-contaminated synthetic cannabinoids.

Contamination of synthetic cannabinoids with toxic coumarin derivatives known as superwarfarins can induce a persistent coagulopathy. In comparison to warfarin, these derivatives have prolonged half-lives and laboratory assays for detection are not readily available in clinical practice. To our knowledge, factor-guided diagnosis of coagulopathy secondary to coumarin-contaminated synthetic cannabinoids has not been described previously. Our case report details a young adult who presented to the hospital with an acute elevation in INR without any reported past medical history or illicit substance use. Factor levels were obtained and resulted quickly revealing deficiencies in factors II, VII, IX, and X, which led to a possible diagnosis of coagulopathy secondary to coumarin-contaminated synthetic cannabinoids. Upon further questioning, the patient admitted to use of synthetic cannabinoids. A bromadiolone assay was sent for testing, which resulted positive after patient discharge. Toxic coumarin derivative assays are not immediately available for reference. Given the patient's confirmed synthetic cannabinoid consumption and the possibility of coagulopathy from coumarin-contamination, factor levels served as a guide for diagnosis and treatment prior to the confirmatory assay. Obtaining factor levels in patients with an unexplained coagulopathy and suspected cannabis or synthetic cannabinoid use may aid clinicians in a more prompt diagnosis and treatment.

The Effects of Cannabinoids on Sleep.

The use of cannabis products to help with sleep and various other medical conditions by the public has increased significantly in recent years. Withdrawal from cannabinoids can lead to sleep disturbance. Here, we describe a patient who developed significant insomnia leading to worsening anxiety, mood, and suicidal ideation in the setting of medical cannabis withdrawal, prompting presentation to the Emergency Department and inpatient admission. There is a limited evidence base for the use of cannabis products for sleep. We provide a comprehensive review evaluating the literature on the use of cannabis products on sleep, including an overview of cannabis and related psychoactive compounds, the current state of the law as it pertains to the prescribing and use of these substances, and potential side effects and drug interactions. We specifically discuss the impact of cannabis products on normal sleep and circadian sleep-wake rhythms, insomnia, excessive daytime sleepiness, sleep apnea, parasomnias, and restless legs syndrome. We also describe the effects of cannabis withdrawal on sleep and how this increases relapse to cannabis use. Most of the studies are observational but the few published randomized controlled trials are reviewed. Our comprehensive review of the effects of cannabis products on normal sleep and sleep disorders, relevant to primary care providers and other clinicians evaluating and treating patients who use these types of products, shows that cannabis products have minimal to no effects on sleep disorders and may have deleterious effects in some individuals. Further research examining the differential impact of the various types of cannabinoids that are currently available on each of these sleep disorders is required.

Visualization of Inflammatory Caspases Induced Proximity in Human Monocyte-Derived Macrophages.

Inflammatory caspases include caspase-1, -4, -5, -11, and -12 and belong to the subgroup of initiator caspases. Caspase-1 is required to ensure correct regulation of inflammatory signaling and is activated by proximity-induced dimerization following recruitment to inflammasomes. Caspase-1 is abundant in the monocytic cell lineage and induces maturation of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-18 to active secreted molecules. The other inflammatory caspases, caspase-4 and -5 (and their murine homolog caspase-11) promote IL-1ß release by inducing pyroptosis. Caspase Bimolecular Fluorescence Complementation (BiFC) is a tool used to measure inflammatory caspase induced proximity as a readout of caspase activation. The caspase-1, -4, or -5 prodomain, which contains the region that binds to the inflammasome, is fused to non-fluorescent fragments of the yellow fluorescent protein Venus (Venus-N [VN] or Venus-C [VC]) that associate to reform the fluorescent Venus complex when the caspases undergo induced proximity. This protocol describes how to introduce these reporters into primary human monocyte-derived macrophages (MDM) using nucleofection, treat the cells to induce inflammatory caspase activation, and measure caspase activation using fluorescence and confocal microscopy. The advantage of this approach is that it can be used to identify the components, requirements, and localization of the inflammatory caspase activation complex in living cells. However, careful controls need to be considered to avoid compromising cell viability and behavior. This technique is a powerful tool for the analysis of dynamic caspase interactions at the inflammasome level as well as for the interrogation of the inflammatory signaling cascades in living MDM and monocytes derived from human blood samples.

Cellular autophagy, an unbidden effect of caspase inhibition by zVAD-fmk.

zVAD-fmk is a widely used pan-caspase inhibitor that blocks apoptosis but has undesirable side effects, including autophagy. In this issue, Needs et al. propose that zVAD-fmk induces autophagy by inhibiting the N-glycanase NGLY1 rather than caspases. NGLY1 is essential for the ERAD response and patients with inactivating mutations in NGLY1 present with neurodevelopmental defects and organ dysfunction. The ability of NGLY1 to inhibit basal levels of autophagy may contribute to this pathology. This study demonstrates possible crosstalk between protein turnover and autophagy while also underscoring the importance of specificity when using chemical tools to interrogate these pathways. Comment on https://doi.org/10.1111/febs.16345.

Caspase-2 regulates S-phase cell cycle events to protect from DNA damage accumulation independent of apoptosis.

In addition to its classical role in apoptosis, accumulating evidence suggests that caspase-2 has non-apoptotic functions, including regulation of cell division. Loss of caspase-2 is known to increase proliferation rates but how caspase-2 is regulating this process is currently unclear. We show that caspase-2 is activated in dividing cells in G1-phase of the cell cycle. In the absence of caspase-2, cells exhibit numerous S-phase defects including delayed exit from S-phase, defects in repair of chromosomal aberrations during S-phase, and increased DNA damage following S-phase arrest. In addition, caspase-2-deficient cells have a higher frequency of stalled replication forks, decreased DNA fiber length, and impeded progression of DNA replication tracts. This indicates that caspase-2 protects from replication stress and promotes replication fork protection to maintain genomic stability. These functions are independent of the pro-apoptotic function of caspase-2 because blocking caspase-2-induced cell death had no effect on cell division, DNA damage-induced cell cycle arrest, or DNA damage. Thus, our data supports a model where caspase-2 regulates cell cycle and DNA repair events to protect from the accumulation of DNA damage independently of its pro-apoptotic function.

Electronic consultations (eConsults): a proof of concept trial in Australia.

BACKGROUND: Electronic consultations (eConsults) allow general practitioners (GP) to seek the advice of a specialist via secure asynchronous digital communication. AIMS: To report the outcomes of a proof of concept (POC) trial of eConsults for patients with diabetes and endocrine disorders. METHODS: A prospective observational study conducted from November 2020 to May 2021. eConsults were provided by endocrinologists from the Princess Alexandra Hospital, Brisbane. The requests for advice were from GP in Brisbane South. An online questionnaire was completed by the GP and endocrinologist after each eConsult. RESULTS: Forty eConsults were performed over 7 months. The majority were in relation to type 2 diabetes (30%) or thyroid conditions (30%). All eConsult responses were performed within the target of 72 h with 92.5% responses provided within 24 h. The average time taken for the endocrinologist to perform the eConsult was 14.2 ± 4.4 min. The GP rated the value of eConsults as excellent 97% of the time. The eConsult resulted in a new or additional course of action 68% (19/28) of the time and confirmed a course of action 32% (9/28) of the time. The eConsult avoided the need for referral of the patient for a face-to-face specialist review in 55% of the eConsults. CONCLUSION: An eConsult service was able to be delivered by endocrinologists from a tertiary hospital to GP in Brisbane South. With an appropriate funding model, the broader implementation and adoption of eConsults has the potential to address specialist waiting lists and facilitate models of integrated care.

Improving Vascular Access Dressing Integrity in the Acute Care Setting: A Quality Improvement Project.

PURPOSE: The purpose of this quality improvement project was to evaluate transparent vascular access dressings and the use of a liquid gum mastic adhesive on improving dressing integrity over peripheral intravenous (PIV) insertion sites without increasing medical adhesive-related skin injuries (MARSIs) such as tears. PARTICIPANTS AND SETTING: A multidisciplinary team consisting of specialists in infection prevention, vascular access, nursing professional development, materials management, and WOC nurses met to review current audit data and available products to trial on 2 intermediate care units in our 2 hospitals in Indiana with a combined average daily unit census of 35 patients. APPROACH: Four dressing protocols-including our existing dressing with education, and an updated dressing with education, and the updated and new dressing, both with education and the addition of a gum mastic adhesive agent-were sequentially implemented by nurses on the units, each over a 2-week period. The goal was for 80% of the dressings to remain with all 4 corners fully intact without reinforcement at day 7, or sooner if PIV was discontinued before day 7. Data were reported as frequencies for intact dressings and skin complications. OUTCOMES: Education combined with the original dressing and the updated dressing did not achieve the goal of 80% fully intact dressings in the samples evaluated. The addition of the adhesive agent to the updated and new dressings with education exceeded the 80% goal. In addition, there were zero exposed PIV insertion sites and no documented MARSI in any of the 4 protocols. IMPLICATIONS FOR PRACTICE: We continued to collect postproject data of 30,049 vascular access sites including central line catheters and observed the same effectiveness of incorporating a gum mastic adhesive on dressing integrity. This practice change has now become standard of care in our institution.

Noncanonical Roles of Caspase-4 and Caspase-5 in Heme-Driven IL-1ß Release and Cell Death.

Excessive release of heme from RBCs is a key pathophysiological feature of several disease states, including bacterial sepsis, malaria, and sickle cell disease. This hemolysis results in an increased level of free heme that has been implicated in the inflammatory activation of monocytes, macrophages, and the endothelium. In this study, we show that extracellular heme engages the human inflammatory caspases, caspase-1, caspase-4, and caspase-5, resulting in the release of IL-1ß. Heme-induced IL-1ß release was further increased in macrophages from patients with sickle cell disease. In human primary macrophages, heme activated caspase-1 in an inflammasome-dependent manner, but heme-induced activation of caspase-4 and caspase-5 was independent of canonical inflammasomes. Furthermore, we show that both caspase-4 and caspase-5 are essential for heme-induced IL-1ß release, whereas caspase-4 is the primary contributor to heme-induced cell death. Together, we have identified that extracellular heme is a damage-associated molecular pattern that can engage canonical and noncanonical inflammasome activation as a key mediator of inflammation in macrophages.