Survival outcomes of patients with HER2/neu-positive breast cancer with germline BRCA mutations.

BACKGROUND: Breast cancer (BC) with germline BRCA1/2 mutations and their association with triple-negative BC has been thoroughly investigated. However, some carriers of BRCA1/2 mutations have human epidermal growth factor receptor 2 (HER2/neu)-positive BC, which has a different targeted therapy approach, and data are scarce for this patient population. The authors sought to characterize the clinical characteristics and outcomes of patients with HER2/neu-positive BC who had germline BRCA1/2 mutations. METHODS: This was a retrospective analysis of data from 1099 patients diagnosed with HER2/neu-positive BC who were screened for germline BRCA mutations between 1996 and 2022. Clinicopathologic features and survival rates were analyzed by BRCA mutation status. Univariate and multivariable Cox proportional hazards regression models were used to analyze the association between clinical variables and outcomes. RESULTS: Of 1099 patients with HER2/neu-positive BC, 73 (6.6%) tested positive for BRCA1/2 mutations. Age, race, and tumor characteristics did not differ between BRCA noncarriers and carriers. At a median follow-up of 78.6 months, the 5-year recurrence-free survival rate was 85% in BRCA carriers and 87% in noncarriers (p = .79), and the 5-year overall survival rate was 94% in BRCA carriers and 94% in noncarriers (p = .78). In a multivariable model, BRCA was not associated with recurrence-free survival (hazard ratio, 0.99; 95% confidence interval, 0.51-1.90; p = .96) or overall survival (hazard ratio, 0.83; 95% confidence interval, 0.33-2.07; p = .69). CONCLUSIONS: BRCA1/2 mutations occurred in 6.6% of patients with HER2/neu-positive BC and did not affect survival outcomes. Assessing the potential benefits of new treatment strategies, such as combining anti-HER2/neu therapies with poly(ADP-ribose) polymerase inhibitors, may lead to enhanced outcomes for these patients.

A Comparison of Palliative Care Delivery between Ethnically Chinese and Non-Chinese Canadians in the Last Year of Life.

BACKGROUND: Ethnically Chinese adults in Canada and the United States face multiple barriers in accessing equitable, culturally respectful care at the end-of-life. Palliative care (PC) is committed to supporting patients and families in achieving goal-concordant, high-quality serious illness care. Yet, current PC delivery may be culturally misaligned. Therefore, understanding ethnically Chinese patients' use of palliative care may uncover modifiable factors to sustained inequities at the end-of-life. OBJECTIVE: To compare the use and delivery of PC in the last year of life between ethnically Chinese and non-Chinese adults. DESIGN: Population-based cohort study. PARTICIPANTS: All Ontario adults who died between January 1st, 2012, and October 31st, 2022, in Ontario, Canada. EXPOSURES: Chinese ethnicity. MAIN MEASURES: Elements of physician-delivered PC, including model of care (generalist; specialist; mixed), timing and location of initiation, and type of palliative care physician at initial consultation. KEY RESULTS: The final study cohort included 527,700 non-Chinese (50.8% female, 77.9 ± 13.0 mean age, 13.0% rural residence) and 13,587 ethnically Chinese (50.8% female, 79.2 ± 13.6 mean age, 0.6% rural residence) adults. Chinese ethnicity was associated with higher likelihoods of using specialist (adjusted odds ratio [aOR] 1.53, 95%CI 1.46-1.60) and mixed (aOR 1.32, 95%CI 1.26-1.38) over generalist models of PC, compared to non-Chinese patients. Chinese ethnicity was also associated with a higher likelihood of PC initiation in the last 30 days of life (aOR 1.07, 95%CI 1.03-1.11), in the hospital setting (aOR 1.24, 95%CI 1.18-1.30), and by specialist PC physicians (aOR 1.33, 95%CI 1.28-1.38). CONCLUSIONS: Chinese ethnicity was associated with a higher likelihood of mixed and specialist models of PC delivery in the last year of life compared to adults who were non-Chinese. These observed differences may be due to later initiation of PC in hospital settings, and potential differences in unmeasured needs that suggest opportunities to initiate early, community-based PC to support ethnically Chinese patients with serious illness.

Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).

A phase II study of neoadjuvant atezolizumab and nab-paclitaxel in patients with anthracycline-resistant early-stage triple-negative breast cancer.

PURPOSE: Neoadjuvant anti-PD-(L)1 therapy improves the pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Given the potential for long-term morbidity from immune-related adverse events (irAEs), optimizing the risk-benefit ratio for these agents in the curative neoadjuvant setting is important. Suboptimal clinical response to initial neoadjuvant therapy (NAT) is associated with low rates of pCR (2-5%) and may define a patient selection strategy for neoadjuvant immune checkpoint blockade. We conducted a single-arm phase II study of atezolizumab and nab-paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02530489). METHODS: Patients with stage I-III, AC-resistant TNBC, defined as disease progression or a < 80% reduction in tumor volume after 4 cycles of AC, were eligible. Patients received atezolizumab (1200 mg IV, Q3weeks × 4) and nab-paclitaxel (100 mg/m2 IV,Q1 week × 12) as the second phase of NAT before undergoing surgery followed by adjuvant atezolizumab (1200 mg IV, Q3 weeks, × 4). A two-stage Gehan-type design was employed to detect an improvement in pCR/residual cancer burden class I (RCB-I) rate from 5 to 20%. RESULTS: From 2/15/2016 through 1/29/2021, 37 patients with AC-resistant TNBC were enrolled. The pCR/RCB-I rate was 46%. No new safety signals were observed. Seven patients (19%) discontinued atezolizumab due to irAEs. CONCLUSION: This study met its primary endpoint, demonstrating a promising signal of activity in this high-risk population (pCR/RCB-I = 46% vs 5% in historical controls), suggesting that a response-adapted approach to the utilization of neoadjuvant immunotherapy should be considered for further evaluation in a randomized clinical trial.

Identifying research practices toward achieving health equity principles within the Cancer Prevention and Control Research Network.

PURPOSE: Although there is national recognition for health equity-oriented research, there is limited guidance for researchers to engage partnerships that promote health equity in cancer research. The Cancer Prevention and Control Research Network's (CPCRN) Health Equity Work Group developed a toolkit to guide researchers in equitable collaborations. METHODS: The CPCRN's Health Equity Work Group collectively outlined health and racial equity principles guiding research collaborations with partners that include communities, community-based organizations, implementing partners in the clinical setting including providers and health care organizations, and policy makers. Using a network-wide survey to crowdsource information around ongoing practices, we leveraged and integrated the network's experience and collaborations. RESULTS: Data from the survey formed the preliminary basis for the toolkit, with a focus on sharing fiscal resources with partners, training and capacity building, collaborative decision-making, community-driven research agenda setting, and sustainability. The final toolkit provides reflection considerations for researchers and collated exemplary resources, supported by the contemporary research. CONCLUSIONS: The toolkit provides a guide to researchers at all experience levels wanting to engage in equitable research collaborations. Future efforts are underway to evaluate whether and how researchers within and outside CPCRN are able to incorporate these principles in research collaborations.

Understanding the Role of Caseworker-Cultural Mediators in Addressing Healthcare Inequities for Patients with Limited-English Proficiency: a Qualitative Study.

BACKGROUND: Patients with limited-English proficiency (LEP) face multiple barriers to equitable healthcare. Interventions that go beyond interpretation, such as the use of bicultural-bilingual patient navigators, hold promise for addressing multi-level barriers. However, data about how to operationalize the tasks that are key to such interventions across diverse LEP communities are lacking. OBJECTIVE: Using our health system's bicultural-bilingual caseworker-cultural mediator (CCM) program serving Amharic-, Cambodian/Khmer-, Somali-, Spanish-, and Vietnamese-speaking patients, we sought to understand the key tasks that comprise the CCMs' role and how these tasks enable them to address barriers to healthcare for patients with LEP. DESIGN: Semi-structured interviews were conducted in 2019 with a purposive sample (n=23) of clinicians, CCMs, and patients with LEP or their family members from all language groups. PARTICIPANTS: Patients or family members receiving CCM services, CCMs, and clinicians who referred patients to the program. APPROACH: Content analysis consisting of a hybrid deductive-inductive qualitative approach. KEY RESULTS: Seven CCM tasks were identified: advocacy, care coordination, navigation, interpretation, education, mediation, and emotional support. Additionally, four key impacts emerged that described the ways in which these tasks enabled the CCMs to facilitate equitable care: bridging the patient, family, community, clinical team, and healthcare system; impacting knowledge of cultural issues and of the healthcare system; troubleshooting cultural barriers and problem solving; and enhancing relationship building. CONCLUSIONS: We identified several tasks and impacts that enabled CCMs to address multi-level barriers to care experienced by patients with LEP and their families across diverse cultural and linguistic groups. Findings suggest opportunities for the generalizability of programs such as ours for multiple LEP populations. Additionally, interventions having a greater scope than interpretation and including relationships with communities may be more successful in addressing barriers to equitable care at the individual, system, and community levels.

Consistency and quality in written accreditation protocols for pediatrician training programs: a mixed-methods analysis of a global sample, and directions for improvement.

BACKGROUND: The World Federation for Medical Education (WFME) defines accreditation as 'certification of the suitability of medical education programs, and of…competence…in the delivery of medical education.' Accreditation bodies function at national, regional and global levels. In 2015, WFME published quality standards for accreditation of postgraduate medical education (PGME). We compared accreditation of pediatric PGME programs to these standards to understand variability in accreditation and areas for improvement. METHODS: We examined 19 accreditation protocols representing all country income levels and world regions. For each, two raters assessed 36 WFME-defined accreditation sub-areas as present, partially present, or absent. When rating "partially present" or "absent", raters noted the rationale for the rating. Using an inductive approach, authors qualitatively analyzed notes, generating themes in reasons for divergence from the benchmark. RESULTS: A median of 56% (IQR 43-77%) of WFME sub-areas were present in individual protocols; 22% (IQR 15-39%) were partially present; and 8.3% (IQR 5.5-21%) were absent. Inter-rater agreement was 74% (SD 11%). Sub-areas least addressed included number of trainees, educational expertise, and performance of qualified doctors. Qualitative themes of divergence included (1) variation in protocols related to heterogeneity in program structure; (2) limited engagement with stakeholders, especially regarding educational outcomes and community/health system needs; (3) a trainee-centered approach, including equity considerations, was not universal; and (4) less emphasis on quality of education, particularly faculty development in teaching. CONCLUSIONS: Heterogeneity in accreditation can be appropriate, considering cultural or regulatory context. However, we identified broadly applicable areas for improvement: ensuring equitable access to training, taking a trainee-centered approach, emphasizing quality of teaching, and ensuring diverse stakeholder feedback.

Autophagy and apoptosis cascade: which is more prominent in neuronal death?

Autophagy and apoptosis are two crucial self-destructive processes that maintain cellular homeostasis, which are characterized by their morphology and regulated through signal transduction mechanisms. These pathways determine the fate of cellular organelle and protein involved in human health and disease such as neurodegeneration, cancer, and cardiovascular disease. Cell death pathways share common molecular mechanisms, such as mitochondrial dysfunction, oxidative stress, calcium ion concentration, reactive oxygen species, and endoplasmic reticulum stress. Some key signaling molecules such as p53 and VEGF mediated angiogenic pathway exhibit cellular and molecular responses resulting in the triggering of apoptotic and autophagic pathways. Herein, based on previous studies, we describe the intricate relation between cell death pathways through their common genes and the role of various stress-causing agents. Further, extensive research on autophagy and apoptotic machinery excavates the implementation of selective biomarkers, for instance, mTOR, Bcl-2, BH3 family members, caspases, AMPK, PI3K/Akt/GSK3ß, and p38/JNK/MAPK, in the pathogenesis and progression of neurodegenerative diseases. This molecular phenomenon will lead to the discovery of possible therapeutic biomolecules as a pharmacological intervention that are involved in the modulation of apoptosis and autophagy pathways. Moreover, we describe the potential role of micro-RNAs, long non-coding RNAs, and biomolecules as therapeutic agents that regulate cell death machinery to treat neurodegenerative diseases. Mounting evidence demonstrated that under stress conditions, such as calcium efflux, endoplasmic reticulum stress, the ubiquitin-proteasome system, and oxidative stress intermediate molecules, namely p53 and VEGF, activate and cause cell death. Further, activation of p53 and VEGF cause alteration in gene expression and dysregulated signaling pathways through the involvement of signaling molecules, namely mTOR, Bcl-2, BH3, AMPK, MAPK, JNK, and PI3K/Akt, and caspases. Alteration in gene expression and signaling cascades cause neurotoxicity and misfolded protein aggregates, which are characteristics features of neurodegenerative diseases. Excessive neurotoxicity and misfolded protein aggregates lead to neuronal cell death by activating death pathways like autophagy and apoptosis. However, autophagy has a dual role in the apoptosis pathways, i.e., activation and inhibition of the apoptosis signaling. Further, micro-RNAs and LncRNAs act as pharmacological regulators of autophagy and apoptosis cascade, whereas, natural compounds and chemical compounds act as pharmacological inhibitors that rescue neuronal cell death through inhibition of apoptosis and autophagic cell death.

Characterizing uncertainty in goals-of-care discussions among black and white patients: a qualitative study.

BACKGROUND: Uncertainty has been associated with distress and poorer quality of life in patients with advanced cancer. Prior studies have focused on prognostic uncertainty; little is known about other types of uncertainty that patients and family members experience when discussing goals of care. Understanding the types of uncertainty expressed and differences between Black and White patients can inform the development of uncertainty management interventions. METHODS: This study sought to characterize the types of uncertainty expressed by Black and White patients and family members within the context of information needs during inpatient goals-of-care discussions. We performed a secondary analysis of transcripts from 62 recorded goals-of-care discussions that occurred between 2012 and 2014 at an urban, academic medical center in the United States. We applied an adapted taxonomy of uncertainty to data coded as describing information needs and used an inductive qualitative analysis method to analyze the discussions. We report the types of uncertainty expressed in these discussions. RESULTS: Fifty discussions included patient or family expressions of information needs. Of these, 40 discussions (n=16 Black and n=24 White) included statements of uncertainty. Black and White patients and families most frequently expressed uncertainty related to processes and structures of care (system-centered uncertainty) and to treatment (scientific uncertainty). Statements of prognostic uncertainty focused on quantitative information among Whites and on qualitative information and expectations for the future among Blacks. CONCLUSIONS: Black and White patients and families frequently expressed system-centered uncertainty, suggesting this may be an important target for intervention. Addressing other sources of uncertainty, such as prognostic uncertainty, may need more tailored approaches.

Defatted silkworm pupae meal as an alternative protein source for cattle.

Silkworm pupae meal (SWP) is a protein-rich by-product of the silk reeling industry, available in a significant quantity. However, there has been little and insignificant research into the use of SWP in ruminants to date. In this view, the present study was conducted in two phases to evaluate the effect of different inclusion levels of defatted silkworm pupae meal (DSWP) on rumen fermentation, microbial protein synthesis and nutrient utilisation in cattle fed on finger millet straw (FMS)-based diet. Four isonitrogenous concentrate mixtures (CM) were prepared with DSWP replacing soybean meal (SBM) protein at 0 (T0), 10 (T1), 20 (T2) and 30% (T3). In phase I, a rumen fermentation experiment was conducted in a 4 × 4 Latin square design using four crossbred steers to study the effect of different levels of DSWP on rumen fermentation. No significant difference (P > 0.05) was observed in rumen fermentation parameters such as pH, ammonia nitrogen (NH3-N) and total volatile fatty acids (VFA) among the experimental groups. In phase II, the digestibility trial was conducted in 20 crossbred cattle (311.2 ± 4.81 kg), which were divided into four experimental groups of five animals each in a completely randomised design to study the effect of different rations (T0, T1, T2, T3) on microbial protein synthesis and nutrient utilisation. The intake and digestibility of nutrients, excretion of urinary purine derivatives and microbial protein synthesis were not significantly different among the experimental groups. In addition, feeding DSWP revealed no significant (P > 0.05) change in the blood biochemical parameters of animals. Furthermore, at the same price as SBM, DSWP provides two units more crude protein. Therefore, the results of the present study indicated that DSWP can be incorporated into the ration of cattle up to 30% by replacing SBM without affecting rumen fermentation pattern and nutrient utilisation.