Are we teaching the health impacts of climate change in a clinically relevant way? A systematic narrative review of biomechanism-focused climate change learning outcomes in medical curricula.

PURPOSE: Introducing biomedical approaches to the health impacts of climate change can improve medical student engagement with relevant climate-related issues, improve the development of medical schemas, and minimise displacement into crowded medical curricula. This paper aims to systematically review the medical education curricula related to climate change, with a particular focus on systems-based biomechanisms for the health impacts of climate change. We do this to provide a clear agenda for further development of learning outcomes (LOs) in this area to maximize the clinical applicability of this knowledge. MATERIAL AND METHODS: A systematic review was undertaken following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA; Liberati et al. 2009) guidelines for both the published and grey literature. Five databases (PubMed, SCOPUS, ERIC, Open Access Thesis and Dissertation, and Proquest Global Dissertation and Theses) were searched for works published between 2011 and June 2023. Full texts that contained LOs were the main inclusion criteria for the final review. Descriptive and content extraction guided the final narrative synthesis. RESULTS: Analysis indicated that biomechanism-related LOs represented about 25% of each published LO set, on average. These outcomes were primarily at the "understand" level of Bloom's taxonomy and were spread across a range of body systems and climate-change aspects. Infectious diseases and extreme heat were strong focuses. Authorship analysis indicated that the majority of these sets of published LOs are from Western contexts and authored by researchers and educators with medical and population health qualifications. CONCLUSIONS: Biomechanism-focused teaching about the health impacts of climate change is relatively rare in published curricula. Of the available sets of LOs, the majority are sourced from Western authors and are focused on a fairly circumscribed set of biomedical topics. There is scope to both broaden and deepen curriculum in this area, and we would recommend the field prioritise collaboration with medical educators from the Global South, where the effects of climate change are already the most acutely felt.

Visualizing the Human Body Using an Artistic Approach.

This chapter describes an innovative approach to the cross-disciplinary study of anatomy and art to facilitate visualization of the human body. We draw upon the literature, together with our own experience of designing, delivering and researching a cross-disciplinary art and anatomy course, to indicate the critical elements of the approach that foster students' visualization of the anatomy of the human body.Visual arts have been linked with anatomy for centuries, but typically biomedical science has existed in a utilitarian relationship with art only used as an aid. In this chapter, we discuss the rationale underpinning a cross-disciplinary anatomy and art course and describe our experience of devising activities and assessment that create a stimulating and mutually beneficial environment for visualizing the experience and physicality of the human body. We describe the structure of the course which integrates art and anatomy to train students in the language of anatomy and visual representation, by engaging them in a process of attempting their own visual communication. The cross-disciplinary nature of our approach creates a unique social environment that offers a supportive environment for exploration and experimentation without fear of failure. Students' personal growth in resilience, tolerance for uncertainty and creativity prepares them for the inclusion of these values in their career.

Diffuse large B-cell lymphoma and red cell autoimmunity: clinical role and pathogenesis.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of B-cell non-Hodgkin lymphoma (B-NHL) with significant morbidity and mortality despite advancements in treatment. Lymphoma and autoimmune disease both result from breakdowns in normal cell regulatory pathways, and epidemiological studies have confirmed both that B-NHL is more likely to develop in the setting of autoimmune diseases and vice versa. Red cell immunity, as evidenced by direct antiglobulin test (DAT) positivity, has been linked to DLBCL and more recently the pathogenic causes of this association have begun to be better understood using molecular techniques. This project aimed to explore the relationship between red cell autoimmunity and DLBCL. DAT positivity was more common in DLBCL as compared to healthy controls (20.4% vs 3.7%, p=0.0005). Univariate analysis found a non-significant trend towards poorer overall survival in the DAT positive (DAT+) compared to the DAT negative (DAT-) groups (p=0.087). High throughput sequencing was used to compare mutations in DLBCL from DAT+ and DAT- patients. The most frequently mutated genes in 15 patient samples were KMT2D (n=13), MYOM2 (n=9), EP300 (n=8), SPEN (n=7), and ADAMTSL3 (n=7), which were mutated in both DAT+ and DAT- groups. BIRC3 (n=3), FOXO1 (n=3) and CARD11 (n=2) were found to be mutated only in samples from the DAT+ group. These gene mutations may be involved in disease development and progression, and potentially represent targets for future therapy. The immunoglobulin genotype IGHV4-34 is seen more frequently in DLBCL clones than in normal B cells and has intrinsic autoreactivity to self-antigens on red cells, which is largely mediated by two motifs within the first framework region (FR1); Q6W7 and A24V25Y.26 These motifs form a hydrophobic patch which determines red cell antigen binding and are frequently mutated away from self-reactivity in normal B cells. If this does not occur this may provide constant B cell receptor signalling which encourages lymphoma development, a theory known as antigen driven lymphomagenesis. As with previous studies, IGHV4-34 was over-represented (15.6%) in our DLBCL cohort. Furthermore, of 6 IGHV4-34-expressing DLBCL samples five had unmutated hydrophobic patch mutations providing further evidence for antigen-driven lymphomagenesis. Mutation analysis of these five samples demonstrated high frequency of mutations in several genes, including CREBBP and NCOR2. Further research could explore if mutations in CREBBP and NCOR2 work in conjunction with the preserved QW and AVY motifs to promote lymphomagenesis in IGHV4-34-expressing B cells, and if so, could guide future targeted therapy.

Clinician perspectives on rapid transition to telehealth during COVID-19 in Australia - a qualitative study.

Objective The coronavirus disease 2019 (COVID-19) pandemic precipitated a major shift in the use of telehealth in Australia. The changes highlighted gaps in our knowledge regarding the efficacy of, and clinician attitudes to, the use of telehealth. The current study expands and deepens the available evidence as a result of being collected in unique circumstances that removed one of the major barriers (lack of Medicare rebates) and also one major enablers (willingness) of telehealth uptake. Methods Using a semi-structured interview, we invited clinicians (N = 39) to share their perspectives, attitudes and experiences of using telehealth. Topics covered included perceptions of the strengths and challenges of telehealth, and how experience of using telehealth during the COVID-19 pandemic had influenced clinicians' views and intentions regarding their future practice. Participants included clinicians from five disciplines across public and private practice: paediatrics, neurology, immunology, rural general practice, and orthopaedics. Results We found three key dimensions for consideration when assessing the suitability of telehealth for ongoing practice: the attributes of the patient population, the attributes of the clinical context and environment, and the risks and benefits of a telehealth approach. These findings map to the existing literature and allow us to infer that the experiences of clinicians who previously would have chosen telehealth did not differ significantly from those of our 'pandemic-conscripted' clinicians. Conclusions Our findings map clearly to the existing literature and allow us to infer that the experiences of the clinicians who have chosen telehealth (and are already represented in the literature) did not differ significantly from those trying out telehealth under the unique circumstances of the removal of the Medicare Benefits Scheme barrier and external pressure that over-rides the 'willingness' enabling factor in uptake decisions.

How conceptualizing obesity as a disease affects beliefs about weight, and associated weight stigma and clinical decision-making in health care.

OBJECTIVES: This study empirically investigated how conceptualizing obesity as a disease (i.e., pathologizing obesity) affects beliefs about weight, and weight stigma and discrimination among health professionals. DESIGN: An experiment that manipulated the pathologization of obesity was completed by a multi-nation sample of health professionals from Australia, UK, and USA (N = 365). METHODS: Participants were randomly assigned to one of two conditions where they were asked to conceptualize obesity as a disease or not a disease; then presented with a hypothetical medical profile of a patient with obesity who was seeking care for migraines. We measured biogenetic causal beliefs about obesity, endorsement of weight as a heuristic for health, negative obesity stereotypes, and treatment decisions. RESULTS: Participants in the disease (vs. non-disease) condition endorsed biogenetic causal beliefs more strongly and made more migraine-related treatment recommendations. No effect of the manipulation was found for the remaining outcomes. Biogenetic causal beliefs about obesity were associated with less weight stigma. Endorsing weight as a heuristic for health was associated with greater weight stigma and differential treatment recommendations focused more on the patient's weight and less on their migraines. CONCLUSIONS: Pathologizing obesity may reinforce biogenetic explanations for obesity. Evidence demonstrates complex associations between weight-related beliefs and weight stigma and discrimination. Biogenetic causal beliefs were associated with less weight stigma, while endorsing weight as a heuristic for health was associated with greater weight stigma and differential treatment. Further research is needed to inform policies that can promote health without perpetuating weight-based rejection in health care.

AKT mutant allele-specific activation dictates pharmacologic sensitivities.

AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism1-8. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy7,8. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.

Natural History and Characteristics of ERBB2-mutated Hormone Receptor-positive Metastatic Breast Cancer: A Multi-institutional Retrospective Case-control Study from AACR Project GENIE.

PURPOSE: We wanted to determine the prognosis and the phenotypic characteristics of hormone receptor-positive advanced breast cancer tumors harboring an ERBB2 mutation in the absence of a HER2 amplification. EXPERIMENTAL DESIGN: We retrospectively collected information from the American Association of Cancer Research-Genomics Evidence Neoplasia Information Exchange registry database from patients with hormone receptor-positive, HER2-negative, ERBB2-mutated advanced breast cancer. Phenotypic and co-mutational features, as well as response to treatment and outcome were compared with matched control cases ERBB2 wild type. RESULTS: A total of 45 ERBB2-mutant cases were identified for 90 matched controls. The presence of an ERBB2 mutation was not associated with worse outcome determined by overall survival (OS) from first metastatic relapse. No significant differences were observed in phenotypic characteristics apart from higher lobular infiltrating subtype in the ERBB2-mutated group. ERBB2 mutation did not seem to have an impact in response to treatment or time-to-progression (TTP) to endocrine therapy compared with ERBB2 wild type. In the co-mutational analyses, CDH1 mutation was more frequent in the ERBB2-mutated group (FDR < 1). Although not significant, fewer co-occurring ESR1 mutations and more KRAS mutations were identified in the ERBB2-mutated group. CONCLUSIONS: ERBB2-activating mutation was not associated with a worse OS from time of first metastatic relapse, or differences in TTP on treatment as compared with a series of matched controls. Although not significant, differences in coexisting mutations (CDH1, ESR1, and KRAS) were noted between the ERBB2-mutated and the control group.

The question of dissection in medical training: Not just "if," but "when"? A student perspective.

While debate about the use of-and alternatives to-human cadaveric dissection in medical training is robust, little attention has been paid to questions about timing. This study explores the perspectives of medical students and recent graduates with regard to two key questions: when in the degree program do students prefer dissection opportunities and what are the students getting out of participating in dissection? Self-report survey data from students in preclinical years (n = 105), clinical years (n = 57), and graduates (n = 13) were analyzed. Most (89%) preferred dissection during the preclinical years, with no effect by training year (χ2  = 1.98, p = 0.16), previous anatomy (χ2  = 3.64, p = 0.31), or dissection (χ2  = 3.84, p = 0.26) experience. Three key findings emerged. First, the majority of students prefer to dissect in the preclinical years because they view dissection as important for developing foundation knowledge and delivering an opportunity for consolidation prior to transitioning to primarily clinical studies. In addition, students recognize that it is a time-consuming activity requiring specialized facilities. Second, three main understandings of the purpose of dissection were reported: depth of learning, learning experience, and real-world equivalence. Third, these student perspectives of the purpose of dissection are associated with timing preferences for dissection opportunities. The results identify the preclinical phase as the optimal time to strategically integrate dissection into medical training in order to maximize the benefits of this unique learning opportunity for students and minimize its impact upon curricular time.

A survey of current practice in reporting third trimester fetal biometry and Doppler in Australia and New Zealand.

INTRODUCTION: Inconsistent reporting practices in third trimester ultrasound, the choice of reference charts in particular, have the potential to misdiagnose abnormal fetal growth. But this may lead to unnecessary anxiety and confusion amongst patients and clinicians and ultimately influence clinical management. Therefore, we sought to determine the extent of variability in choice of fetal biometry and Doppler reference charts and reporting practices in Australia and New Zealand. METHODS: Clinicians performing and/or reporting obstetric ultrasound were invited to answer questions about fetal biometry and Doppler charts in a web-based survey. RESULTS: At least four population-based charts are in current use. The majority of respondents (78%) report the percentile for known gestational age (GA) alongside measurements and 63% using a cut-off of estimated fetal weight (EFW) < 10th percentile when reporting small for gestational age (SGA) and/or fetal growth restriction (FGR). The thresholds for the use of fetal and maternal Doppler in third trimester ultrasound varied in terms of the GA, EFW cut-off, and how measures were reported. The majority of respondents were not sure of which Doppler charts were used in their practice. CONCLUSION: This survey revealed inconsistencies in choice of reference chart and reporting practices. The potential for misdiagnosis of abnormal fetal growth remains a significant issue.

Utility of Serial cfDNA NGS for Prospective Genomic Analysis of Patients on a Phase I Basket Study.

PURPOSE: Cell-free DNA (cfDNA) analysis offers a noninvasive means to access the tumor genome. Despite limited sensitivity of broad-panel sequencing for detecting low-frequency mutations in cfDNA, it may enable more comprehensive genomic characterization in patients with sufficiently high disease burden. We investigated the utility of large-panel cfDNA sequencing in patients enrolled to a Phase I AKT1-mutant solid tumor basket study. METHODS: Patients had AKT1 E17K-mutant solid tumors and were treated on the multicenter basket study (ClinicalTrials.gov identifier: NCT01226316) of capivasertib, an AKT inhibitor. Serial plasma samples were prospectively collected and sequenced using exon-capture next-generation sequencing (NGS) analysis of 410 genes (Memorial Sloan Kettering [MSK]-Integrated Molecular Profiling of Actionable Cancer Target [IMPACT]) and allele-specific droplet digital polymerase chain reaction (ddPCR) for AKT1 E17K. Tumor DNA (tDNA) NGS (MSK-IMPACT) was also performed on available pretreatment tissue biopsy specimens. RESULTS: Among 25 patients, pretreatment plasma samples were sequenced to an average coverage of 504×. Somatic mutations were called in 20/25 (80%), with mutant allele fractions highly concordant with ddPCR of AKT1 E17K (r 2 = 0.976). Among 17 of 20 cfDNA-positive patients with available tDNA for comparison, mutational concordance was acceptable, with 82% of recurrent mutations shared between tissue and plasma. cfDNA NGS captured additional tumor heterogeneity, identifying mutations not observed in tDNA in 38% of patients, and revealed oncogenic mutations in patients without available baseline tDNA. Longitudinal cfDNA NGS (n = 98 samples) revealed distinct patterns of clonal dynamics in response to therapy. CONCLUSION: Large gene panel cfDNA NGS is feasible for patients with high disease burden and is concordant with single-analyte approaches, providing a robust alternative to ddPCR with greater breadth. cfDNA NGS can identify heterogeneity and potentially biologically informative and clinically relevant alterations.

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

PURPOSE: Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. METHODS: This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. RESULTS: We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. CONCLUSION: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer.

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.

Examining the Short-, Medium-, and Long-Term Success of an Embodied Learning Activity in the Study of Hand Anatomy for Clinical Application.

A student's own body provides an often disregarded site of knowledge production and corporeal wisdom. Learning via cognitive processes anchored in physical movement and body awareness, known as embodied learning, may aid students to visualize structures and understand their functions and clinical relevance. Working from an embodied learning perspective, the current article evaluates the use of an offline physical learning tool (Anatomical Glove Learning System; AGLS) for teaching hand anatomy for clinical application in medical students. Two student samples (N1  = 105; N2  = 94) used the AGLS in two different ways. In the first sample, the AGLS was compared to a traditional approach using hand bones, models and prosected specimens. Secondly, the AGLS and traditional approach were combined. The evaluation consisted of three outcomes: short-term learning (post-test), medium-term applications (mock-objective structured clinical examination, MOSCE), and longer-term assessment (objective structured clinical examination, OSCE). Findings from the first sample indicated no significant differences between the AGLS and traditional laboratory groups on short- (F(1,78) = 0.036, P = 0.849), medium- (F(1,50) = 0.743, P = 0.393), or longer-term (F(1,82) = 0.997, P = 0.321) outcomes. In the second sample using the AGLS in combination with a traditional approach was associated with significantly better short-term post-test scores (F(2,174) = 5.98, P = 0.003) than using the AGLS alone, but demonstrated no effect for long-term OSCE scores. These results suggest an embodied learning experience alone does not appear to be advantageous to student learning, but when combined with other methods for studying anatomy there are learning gains.

Carboplatin and hypomagnesemia: Is it really a problem?

BACKGROUND: Carboplatin has largely replaced cisplatin in ovarian/peritoneal/tubal cancer (OC) due to comparable activity and reduced toxicity, particularly nephrotoxicity and hypomagnesemia. Anecdotally hypomagnesemia occurs commonly with carboplatin, however there are limited data available regarding frequency or severity. AIMS: To quantify incidence and severity of hypomagnesemia in patients receiving carboplatin-based chemotherapy for OC; to explore a dose-response relationship with carboplatin and assess potential confounding variables. METHODS: A retrospective single-center review of all OC patients receiving carboplatin-based chemotherapy as first/subsequent line between 2012 and 2018 was performed. Data on patient/disease characteristics, potential confounders (gastrointestinal/renal impairment, premorbid hypomagnesemia and concomitant medications), dose, electrolytes, and magnesium replacement were collected. RESULTS: One hundred four of 144 (72%) patients had at least one hypomagnesemia event, 11 of 104 (11%) grade 2, and 11 of 104 (11%) grade 3/4 in severity. Multivariate analysis showed a significant association between hypomagnesemia and treatment duration (P < .001). Premorbid hypomagnesemia was associated with a significantly longer duration and higher grade of hypomagnesemia (P = .021 and P < .001, respectively). Vomiting, diarrhea, and confounding medications were associated with hypomagnesemia (P = .019 and P = .028, respectively). Fourteen percent of hypomagnesemia events never resolved suggesting a significant cohort post-carboplatin are at risk of long-term renal toxicity. The effect of magnesium replacement could not be accurately assessed due to limited documentation of replacement. CONCLUSION: Hypomagnesemia is common in patients receiving carboplatin-based chemotherapy for OC, and although generally mild, a significant minority were severe. Several high-risk groups were identified including patients with premorbid hypomagnesemia, vomiting, diarrhea, or taking certain medications. Further research is warranted to understand when hypomagnesemia is clinically relevant and determine the impact of interventions.

High proportion of anergic B cells in the bone marrow defined phenotypically by CD21(-/low)/CD38- expression predicts poor survival in diffuse large B cell lymphoma.

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) is the commonest lymphoma that is highly aggressive where one-third of the patients relapse despite effective treatment. Interaction between the lymphoma cells and the non-clonal immune cells within the bone marrow microenvironment is thought to play a critical role in the pathogenesis of DLBCL. METHODS: We used flow cytometry to characterize the proportion of B cell subpopulations in the bone marrow (N = 47) and peripheral blood (N = 54) of 75 DLBCL patients at diagnosis and study their impact on survival. RESULTS: Anergic B cells in the bone marrow (BM), characterized as having CD21(-/low)/CD38- expression, influenced survival with high numbers (defined as > 13.9%) being associated with significantly shorter overall survival (59.7 months vs 113.6 months, p = 0.0038). Interestingly, low numbers of anergic B cells in the BM (defined as ≤13.9%) was associated with germinal center B cell type of DLBCL (p = 0.0354) that is known to have superior rates of survival when compared to activated B cell type. Finally, Cox regression analysis in our cohort of patients established that the inferior prognosis of having high numbers of anergic B cells in the bone marrow was independent of the established Revised International Prognostic Index (R-IPI) score. CONCLUSIONS: High proportion of anergic B cells in the BM characterized by CD21(-/low)/CD38- expression predicts poor survival outcomes in DLBCL.

Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.

PURPOSE: The activating mutation AKT1 E17K occurs in approximately 7% of estrogen receptor-positive (ER+) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1 E17K-mutant ER+ MBC. PATIENTS AND METHODS: Patients with an AKT1 E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort. RESULTS: From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although the latter group may have had more aggressive disease at baseline. AKT1 E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (76%, 31/41). A ≥50% decrease in AKT1 E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy [most frequent grade ≥3 adverse events: rash (9% vs. 20%), hyperglycemia (5% vs. 30%), diarrhea (5% vs. 10%)]. CONCLUSIONS: Capivasertib demonstrated clinically meaningful activity in heavily pretreated patients with AKT1 E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.

Characteristics and Outcome of AKT1 E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry.

AKT inhibitors have promising activity in AKT1 E17K-mutant estrogen receptor (ER)-positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1 E17K-mutant (n = 153) and AKT1-wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1-wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to define outcomes in a rare genomically defined cancer subtype, an approach with broad applicability to precision oncology. SIGNIFICANCE: We delineate the natural history of a rare genomically distinct cancer, AKT1 E17K-mutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data.See related commentary by Castellanos and Baxi, p. 490.

How Can We Show You, If You Can't See It? Trialing the Use of an Interactive Three-Dimensional Micro-CT Model in Medical Education.

Teaching internal structures obscured from direct view is a major challenge of anatomy education. High-fidelity interactive three-dimensional (3D) micro-computed tomography (CT) models with virtual dissection present a possible solution. However, their utility for teaching complex internal structures of the human body is unclear. The purpose of this study was to investigate the use of a realistic 3D micro-CT interactive visualization computer model to teach paranasal sinus anatomy in a laboratory setting during pre-clinical medical training. Year 1 (n = 79) and Year 2 (n = 59) medical students undertook self-directed activities focused on paranasal sinus anatomy in one of two laboratories (traditional laboratory and 3D model). All participants completed pre and posttests before and after the laboratory session. Results of regression analyses predicting post-laboratory knowledge indicate that, when students were inexperienced with the 3D computer technology, use of the model was detrimental to learning for students with greater prior knowledge of the relevant anatomy (P < 0.05). For participants experienced with the 3D computer technology, however, the use of the model was detrimental for students with less prior knowledge of the relevant anatomy (P < 0.001). These results emphasize that several factors need to be considered in the design and effective implementation of such models in the classroom. Under the right conditions, the 3D model is equal to traditional laboratory resources when used as a learning tool. This paper discusses the importance of preparatory training for students and the technical consideration necessary to successfully integrate such models into medical anatomical curricula.

Efficacy and Determinants of Response to HER Kinase Inhibition in HER2-Mutant Metastatic Breast Cancer.

HER2 mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, alone or with fulvestrant, in 81 patients with HER2-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER+ patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating HER2 or HER3 alterations were associated with poor treatment outcome. Similarly, acquisition of multiple HER2-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define HER2 mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both de novo and acquired resistance to neratinib. SIGNIFICANCE: HER2 mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.This article is highlighted in the In This Issue feature, p. 161.

Efficacy and Safety of Gemcitabine With Trastuzumab and Pertuzumab After Prior Pertuzumab-Based Therapy Among Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: A Phase 2 Clinical Trial.

Importance: Taxanes with trastuzumab and pertuzumab for initial treatment of human epidermal growth factor receptor 2 (ERBB2, formerly HER2)-positive metastatic breast cancer is associated with improved progression-free survival (PFS) and overall survival. While continued use of trastuzumab in therapeutic combinations after disease progression is standard, the efficacy of continuing pertuzumab is unknown. Objective: To evaluate the efficacy and safety of pertuzumab in combination with gemcitabine and trastuzumab after prior treatment with pertuzumab for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants: This is a phase 2 single-arm clinical trial of dual anti-ERBB2 therapy after prior treatment with pertuzumab. The study took place at a single academic center from March 2015 to April 2017 among women with ERBB2-positive metastatic breast cancer, prior pertuzumab-based treatment, and 3 or fewer prior chemotherapy regimens. Data were analyzed between January 2019 and March 2019. Intervention: Treatment consisted of gemcitabine, 1200 mg/m2 (later amended to 1000 mg/m2) on days 1 and 8 every 3 weeks, plus trastuzumab (8-mg/kg loading dose, then 6 mg/kg) and pertuzumab (840-mg loading dose, then 420 mg) once every 3 weeks. Main Outcomes and Measures: The primary end point was 3-month PFS. Based on prior trials, a target rate of 70% or higher was selected as the promising progression-free rate at 3 months. Secondary outcomes included safety, tolerability, and overall survival. Results: A total of 45 patients (median [range] age, 57.1 [31.7-77.2] years) were enrolled; 22 (49%) were treated in the second-line setting, and 23 (51%) were treated in the third-line setting or beyond. Of these, 22 (49%) received prior trastuzumab emtansine (T-DM1). At a median (range) follow-up of 27.6 (8.3-36.0) months, 3-month PFS was 73.3% (95% CI, 61.5%-87.5%). Overall, median PFS was 5.5 months (95% CI, 5.4-8.2 months). Treatment was well tolerated, with no occurrences of febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusions and Relevance: In this phase 2 trial, treatment with gemcitabine, trastuzumab, and pertuzumab after prior pertuzumab-based therapy for ERBB2-positive metastatic breast cancer was associated with a 3-month PFS rate of 73.3% and was well tolerated. Continuation of pertuzumab beyond progression was associated with apparent clinical benefit. Trial Registration: ClinicalTrials.gov identifier: NCT02252887.