Brain Metastasis Incidence and Patterns of Presentation After Definitive Treatment of Locally Advanced Non-Small Cell Lung Cancer: A Potential Argument for Brain Magnetic Resonance Imaging Surveillance.

Purpose: Brain metastases (BMs) are a common source of morbidity and mortality. Guidelines do not advise brain surveillance for locally advanced non-small cell lung cancer (LA-NSCLC). We describe the incidence, time to development, presentation, and management of BMs after definitive chemoradiotherapy (CRT). Methods and Materials: We reviewed records of patients with LA-NSCLC treated with CRT within the period from 2013 to 2020. Descriptive statistics were used to characterize the population and the Kaplan-Meier method was used to estimate time to BM. Fisher exact tests and Wilcoxon rank-sum tests were used to compare outcomes between symptomatic and asymptomatic patients. Results: A total of 219 patients were reviewed including 96 with squamous cell carcinoma, 88 with adenocarcinoma, and 35 with large cell/not otherwise specified (LC/NOS). Thirty-nine patients (17.8%) developed BMs: 35 (90%) symptomatic and 4 (10%) asymptomatic. The rate of BM was highest in LC/NOS (34.3%) and adenocarcinoma (23.9%). Ninety percent of BMs occurred within 2 years. All asymptomatic patients underwent stereotactic radiosurgery alone, compared with 40% of symptomatic patients (P = .04). Symptomatic patients were more likely to require hospitalization (65.7% vs 0%, P = .02), craniotomy (25.7% vs 0%, not significant), and steroids (91.4% vs 0%, P < .001). Cumulative BM volume was higher for symptomatic patients (4 vs 0.24 cm3, P < .001) as was median greatest axial dimension (2.18 vs 0.52 cm, P < .001). Conclusions: We identified a high rate of BMs, particularly in LC/NOS and adenocarcinoma histology NSCLC. The majority were symptomatic. These results provide rationale for post-CRT magnetic resonance imaging brain surveillance for patients at high risk of BM.

Five-year survivors from brain metastases treated with stereotactic radiosurgery: Biology, improving treatments, or just plain luck?

Background: Improvements in therapies have led to an increasing number of long-term survivors of brain metastases. The present series compares a population of 5-year survivors of brain metastases to a generalized brain metastases population to assess for factors attributable to long-term survival. Methods: A single institution retrospective review was performed to identify 5-year survivors of brain metastases who received stereotactic radiosurgery (SRS). A historical control population of 737 patients with brain metastases was used to assess similarities and differences between the long-term survivor population and the general population treated with SRS. Results: A total of 98 patients with brain metastases were found to have survived over 60 months. No differences between long-term survivors and controls were identified with regards to the age at first SRS (P = .19), primary cancer distribution (P = .80), and the number of metastases at first SRS (P = .90). Cumulative incidence of neurologic death at 6, 8 and 10 years for the long-term survivor cohort was 4.8%, 16%, and 16% respectively. In the historical controls, cumulative incidence of neurologic death reached a plateau at 40% after 4.9 years. A significant difference in the distribution of burden of disease at the time of the first SRS was found between the 5-year survivors and the control (P = .0049). 58% of 5-year survivors showed no evidence of clinical disease at the last follow-up. Conclusion: Five-year survivors of brain metastases represent a diverse histologic population, suggesting a small population of oligometastatic and indolent cancers exist for each cancer type.

Long term survivors of stereotactic radiosurgery for brain metastases: do distant brain failures reach a plateau and what factors are associated with a brain metastasis velocity of zero?

PURPOSE: Life expectancy continues to increase for patients with brain metastases treated with stereotactic radiosurgery (SRS). The present study sought to retrospectively analyze brain metastasis patients who have survived 2 years or more, and assess for what factors may predict for a final brain metastasis velocity (BMV) of zero. METHODS: This was a single-institution retrospective study of 300 patients treated with SRS from 2001 to 2019 for brain metastases who survived greater than 2 years after first SRS. Final BMV is calculated by summing all metastases through the observed time divided by the total time in years. A BMV of zero is defined as at least 2 years of imaging follow-up without distant brain failure (DBF). RESULTS: Median age at first SRS is 61 (IQR: 53, 70). Kaplan-Meier estimated median overall survival is 4.9 years and time to DBF is 1.5 years (95% CI 1.2, 2.0). Twenty-eight (9.3%) patients underwent subsequent WBRT. One hundred and one (33.7%) patients never had any further brain metastases (BMV = 0) at a median follow-up time of 3.3 years. Median BMV is 0.4 (IQR: 0, 1.4). Distant brain failures reach a plateau at 4 years where the cumulative incidence of DBF is 82%. 70% of first time DBFs have occurred by 2 years. Factors significantly associated with a BMV of zero include fewer brain metastases at first SRS (HR 1.1; p = 0.0004) and Caucasian race (HR 1.5; p = 0.03). CONCLUSION: Approximately one third of brain metastasis patients who live beyond 2 years after initial SRS have a BMV of zero. DBFs appear to reach a plateau at 4 years. Factors significantly associated with a BMV of zero include Caucasian race and having had a single brain metastasis at first SRS.

Upstage Rate of Complex Sclerosing Lesions/Radial Scars.

BACKGROUND: Radial scars (RS) and complex sclerosing lesions (CSL) are breast radiologic findings described as small, stellate lesions causing architectural distortion. This can mimic malignancy. Core needle biopsy (CNB) is often performed. Advances in breast imaging have led to increased detection of RS/CSL. The upstage rate of RS/CSL to in situ or invasive disease is 0-40%. We sought to determine the upstaging rate of RS/CSL to in situ, invasive disease, or high-risk lesion at our institution to create excision guidelines. METHODS: The pathology database of a single center was searched for RS/CSL, from January 2013 to September 2020. We included CNB without malignancy or high-risk lesion (eg, atypical ductal hyperplasia). Patient demographics, indications for biopsy, imaging findings, biopsy procedure, and final pathology were collected. RESULTS: Forty-four patients were included. 52.3% had CNB for architectural distortion on mammography, 18.2% for mass, 11.4% for calcifications, 2.3% for abnormal MRI, and 15.9% for multiple reasons (eg, calcifications and mass). Most had an ultrasound: 43.2% had no abnormality and 34.1% had a mass. All CNB were vacuum assisted, 65.9% with 9-gauge needle, and averaged 10.0 cores. 77.3% were stereotactic biopsies, 13.6% ultrasound, and 6.8% MRI. 59.1% had excision after CNB. 82.1% of patients did not upstage. One patient upstaged to invasive ductal carcinoma (3.6%) and two patients to high-risk lesion (7.1%). DISCUSSION: There was low upstage rate of RS/CSL on excisional biopsy. Centers could consider close surveillance for RS/CSL on CNB. Longer follow-up in cases of deferred excision is needed to ensure oncologic safety.

Research lessons during the COVID-19 pandemic: collecting longitudinal physical and mental health outcomes.

BACKGROUND: Participant enrolment, assessment and/or delivery of intervention in many clinical trials during the COVID-19 pandemic were severely impacted by public health measures limiting physical contact. This report describes the lessons learned in completing a repeated measures cohort study involving suspected and confirmed COVID-19 survivors at three sites in Perth, Western Australia. MAIN BODY: An observational analysis of the conduct and data completeness results of the LATER-19 trial. People with COVID19 symptoms who were tested between February and November 2020 were recruited. In both those who tested positive and those who tested negative (control group) for COVID19, data on physical function and mental health were collected at two time points up to eight months after COVID19 testing. Recruitment of the controls was targeted from hospital records for comparison, it was balanced for age and sex and for the non-hospitalised group also comorbidities. A sample of 344 participants was recruited: 155 (45.1%) COVID-19 positive. Taking the research design and environmental adaptations into account, we recorded > 90% participant engagement during the trial. Of the 637 planned assessments, objective measures were completed on 602 (94.5%) occasions; 543 (90.2%) were on-site and 59 (9.8%) were remote. A total of 577 (90.6%) mental health/symptoms surveys, 569 (89.3%) 1-min sit-to-stand tests, and 520 (81.6%) handgrip strength tests were completed. CONCLUSION: The sample size and high completion rate of planned assessments during the LATER-19 trial potentially increases the contextual, groupwise generalisability of the results. The results demonstrate the effectiveness of a simple, rapid, reproducible and adaptable battery of assessments, leveraging telehealth and digital solutions. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trial Registration (ANZCTR): ACTRN12621001067864 .

Evaluation of the Axillary Surgery Performed in Clinically Node-Positive Breast Cancer Patients Following Neoadjuvant Chemotherapy.

BACKGROUND: The American College of Surgeons Oncology Group Z1071 trial in 2013 demonstrated the fesability of sentinel lymph node biopsy in clinically node-positive patients following neoadjuvant chemotherapy. The goal of this study was to determine the continued impact of this study on our practice pattern. MATERIALS AND METHODS: This is a retrospective review of institutional changes in the management of axillary nodal disease following the publication of Z1071. Patients with clinically node-positive disease that completed neoadjuvant chemotherapy between 2014 and 2020 were included. The Cocoran-Armitage trend test was used to analyze change in categorical variables over time, and the Spearman's rank coefficient was used to analyze two-ranked variables. RESULTS: A cohort of 102 patients were included in the study and demonstrated that the number of sentinel lymph node biopsies to evaluate axillary disease increased over time. Additionally, the number of biopsies of suspicious nodes, and the use of marker clips on the biopsied nodes increased over time. CONCLUSION: Our institution has continued to incorporate the result from Z1071 in our practice patterns.

Metabolic Response of Triple-Negative Breast Cancer to Folate Restriction.

BACKGROUND: Triple-negative breast cancers (TNBCs), accounting for approximately 15% of breast cancers, lack targeted therapy. A hallmark of cancer is metabolic reprogramming, with one-carbon metabolism essential to many processes altered in tumor cells, including nucleotide biosynthesis and antioxidant defenses. We reported that folate deficiency via folic acid (FA) withdrawal in several TNBC cell lines results in heterogenous effects on cell growth, metabolic reprogramming, and mitochondrial impairment. To elucidate underlying drivers of TNBC sensitivity to folate stress, we characterized in vivo and in vitro responses to FA restriction in two TNBC models differing in metastatic potential and innate mitochondrial dysfunction. METHODS: Metastatic MDA-MB-231 cells (high mitochondrial dysfunction) and nonmetastatic M-Wnt cells (low mitochondrial dysfunction) were orthotopically injected into mice fed diets with either 2 ppm FA (control), 0 ppm FA, or 12 ppm FA (supplementation; in MDA-MB-231 only). Tumor growth, metabolomics, and metabolic gene expression were assessed. MDA-MB-231 and M-Wnt cells were also grown in media with 0 or 2.2 µM FA; metabolic alterations were assessed by extracellular flux analysis, flow cytometry, and qPCR. RESULTS: Relative to control, dietary FA restriction decreased MDA-MB-231 tumor weight and volume, while FA supplementation minimally increased MDA-MB-231 tumor weight. Metabolic studies in vivo and in vitro using MDA-MB-231 cells showed FA restriction remodeled one-carbon metabolism, nucleotide biosynthesis, and glucose metabolism. In contrast to findings in the MDA-MB-231 model, FA restriction in the M-Wnt model, relative to control, led to accelerated tumor growth, minimal metabolic changes, and modest mitochondrial dysfunction. Increased mitochondrial dysfunction in M-Wnt cells, induced via chloramphenicol, significantly enhanced responsiveness to the cytotoxic effects of FA restriction. CONCLUSIONS: Given the lack of targeted treatment options for TNBC, uncovering metabolic vulnerabilities that can be exploited as therapeutic targets is an important goal. Our findings suggest that a major driver of TNBC sensitivity to folate restriction is a high innate level of mitochondrial dysfunction, which can increase dependence on one-carbon metabolism. Thus, folate deprivation or antifolate therapy for TNBCs with metabolic inflexibility due to their elevated levels of mitochondrial dysfunction may represent a novel precision-medicine strategy.

Dietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer.

Cancer cells experience unique and dynamic shifts in their metabolic function in order to survive, proliferate, and evade growth inhibition in the resource-scarce tumor microenvironment. Therefore, identification of pharmacological agents with potential to reprogram cancer cell metabolism may improve clinical outcomes in cancer therapy. Cancer cells also often exhibit an increased dependence on the process known as autophagy, both for baseline survival and as a response to stressors such as chemotherapy or a decline in nutrient availability. There is evidence to suggest that this increased dependence on autophagy in cancer cells may be exploitable clinically by combining autophagy modulators with existing chemotherapies. In light of the increased metabolic rate in cancer cells, interest is growing in approaches aimed at "starving" cancer through dietary and pharmacologic interventions that reduce availability of nutrients and pro-growth hormonal signals known to promote cancer progression. Several dietary approaches, including chronic calorie restriction and multiple forms of fasting, have been investigated for their potential anti-cancer benefits, yielding promising results in animal models. Induction of autophagy in response to dietary energy restriction may underlie some of the observed benefit. However, while interventions based on dietary energy restriction have demonstrated safety in clinical trials, uncertainty remains regarding translation to humans as well as feasibility of achieving compliance due to the potential discomfort and weight loss that accompanies dietary restriction. Further induction of autophagy through dietary or pharmacologic metabolic reprogramming interventions may enhance the efficacy of autophagy inhibition in the context of adjuvant or neo-adjuvant chemotherapy. Nonetheless, it remains unclear whether therapeutic agents aimed at autophagy induction, autophagy inhibition, or both are a viable therapeutic strategy for improving cancer outcomes. This review discusses the literature available for the therapeutic potential of these approaches.

Wisdom in clinical reasoning and medical practice.

Exploring informal components of clinical reasoning, we argue that they need to be understood via the analysis of professional wisdom. Wise decisions are needed where action or insight is vital, but neither everyday nor expert knowledge provides solutions. Wisdom combines experiential, intellectual, ethical, emotional and practical capacities; we contend that it is also more strongly social than is usually appreciated. But many accounts of reasoning specifically rule out such features as irrational. Seeking to illuminate how wisdom operates, we therefore build on Aristotle's work on informal reasoning. His account of rhetorical communication shows how non-formal components can play active parts in reasoning, retaining, or even enhancing its reasonableness. We extend this account, applying it to forms of healthcare-related reasoning which are characterised by the need for wise decision-making. We then go on to explore some of what clinical wise reasoning may mean, concluding with a case taken from psychotherapeutic practice.

The practice of health care: wisdom as a model.

Reasoning and judgement in health care entail complex responses to problems whose demands typically derive from several areas of specialism at once. We argue that current evidence- or value-based models of health care reasoning, despite their virtues, are insufficient to account for responses to such problems exhaustively. At the same time, we offer reasons for contending that health professionals in fact engage in forms of reasoning of a kind described for millennia under the concept of wisdom. Wisdom traditions refer to forms of deliberation which combine knowledge, reflection and life experience with social, emotional and ethical capacities. Wisdom is key in dealing with problems which are vital to human affairs but lack prescribed solutions. Uncertainty and fluidity must be tolerated in seeking to resolve them. We illustrate the application of wisdom using cases in psychiatry, where non-technical aspects of problems are often prominent and require more systematic analysis than conventional approaches offer, but we argue that our thesis applies throughout the health care field. We argue for the relevance of a threefold model of reasoning to modern health care situations in which multifaceted teamwork and complex settings demand wise judgement. A model based on practical wisdom highlights a triadic process with features activating capacities of the self (professional), other (patient and/or carers and/or colleagues) and aspects of the problem itself. Such a framework could be used to develop current approaches to health care based on case review and experiential learning.

Infection and food: a factor in sudden infant death syndrome?

Despite the identification of risk factors for sudden infant death syndrome (SIDS) and decreased SIDS rates in many countries, there is still no coherent, widely accepted, mechanistic explanation for SIDS. As an extension of our work on the infectious aetiology of SIDS, we have explored the prediction that infectious agents might reach susceptible infants and babies, via particular sources of food. In this ecological study, we demonstrated significant correlations between SIDS rates and exposure to meat from some sources, and we propose that more detailed studies be carried out.