The Controversies of Coronary Artery Disease in End-Stage Kidney Disease Patients: A Narrative Review.

Cardiovascular disease (CVD) accounts for more than 50% of deaths among patients with end-stage kidney disease (ESKD). Approximately 40-50% of ESKD patients have clinically significant coronary artery disease (CAD) due to atherosclerosis which accounts for a significant proportion of CVD risk. However, other CVD pathologies including myocardial fibrosis, vascular calcification and arterial stiffening play important contributory roles. The pathophysiology of CAD in ESKD is distinct from the general population. ESKD patients is typically have diffuse multi-vessel involvement with increased calcification that involves both intimal and medial layers of the arterial wall. There is a complex interplay between an increased burden of traditional Framingham risk factors and exposure to non-traditional risk factors including chronic inflammation and dialysis per se. Established treatments for CAD risk factors including cholesterol lowering with statin therapy have attenuated effects and ESKD patients also have worse outcomes after revascularisation. Recent trials such as the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) have established that direct modulation of inflammation improves CVD outcomes in the general population, which may prove to be a potential attractive therapeutic target in ESKD patients. Multiple retrospective observational studies comparing mortality outcomes between haemodialysis (HD) and peritoneal dialysis (PD) patients have been inconclusive. Randomised trials on this issue of clinical equipoise are clearly warranted but are unlikely to be feasible. Screening for stable CAD in asymptomatic ESKD patients remains a clinical dilemma which is unique to chronic dialysis patients being assessed for kidney transplantation. This has become particularly relevant in light of the recent ISCHEMIA-CKD trial which demonstrated no difference between optimal medical therapy and revascularisation upon CVD outcomes or mortality. The optimal strategy for screening is currently being investigated in the ongoing large international multi-centre CARSK trial. Here we discuss the pathophysiology, risk modification, treatment, screening and future directions of CAD in ESKD.

ALK-Rearranged Non-Small Cell Lung Cancer in 2020: Real-World Triumphs in an Era of Multigeneration ALK-Inhibitor Sequencing Informed by Drug Resistance Profiling.

Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. KEY POINTS: This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative.

Interventional Mental Health: A Transdisciplinary Approach to Novel Psychiatric Care Delivery.

Mental health disorders are among the most common health conditions in the United States. Traditional clinical treatments rely on psychiatric counseling and, in many cases, prescription medications. We propose an innovative model, Interventional Mental Health, which employs a combination of modalities through a multifaceted approach to treat conditions that have exhibited limited responsiveness to traditional methods and individuals afflicted with multiple comorbidities simultaneously. We hypothesize that creating a unique treatment algorithm combining current therapeutic modalities such as Stellate Ganglion Blocks (SGB), Transcranial Magnetic Stimulation (TMS) therapy, and ketamine therapy, within a consolidated timeframe, will yield synergistic outcomes among patients presenting with comorbid post-traumatic stress disorder (PTSD), depression, and/or anxiety.

Molecular Biomarkers for Contemporary Therapies in Hormone Receptor-Positive Breast Cancer.

Systemic treatment of hormone receptor-positive (HR+) breast cancer is undergoing a renaissance, with a number of targeted therapies including CDK4/6, mTOR, and PI3K inhibitors now approved for use in combination with endocrine therapies. The increased use of targeted therapies has changed the natural history of HR+ breast cancers, with the emergence of new escape mechanisms leading to the inevitable progression of disease in patients with advanced cancers. The identification of new predictive and pharmacodynamic biomarkers to current standard-of-care therapies and discovery of new therapies is an evolving and urgent clinical challenge in this setting. While traditional, routinely measured biomarkers such as estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2) still represent the best prognostic and predictive biomarkers for HR+ breast cancer, a significant proportion of patients either do not respond to endocrine therapy or develop endocrine resistant disease. Genomic tests have emerged as a useful adjunct prognostication tool and guide the addition of chemotherapy to endocrine therapy. In the treatment-resistant setting, mutational profiling has been used to identify ESR1, PIK3CA, and AKT mutations as predictive molecular biomarkers to newer therapies. Additionally, pharmacodynamic biomarkers are being increasingly used and considered in the metastatic setting. In this review, we summarise the current state-of-the-art therapies; prognostic, predictive, and pharmacodynamic molecular biomarkers; and how these are impacted by emerging therapies for HR+ breast cancer.

Case Report: Paclitaxel-Induced Pneumonitis in Early Breast Cancer: A Single Institution Experience and Review.

Taxane-based chemotherapy regimens are in widespread use as standard of care treatment for patients with early breast cancer, though rarely its use can be complicated by taxane-induced pneumonitis (TIP). While breast cancer is the most diagnosed cancer in women worldwide, TIP remains under-described in this setting. Key questions relate to its incidence, diagnosis and management, potential predictive biomarkers, and the balance between this life-threatening toxicity and curatively intended treatment. At a single Australian institution, 6 cases of TIP are identified among 132 patients treated with a paclitaxel-containing regimen for early breast cancer (4.55%, 95% confidence interval 1.69-9.63%). This review first outlines the presentation, management, and outcomes for these cases, then answers these questions and proposes an approach to suspected TIP in patients with breast cancer.

Imaging true 3D endoscopic anatomy by incorporating magnetic tracking with optical coherence tomography: proof-of-principle for airways.

Endoscopic imaging using optical coherence tomography (OCT) has been demonstrated as clinically useful in the assessment of human airways. These airways have a complex 3D structure, bending, tapering and bifurcating. Previously published 3D OCT reconstructions have not accounted for changes in the orientation and trajectory of the endoscopic probe as it moves through the airway during imaging. We propose a novel endoscopic setup incorporating a magnetic tracking system that accounts for these changes, yielding reconstructions that reveal the true 3D nature of the imaged anatomy. We characterize the accuracy of the system, and present the first published magnetic tracker-assisted endoscopic OCT reconstructions using a phantom airway.

Clinical Trials Eligibility of Patients With Malignant Pleural Mesothelioma: Use of Novel Therapies and Outcomes.

INTRODUCTION: Studies of bevacizumab and pembrolizumab in the treatment of malignant pleural mesothelioma suggest anticancer efficacy; clinical trial populations are not reflective of real-world patients. We aimed to determine the proportion of real-world patients who would be eligible for trials, identify patients who participated in clinical trials, and examine treatment and outcome data. PATIENTS AND METHODS: Consecutive patients with unresectable malignant pleural mesothelioma seen at our center from January 2012 to July 2018 were assessed with regards to their eligibility for Mesothelioma Avastin Cisplatin Study (MAPS) and KEYNOTE-028 clinical trials. Prognostic information, treatment use, and overall survival (OS) data were also collected. RESULTS: A total of 133 patients were included: 50% and 37%, respectively, did not meet trial eligibility for MAPS or KEYNOTE-028, most commonly owing to age ≥75 (23%), Eastern Cooperative Oncology Group performance status of ≥2 (21%), concomitant medication (21%), or comorbidity (12%). MAPS eligibility did not correlate with use of bevacizumab (P = .30) or improved OS (P = .87). Eligibility for KEYNOTE-028 correlated with pembrolizumab use (P < .001), but not improved OS (P = .21). Patients who received an investigational anticancer therapy on any clinical trial had improved OS: 32.4 (95% CI, 23.9-40.9) months versus 20.5 (95% CI, 15.8-25.3) months (P = .01). CONCLUSION: Only ≤63% of our patients were eligible for these trials, highlighting the differences between real-world patients and the highly select trial population. Our patients who participated in clinical trials had superior OS, further emphasizing the selection bias in the trial population.

Pathological complete response in malignant pleural mesothelioma patients following induction chemotherapy: Predictive factors and outcomes.

A small proportion of patients with malignant pleural mesothelioma (MPM) achieve pathological complete response (CR) following treatment with current practice induction chemotherapy. Our analysis of 58 patients with MPM treated with platinum-based chemotherapy showed 4 patients (7%) attained pathological CR at subsequent extrapleural pneumonectomy (EPP). Patient and tumour factors such as age, gender, smoking habit, histological subtype, and clinical stage were not found to be associated with pathological CR. Patients with pathological CR had longer disease-free survival (29.2 vs. 13.8 months; p=0.08) and overall survival (76.4 vs. 23.4 months; p=0.06) but this did not reach statistical significance. Our study suggests that patients who achieve pathological CR after chemotherapy may have improved survival in MPM.

Loss of Navß4-Mediated Regulation of Sodium Currents in Adult Purkinje Neurons Disrupts Firing and Impairs Motor Coordination and Balance.

The resurgent component of voltage-gated Na+ (Nav) currents, INaR, has been suggested to provide the depolarizing drive for high-frequency firing and to be generated by voltage-dependent Nav channel block (at depolarized potentials) and unblock (at hyperpolarized potentials) by the accessory Navß4 subunit. To test these hypotheses, we examined the effects of the targeted deletion of Scn4b (Navß4) on INaR and on repetitive firing in cerebellar Purkinje neurons. We show here that Scn4b-/- animals have deficits in motor coordination and balance and that firing rates in Scn4b-/- Purkinje neurons are markedly attenuated. Acute, in vivo short hairpin RNA (shRNA)-mediated "knockdown" of Navß4 in adult Purkinje neurons also reduced spontaneous and evoked firing rates. Dynamic clamp-mediated addition of INaR partially rescued firing in Scn4b-/- Purkinje neurons. Voltage-clamp experiments revealed that INaR was reduced (by ∼50%), but not eliminated, in Scn4b-/- Purkinje neurons, revealing that additional mechanisms contribute to generation of INaR.