Implementation of Cholesterol-Lowering Therapy to Reduce Cardiovascular Risk in Persons Living with HIV.

The widespread availability of highly effective antiretroviral therapies has reduced mortality from opportunistic infections in persons living with HIV (PLHIV), resulting in an increase in atherosclerotic cardiovascular disease (ASCVD) and other chronic illnesses (Samji et al. 2013). Although there has been a decline in morbidity and mortality from ASCVD in the past several decades, contemporary studies continue to report higher rates of cardiovascular events (Rosenson et al. 2020). HIV has been identified as a risk enhancer for ASCVD by multiple professional guideline writing committees (Grundy Scott et al. 2019, Mach et al. 2020); however, the utilization of cholesterol-lowering therapies in PLHIV remains low (Rosenson et al. 2018). Moreover, the use of statin therapy in PLHIV is complicated by drug-drug interactions that may either elevate or lower the blood statin concentrations resulting in increased toxicity or reduced efficacy respectively. Other comorbidities commonly associated with HIV present other challenges for the use of cholesterol-lowering therapies. This review will summarize the data on lipoprotein-associated ASCVD risk in PLHIV and discuss the challenges with effective treatment. Finally, we present a clinical algorithm to optimize cardiovascular risk reduction in this high-risk population.

Coronary anatomy and comorbidities impact on elective PCI outcomes in left main and multivessel coronary artery disease.

INTRODUCTION: The effects of coronary anatomy, lesion complexity, and comorbidities on outcomes of elective percutaneous coronary intervention (PCI) in high-risk patients with left main (LM) and/or multivessel coronary artery disease (CAD) are not well studied, as these patients are typically underrepresented in the clinical trials. METHODS: This cohort study involved 33,568 consecutive elective PCI cases, excluding patients with prior coronary artery bypass graft, acute coronary syndrome within 24 hr of index PCI, or shock. All data were obtained from the New York State's PCI Reporting System from the calendar year 2015. In-hospital mortality was the primary outcome of study. Logistic regression models were built to calculate odds ratios (OR) with 95% confidence intervals (CI) for in-hospital mortality after adjustment for coronary anatomy and significant clinical comorbidities. RESULTS: In this cohort of elective PCI cases all cause in-hospital mortality was low (0.3%), with a clear mortality gradient according to the extent of CAD: 0.1% in 1 vessel disease, 0.4% in 2 vessel, 0.5% in 3 vessel disease, and 3.2% in patients with LM CAD (p < .001). Mortality was also significantly increased in patients with multiple comorbidities: 0.1% in patients with 1 comorbidity, 0.7% with 2, 2.5% with 3, and 7.4% with 4 or more studied comorbidities (p < .0001). When adjusted for coronary anatomy and lesion complexity, having any 4 or more comorbidities was associated with significantly increased odds of dying after elective PCI (OR 25.9, 95% CI 8.152-82.063, p < .0001). Furthermore, when compared to patients with 3-vessel CAD, and accounted for comorbidities, the patients with LM disease still had significantly increased (OR 5.254, 95% CI 3.104-8.891, p < .0001) odds of dying after elective PCI. CONCLUSIONS: In patients undergoing elective PCI, multivessel CAD and particularly LM disease are associated with significantly increased all-cause mortality. Furthermore, when adjusted for the extent of CAD and lesion complexity, comorbidity burden remains an important predictor of mortality.

SULT4A1 Protects Against Oxidative-Stress Induced Mitochondrial Dysfunction in Neuronal Cells.

Sulfotransferase 4A1 (SULT4A1), a member of cytosolic sulfotransferases (SULT), is exclusively expressed in neurons with no known function. Severe phenotype and early postnatal death in SULT4A1 knockout mice revealed that SULT4A1 is an essential neuronal protein. Localization of SULT4A1 in different cytosolic compartments, including mitochondria, suggests multiple roles for this protein. We observed that knockdown of SULT4A1 results in the accumulation of reactive oxygen species in primary cortical neurons, suggesting a potential role of SULT4A1 in regulating redox homeostasis. Expression of SULT4A1 in the human neuroblastoma SH-SY5Y cells revealed a defused but nonuniform staining pattern in the cytoplasm, with increased density around mitochondria. Subcellular fractionation of SULT4A1 expressing SH-SY5Y cells confirms the presence of SULT4A1 in mitochondrial fractions. SULT4A1 expressing cells display significant protection against H2O2-mediated defects in mitochondrial function and loss of mitochondrial membrane potential. Expression of SULT4A1 in SH-SY5Y cells also protects against H2O2-induced cell death. These data indicate that SULT4A1 protects mitochondria against oxidative damage and may serve as a potential pharmacological target in neural diseases involving mitochondrial dysfunction and oxidative stress. SIGNIFICANCE STATEMENT: Studies on SULT4A1 knockout mice suggest that SULT4A1 plays a vital role in neuronal function and survival via yet undefined mechanisms. Our data demonstrate that depletion of SULT4A1 induces oxidative stress in neurons and expression of SULT4A1 in SH-SY5Y cells protects against oxidative-stress-induced mitochondrial dysfunction and cell death. These results suggest that SULT4A1 may have a crucial protective function against mitochondrial dysfunction and oxidative stress, and may serve a potential therapeutic target in different neurological diseases involving mitochondrial dysfunction and oxidative stress.

Oral Anticoagulation for Atrial Fibrillation Thromboembolism Prophylaxis in the Chronic Kidney Disease Population: the State of the Art in 2019.

Atrial fibrillation (AF) is the most common cardiac rhythm disturbance and is associated with increased risk of thromboembolism. Oral anticoagulants are effective at reducing rates of thromboembolism in patients with AF in the general population. Patients with AF and concurrent chronic kidney disease (CKD) have higher risk of thromboembolism and bleeding compared with patients with normal renal function. Among moderate CKD and end-stage renal disease (ESRD) patients on chronic dialysis, the use of oral anticoagulants is controversial. Use of warfarin, while beneficial in non-CKD patients, raises a number of concerns such as increased bleeding risk, labile anticoagulant effect, and calciphylaxis, especially in the ESRD population. The newer direct oral anticoagulant (DOAC) agents have demonstrated comparable efficacy and improved safety profiles compared with coumadin but are not as well studied in the CKD population. This review highlights the efficacy and safety of coumadin and the DOACs for thromboembolism prophylaxis in non-valvular AF patients with CKD.

Incremental role of resting myocardial computed tomography perfusion for predicting physiologically significant coronary artery disease: A machine learning approach.

BACKGROUND: Evaluation of resting myocardial computed tomography perfusion (CTP) by coronary CT angiography (CCTA) might serve as a useful addition for determining coronary artery disease. We aimed to evaluate the incremental benefit of resting CTP over coronary stenosis for predicting ischemia using a computational algorithm trained by machine learning methods. METHODS: 252 patients underwent CCTA and invasive fractional flow reserve (FFR). CT stenosis was classified as 0%, 1-30%, 31-49%, 50-70%, and >70% maximal stenosis. Significant ischemia was defined as invasive FFR < 0.80. Resting CTP analysis was performed using a gradient boosting classifier for supervised machine learning. RESULTS: On a per-patient basis, accuracy, sensitivity, specificity, positive predictive, and negative predictive values according to resting CTP when added to CT stenosis (>70%) for predicting ischemia were 68.3%, 52.7%, 84.6%, 78.2%, and 63.0%, respectively. Compared with CT stenosis [area under the receiver operating characteristic curve (AUC): 0.68, 95% confidence interval (CI) 0.62-0.74], the addition of resting CTP appeared to improve discrimination (AUC: 0.75, 95% CI 0.69-0.81, P value .001) and reclassification (net reclassification improvement: 0.52, P value < .001) of ischemia. CONCLUSIONS: The addition of resting CTP analysis acquired from machine learning techniques may improve the predictive utility of significant ischemia over coronary stenosis.

Recent Insights into Pharmacologic Cardiovascular Risk Reduction in Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) affects nearly 30 million Americans and carries an increased risk of macrovascular complications of myocardial infarction, stroke, and cardiovascular death. While aggressive cardiovascular risk factor reduction has long been advocated in patients with diabetes, clinical trials have only recently demonstrated that such reductions result in improved outcomes. This review discusses recent evidence for risk reduction strategies and therapies with a focus on the management of glycemia, dyslipidemia, and hypertension. Although the degree to which aggressive glycated hemoglobin reduction decreases the risk of macrovascular outcomes remains unclear, the use of specific agents, such as the newer sodium glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists, may reduce cardiovascular events in patients with diabetes, irrespective of glycated hemoglobin reduction. Statins have been the mainstay of dyslipidemia management, with recent guidelines recommending statin use in all patients aged 40-75 years with diabetes. There is an emerging role for the recently developed proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in diabetes, as these agents further reduce serum cholesterol and clinical cardiovascular events beyond the maximum tolerated statin therapy. Lastly, most evidence suggests that aggressive blood pressure lowering in diabetic patients with hypertension reduces macrovascular events. Recent studies have re-affirmed a goal blood pressure of 140/90, and a lower pressure is likely prudent in most patients with diabetes. Specifically, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may reduce cardiovascular risk in patients with diabetes beyond their blood pressure-lowering effect. In conclusion, there is a growing literature which shows that the risk of cardiovascular outcomes can be reduced in most patients with diabetes, as outlined in this review.

Chelation Therapy as a Cardiovascular Therapeutic Strategy: the Rationale and the Data in Review.

Chelation therapy, typically used to remove heavy metal toxins, has also been controversially used as a treatment for coronary artery disease. The first Trial to Assess Chelation Therapy (TACT) aimed to provide evidence on chelation therapy's potential for benefit or harm. Although TACT had some significant results, the trial does not provide enough evidence to recommend routine chelation therapy and has limitations. The second TACT was recently funded reigniting a discussion about the value of chelation therapy, its efficacy, and allocation of research resources. Despite limited evidence, patients continue to pursue chelation therapy as a treatment for coronary artery disease. As the medical community has a responsibility to understand all treatments patients pursue, it is important to comprehensively appraise chelation therapy for cardiovascular disease. Understanding the background of heavy metal toxicity, the putative target of chelation therapy, on the cardiovascular system is important to contextualize the role of chelation therapy in cardiovascular disease prevention. We review the clinical evidence of heavy metal toxicity and cardiovascular disease, and available clinical trial data on use of chelation therapy to minimize the cardiovascular burden of heavy metal toxicity.

Spinal dural arteriovenous fistulas: a review.

Spinal dural arteriovenous fistulas (SDAVF) are a rare pathologic entity with a diverse and often misleading clinical presentation. While digital subtraction spinal angiography remains the gold standard, recent advances in noninvasive vascular imaging have improved the diagnosis of SDAVF. As this condition can result in permanent spinal cord injury, all patients require treatment, which consists of surgical or endovascular occlusion of the fistula. Failure to recognize and treat SDAVF in a timely fashion can result in irreversible neurologic disability, including myelopathy, lower extremity weakness and bowel, bladder and sexual dysfunction. This article reviews the clinical features, pathogenesis, radiographic features and current treatment strategies for these complex lesions.

Femoral nerve neuromonitoring for lateral lumbar interbody fusion surgery.

BACKGROUND CONTEXT: The transpsoas lateral lumbar interbody fusion (LLIF) technique is an effective alternative to traditional anterior and posterior approaches to the lumbar spine; however, nerve injuries are the most reported postoperative complication. Commonly used strategies to avoid nerve injury (eg, limiting retraction duration) have not been effective in detecting or preventing femoral nerve injuries. PURPOSE: To evaluate the efficacy of emerging intraoperative femoral nerve monitoring techniques and the importance of employing prompt surgical countermeasures when degraded femoral nerve function is detected. STUDY DESIGN/SETTING: We present the results from a retrospective analysis of a multi-center study conducted over the course of 3 years. PATIENT SAMPLE: One hundred and seventy-two lateral lumbar interbody fusion procedures were reviewed. OUTCOME MEASURES: Intraoperative femoral nerve monitoring data was correlated to immediate postoperative neurologic examinations. METHODS: Femoral nerve evoked potentials (FNEP) including saphenous nerve somatosensory evoked potentials (snSSEP) and motor evoked potentials with quadriceps recordings were used to detect evidence of degraded femoral nerve function during the time of surgical retraction. RESULTS: In 89% (n=153) of the surgeries, there were no surgeon alerts as the FNEP response amplitudes remained relatively unchanged throughout the surgery (negative group). The positive group included 11% of the cases (n=19) where the surgeon was alerted to a deterioration of the FNEP amplitudes during surgical retraction. Prompt surgical countermeasures to an FNEP alert included loosening, adjusting, or removing surgical retraction, and/or requesting an increase in blood pressure from the anesthesiologist. All the cases where prompt surgical countermeasures were employed resulted in recovery of the degraded FNEP amplitudes and no postoperative femoral nerve injuries. In two cases, the surgeons were given verbal alerts of degraded FNEPs but did not employ prompt surgical countermeasures. In both cases, the degraded FNEP amplitudes did not recover by the time of surgical closure, and both patients exhibited postoperative signs of sensorimotor femoral nerve injury including anterior thigh numbness and weakened knee extension. CONCLUSIONS: Multimodal femoral nerve monitoring can provide surgeons with a timely alert to hyperacute femoral nerve conduction failure, enabling prompt surgical countermeasures to be employed that can mitigate or avoid femoral nerve injury. Our data also suggests that the common strategy of limiting retraction duration may not be effective in preventing iatrogenic femoral nerve injuries.

Preferences and Attitudes of Cardiologists in Management of Patients with Cancer.

Background: With recent improvements in survival of cancer patients and common use of high-value care at end of life, the management of cardiovascular disease (CVD) in patients with cancer is increasingly important. To our knowledge, there are no current U.S. data examining how the presence and extent of cancer influence cardiologists' decision making for common cardiovascular conditions. Methods: An anonymous online vignette-based survey of cardiologists was conducted at five U.S. institutions investigating how the extent of gastrointestinal and thoracic malignancies (prior/localized, metastatic) would influence treatment recommendations for atrial fibrillation (AF), aortic stenosis, unstable angina (UA), and obstructive coronary artery disease (CAD). Results: Thirty-three percent (86/259) of cardiologists completed the survey between September and November 2019. Participants were 67% male, 51% below age 40, and 58% had five or more years of clinical experience. Majority of cardiologists practiced at teaching hospitals (72%) and were noninterventional (63%). Cardiologists were more likely to recommend procedural interventions for patients with localized cancer than for those with metastatic disease: AF (left atrial appendage occlusion: 20% vs. 8%), atrial stenosis (aortic valve repair: 83% vs. 11%), UA (left heart catheter: 70% vs. 27%), and obstructive CAD (percutaneous coronary intervention: 81% vs. 38%). In patients with metastatic cancer, most cardiologists sought an oncology (82%) or a palliative care (69%) consultation. However, a persistent trend of undertreatment in patients with localized cancers and overtreatment in patients with end-of-life disease was apparent. Conclusions: Cardiologists were less likely to recommend invasive cardiovascular therapies to patients with metastatic cancer. This preference pattern likely reflects the influence of comorbidities and quality of life expectation on cardiologists' treatment recommendations but may also be related to the stigma of advanced cancer. Better communication between cardiologists and oncologists is necessary to provide a personalized care of patients with cancer and CVD that would maximize treatment benefit with least morbidity.

Neurosurgery for brain tumors: update on recent technical advances.

Advances in diagnostic imaging modalities and improved access to specialty care have led directly to an increased diagnosis of both metastatic and primary brain tumors. As technology has improved, so has the ability to treat this larger patient population. Diffusion tensor imaging (DTI) has recently shown the potential to aid in histologic diagnosis as well as to identify local brain invasion outside of that readily identifiable by conventional MRI. Similar to DTI, functional MRI provides a noninvasive means of delineating tumor margin from eloquent cortex and aids in preoperative surgical planning. As the literature shows increasing support for the advantages of extensive resection in glioma patients, modalities that aid in this regard are displaying increased importance. Surgeons have recently demonstrated the utility of intraoperative MRI in increasing extent of resection in both low- and high-grade glioma patients. Intraoperative tumor fluorescence provided by the chemical compound 5-aminolevulinic acid assists surgeons in identifying the true tumor margin during resection of glial neoplasms consequently increasing extent of resection. Finally, laser interstitial thermal therapy is an emerging treatment modality allowing surgeons to treat small intracranial lesions with potentially decreased morbidity via this minimally invasive approach. The following review analyzes the recent literature in an effort to describe how these modalities can and should be used in the treatment of patients with intracranial pathology.

Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: long-term outcomes and predictors of response.

OBJECTIVE: The goal of this study was to assess the efficacy and safety of vagus nerve stimulation in a consecutive series of adults and children with treatment-resistant epilepsy (TRE). METHODS: In this retrospective review of a prospectively created database of 436 consecutive patients who underwent vagus nerve stimulator implantation for TRE between November 1997 and April 2008, there were 220 (50.5%) females and 216 (49.5%) males ranging in age from 1 to 76 years at the time of implantation (mean: 29.0 ± 16.5). Thirty-three patients (7.6%) in the primary implantation group had inadequate follow-up (<3 months from implantation) and three patients had early device removal because of infection and were excluded from seizure control outcome analyses. RESULTS: Duration of vagus nerve stimulation treatment varied from 10 days to 11 years (mean: 4.94 years). Mean seizure frequency significantly improved following implantation (mean reduction: 55.8%, P<0.0001). Seizure control ≥ 90% was achieved in 90 patients (22.5%), ≥ 75% seizure control in 162 patients (40.5%), ≥ 50% improvement in 255 patients (63.75%), and <50% improvement in 145 patients (36.25%). Permanent injury to the vagus nerve occurred in 2.8% of patients. CONCLUSION: Vagus nerve stimulation is a safe and effective palliative treatment option for focal and generalized TRE in adults and children. When used in conjunction with a multidisciplinary and multimodality treatment regimen including aggressive antiepileptic drug regimens and epilepsy surgery when appropriate, more than 60% of patients with TRE experienced at least a 50% reduction in seizure burden. Good results were seen in patients with non-U.S. Food and Drug Administration-approved indications. Prospective, randomized trials are needed for patients with generalized epilepsies and for younger children to potentially expand the number of patients who may benefit from this palliative treatment.

PARP-1 activation leads to cytosolic accumulation of TDP-43 in neurons.

Oxidative stress in neurodegenerative disease leads to poly(ADP-ribose) polymerase 1 (PARP-1) overactivation and subsequent cell death via excessive generation of Poly(ADP-ribose) polymer (PAR). PAR binds to neurodegenerative disease linked protein TAR DNA binding protein of 43 kDa (TDP-43). However, the consequence of this interaction is not yet fully understood. TDP-43 translocates from the nucleus to the cytoplasm in response to oxidative stress, but the mechanism of stress-induced translocation remains unknown. We used N-methyl-N-nitroso-N'-nitroguanidine (MNNG) and oxygen-glucose deprivation (OGD) in mouse neuronal cultures to activate PARP-1 and observed that pharmacological inhibition of PARP-1 blocked the cytosolic translocation of TDP-43. PARP-1 inhibition is also neuroprotective against both MNNG and OGD, suggesting that PARP inhibitors could play a role in the neuroprotective role in neurodegenerative diseases involving TDP-43. Together, these data present the novel finding that TDP-43 translocation depends on PARP-1 activation and set a ground for future research of how PARP-1 activation or PAR binding to TDP-43 may facilitate its cytosolic accumulation.

Sex Differences Remain Under-Reported in Cardiovascular Publications.

Background: For the past two decades, there has been increased interest from medical journals and calls to action from various organizations such as the National Institutes of Health to study sex differences in cardiovascular (CV) disease. It is unknown whether this emphasis has translated to a growth in publications addressing sex differences in CV disease. Materials and Methods: We performed a bibliometric analysis of all CV publications from 2006 to 2015. The National Library of Medicine's PubMed database was searched for articles containing the phrases "cardiac," "cardiovascular" or "cardiology," in the first author affiliation field. This was followed by a subsequent search for publications containing any of the following phrases in the title and/or abstract: "woman," "women," "female," "females," "gender," or "sex." The presence of such terms defined the publication as sex-specific. Trends over time were analyzed for specified subgroups, including publication category and funding source. Results: A total of 189,543 CV publications were identified, out of which there were 24,615 (12.99%) sex-specific publications. For the 10-year period, there were no significant changes in the relative proportion of sex-specific publications. When specific publication categories were analyzed, there were significant proportional increase of sex-specific publications in general articles category, but not for reviews, clinical trials, meta-analysis, or letters. Conclusion: Despite calls for greater attention, only a small fraction of publications for the past decade have reported on sex differences. There was no significant proportional growth of sex-specific publications for a recent 10-year period, except for the general research articles.

Restoration of CTSD (cathepsin D) and lysosomal function in stroke is neuroprotective.

Stroke is a leading cause of death and disability. The pathophysiological mechanisms associated with stroke are very complex and not fully understood. Lysosomal function has a vital physiological function in the maintenance of cellular homeostasis. In neurons, CTSD (cathepsin D) is an essential protease involved in the regulation of proteolytic activity of the lysosomes. Loss of CTSD leads to lysosomal dysfunction and accumulation of different cellular proteins implicated in neurodegenerative diseases. In cerebral ischemia, the role of CTSD and lysosomal function is not clearly defined. We used oxygen-glucose deprivation (OGD) in mouse cortical neurons and the middle cerebral artery occlusion (MCAO) model of stroke to assess the role of CTSD in stroke pathophysiology. Our results show a time-dependent decrease in CTSD protein levels and activity in the mouse brain after stroke and neurons following OGD, with concurrent defects in lysosomal function. We found that shRNA-mediated knockdown of CTSD in neurons is sufficient to cause lysosomal dysfunction. CTSD knockdown further aggravates lysosomal dysfunction and cell death in OGD-exposed neurons. Restoration of CTSD protein levels via lentiviral transduction increases CTSD activity in neurons and, thus, renders resistance to OGD-mediated defects in lysosomal function and cell death. This study indicates that CTSD-dependent lysosomal function is critical for maintaining neuronal survival in cerebral ischemia; thus, strategies focused on maintaining CTSD function in neurons are potentially novel therapeutic approaches to prevent neuronal death in stroke.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; CQ: chloroquine; CTSB: cathepsin B; CTSD: cathepsin D; CTSL: cathepsin L; FTD: frontotemporal dementia, HD: Huntington disease; LAMP1: lysosomal associated membrane protein 1; LSD: lysosomal storage disease; MCAO: middle cerebral artery occlusion; OGD: oxygen glucose deprivation; OGR: oxygen glucose resupply; PD: Parkinson disease; SQSMT1: sequestosome 1; TCA: trichloroacetic acid; TTC: triphenyl tetrazolium chloride.

Pre-hospital ECG for acute coronary syndrome in urban India: a cost-effectiveness analysis.

BACKGROUND: Patients with acute coronary syndrome (ACS) in India have increased pre-hospital delay and low rates of thrombolytic reperfusion. Use of ECG could reduce pre-hospital delay among patients who first present to a general practitioner (GP). We assessed whether performing ECG on patients with acute chest pain would improve long-term outcomes and be cost-effective. METHODS: We created a Markov model of urban Indian patients presenting to a GP with acute chest pain to compare a GP's performing an ECG versus not performing one. Variables describing the accuracy of a GP's referral decision in chest pain and ACS, ACS treatment patterns, the effectiveness of thrombolytic reperfusion, and costs were derived from Indian data where available and other developed world studies. The model was used to estimate the incremental cost-effectiveness ratio (ICER) of the intervention in 2007 US dollars per quality adjusted life years (QALY) gained. RESULTS: Under baseline assumptions, the ECG strategy cost an additional $12.65 per QALY gained compared to no ECG. Sensitivity analyses around the cost of the ECG, cost of thrombolytic, and referral accuracy of the GP yielded ICERs for the ECG strategy ranging between cost-saving and $1124/QALY. All results indicated the intervention is cost-effective under current World Health Organization recommendations. CONCLUSIONS: While direct presentation to the hospital with acute chest pain is preferable, in urban Indian patients presenting first to a GP, an ECG performed by the GP is a cost-effective strategy to reduce disability and mortality. This strategy should be clinically studied and considered until improved emergency transport services are available.

Preclinical and Dose-Finding Phase I Trial Results of Combined Treatment with a TORC1/2 Inhibitor (TAK-228) and Aurora A Kinase Inhibitor (Alisertib) in Solid Tumors.

PURPOSE: The purpose of this study was to evaluate the rational combination of TORC1/2 inhibitor TAK-228 and Aurora A kinase inhibitor alisertib in preclinical models of triple-negative breast cancer (TNBC) and to conduct a phase I dose escalation trial in patients with advanced solid tumors. EXPERIMENTAL DESIGN: TNBC cell lines and patient-derived xenograft (PDX) models were treated with alisertib, TAK-228, or the combination and evaluated for changes in proliferation, cell cycle, mTOR pathway modulation, and terminal cellular fate, including apoptosis and senescence. A phase I clinical trial was conducted in patients with advanced solid tumors treated with escalating doses of alisertib and TAK-228 using a 3+3 design to determine the maximum tolerated dose (MTD). RESULTS: The combination of TAK-228 and alisertib resulted in decreased proliferation and cell-cycle arrest in TNBC cell lines. Treatment of TNBC PDX models resulted in significant tumor growth inhibition and increased apoptosis with the combination. In the phase I dose escalation study, 18 patients with refractory solid tumors were enrolled. The MTD was alisertib 30 mg b.i.d. days 1 to 7 of a 21-day cycle and TAK-228 2 mg daily, continuous dosing. The most common treatment-related adverse events were neutropenia, fatigue, nausea, rash, mucositis, and alopecia. CONCLUSIONS: The addition of TAK-228 to alisertib potentiates the antitumor activity of alisertib in vivo, resulting in increased cell death and apoptosis. The combination is tolerable in patients with advanced solid tumors and should be evaluated further in expansion cohorts with additional pharmacodynamic assessment.

Cryptococcal meningitis initially presenting with ST elevations and elevated cardiac biomarkers.

Acute neurological events are a common cause of ECG abnormalities and transient elevations in cardiac biomarkers. This case describes an uncommon presentation of cryptococcal meningitis in a non-immunosuppressed patient, presenting with altered sensorium and derangements in cardiac profile. Delay in diagnosing meningitis was avoided by paying close attention to the patient's presenting symptoms and by pursuing non-cardiac causes of ECG changes and elevations in cardiac troponin. Expeditious treatment and involvement of the infectious disease consultant resulted in excellent clinical response without permanent neurological sequelae.