Identifying genes associated with disease outcomes using joint sparse canonical correlation analysis-An application in renal clear cell carcinoma.

Somatic changes like copy number aberrations (CNAs) and epigenetic alterations like methylation have pivotal effects on disease outcomes and prognosis in cancer, by regulating gene expressions, that drive critical biological processes. To identify potential biomarkers and molecular targets and understand how they impact disease outcomes, it is important to identify key groups of CNAs, the associated methylation, and the gene expressions they impact, through a joint integrative analysis. Here, we propose a novel analysis pipeline, the joint sparse canonical correlation analysis (jsCCA), an extension of sCCA, to effectively identify an ensemble of CNAs, methylation sites and gene (expression) components in the context of disease endpoints, especially tumor characteristics. Our approach detects potentially orthogonal gene components that are highly correlated with sets of methylation sites which in turn are correlated with sets of CNA sites. It then identifies the genes within these components that are associated with the outcome. Further, we aggregate the effect of each gene expression set on tumor stage by constructing "gene component scores" and test its interaction with traditional risk factors. Analyzing clinical and genomic data on 515 renal clear cell carcinoma (ccRCC) patients from the TCGA-KIRC, we found eight gene components to be associated with methylation sites, regulated by groups of proximally located CNA sites. Association analysis with tumor stage at diagnosis identified a novel association of expression of ASAH1 gene trans-regulated by methylation of several genes including SIX5 and by CNAs in the 10q25 region including TCF7L2. Further analysis to quantify the overall effect of gene sets on tumor stage, revealed that two of the eight gene components have significant interaction with smoking in relation to tumor stage. These gene components represent distinct biological functions including immune function, inflammatory responses, and hypoxia-regulated pathways. Our findings suggest that jsCCA analysis can identify interpretable and important genes, regulatory structures, and clinically consequential pathways. Such methods are warranted for comprehensive analysis of multimodal data especially in cancer genomics.

A phase I dose-escalation study of pulsatile afatinib in patients with recurrent or progressive brain cancer.

Background: Afatinib (BIBW2992; Gilotrif®) is a selective and irreversible inhibitor of the epidermal growth factor receptor (ErbB; EGFR) family. It inhibits EGFR, HER2, and HER4 phosphorylation, resulting in tumor growth inhibition and regression. This phase I dose-escalation trial of pulsatile afatinib examined the safety, drug penetration into the central nervous system, preliminary antitumor activity, and recommended phase II dose in patients with progressive or recurrent brain cancers. Methods: Afatinib was taken orally once every 4 days or once every 7 days depending on dose cohort, until disease progression or unacceptable toxicity. Results: A total of 24 patients received the investigational agent and were evaluable for safety analyses, and 21 patients were evaluable for efficacy. Dosing was administered at 80 mg every 4 days, 120 mg every 4 days, 180 mg every 4 days, or 280 mg every 7 days. A recommended phase II dose of pulsatile afatinib was established at 280 mg every 7 days as there were no dose-limiting toxicities in any of the dosing cohorts and all toxicities were deemed manageable. The most common drug-related toxicities were diarrhea, rash, nausea, vomiting, fatigue, stomatitis, pruritus, and limb edema. Out of the 21 patients evaluable for efficacy, 2 patients (9.5%) exhibited partial response based on Response Assessment in Neuro-Oncology criteria and disease stabilization was seen in 3 patients (14.3%). Conclusions: Afatinib taken orally was safe and well-tolerated up to 280 mg every 7 days in brain cancer patients.

Association of Inflammatory Markers With Disease Progression and the Severity of COVID-19.

Introduction In December 2019, there was a massive outbreak of viral pneumonia, which had a high case fatality rate. Genetic sequencing of the virus showed similarity with severe acute respiratory syndrome coronavirus (SARS-CoV). It was later named novel coronavirus 2019 while the disease it caused was given the nomenclature of COVID-19. This deadly pneumonia outbreak was declared a pandemic by the World Health Organization (WHO). Aim To derive the strength of the correlation between blood levels of various inflammatory markers with the severity of COVID-19 pneumonia in patients affected with novel coronavirus 2019. Materials and methodology A prospective study was conducted on 300 confirmed cases of COVID-19 infection from August 2020 to July 2021 in SSG Hospital, Vadodara. Diagnosis of patients as confirmed cases of COVID-19 infection was done according to the WHO interim guidance for COVID-19. Their inflammatory markers were done for this study. All COVID-19-positive patients who had given negative consent for enrollment were excluded from the study. Patients were classified based on the severity of acute respiratory distress syndrome (ARDS). Comprehensive medical record information, encompassing biodata, clinical symptoms, comorbidities, and laboratory investigations, was systematically collected. Patients were given the standard treatment protocol as per guidelines. Patients were subjected to detailed investigations comprising complete blood counts and inflammatory markers like C-reactive protein (CRP), lactate dehydrogenase (LDH), serum ferritin, and D-dimer. Patients were further investigated by chest X-ray (posteroanterior view) or high-resolution computed tomography of the thorax. Results A total of 300 confirmed cases of COVID-19 infection were included in this study. Most of them were males (52%) with a mean age of 51 years and 48% were females with a mean age of 55 years. The majority of patients (40%) did not have ARDS, 23.3% of patients had mild, 16.7% of patients had moderate, and 20% of patients had severe ARDS. Higher CRP levels, serum ferritin, and serum D-dimer were significantly associated with the severity of COVID-19 infection as compared to those having no symptoms (p < 0.05). Increased levels were associated with severe clinical manifestations of COVID-19. The sensitivity of CRP is 69% and specificity is 100% as a diagnostic marker for COVID-19 pneumonia in terms of ARDS. The sensitivity of ferritin is 88% and specificity is 81% as a diagnostic marker for COVID-19 pneumonia in terms of ARDS. The sensitivity of D-dimer is 94% and specificity is 89% as a diagnostic marker for COVID-19 pneumonia in terms of ARDS. The sensitivity of LDH is 93% and specificity is 84% as a diagnostic marker for COVID-19 pneumonia in terms of ARDS. Conclusions Current evidence from our study showed that higher levels of inflammatory markers such as CRP, LDH, D-dimer, and ferritin are associated with the severity of COVID-19 in terms of ARDS and thus could be used as significant prognostic factors of the disease. These indicators might support clinical decisions to identify high fatality cases and poor diagnosis in the initial admission phase.

Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma.

PURPOSE: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. PATIENTS AND METHODS: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. RESULTS: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.

The menopausal transition period and cardiovascular risk.

The menopausal transition period spans, on average, 2-8 years before the final menstrual period and is associated with an increase in clinical and subclinical cardiovascular risk. In this Review, we discuss the metabolic and cardiovascular changes that occur during the menopausal transition period and the role of ovarian ageing, chronological ageing and other ageing-related risk factors in mediating these changes. Disentangling the relative contributions of chronological and reproductive ageing to cardiovascular risk is challenging, but data from longitudinal studies in women transitioning from premenopause to post-menopause have provided valuable insights. We also discuss evidence on how cardiovascular risk is altered by premature or early menopause, surgical menopause, and vasomotor and other menopausal symptoms. Whether targeted interventions can slow the progression of atherosclerosis and subclinical disease during the menopausal transition, thus delaying or preventing the onset of cardiovascular events, remains to be determined. Furthermore, we consider the recommended strategies for cardiovascular risk reduction in women undergoing menopausal transition using the framework of the American Heart Association's Life's Essential 8 key measures for improving and maintaining cardiovascular health, and discuss the cardiovascular risks and benefits of menopausal hormone therapy. Finally, we also discuss novel therapies that might benefit this population in reducing cardiovascular risk.

Response to OKN-007 and NAC in a Patient with Unilateral Hearing Loss and Chronic Tinnitus from Vestibular Schwannoma.

BACKGROUND: Tinnitus is the perception of sound in the absence of external acoustic stimulation. Being one of the most common diseases of the ear, it has a global prevalence ranging from 4.1 to 37.2%. To date, it has been difficult to treat tinnitus as its pathophysiology is poorly understood and there are limited treatment options. OBJECTIVE: To investigate the effect of OKN-007 (also known as HPN-07), a nitrone-based investigational drug, in combination with oral N-acetylcycsteine (NAC), for the treatment of hearing loss and chronic tinnitus under an individual expanded access protocol. PATIENT CASE: We report the case of a patient who presented with left-sided ear fullness, mild tinnitus, and mild high frequency sensorineural hearing loss with 100% word recognition. A large enhancing mass seen on MRI revealed a vestibular schwannoma. He underwent subtotal resection of the tumor resulting in a moderate-to-profound sensorineural hearing loss and catastrophic tinnitus. The patient was treated with intravenous OKN-007 at 60 mg/kg dosed three times per week and oral NAC 2500 mg twice daily. RESULTS: Post-treatment audiometric testing revealed an average of 16.66 dB in hearing threshold improvement in three frequencies (125, 250 and 500 Hz) with residual hearing in the affected left ear. His tinnitus loudness matching improved from 90 dB to 19 dB post-treatment. His Tinnitus Handicap Inventory improved from 86/100 (Catastrophic) to 40/100 (Moderate). He also experienced improvements in sleep, concentration, hearing, and emotional well-being, and reported significantly decreased levels of tinnitusrelated distress. CONCLUSIONS: This case report highlights the feasibility and therapeutic potential of the combination of OKN-007 and NAC in treating hearing loss and tinnitus that warrants further investigation.

Regulation of oxytocin-induced calcium transients and gene expression in engineered myometrial tissues by tissue architecture and matrix rigidity.

The uterus is susceptible to benign tumors known as fibroids, which have been associated with many pregnancy complications, including preterm labor. However, the impact of fibrotic tissue remodeling on the physiology of the myometrium, the smooth muscle layer of the uterus, is poorly understood, in large part due to a lack of model systems. In this study, we engineered healthy-like and fibrotic-like myometrium by culturing human myometrial smooth muscle cells on polyacrylamide hydrogels micropatterned with fibronectin to independently tune matrix rigidity and tissue alignment, respectively. We then evaluated calcium transients in response to oxytocin stimulation. Isotropic myometrial tissues on stiff substrates (representing fibrotic myometrium) had shorter calcium transients due to shorter decay time compared to aligned myometrial tissues on soft substrates (representing healthy myometrium). Calcium transients in aligned tissues had longer response times and longer decay times than isotropic tissues, irrespective of substrate stiffness. The amplitude of calcium transients was also higher on soft substrates compared to stiff substrates, irrespective of tissue alignment. We also performed RNA sequencing to detect differentially expressed genes between healthy- and fibrotic-like tissues, which revealed that a bitter taste receptor shown to induce smooth muscle relaxation, TAS2R31, was down-regulated in fibrotic-like tissues. Finally, we measured oxytocin-induced calcium transients in response to pre-treatment with progesterone, caffeine, thrombin, and nifedipine to demonstrate applications for our model system in drug screening. Both progesterone and caffeine caused a decrease in calcium transient duration, as expected, while thrombin and nifedipine had less impact. Collectively, our engineered model of the myometrium enables new insights into myometrial mechanobiology and can be extended to identify or screen novel drug targets.

Experiences and lessons learned from community-engaged recruitment for the South Asian breast cancer study in New Jersey during the COVID-19 pandemic.

BACKGROUND: South Asians are a rapidly growing population in the United States. Breast cancer is a major concern among South Asian American women, who are an understudied population. We established the South Asian Breast Cancer (SABCa) study in New Jersey during early 2020 to gain insights into their breast cancer-related health attitudes. Shortly after we started planning for the study, the COVID-19 disease spread throughout the world. In this paper, we describe our experiences and lessons learned from recruiting study participants by partnering with New Jersey's community organizations during the COVID-19 pandemic. METHODS: We used a cross-sectional design. We contacted 12 community organizations and 7 (58%) disseminated our study information. However, these organizations became considerably busy with pandemic-related needs. Therefore, we had to pivot to alternative recruitment strategies through community radio, Rutgers Cancer Institute of New Jersey's Community Outreach and Engagement Program, and Rutgers Cooperative Extension's community health programs. We recruited participants through these alternative strategies, obtained written informed consent, and collected demographic information using a structured survey. RESULTS: Twenty five women expressed interest in the study, of which 22 (88%) participated. Nine (41%) participants learned about the study through the radio, 5 (23%) through these participants, 1 (4.5%) through a non-radio community organization, and 7 (32%) through community health programs. Two (9%) participants heard about the study from their spouse. All participants were born outside the US, their average age was 52.4 years (range: 39-72 years), and they have lived in the US for an average of 26 years (range: 5-51 years). CONCLUSION: Pivoting to alternative strategies were crucial for successful recruitment. Findings suggest the significant potential of broadcast media for community-based recruitment. Family dynamics and the community's trust in our partners also encouraged participation. Such strategies must be considered when working with understudied populations.

Advancing Social and Environmental Research in Cancer Registries Using Geomasking for Address-Level Data.

Understanding the social and environmental causes of cancer in the United States, particularly in marginalized communities, is a major research priority. Population-based cancer registries are essential for advancing this research, given their nearly complete capture of incident cases within their catchment areas. Most registries limit the release of address-level geocodes linked to cancer outcomes to comply with state health departmental regulations. These policies ensure patient privacy, uphold data confidentiality, and enhance trust in research. However, these restrictions also limit the conduct of high-quality epidemiologic studies on social and environmental factors that may contribute to cancer burden. Geomasking refers to computational algorithms that distort locational data to attain a balance between effectively "masking" the original address location while faithfully maintaining the spatial structure in the data. We propose that the systematic deployment of scalable geomasking algorithms could accelerate research on social and environmental contributions across the cancer continuum by reducing measurement error bias while also protecting privacy. We encourage multidisciplinary teams of registry officials, geospatial analysts, cancer researchers, and others engaged in this form of research to evaluate and apply geomasking procedures based on feasibility of implementation, accuracy, and privacy protection to accelerate population-based research on social and environmental causes of cancer.

Long-term survival after salvage pemetrexed for refractory primary T-cell lymphoma of the CNS.

Primary T-cell CNS lymphoma is a rare and aggressive malignancy. High-dose methotrexate (MTX) based chemotherapy regimens are used as standard first-line treatment, followed by consolidative strategies to improve the duration of response. Although MTX-based therapy has been shown to be efficacious, treatment options for MTX-refractory disease are not well-defined. Here, we report a case of a 38-year-old man with refractory primary T-cell CNS lymphoma who demonstrated a complete response to pemetrexed treatment. He subsequently received conditioning chemotherapy consisting of thiotepa, busulfan and cyclophosphamide followed by autologous stem cell transplantation. The patient continues to remain recurrence-free to date at 9 years post-treatment.

Activity of pemetrexed in pre-clinical chordoma models and humans.

Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042).

Sociodemographic disparities in targeted therapy in ovarian cancer in a national sample.

Background: The treatment landscape for ovarian cancer has changed in recent years with the introduction of targeted therapies to treat patients with advanced disease. We investigated patient demographic and clinical factors associated with use of targeted therapies as a part of the first-line treatment for ovarian cancer. Methods: This study included patients diagnosed with stage I-IV ovarian cancer between 2012 and 2019 from the National Cancer Database. Information on demographic and clinical characteristics were collected and described using frequency and percent across receipt of targeted therapy. Logistic regression was used to compute the odds ratios (ORs) and 95% confidence intervals (CI) associating patient demographic and clinical factors with receipt of targeted therapy. Results: Among 99,286 ovarian cancer patients (mean age 62 years), 4.1% received targeted therapy. The rate of targeted therapy receipt across racial and ethnic groups over the study period was fairly similar; however, non-Hispanic Black women were less likely to receive targeted therapy than their non-Hispanic White counterparts (OR=0.87, 95% CI: 0.76-1.00). Patients who received neoadjuvant chemotherapy were more likely to receive targeted therapy than those who received adjuvant chemotherapy (OR=1.26; 95% CI: 1.15-1.38). Moreover, among patients who received targeted therapy, 28% received neoadjuvant targeted therapy, with non-Hispanic Black women being most likely to receive neoadjuvant targeted therapy (34%) compared with other racial and ethnic groups. Conclusions: We observed differences in receipt of targeted therapy by factors such as age at diagnosis, stage, and comorbidities present at diagnosis, as well as factors related to healthcare access-including neighborhood education level and health insurance status. Approximately 28% of patients received targeted therapy in the neoadjuvant setting, which could negatively impact treatment outcomes and survival due to the increased risk of complications associated with targeted therapies that may delay or prevent surgery. These results warrant further evaluation in a cohort of patients with more comprehensive treatment information.

Management of Menopausal Symptoms: A Review.

Importance: Menopause, due to loss of ovarian follicular activity without another pathological or physiological cause, typically occurs between the ages of 45 years and 56 years. During the menopausal transition, approximately 50% to 75% of women have hot flashes, night sweats, or both (vasomotor symptoms) and more than 50% have genitourinary symptoms (genitourinary syndrome of menopause [GSM]). Observations: Vasomotor symptoms typically last more than 7 years and GSM is often chronic. Efficacious treatments for women with bothersome vasomotor symptoms or GSM symptoms include hormonal and nonhormonal options. Systemic estrogen alone or combined with a progestogen reduces the frequency of vasomotor symptoms by approximately 75%. Oral and transdermal estrogen have similar efficacy. Conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) were the only hormonal treatments for which clinical trials were designed to examine cardiovascular events, venous thromboembolism, and breast cancer risk. Compared with placebo, the increased risk of stroke and venous thromboembolism associated with CEE (with or without MPA) and breast cancer (with use of CEE plus MPA) is approximately 1 excess event/1000 person-years. Low-dose CEE plus bazedoxifene is not associated with increased risk of breast cancer (0.25%/year vs 0.23%/year with placebo). Bioidentical estrogens approved by the US Food and Drug Administration (with identical chemical structure to naturally produced estrogens, and often administered transdermally) also are available to treat vasomotor symptoms. For women who are not candidates for hormonal treatments, nonhormonal approaches such as citalopram, desvenlafaxine, escitalopram, gabapentin, paroxetine, and venlafaxine are available and are associated with a reduction in frequency of vasomotor symptoms by approximately 40% to 65%. Low-dose vaginal estrogen is associated with subjective improvement in GSM symptom severity by approximately 60% to 80%, with improvement in severity by 40% to 80% for vaginal prasterone, and with improvement in severity by 30% to 50% for oral ospemifene. Conclusions and Relevance: During the menopausal transition, approximately 50% to 75% of women have vasomotor symptoms and GSM symptoms. Hormonal therapy with estrogen is the first-line therapy for bothersome vasomotor symptoms and GSM symptoms, but nonhormonal medications (such as paroxetine and venlafaxine) also can be effective. Hormone therapy is not indicated for the prevention of cardiovascular disease.

Double-blinded placebo-controlled clinical trial of prophylactic omeprazole in dogs treated surgically for acute thoracolumbar intervertebral disc extrusion.

BACKGROUND: Proton pump inhibitors are administered prophylactically in dogs treated surgically for acute thoracolumbar intervertebral disc extrusion (TL-IVDE). However, their efficacy in decreasing gastrointestinal (GI) complications is unknown. HYPOTHESIS: Omeprazole does not decrease the frequency of GI complications compared to placebo in dogs treated surgically for acute TL-IVDE. ANIMALS: Thirty-seven client-owned dogs undergoing hemilaminectomy for acute TL-IVDE. METHODS: Randomized double-blinded placebo-controlled prospective clinical trial. Dogs received PO placebo or omeprazole at 1 mg/kg q12h for 5 days during hospitalization. Development of GI signs (e.g., diarrhea, vomiting, regurgitation, hematochezia, melena) was recorded daily. Clinicopathologic testing performed during hospitalization and at 2 and 4-week re-evaluations included: fecal occult blood, PCV, blood urea nitrogen/creatinine ratio, fecal calprotectin, canine pancreatic lipase immunoreactivity and fecal alpha-1 proteinase inhibitor concentrations. Omeprazole and placebo groups were compared using chi-squared or Fisher's exact tests. RESULTS: Gastrointestinal signs developed in 10/20 (50%) dogs in the omeprazole group and in 7/17 (41%) dogs in the placebo group (P = .59). Diarrhea was common (8/20 omeprazole, 5/17 placebo), hematochezia was rare (1/20 omeprazole, 1/17 placebo); melena was not observed. Clinicopathologic evidence suggestive of bleeding was present in 9/20 dogs treated with omeprazole and in 11/17 dogs that received placebo (P = .23). Fecal occult blood positivity was more common in dogs with GI signs (P = .03). Canine pancreatic lipase immunoreactivity was higher during hospitalization compared to re-evaluations (P = .01). CONCLUSIONS AND CLINICAL IMPORTANCE: Short-term, prophylactic omeprazole treatment did not decrease clinically detectable GI complications in dogs with acute TL-IVDE.

Handgrip Strength Is Related to Hippocampal and Lobar Brain Volumes in a Cohort of Cognitively Impaired Older Adults with Confirmed Amyloid Burden.

BACKGROUND: Strength and mobility are essential for activities of daily living. With aging, weaker handgrip strength, mobility, and asymmetry predict poorer cognition. We therefore sought to quantify the relationship between handgrip metrics and volumes quantified on brain magnetic resonance imaging (MRI). OBJECTIVE: To model the relationships between handgrip strength, mobility, and MRI volumetry. METHODS: We selected 38 participants with Alzheimer's disease dementia: biomarker evidence of amyloidosis and impaired cognition. Handgrip strength on dominant and non-dominant hands was measured with a hand dynamometer. Handgrip asymmetry was calculated. Two-minute walk test (2MWT) mobility evaluation was combined with handgrip strength to identify non-frail versus frail persons. Brain MRI volumes were quantified with Neuroreader. Multiple regression adjusting for age, sex, education, handedness, body mass index, and head size modeled handgrip strength, asymmetry and 2MWT with brain volumes. We modeled non-frail versus frail status relationships with brain structures by analysis of covariance. RESULTS: Higher non-dominant handgrip strength was associated with larger volumes in the hippocampus (p = 0.02). Dominant handgrip strength was related to higher frontal lobe volumes (p = 0.02). Higher 2MWT scores were associated with larger hippocampal (p = 0.04), frontal (p = 0.01), temporal (p = 0.03), parietal (p = 0.009), and occipital lobe (p = 0.005) volumes. Frailty was associated with reduced frontal, temporal, and parietal lobe volumes. CONCLUSION: Greater handgrip strength and mobility were related to larger hippocampal and lobar brain volumes. Interventions focused on improving handgrip strength and mobility may seek to include quantified brain volumes on MR imaging as endpoints.

Neoadjuvant Chemotherapy in Ovarian Cancer: Are There Racial Disparities in Use and Survival?

BACKGROUND: We investigated racial and ethnic disparities in treatment sequence [i.e., neoadjuvant chemotherapy (NACT) plus interval debulking surgery (IDS) versus primary debulking surgery (PDS) plus adjuvant chemotherapy] among patients with ovarian cancer and its contribution to disparities in mortality. METHODS: Study included 37,566 women ages ≥18 years, diagnosed with stage III/IV ovarian cancer from the National Cancer Database (2004-2017). Logistic regression was used to compute ORs and 95% confidence intervals (CI) for racial and ethnic disparities in treatment sequence. Cox proportional hazards regression was used to estimate HRs and 95% CI for racial and ethnic disparities in all-cause mortality. RESULTS: Non-Hispanic Black (NHB) and Asian women were more likely to receive NACT plus IDS relative to PDS plus adjuvant chemotherapy than non-Hispanic White (NHW) women (OR: 1.12; 95% CI: 1.02-1.22 and OR: 1.12; 95% CI: 0.99-1.28, respectively). Compared with NHW women, NHB women had increased hazard of all-cause mortality (HR: 1.14; 95% CI: 1.09-1.20), whereas Asian and Hispanic women had a lower hazard of all-cause mortality (HR: 0.81; 95% CI: 0.74-0.88 and HR: 0.83; 95% CI: 0.77-0.88, respectively), which did not change after accounting for treatment sequence. CONCLUSIONS: NHB women were more likely to receive NACT plus IDS and experience a higher all-cause mortality rates than NHW women. IMPACT: Differences in treatment sequence did not explain racial disparities in all-cause mortality. Further evaluation of racial and ethnic differences in treatment and survival in a cohort of patients with detailed treatment information is warranted.

Differentiation of Subjective Cognitive Decline, Mild Cognitive Impairment, and Dementia Using qEEG/ERP-Based Cognitive Testing and Volumetric MRI in an Outpatient Specialty Memory Clinic.

BACKGROUND: Distinguishing between subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia in a scalable, accessible way is important to promote earlier detection and intervention. OBJECTIVE: We investigated diagnostic categorization using an FDA-cleared quantitative electroencephalographic/event-related potential (qEEG/ERP)-based cognitive testing system (eVox® by Evoke Neuroscience) combined with an automated volumetric magnetic resonance imaging (vMRI) tool (Neuroreader® by Brainreader). METHODS: Patients who self-presented with memory complaints were assigned to a diagnostic category by dementia specialists based on clinical history, neurologic exam, neuropsychological testing, and laboratory results. In addition, qEEG/ERP (n = 161) and quantitative vMRI (n = 111) data were obtained. A multinomial logistic regression model was used to determine significant predictors of cognitive diagnostic category (SCD, MCI, or dementia) using all available qEEG/ERP features and MRI volumes as the independent variables and controlling for demographic variables. Area under the Receiver Operating Characteristic curve (AUC) was used to evaluate the diagnostic accuracy of the prediction models. RESULTS: The qEEG/ERP measures of Reaction Time, Commission Errors, and P300b Amplitude were significant predictors (AUC = 0.79) of cognitive category. Diagnostic accuracy increased when volumetric MRI measures, specifically left temporal lobe volume, were added to the model (AUC = 0.87). CONCLUSION: This study demonstrates the potential of a primarily physiological diagnostic model for differentiating SCD, MCI, and dementia using qEEG/ERP-based cognitive testing, especially when combined with volumetric brain MRI. The accessibility of qEEG/ERP and vMRI means that these tools can be used as adjuncts to clinical assessments to help increase the diagnostic certainty of SCD, MCI, and dementia.

A model for an undergraduate research experience program in quantitative sciences.

We developed a summer research experience program within a freestanding comprehensive cancer center to cultivate undergraduate students with an interest in and an aptitude for quantitative sciences focused on oncology. This unconventional location for an undergraduate program is an ideal setting for interdisciplinary training in the intersection of oncology, statistics, and epidemiology. This paper describes the development and implementation of a hands-on research experience program in this unique environment. Core components of the program include faculty-mentored projects, instructional programs to improve research skills and domain knowledge, and professional development activities. We discuss key considerations such as effective partnership between research and administrative units, recruiting students, and identifying faculty mentors with quantitative projects. We describe evaluation approaches and discuss post-program outcomes and lessons learned. In its initial two years, the program successfully improved students' perception of competence gained in research skills and statistical knowledge across several knowledge domains. The majority of students also went on to pursue graduate degrees in a quantitative field or work in oncology-centric academic research roles. Our research-based training model can be adapted by a variety of organizations motivated to develop a summer research experience program in quantitative sciences for undergraduate students.