NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023.

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

Long-Term Treatment with the Combination of Rivaroxaban and Aspirin in Patients with Chronic Coronary or Peripheral Artery Disease: Outcomes During the Open Label Extension of the COMPASS trial.

AIMS: To describe outcomes of patients with chronic coronary artery disease (CAD) and/or peripheral artery disease (PAD) enrolled in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial who were treated with the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily during long-term open-label extension (LTOLE). METHODS AND RESULTS: Of the 27 395 patients enrolled in COMPASS, 12 964 (mean age at baseline 67.2 years) from 455 sites in 32 countries were enrolled in LTOLE and treated with the combination of rivaroxaban and aspirin for a median of 374 additional days (range 1-1191 days). During LTOLE, the incident events per 100 patient years were as follows: for the primary outcome [cardiovascular death, stroke, or myocardial infarction (MI)] 2.35 [95% confidence interval (CI) 2.11-2.61], mortality 1.87 (1.65-2.10), stroke 0.62 (0.50-0.76), and MI 1.02 (0.86-1.19), with CIs that overlapped those seen during the randomized treatment phase with the combination of rivaroxaban and aspirin. The incidence rates for major and minor bleeding were 1.01 (0.86-1.19) and 2.49 (2.24-2.75), compared with 1.67 (1.48-1.87) and 5.11 (95% CI 4.77-5.47), respectively, during the randomized treatment phase with the combination. CONCLUSION: In patients with chronic CAD and/or PAD, extended combination treatment for a median of 1 year and a maximum of 3 years was associated with incidence rates for efficacy and bleeding that were similar to or lower than those seen during the randomized treatment phase, without any new safety signals.

Rivaroxaban for Prevention of Covert Brain Infarcts and Cognitive Decline: The COMPASS MRI Substudy.

BACKGROUND AND PURPOSE: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. METHODS: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. RESULTS: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38-0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37-1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27-1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. CONCLUSIONS: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.

Women's Experiences After Ovarian Cancer Surgery: Distress, Uncertainty, and the Need for Occupational Therapy.

IMPORTANCE: Despite the growing literature on the association of functional, physical, and quality-of-life (QOL) deficits with poor postoperative outcomes, there is a gap in the literature identifying women's occupational performance needs after ovarian cancer surgery. OBJECTIVE: To describe the experiences of women hospitalized after ovarian cancer surgery to identify potential areas for intervention. Goals were to (1) identify functional needs and limitations at time of discharge as measured by the typical acute care occupational therapy evaluation and semistructured interview and (2) understand the women's perspectives of their needs for occupational therapy and a safe return to home. DESIGN: Single-arm, cross-sectional descriptive study. Mixed-methods data collection and analysis. SETTING: Academic cancer center. PARTICIPANTS: Women with ovarian cancer (N = 11) who had completed surgery. INTERVENTION: Semistructured interviews and patient-reported outcome measures (PROMs) completed postsurgery. OUTCOMES AND MEASURES: PROMs included the National Comprehensive Cancer Network (NCCN) Distress Thermometer and Problem List, the PROMIS® Global Physical Health (GPH) and Global Mental Health (GMH) scales, and the Possibilities for Activity Scale-Women (PActS-W). RESULTS: The mean NCCN Distress score was 6.0 (standard deviation [SD] = 3.1, with the top three concerns being pain (80%), worry (80%), and fatigue (78%). Mean GPH and GMH T scores were 38.0 (SD = 8.8) and 48.2 (SD = 8.4), respectively. Women scored a mean of 39.2 (SD = 11.2, range = 26-58) on the PActS-W. Thematic analyses found that the women were uncertain about potential functional limitations and significantly distressed. CONCLUSION AND RELEVANCE: Women with ovarian cancer experienced high levels of uncertainty and distress after surgery. Integrating in-home or community-based occupational therapy into routine care could decrease functional distress and uncertainty and help women manage concerns related to pain, worry, and fatigue. WHAT THIS ARTICLE ADDS: This study suggests that occupational therapy evaluation and intervention are needed to decrease distress and improve QOL of women upon discharge after ovarian cancer surgery.

Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease: Insights From the COMPASS Trial.

BACKGROUND: Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events. METHODS: In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding. RESULTS: There were 10 341 patients with diabetes mellitus and 17 054 without diabetes mellitus in the overall trial. A consistent and similar relative risk reduction was seen for benefit of rivaroxaban plus aspirin (n=9152) versus placebo plus aspirin (n=9126) in patients both with (n=6922) and without (n=11 356) diabetes mellitus for the primary efficacy end point (hazard ratio, 0.74, P=0.002; and hazard ratio, 0.77, P=0.005, respectively, Pinteraction=0.77) and all-cause mortality (hazard ratio, 0.81, P=0.05; and hazard ratio, 0.84, P=0.09, respectively; Pinteraction=0.82). However, although the absolute risk reductions appeared numerically larger in patients with versus without diabetes mellitus, both subgroups derived similar benefit (2.3% versus 1.4% for the primary efficacy end point at 3 years, Gail-Simon qualitative Pinteraction<0.0001; 1.9% versus 0.6% for all-cause mortality, Pinteraction=0.02; 2.7% versus 1.7% for major vascular events, Pinteraction<0.0001). Because the bleeding hazards were similar among patients with and without diabetes mellitus, the prespecified net benefit for rivaroxaban appeared particularly favorable in the patients with diabetes mellitus (2.7% versus 1.0%; Gail-Simon qualitative Pinteraction=0.001). CONCLUSIONS: In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

Understanding fall risk for older adults with cancer: An evaluation of experts' perceptions.

OBJECTIVE: Older adults with cancer have elevated risk of falling. However, cancer-specific fall risk factors are not well understood. METHODS: A pragmatic, qualitative study utilized semi-structured interviews to investigate expert's perceptions of fall risk for older adults with cancer. Interview questions were guided by the International Classification of Functioning and Disability (ICF) constructs and the Cancer Aging Research Group's model of fall risk factors. Themes were identified deductively from interview transcriptions. Transcripts were coded using Nvivo software. RESULTS: Ten multidisciplinary experts participated (n = 5 clinical, n = 5 research). Two themes in fall risk factors emerged from interview data: 1) cancer-specific factors aligned with each ICF construct: body function and structures (BF&S), activity and participation (A&P), personal and environmental factors; and 2) a cycle among factors. Experts described that treatment-related limitations in A&P produced or exacerbated impairments in BF&S (physical and mental), leading to falls and further limitations in A&P. Personal and environmental factors influencing this cycle included: cancer-related distress, social support, and perceptions of aging and treatment. CONCLUSION: Experts identified a cycle among cancer-specific fall risk factors for older adults and emphasized the importance of a "holistic" view of the patient to evaluate fall risk. Cancer-related distress, social support and expectations of aging and treatment may influence the cycle between risk factors, with potential negative or protective effects. Future prospective, longitudinal implementation of geriatric assessments and analysis of data may inform risk factors and relationships among factors. Patient interviews could further inform the understanding of fall risk for older adults with cancer.

Embracing the complexity: Older adults with cancer-related cognitive decline-A Young International Society of Geriatric Oncology position paper.

Cancer-related cognitive decline (CRCD) may have particularly significant consequences for older adults, impacting their functional and physical abilities, level of independence, ability to make decisions, treatment adherence, overall quality of life, and ultimately survival. In honor of Dr. Hurria's work we explore and examine multiple types of screening, assessment and non-pharmacologic treatments for CRCD. We then suggest future research and clinical practice questions to holistically appreciate the complexity of older adults with cancer's experiences and fully integrate the team-based approach to best serve this population.

A Phase 2 Study of Galunisertib (TGF-ß1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma.

INTRODUCTION: Inhibition of tumor growth factor-ß (TGF-ß) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-ß1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. METHODS: The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-ß1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). RESULTS: Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-ß1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). DISCUSSION: The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.

Antimicrobial stewardship impact on Pseudomonas aeruginosa susceptibility to meropenem at a tertiary pediatric institution.

An antimicrobial stewardship program was implemented throughout 2012 at a tertiary pediatric institution with guideline development preceding prospective audit and feedback starting in 2013. Meropenem use decreased over 62% during the next 5 years. Non-cystic fibrosis Pseudomonas aeruginosa isolate susceptibility to meropenem increased from 89% in 2011 to 98% in 2017 (P < .001) and correlated with meropenem use the preceding year (Rs: -0.78, P = .008).

Older Adults with Cancer: A Randomized Controlled Trial of Occupational and Physical Therapy.

OBJECTIVES: The impact of occupational therapy (OT) and physical therapy (PT) on functional outcomes in older adults with cancer is unknown. DESIGN: Two-arm single-institution randomized controlled trial of outpatient OT/PT. SETTING: Comprehensive cancer center with two off-site OT/PT clinics. PARTICIPANTS: We recruited adults 65 years and older with a recent diagnosis or recurrence of cancer within 5 years, with at least one functional limitation as identified by a geriatric assessment. Participants were randomized to OT/PT or usual care. INTERVENTION: Rehabilitation consisted of individualized OT and PT that addressed functional activities and strength/endurance needs. MEASUREMENTS: Primary outcome was functional status as measured by the Nottingham Extended Activities of Daily Living scale. Secondary outcomes were Patient-Reported Outcomes Measurement Information System-Global Mental Health (GMH) and Global Physical Health (GPH), ability to participate in Social Roles (SR), physical function, and activity expectations and self-efficacy (Possibilities for Activity Scale [PActS]). RESULTS: Among those recruited (N = 63), only 45 patients (71%) were evaluable due to loss of follow-up and/or nonreceipt of intervention. The median age was 74 years; 53% were female, and 91% were white. Overall, 30% patients had hematologic malignancies, 30% breast cancer, and 16% colorectal cancers. A total of 65% were in active treatment; 49% had stage 3 or 4 disease. At follow-up, both OT/PT (P = .02) and usual care (P = .03) groups experienced a decline in functional status. PActS scores between groups (P = .04) was significantly improved in the intervention group. GMH and SR met criteria for minimally important clinical difference favoring the intervention, but not statistical significance. Several barriers were noted in the implementation of the intervention program: recruitment, concerns about cost, distance, scheduling, and limited treatment provided. CONCLUSION: OT/PT may positively influence activity expectations and self-efficacy. Future research needs to address significant barriers to implementation to increase use of OT/PT services and access to quality care. J Am Geriatr Soc 67:953-960, 2019.

Maternal omega-3 polyunsaturated fatty acid supplementation on offspring hip joint conformation.

Unsaturated omega-3 fatty acids, especially docosahexaenoic acid (DHA), when fed to dogs improves cognitive and neurological development. Supplementation with omega-3 fatty acids such as DHA and eicosapentaenoic acid (EPA) has also been associated with lipid peroxidation, which in turn has been implicated in reduced body weight and altered bone formation. To assess the impact of omega-3 fatty acid supplementation on skeletal growth, diets containing three levels of DHA and EPA (0.01 and 0.01%, 0.14 and 0.12%, and 0.21 and 0.18%, respectively) were fed to bitches during gestation and lactation with puppies also supplemented through weaning. Thus, the subjects studied were the puppies supplemented with DHA and EPA through gestation and early postnatal life. The hip joint conformation of the puppies (n = 676) was recorded at adulthood using two radiographic, non-invasive evaluations. In this population, females had higher hip distraction indices (DI) than males. Males from the lower two levels of DHA and EPA supplementation had significantly smaller hip DI than all females and males from the highest DHA and EPA supplementation. In contrast, there were no diet effects on anatomical indicators of hip joint conformation and no visible arthritic changes. These data suggest that dietary supplementation of DHA and EPA during gestation and the perinatal period to weaning does not adversely influence hip joint formation of dogs.

Molecular Analysis of Resistance and Detection of Non-Wild-Type Strains Using Etest Epidemiological Cutoff Values for Amphotericin B and Echinocandins for Bloodstream Candida Infections from a Tertiary Hospital in Qatar.

A total of 301 Candida bloodstream isolates collected from 289 patients over 5 years at a tertiary hospital in Qatar were evaluated. Out of all Candida infections, 53% were diagnosed in patients admitted to the intensive care units. Steady increases in non-albicans Candida species were reported from 2009 to 2014 (30.2% for Candida albicans versus 69.8% for the other Candida species). Etest antifungal susceptibility testing was performed on all recovered clinical isolates to determine echinocandin (micafungin and anidulafungin) and amphotericin B susceptibilities and assess non-wild-type (non-WT) strains (strains for which MICs were above the epidemiological cutoff values). DNA sequence analysis was performed on all isolates to assess the presence of FKS mutations, which confer echinocandin resistance in Candida species. A total of 3.9% of isolates (12/301) among strains of C. albicans and C. orthopsilosis contained FKS hot spot mutations, including heterozygous mutations in FKS1 For C. tropicalis, the Etest appeared to overestimate strains non-WT for micafungin, anidulafungin, and amphotericin B, as 14%, 11%, and 35% of strains, respectively, had values above the epidemiological cutoff value. However, no FKS mutations were identified in this species. For all other species, micafungin best reported the echinocandin non-WT strains relative to the FKS genotype, as anidulafungin tended to overestimate non-wild-type strains. Besides C. tropicalis, few strains were classified as non-WT for amphotericin B.

Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease. METHODS: In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. FINDINGS: Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012). INTERPRETATION: In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide. FUNDING: Bayer AG.

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease.

BACKGROUND: We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention. METHODS: In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. RESULTS: The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group. CONCLUSIONS: Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).

Delta-frequency stimulation of cerebellar projections can compensate for schizophrenia-related medial frontal dysfunction.

Schizophrenia involves abnormalities in the medial frontal cortex that lead to cognitive deficits. Here we investigate a novel strategy to normalize medial frontal brain activity by stimulating cerebellar projections. We used an interval timing task to study elementary cognitive processing that requires both frontal and cerebellar networks that are disrupted in patients with schizophrenia. We report three novel findings. First, patients with schizophrenia had dysfunctional delta rhythms between 1-4 Hz in the medial frontal cortex. We explored cerebellar-frontal interactions in animal models and found that both frontal and cerebellar neurons were modulated during interval timing and had delta-frequency interactions. Finally, delta-frequency optogenetic stimulation of thalamic synaptic terminals of lateral cerebellar projection neurons rescued timing performance as well as medial frontal activity in a rodent model of schizophrenia-related frontal dysfunction. These data provide insight into how the cerebellum influences medial frontal networks and the role of the cerebellum in cognitive processing.

Payer Coverage for Hereditary Cancer Panels: Barriers, Opportunities, and Implications for the Precision Medicine Initiative.

Background: Hereditary cancer panels (HCPs), testing for multiple genes and syndromes, are rapidly transforming cancer risk assessment but are controversial and lack formal insurance coverage. We aimed to identify payers' perspectives on barriers to HCP coverage and opportunities to address them. Comprehensive cancer risk assessment is highly relevant to the Precision Medicine Initiative (PMI), and payers' considerations could inform PMI's efforts. We describe our findings and discuss them in the context of PMI priorities. Methods: We conducted semi-structured interviews with 11 major US payers, covering >160 million lives. We used the framework approach of qualitative research to design, conduct, and analyze interviews, and used simple frequencies to further describe findings. Results: Barriers to HCP coverage included poor fit with coverage frameworks (100%); insufficient evidence (100%); departure from pedigree/family history-based testing toward genetic screening (91%); lacking rigor in the HCP hybrid research/clinical setting (82%); and patient transparency and involvement concerns (82%). Addressing barriers requires refining HCP-indicated populations (82%); developing evidence of actionability (82%) and pathogenicity/penetrance (64%); creating infrastructure and standards for informing and recontacting patients (45%); separating research from clinical use in the hybrid clinical-research setting (44%); and adjusting coverage frameworks (18%). Conclusions: Leveraging opportunities suggested by payers to address HCP coverage barriers is essential to ensure patients' access to evolving HCPs. Our findings inform 3 areas of the PMI: addressing insurance coverage to secure access to future PMI discoveries; incorporating payers' evidentiary requirements into PMI's research agenda; and leveraging payers' recommendations and experience to keep patients informed and involved.

High-gamma band fronto-temporal coherence as a measure of functional connectivity in speech motor control.

The neural basis of human speech is unclear. Intracranial electrophysiological recordings have revealed that high-gamma band oscillations (70-150Hz) are observed in the frontal lobe during speech production and in the temporal lobe during speech perception. Here, we tested the hypothesis that the frontal and temporal brain regions had high-gamma coherence during speech. We recorded electrocorticography (ECoG) from the frontal and temporal cortices of five humans who underwent surgery for medically intractable epilepsy, and studied coherence between the frontal and temporal cortex during vocalization and playback of vocalization. We report two novel results. First, we observed high-gamma band as well as theta (4-8Hz) coherence between frontal and temporal lobes. Second, both high-gamma and theta coherence were stronger when subjects were actively vocalizing as compared to playback of the same vocalizations. These findings provide evidence that coupling between sensory-motor networks measured by high-gamma coherence plays a key role in feedback-based monitoring and control of vocal output for human vocalization.

Adherence to statins and LDL-cholesterol goal attainment.

OBJECTIVES: To examine the relationship between low-density lipoprotein cholesterol (LDL-C) goal attainment and adherence to statin medications in patients with coronary artery disease (CAD). STUDY DESIGN: Cross-sectional study of CAD patients 18 years of age or older in an integrated healthcare system. METHODS: Patients dispensed 2 or more statin prescriptions between May 2009 and May 2010, were identified. Medication possession ratio (MPR) was calculated to estimate adherence. The LDL-C value closest to May 27, 2010, was used to determine goal. Adherence and LDL-C goal were defined as 80% or greater MPR and less than 100 mg/dL or less than 70 mg/dL, respectively. Electronic medical records were used to identify patient demographics and clinical information. Logistic regression was used to estimate the effect of these factors on goal attainment. RESULTS: A total of 67,100 CAD patients were identified. Overall, 85.8% had LDL-C less than 100 mg/dL, 32.4% had LDL less than 70 mg/dL, and 79.8% were adherent to their statin medication. Over 65% of patients not at LDL-C goal less than 100 mg/dL were adherent. Among patients with LDL-C less than 100 mg/dL, 17.9% were not adherent. Increasing medication adherence was associated with improved LDL-C levels. Adherence to statins, male sex, Asian and Hispanic race/ethnicity, a higher number of concurrent prescriptions, higher Charlson Comorbidity Index, and hypertension were associated with LDL-C goal attainment. CONCLUSIONS: Incorporating LDL-C levels and medication adherence at the point of care allows providers to focus interventions to address either adherence challenges or the need for medication titration in an effort to improve LDL-C goal attainment and ultimately reduce morbidity and mortality.

Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates.

BACKGROUND: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. RESULTS: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients. CONCLUSION: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.