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Introduction: H3K27M-mutated diffuse intrinsic pontine glioma (DIPG) and spinal cord diffuse midline glioma (DMG) are universally lethal central nervous system (CNS) tumors in children and young adults. We previously demonstrated safety and activity of GD2.41BB.z chimeric antigen receptor T cells (CAR-Ts) at dose level 1, 1x106 GD2 CAR-T/kg (Majzner/Ramakrishna et al. Nature 2022) and reported results of dose level 2, 3x106 GD2 CAR-T/kg (Majzner et al. AACR 2022). Here, we present in depth high-dimensional analyses to define the immune states that contribute to CAR-T activity in patients. Methods: Thirteen patients (10 DIPG/3 spinal DMG; 4-30 years old; 7F/6M) were enrolled in this GD2 CAR-T phase 1 clinical trial (NCT04196413). GD2 CAR-Ts were administered to 12/13 enrolled patients. In the first cohort, CAR-Ts were administered initially intravenously (IV), followed by serial intracerebroventricular infusions (ICV; range 0-11 infusions/patient). Patient GD2 CAR-T product, peripheral blood, and cerebrospinal fluid (CSF) samples were evaluated for CAR-T expansion (qPCR; flow cytometry), cytokine signatures (Multiplex Luminex), and immune cell profiles (single cell RNA-sequencing). Data were analyzed in the context of clinical trajectory and patient response. Results: 10/12 infused subjects demonstrated clinical and/or radiographic benefit, with less systemic toxicity following ICV compared to IV infusion. CAR-T expansion was noted in the periphery and CSF of all treated patients and following serial ICV infusions. In peripheral blood, cytokine concentrations, including IFN-gamma, IL6, and CXCL9, were higher after IV compared to ICV CAR-T infusions, correlating with increased systemic inflammation. Conversely in CSF, cytokine concentrations, such as CCL2 and CXCL9, were higher following ICV compared to IV CAR-T infusions. Transcriptomic analysis was conducted on 576,199 single cells from 91 samples, including GD2 CAR-T products and patient CSF. This is the largest CAR-T dataset in CNS tumors. Patient CSF samples were dominated by T cell and myeloid populations. After IV CAR-T infusion, patient CSF exhibited an increased fraction of regulatory T cells and suppressive myeloid populations from baseline. These immune suppressive cells reduced after ICV infusion. Ongoing analyses are underway to explore the relation of these immune populations to patient response. Conclusions: H3K27M-mutated DIPG/DMG patients demonstrate continued clinical response with serial ICV GD2 CAR-T infusions, with heterogeneity in the durability of response across patients. In-depth correlative analyses profile distinct immune populations and demonstrate population shifts depending on route of administration and over the course of treatment. Key findings from these data will allow for iterative improvement in CAR-T therapies for H3K27M+ DIPG/DMG patients, providing hope to shift the paradigm of this fatal disease. Citation Format: Sneha Ramakrishna, Zinaida Good, Moksha Desai, Daniel Zamler, Rebecca Mancusi, Jasia Mahdi, Robbie Majzner, Liora Schultz, Rebecca Richards, Jennifer Kamens, Valentin Barsan, Cynthia Campen, Sonia Partap, Zachary Ehlinger, Warren Reynolds, Yiyun Chen, Mark P. Hamilton, Jennifer Moon, Christina Baggott, Michael Kunicki, Michelle Fujimoto, Amy Li, Sneha Jariwala, Sharon Mavroukakis, Emily Egeler, Ashley Jacobs, Courtney Erickson, Karen Yamabe-Kwong, Snehit Prabhu, Kara Davis, Steve Feldman, Bita Sahaf, Crystal L. Mackall, Michelle Monje. Immune signatures of GD2 CAR T cell activity in H3K27M+ diffuse midline glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 959.

BACKGROUND: H3K27M-mutated DMGs express high levels of the disialoganglioside GD2 and GD2-CAR T-cells (GD2-CART) regress DMG in preclinical models. METHODS: NCT04196413 is a 3 + 3 Phase I dose escalation trial testing GD2-CART in patients with biopsy-proved H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1=1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART infusions (10-30e6 GD2-CART) administered via Ommaya without LD. RESULTS: Twelve subjects were treated after standard radiotherapy, 7 of whom began treatment at the time of progression [n=4 DL1 (3 DIPG/1 sDMG); n=8 DL2 (6 DIPG/2 sDMG)]. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade-4 cytokine release syndrome (CRS). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN); no DLT due to TIAN has occurred. Ten subjects experienced radiographic and/or clinical benefit after IV infusion and received subsequent ICV infusions (median=4 ICV infusions/pt, range=1-7). ICV infusions were not associated with high-grade CRS. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit, currently 7-11 months following enrollment. Two patients (one sDMG, one DIPG) have experienced near-complete (>95%) tumor volume reduction. CONCLUSIONS: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with frequent high-grade CRS at 3e6/kg. ICV GD2-CART has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD.

Background: H3K27M-mutated DMGs are universally lethal central nervous system tumors that express high levels of the disialoganglioside GD2. IV administered GD2-CAR T cells (GD2-CART) regress DMG in preclinical models, and locoregionally delivered CARs demonstrate enhanced activity in xenograft models of brain tumors. Methods: NCT04196413 is a 3+3 Phase I dose escalation trial testing GD2-CART in patients with H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1: 1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART (10-30e6 GD2-CART) administered via Ommaya catheter without LD every 4-8 weeks for a maximum of 12 doses. We previously reported early results from 4 patients treated on DL1, which demonstrated clinical activity and manageable toxicity. Here we provide updated results for DL1 and DL2. Results: Thirteen subjects were enrolled and 11 treated [n=4 DL1 (3 DIPG/1 sDMG); n=9 DL2 (7 DIPG/2 sDMG)]. Two subjects were removed prior to treatment due to rapid progression. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade 4 cytokine release syndrome (CRS), successfully managed with tocilizumab, anakinra, and corticosteroids. CRS occurred earlier on DL2 vs. DL1 (Day 3 vs 7). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN), which was successfully managed with anakinra and, in some cases, CSF drainage and dexamethasone. No DLT due to TIAN has occurred. Ten patients have had adequate follow-up to assess benefit. Nine experienced radiographic and/or clinical benefit after IV infusion, and they received subsequent ICV GD2-CART infusions (median= 4 ICV infusions/pt, range 1-6). ICV infusions were not associated with high-grade CRS, although some subjects developed transient fever, headache, meningismus, nausea, and/or vomiting, and several subjects developed TIAN. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit at 11+, 9.5+, 8+ and 7+ months following enrollment. A 31-year-old with sDMG has experienced a near-complete (>95%) reduction in tumor volume and a 17-year-old with DIPG experienced a near-complete (>98%) reduction in volume of a pontine tumor. Conclusions: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with unacceptable rates of high-grade CRS at 3e6/kg. ICV GD2-CART without LD, administered following a previous course of IV GD2-CART with LD, has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD. Patients are eligible for up to 12 ICV infusions of GD2-CART administered every 4-6 weeks. Clinical benefit will be formally assessed using patient-reported outcomes. GD2-CART has the potential to transform therapy for patients with H3K27M+ DIPG/sDMG. Citation Format: Robbie G. Majzner, Jasia Mahdi, Sneha Ramakrishna, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, Valentin Barsan, Rebecca Richards, Cynthia Campen, Agnes Reschke, Angus Martin Shaw Toland, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Ashley Jacobs, Karen Yamabe-Kwong, Lindsey Rasmussen, Esther Nie, Sean Green, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Warren Reynolds, Snehit Prabhu, Katherine E. Warren, Tim Cornell, Sonia Partap, Paul Fisher, Gerald Grant, Hannes Vogel, Bita Sahaf, Kara Davis, Steven Feldman, Michelle Monje, Crystal L. Mackall. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT001.

Purpose To evaluate the feasibility of implementing systematic patient symptom monitoring during treatment using a smartphone. Methods Endometrial [n = 50], ovarian [n = 70] and breast [n = 193] cancer patients participated in text-based symptom reporting for up to 12 months. In order to promote equity, patients without a smartphone were provided with a device, with the phone charges paid by program funds. Each month, patients completed the Patient Health Questionnaire (PHQ-9), and 4 single items assessing fatigue, sleep quality, pain, and global quality of life during the past 7 days rated on a 0 (low) –10 (high) scale. Patients’ responses were captured using REDCap, with oncologists receiving monthly feedback. Lay navigators provided assistance to patients with non-medical needs. Results Patients utilizing this voluntary program had an overall mean age of 60.5 (range 26–87), and 85% were non-Hispanic white. iPhones were provided to 42 patients, and navigation services were used by 69 patients. Average adherence with monthly surveys ranged between 75–77%, with breast patients having lower adherence after 5 months. The most commonly reported symptoms across cancer types were moderate levels (scores of 4–7) of fatigue and sleep disturbance. At 6 months, 71–77% of all patients believed the surveys were useful to them and their health care team. Conclusions We established the feasibility of initiating and managing patients in a monthly text-based symptom-monitoring program. The provision of smartphones and patient navigation were unique and vital components of this program.

Background: Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal central nervous system tumors. We previously discovered that the disialoganglioside GD2 is highly and homogenously expressed on H3K27M+ gliomas and demonstrated that GD2 CAR T cells are effective in preclinical models (Mount/Majzner et al., Nat Med, 2018). Methods: Four subjects (3 DIPG, 1 spinal cord DMG; 4-25 yr; 1M/3F) were enrolled at DL1. Three subjects with H3K27M+ DIPG received 1e6 autologous GD2 CAR T cells/kg intravenously (IV) on study. One patient, a 25 y/o with spinal cord DMG, developed rapidly progressive disease after enrollment, resulting in complete paraparesis that led to removal from the study prior to cell infusion; she was treated on a single patient eIND with the same treatment regimen as DL1. We utilized a retroviral vector expressing a 14g2a.4-1BB.z CAR construct and an inducible iCasp9 safety switch. Manufacturing was performed in the Miltenyi Prodigy on CD4/CD8 enriched apheresis product. CAR T cells were cultured in the presence of dasatinib to improve T cell fitness (Weber et al., Science, 2021). An Ommaya reservoir was placed in all patients for monitoring of intracranial pressure (ICP). Results: We generated GD2 CAR T cell products meeting release criteria for all four patients. All subjects received lymphodepletion with cyclophosphamide and fludarabine and remained inpatient for 14+ days after infusion. All patients developed cytokine release syndrome (Grade 1-3) manifested by fever, tachycardia and hypotension, beginning 6-7 days after infusion. Due to concern for tumoral edema and increased ICP, patients were managed with conservative fluid resuscitation, and early intervention with tocilizumab and anakinra +/- corticosteroids. Other toxicities included ICANS (Grade 1-2) and neurotoxicity mediated by inflammation in sites of disease which we have termed Tumor Inflammation-Associated Neurotoxicity (TIAN). TIAN most often manifested as worsening of existing deficits, but one patient developed symptoms of increased ICP which quickly resolved upon removal of CSF via the Ommaya. No evidence of on-target, off-tumor toxicity was observed in any patients. No dose-limiting toxicities occurred.CAR T cells trafficked to the CNS and were detected in both the CSF and peripheral blood. Inflammatory cytokines including IL-6 were elevated in the CSF and blood. 3/4 patients exhibited marked improvement or resolution of neurological deficits and some radiographic improvement. The patient treated on a single patient eIND exhibited a >90% reduction in her spinal cord DMG tumor volume at two months post-infusion. Durability of the therapeutic benefit remains to be determined. Conclusions: This is the first report of GD2 CAR T cell therapy for DIPG and spinal cord DMG. Toxicities are similar to other CAR T cells with additional, manageable complications due to inflammation at CNS sites of tumor. Treatment at DL1 demonstrated a tolerable safety profile and clear signs of T cell expansion and activity including clinical responses. This approach has the potential to transform therapy for patients with H3K27M+ DIPG/DMG. Further correlative studies, including single-cell RNAseq, longer-term outcomes and results from patients on subsequent dose levels will also be presented. Citation Format: Robbie G. Majzner, Sneha Ramakrishna, Aaron Mochizuki, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, Rebecca Richards, Cynthia Campen, Agnes Reschke, Jasia Mahdi, Angus Martin Shaw Toland, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Kayla Landrum, Courtney Erickson, Lindsey Rasmussen, Valentin Barsan, John S. Tamaresis, Anne Cunniffe Marcy, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Sreevidya Kurra, Timothy Cornell, Sonia Partap, Paul Fisher, Gerald Grant, Hannes Vogel, Bita Sahaf, Kara Davis, Steven Feldman, Crystal L. Mackall, Michelle Monje. GD2 CAR T cells mediate clinical activity and manageable toxicity in children and young adults with DIPG and H3K27M-mutated diffuse midline gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT031.

Introduction We are conducting a Phase I clinical trial utilizing chimeric antigen receptor (CAR) T-cells targeting GD2 (NCT04196413) for H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) and spinal cord diffuse midline glioma (DMG). Cerebrospinal fluid (CSF) is collected for correlative studies at the time of routine intracranial pressure monitoring via Ommaya catheter. Here we present single cell RNA-sequencing results from the first 3 subjects. Methods Single cell RNA-sequencing was performed utilizing 10X Genomics on cells isolated from CSF at various time points before and after CAR T-cell administration and on the CAR T-cell product. Output was aligned with Cell Ranger and analyzed in R. Results As detailed in the Majzner et al. abstract presented at this meeting, three of four subjects treated at dose-level one exhibited clear radiographic and/or clinical benefit. We have to date completed single cell RNA-sequencing for three of these four subjects (two with benefit, one without). After filtering out low-quality signals and doublets, 89,604 cells across 3 subjects were analyzed. Of these, 4,122 cells represent cells isolated from CSF and 85,482 cells represent CAR T-cell product. Two subjects who demonstrated clear clinical and radiographic improvement exhibited fewer S100A8+S100A9+ myeloid suppressor-cells and CD25+FOXP3+ regulatory T-cells in the CSF pre-infusion compared to the subject who did not derive a therapeutic response. In one subject with DIPG who demonstrated improvement, polyclonal CAR T-cells detectable in CSF at Day +14 demonstrated enrichment of CD8A, GZMA, GNLY and PDCD1 compared to the pre-infusion CAR T-cells by trajectory analysis, suggesting differentiation toward a cytotoxic phenotype; the same subject exhibited increasing numbers of S100A8+S100A9+ myeloid cells and CX3CR1+P2RY12+ microglia over time. Further analyses will be presented as data become available. Conclusions The presence of immunosuppressive myeloid populations, detectable in CSF, may correlate to clinical response in CAR T cell therapy for DIPG/DMG.

255 Background: With advances in technology, smartphones are being used for multiple research and clinical care functions. However, not all patients have these devices, leading to disparities in participation. We report on a quality improvement program that provided smartphones to patients without these devices. Methods: Gynecologic (n = 120) and breast (n = 193) cancer patients under active treatment were enrolled in a 12-month text-based symptom monitoring program to facilitate communication and optimize patient management. Patients without a smartphone were provided with an iPhone through a partnership with a U.S. wireless company. The company provided smartphone devices at zero cost, and program funds paid for 12 months of phone service. Program staff helped patients set up the iPhones, and provided basic education and ongoing phone support. After 12 months, patients were able to keep their iPhones, but had to secure their own phone plan for calling and texting functions. Results: iPhones were provided to 42 (13.4%) patients across all cancer types. Patients who received iPhones, compared with those who had a smartphone, had incomes below $50,000/year (p = 0.03) and an educational level of < high school (p < 0.0001). Program staff had few difficulties training patients to operate the phones or in patients’ adherence to symptom monitoring after receiving the iPhones. Phone service charges averaged $40 per month or $500 per person for 12 months. Greater than 90% of patients believed the phones enabled them to better communicate with their health care team and family/support networks, and 95% believed the phones had a positive impact on their life. However, only 70% planned on getting a phone service plan at the end of the 12 months, due to cost or believing a smartphone was not a necessity. Conclusions: Providing smartphones to patients enabled them to better communicate with their health care team and families, and participate in remote symptom monitoring during active treatment. Programs such as these are needed to reduce disparities in patient care, and support quality improvement efforts using electronic devices.

e19173 Background: Unreported symptoms during cancer treatment can lead to poorer patient care and quality of life. eHealth technologies enable effective means to track patients’ health in real time to provide assistance in meeting patients’ needs and facilitating symptom management. Methods: Gynecologic (endometrial and ovarian) and breast oncology patients were enrolled in a quality improvement program post-surgically to respond to 12-monthly, text-based symptom surveys assessing fatigue, sleep quality, pain, and depression (PHQ-9). At baseline, 6 and 12 months, patients also completed the PROMIS-10 to assess their physical and mental health functioning. All patient responses were captured in REDCap and monitored by program staff, with patients’ oncologists receiving monthly feedback for patient follow-up. Patient navigators were also engaged for patients needing assistance with non-medical concerns. We provide the interim results of this program on PROMIS-10 scores from baseline to 6 months. Results: 198 breast and 120 gynecologic oncology patients (ovarian [n = 70] and endometrial [n = 50]) were enrolled. Multiple regression examined the impact of demographic (age, race, education), clinical (stage, chemotherapy, radiation), and monitoring program variables (# of monthly surveys completed, navigation services [yes/no]) on PROMIS-10 physical and mental health subscale scores at 6 months, adjusting for baseline PROMIS scores. For the breast patients, the only significant predictor of worse PROMIS physical health scores was a cancer stage of 4 vs 1 (p = 0.049), whereas a higher number of symptom surveys completed was associated with worse mental health functioning (p = 0.033). For the gynecologic oncology patients, worse PROMIS physical health scores were only associated with higher age (p = 0.037), but higher PROMIS mental health was also associated with higher age (p = 0.029) and borderline significantly associated with not using navigation services (p = 0.07). Conclusions: These results indicate that greater adherence in completing monthly symptom surveys and using navigation services were more likely to be associated with patients reporting lower mental health. PROMIS physical health scores, however, were not significantly associated with adherence to monthly surveys or navigation services. These interim results suggest that monitoring programs, such as this, may assist in identifying and treating patients with lower mental health functioning during treatment.

OBJECTIVES Current osteoarthritis therapies aim to alleviate pain and maintain joint function. Non-prescription oral non-steroidal anti-inflammatory drugs are frequently used alone for pain relief in osteoarthritis. This post-hoc pooled analysis evaluated the analgesic efficacy and safety of two non-prescription doses of naproxen sodium for short-term use in patients with osteoarthritis of the knee or hip. A separate sub-group analysis of older patients who were administered a lower dose of naproxen sodium was performed. METHODS In four multi-center, multi-dose, randomized, parallel, double-blind, placebo-controlled studies, oral naproxen sodium (age-based dosing regimen

More than 25 years of clinical trial data have established statins as first-line therapy for the prevention and treatment of atherosclerotic cardiovascular disease. With regard to low-density lipoprotein cholesterol, a wealth of evidence indicates that ‘lower is better,’ although recent guidelines from the American College of Cardiology and the American Heart Association take a different approach. A variety of approved and experimental lipid-lowering agents may be used as supplements or alternatives to statin therapy in patient subgroups, including those with familial hypercholesterolemia, mixed dyslipidemia or statin intolerance. Strategies to achieve further reductions in low-density lipoprotein cholesterol, target high-density lipoprotein cholesterol and triglycerides or reduce inflammation may help address residual cardiovascular risk, although early lifestyle interventions are crucial to prevention strategies.

Increasing student body diversity is a priority for national health education and professional organizations and for many medical schools. However, national rankings of medical schools, such as those published by U.S. NewsWorld Report, place a heavy emphasis on grade point average (GPA) and Medical College Admissions Test (MCAT) scores, without considering student body diversity. These rankings affect organizational reputation and admissions outcomes, even though there is considerable controversy surrounding the predictive value of GPA and MCAT scores.Our aim in this article was to explore the relationship between standard admissions practices, which typically aim to attract students with the highest academic scores, and student body diversity. We examined how changes in GPA and MCAT scores over 5 years correlated with the percentage of enrolled students who are underrepresented in medicine. In a majority of medical schools in the United States from 2005 to 2009, average GPA and MCAT scores of applicants increased, whereas the percentage of enrolled students who are underrepresented in medicine decreased.Our findings suggest that efforts to increase the diversity of medical school student bodies may be complicated by a desire to maintain high average GPA and MCAT scores. We propose that U.S. News revise its ranking methodology by incorporating a new diversity score into its student selectivity score and by reducing the weight placed on GPA and MCAT scores.

Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.

e18299 Background: Unreported symptoms during cancer treatment can lead to poorer patient care and quality of life. Newer technology enables effective means to track patients’ health in real time. We evaluated the feasibility of implementing systematic patient symptom monitoring during the first 12 months after diagnosis. Methods: Newly diagnosed endometrial and ovarian cancer patients were enrolled post-surgically to respond to monthly text message symptom surveys. Patients’ fatigue, sleep quality, pain, and quality of life during the past 7 days were rated on a 0 (worst) -10 (best) scale, and depressive symptoms were assessed using the Patient Health Questionnaire (PHQ-9). Patients’ responses were captured in REDCap and monitored by program staff, with patients’ oncologists receiving monthly feedback. Patient navigators were also engaged for patients needing assistance during treatment. We provide the results of the first 6 months of this program. Results: 134 patients were approached, and 120 patients (ovarian [n = 70] and endometrial [n = 50]) were enrolled among 5 physicians. The mean participant age was 63 (range: 35-87), 85% were non-Hispanic White, and 66% had education beyond high school. The most commonly reported monthly symptoms for both cancer types were moderate levels (scores of ≥ 4-7) of fatigue and sleep disturbance. 35 patients with PHQ-9 scores ≥ 10 and/or with suicidal ideation were reported to their oncologists for appropriate follow-up. At the 6 month survey, patients were asked to evaluate the text messaging program: 97% found the symptom surveys easy to complete on their smart phone or computer; 77% believed reporting their symptoms monthly was useful all or most of the time; 78% liked being monitored for symptoms all or most of the time; and 89% liked being asked if they needed any assistance prior to their next clinic visit. Patient navigators were used by 13 patients, and 17 patients dropped from the program over the 6 months due to death (n = 9) or lack of need/interest (n = 8). Average monthly compliance was 81%. Conclusions: We established the feasibility of enrolling patients in a monthly text-based monitoring program to facilitate symptom management during treatment. Patient follow-up is continuing.

Results from multiple clinical trials, primarily with the class of lipid-lowering agents known as statins, have shown that reductions in low-density lipoprotein (LDL) cholesterol are associated with reduced risk of coronary artery disease. Although LDL cholesterol is the primary target of cholesterol management strategies, increasing attention has focused on the role of inflammation, high-density lipoprotein cholesterol, and triglycerides in atherosclerosis and cardiovascular disease. We review major trials with lipid-modifying therapies published since the 2004 update of the Adult Treatment Panel (ATP) III guidelines. A pivotal trial was the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), which demonstrated significant reductions in cardiovascular morbidity and mortality in healthy individuals without elevated LDL cholesterol but with high levels of the inflammatory marker high-sensitivity C-reactive protein. Additional trials demonstrated the efficacy of intensive statin therapy in secondary prevention, whereas other agents, including fibrates, omega-3 fatty acids, niacin, ezetimibe, and experimental cholesteryl ester transfer protein inhibitors, have been evaluated for their ability to reduce residual cardiovascular risk.

Strategies to reduce cardiovascular risk in primary and secondary prevention focus on optimization of low-density lipoprotein (LDL) cholesterol levels. Since the 2004 update of the Adult Treatment Panel (ATP) III guidelines, developments in the field of preventive cardiology have included new guidelines for women and for familial hypercholesterolemia; a risk assessment algorithm incorporating the inflammatory marker high-sensitivity C-reactive protein (hsCRP); and clinical trial data confirming the efficacy of aggressive lipid management. Within secondary prevention in particular, there is a need for more widespread use of intensive statin therapy to achieve low LDL cholesterol levels to reduce cardiovascular morbidity and mortality in patients at high risk for recurrent events. Within primary prevention, individuals with diabetes mellitus, mixed dyslipidemia, or elevated hsCRP also are at increased risk and may warrant treatment with aggressive lipid-modifying therapy. In this article, we provide an update on recent guidelines, risk algorithms, and trials related to the prevention and treatment of coronary artery disease.

Pitavastatin is a new, synthetic member of the statin class of lipid-lowering drugs. Compared with other available statins, it has a unique cyclopropyl group on its base structure that is believed to increase 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition by a factor of five and to significantly increase the transcription and activity of LDL receptors. Pitavastatin is primarily metabolized via glucuronidation and is not a substrate for the cytochrome P450 3A4 enzyme, thus avoiding the potential for cytochrome P450-mediated drug-drug interactions. Clinical trials have shown that pitavastatin is comparable to atorvastatin and simvastatin in improving lipid measures, and more potent than pravastatin. Pitavastatin is effective in reducing triglycerides and increasing HDL-cholesterol, so it will be particularly beneficial in treating patients with mixed dyslipidemia. Its safety and adverse event profile is similar to that of other available statins, and it has an established history of use in Asia indicating tolerability and safety for treatment lasting up to 7 years.

e12523Background: Despite the proven clinical efficacy of adjuvant hormone therapy (AHT) for breast cancer survivors, evidence suggests that up to 50% of patients do not complete treatment as recom...

Plants depend on light signals to modulate many aspects of their development and optimize their photosynthetic capacity. Phytochromes (phys), a family of photoreceptors, initiate a signal transduction pathway that alters expression of a large number of genes to induce these responses. Recently, phyA and phyB were shown to bind members of a basic helix–loop–helix family of transcription factors called phy-interacting factors (PIFs). PIF1 negatively regulates chlorophyll biosynthesis and seed germination in the dark, and light-induced degradation of PIF1 relieves this negative regulation to promote photomorphogenesis. Here, we report that PIF1 regulates expression of a discrete set of genes in the dark, including protochlorophyllide oxidoreductase ( POR ), ferrochelatase ( FeChII ), and heme oxygenase ( HO3 ), which are involved in controlling the chlorophyll biosynthetic pathway. Using ChIP and DNA gel-shift assays, we demonstrate that PIF1 directly binds to a G-box (CACGTG) DNA sequence element present in the PORC promoter. Moreover, in transient assays, PIF1 activates transcription of PORC in a G-box-dependent manner. These data strongly suggest that PIF1 directly and indirectly regulates key genes involved in chlorophyll biosynthesis to optimize the greening process in Arabidopsis .

Statins are the mainstay of therapy for the management of dyslipidemia, and particularly elevations in low-density lipoprotein cholesterol (LDL-C). Currently available statins include atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin. The advent of statin therapy has contributed to a substantial decrease in cardiovascular mortality over the past several decades. Results from multiple clinical trials have shown conclusively that lowering LDL-C levels leads to clinical event reduction in primary and secondary prevention, for both men and women, and across various other patient subgroups. Extensive clinical experience indicates that statin therapy may be initiated and maintained over the long term with a high degree of safety, and adverse effects associated with statin use are outweighed by their proven benefits in clinical event reduction.

Regulated protein degradation contributes to plant development by mediating signaling events in many hormone, light, and developmental pathways. Ubiquitin ligases recognize and ubiquitinate target proteins for subsequent degradation by the 26S proteasome. The multisubunit SCF is the best-studied class of ubiquitin ligases in Arabidopsis (Arabidopsis thaliana). However, the extent of SCF participation in signaling networks is unclear. SCFs are composed of four subunits: CULLIN 1 (CUL1), ASK, RBX1, and an F-box protein. Null mutations in CUL1 are embryo lethal, limiting insight into the role of CUL1 and SCFs in later stages of development. Here, we describe a viable and fertile weak allele of CUL1, called cul1-6. cul1-6 plants have defects in seedling and adult morphology. In addition to reduced auxin sensitivity, cul1-6 seedlings are hyposensitive to ethylene, red, and blue light conditions. An analysis of protein interactions with the cul1-6 gene product suggests that both RUB (related to ubiquitin) modification and interaction with the SCF regulatory protein CAND1 (cullin associated and neddylation dissociated) are disrupted. These findings suggest that the morphological defects observed in cul1-6 plants are caused by defective SCF complex formation. Characterization of weak cul1 mutants provides insight into the role of SCFs throughout plant growth and development.

Summary Light signals perceived by the phytochrome (phy) family of sensory photoreceptors control multiple aspects of plant development. Recently, PIF1, a phy-interacting basic helix-loop-helix (bHLH) transcription factor, has been shown to negatively regulate facets of the photomorphogenesis of seedlings. Moreover, the transcriptional activation activity of PIF1 is reduced in a phy-dependent manner. In this study we use the luciferase (LUC) activity of the LUC–PIF1 fusion protein as an indicator of the stability of PIF1 in various light conditions. We found that the activity of LUC–PIF1 in both transient and stable transgenic lines is rapidly reduced in light, while the LUC-only control is stable under the same conditions, suggesting that PIF1 is degraded in response to light. Fluence-rate response curves indicate that PIF1 degradation is very sensitive to the quality and quantity of light. The half-life of PIF1 is about 16 min under 10 μmol m−2 sec−1 red light. PIF1 reaccumulates in the subsequent dark period after light-induced degradation, signifying that PIF1 not only functions in the dark and during the transition from etiolated to de-etiolated growth, but may also function during diurnal cycles. Inhibitors of the 26S proteasome increased the stability of PIF1, indicating that degradation of PIF1 is mediated by the ubiquitin-26S proteasome pathway. Further, de novo protein synthesis is not required for degradation of PIF1, as the presence of cycloheximide does not prevent degradation of PIF1 in the light. Taken together, these results suggest that the light signals perceived by phys induce the degradation of PIF1 and other phy-interacting factors to optimize photomorphogenesis.

The importance of the ubiquitin-proteasome pathway to cellular regulation in eukaryotes has become increasingly apparent during the last several years. This fact was formally acknowledged recently by the awarding of the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko, and Irwin

This study tested prefrontal and hippocampal functions in a sample of 28 school-aged (M = 14.7 years, SD = 2.7) individuals with Down syndrome (DS) compared with 28 (M = 4.9 years, SD = .75) typically developing children individually matched on mental age (MA). Both neuropsychological domains were tested with multiple behavioral measures. Benchmark measures of verbal and spatial function demonstrated that this DS sample was similar to others in the literature. The main finding was a significant Group x Domain interaction effect indicating differential hippocampal dysfunction in the group with DS. However, there was a moderate partial correlation (r = .54, controlling for chronological age) between hippocampal and prefrontal composite scores in the DS group, and both composites contributed unique variance to the prediction of MA and adaptive behavior in that group. In sum, these results indicate a particular weakness in hippocampal functions in DS in the context of overall cognitive dysfunction. It is interesting that these results are similar to what has been found in a mouse model of DS. Such a model will make it easier to understand the neurobiological mechanisms that lead to the development of hippocampal dysfunction in DS.

Aim We aim to evaluate the efficacy and safety of determining the presence of true biventricular pacing by administration of intravenous adenosine. This aims to determine whether non-response to biventricular pacing therapy is partially explained by over-counting of the percentage of pacing therapy by the presence of fusion beats. We compared the proportion of patients with fusion beats in non-responders compared to responders Methods This will be a single centre, prospective, cohort study. 71 consecutive patients with implanted cardiac resynchronisation devices between July 2006 and November 2015 were identified. Patients underwent the adenosine trial at least 12 months post CRT device implantation to detect the presence of potentially ineffective biventricular pacing. This was compared with the recorded percentage of biventricular pacing reported during device interrogation. Correlation was made between response to CRT therapy and presence of effective biventricular pacing. Results Preliminary results from 24 patients demonstrate that symptomatic adenosine administration was successful in identifying true effective biventricular paced beats. This has allowed us to identify patients with fusion beats. 8 patients were non-responders to CRT, whereas 16 patients were responders. 50% (n=4) of non-responders and 12.5% (n=2) of responders had definite electrocardiography (ECG) changes through the symptomatic adenosine administration, showing that a percentage of the paced beats counted by the CRT device may in fact be fusion beats. Figure 1 shows the clear change in the morphology of the QRS complex in one of the non-responders. Figure 1 Electrocardiogram of a non-responder during symptomatic adenosine administration Conclusion Preliminary results suggest that symptomatic adenosine administration is successful in identifying true effective biventricular paced beats which may be overestimated by CRT device interrogation. Correlation with response to CRT is yet to be established, but in 50% of the non-responders we identified a definite change in the morphology of the paced rhythm during the symptomatic response to adenosine. This raises a question of whether the poor response to CRT for these patients is actually due to the insufficient percentage of effective biventricular pacing (

The widespread clinical use of statins has contributed to significant reductions in the rate of cardiovascular morbidity and mortality over the past 3 decades, and statins are considered first-line therapy for the prevention and treatment of atherosclerotic vascular disease. Nevertheless, various other lipid-lowering agents can provide clinical benefit by supplementing or augmenting statin therapy in patients with severe hypercholesterolaemia or mixed dyslipidaemia, or by providing an alternative for patients who are intolerant to statins. Bile acid resins and niacin were prescribed for lipid modification for years before the introduction of the statins, and new data continue to emerge regarding their use in different patient groups and for specific conditions. Ezetimibe can be appropriate for patients whose primary lipid abnormality is an elevated LDL-cholesterol level, whereas the fibrates seem to be most beneficial in patients with low levels of HDL cholesterol and elevated triglycerides. At the end of 2012 and the beginning of 2013, the first microsomal triglyceride transfer protein inhibitor, lomitapide, and the first antisense therapy to target apolipoprotein B, mipomersen, were approved for the treatment of individuals with extremely elevated LDL-cholesterol levels caused by homozygous familial hypercholesterolaemia. Although two agents in the experimental class of cholesteryl ester transfer protein inhibitors have failed to show a benefit in clinical trials, newer drugs in this class could provide an additional strategy to address residual cardiovascular risk in patients treated with statins.

The aim of this study was to assess the effects on lipids and safety during a 12-week reversal period after 18 months of treatment with anacetrapib. The cholesteryl ester transfer protein inhibitor anacetrapib was previously shown to reduce low-density lipoprotein cholesterol by 39.8% (estimated using the Friedewald equation) and increase high-density lipoprotein (HDL) cholesterol by 138.1%, with an acceptable side-effect profile, in patients with or at high risk for coronary heart disease in the Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib (DEFINE) trial. A total of 1,398 patients entered the 12-week reversal-phase study, either after completion of the active-treatment phase or after early discontinuation of the study medication. In patients allocated to anacetrapib, placebo-adjusted mean percentage decreases from baseline were observed at 12 weeks off the study drug for Friedewald-calculated low-density lipoprotein cholesterol (18.6%), non-HDL cholesterol (17.6%), and apolipoprotein B (10.2%); placebo-adjusted mean percentage increases were observed for HDL cholesterol (73.0%) and apolipoprotein A-I (24.5%). Residual plasma anacetrapib levels (about 40% of on-treatment apparent steady-state trough levels) were also detected 12 weeks after cessation of anacetrapib. No clinically important elevations in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the reversal phase. Preliminary data from a small cohort (n = 30) revealed the presence of low concentrations of anacetrapib in plasma 2.5 to 4 years after the last anacetrapib dose. In conclusion, after the cessation of active treatment, anacetrapib plasma lipid changes and drug levels decreased to approximately 40% of on-treatment trough levels at 12 weeks after dosing, but modest HDL cholesterol elevations and low drug concentrations were still detectable 2 to 4 years after the last dosing.

A practical and scalable preparation of 1-(7-fluoronaphthalen-1-yl)-piperazine hydrochloride (1) is reported. The original route for the synthesis of this compound involved the use of 1-amino-7-fluoronaphthalene and bis(2-chloroethyl)amine hydrochloride, two highly toxic compounds. A new protocol has been developed that employs a palladium-catalyzed Buchwald–Hartwig cross-coupling reaction between 1-Boc-piperazine and 1-bromo-7-fluoronaphthalene followed by piperazine deprotection with HCl gas. In addition, an efficient palladium removal protocol allowed for the preparation of the target molecule with less than 20 ppm of this metal. This methodology has been successfully implemented to produce multigram quantities of 1 with excellent purity and low palladium content.

Light signals perceived by the phytochrome (phy) family of sensory photoreceptors control multiple aspects of plant development. Recently, PIF1, a phy-interacting basic helix-loop-helix (bHLH) transcription factor, has been shown to negatively regulate facets of the photomorphogenesis of seedlings. Moreover, the transcriptional activation activity of PIF1 is reduced in a phy-dependent manner. In this study we use the luciferase (LUC) activity of the LUC-PIF1 fusion protein as an indicator of the stability of PIF1 in various light conditions. We found that the activity of LUC-PIF1 in both transient and stable transgenic lines is rapidly reduced in light, while the LUC-only control is stable under the same conditions, suggesting that PIF1 is degraded in response to light. Fluence-rate response curves indicate that PIF1 degradation is very sensitive to the quality and quantity of light. The half-life of PIF1 is about 16 min under 10 micromol m-2 sec-1 red light. PIF1 reaccumulates in the subsequent dark period after light-induced degradation, signifying that PIF1 not only functions in the dark and during the transition from etiolated to de-etiolated growth, but may also function during diurnal cycles. Inhibitors of the 26S proteasome increased the stability of PIF1, indicating that degradation of PIF1 is mediated by the ubiquitin-26S proteasome pathway. Further, de novo protein synthesis is not required for degradation of PIF1, as the presence of cycloheximide does not prevent degradation of PIF1 in the light. Taken together, these results suggest that the light signals perceived by phys induce the degradation of PIF1 and other phy-interacting factors to optimize photomorphogenesis.