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A radiomics nomogram for pretreatment prediction of TACE refractoriness was developed and validated for hepatocellular carcinoma (HCC) without extrahepatic metastasis or macrovascular invasion. This study included 80 patients with HCC without extrahepatic metastasis or macrovascular involvement treated with TACE between July 2016 and November 2018. The datasets were divided into a training set (80%) and a test set (20%) for feature selection and tenfold cross-validation. Forty radiomic features were extracted from arterial-phase computed tomography (CT) using the Local Image Features Extraction software. The Lasso regression model was used for radiomics signature selection. The Lasso regression model was used for radiomics signature selection and the selected signatures were validated using the Mann–Whitney U-test. The radiomics nomogram was developed based on a multivariate logistic regression model incorporating the Rad-score, CT imaging factors, and clinical factors, and it was validated. The Rad-score, which consists of the Gray-Level Zone Length Matrix (GLZLM)—Long-Zone Low Gray-Level Emphasis (LZLGE) and GLZLM—Gray-Level Non-Uniformity (GLNU), T-stage, log α-fetoprotein (AFP), and bilobar distribution were significantly associated with TACE refractoriness (p

Glioblastoma (GBM) patients can use tumor-treating fields (TTFs) with adjuvant temozolomide (TMZ) to treat their disease. TTFs involve wearing transfixed transducers to the shaved scalp, and the transducers are wired to a battery pack that is either fixed or carried (weighing 2.7 pounds). EF-14 clinical trial did evaluate health-related quality of life with standardized patient-report outcome measures but did not measure exercise behavior. We sought to evaluate the exercise behavior of GBM patients using TTFs. We consented GBM patients who intended to use TTFs with adjuvant TMZ after completion of chemoradiation. After informed consent and before starting TTFs, patients completed a self-administered questionnaire, Godin Leisure-Time Exercise Questionnaire, to assess exercise behavior/physical function. To calculate our primary outcome of total exercise behavior, the frequency of exercise sessions per week within each intensity category was multiplied by the average reported duration, weighted by an estimate of the MET, summed across all intensities, and expressed as average MET-hr/wk. Prior work has defined that physical function can be compared as < 9 MET-h/wk vs. ≥ 9 MET-h/wk. We evaluated at baseline and up to 24-week exercise behavior in patients with TTFs vs. historical controls not using TTFs. We enrolled 19 total GBM patients, with 14 proceeding to use TTFs. Of the 14 patients on TTFs, seven patients (50%) completed ≥ 9 MET-h/wk of exercise, and this level was maintained 8, 16, and 24 weeks after starting TTFs. Six months after the completion of chemoradiation, mean MET-h/wk was decreased in the TTFs group (n=6) (10.71 sd=7.06) vs. historical controls (n=38) (27.35 sd=46.94). TTFs did not interfere with exercise behavior in our GBM cohort, but when compared to GBM patients not utilizing TTFs, there could be a long-term impact on exercise behavior. More research is needed to evaluate exercise behavior in GBM patients using TTFs.

Background It is unclear whether catheter ablation is beneficial in frail patients with AF. Purpose This study aimed to evaluate whether catheter ablation reduces death and other outcomes in real-world frail patients with atrial fibrillation (AF). Methods Out of 801,710 patients with AF in the Korean National Health Insurance Service database from 2006 to 2015, 1,411 frail patients underwent AF ablations. The Hospital Frailty Risk Score were calculated retrospectively. Inverse probability of treatment weighting (IPTW) was used to categorize ablation and non-ablation frail groups. Results After IPTW, the two cohorts had similar background characteristics. During a median follow-up of 4.7 years (interquartile range: 2.2–7.8), the risk of death in frail patients with ablations was reduced by 65% compared to frail patients without ablations (2.0 and 6.4 per 100 person-years, respectively; hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.25–0.50; P Conclussion Ablation may be associated with lower incidences of death, heart failure, and acute myocardial infarction in real-world frail patients with AF, supporting the role of AF ablation in these patients. The effect of frailty risk on the outcome of ablation should be evaluated in further studies. Funding Acknowledgement Type of funding source: None

Background There is consistent evidence of the association between ideal cardiovascular health and lower incident cardiovascular disease (CVD); however, most studies used a single measure of cardiovascular health. Purpose To examine the association of change in cardiovascular health with subsequent incident CVD and mortality in elderly population. Methods In the Korea National Health Insurance Service-Senior (≥60 years) cohort, 312,736 participants who received national health check-ups between 2005–2012 were assessed for eligibility. Using the 7metrics of the American Heart Association (nonsmoking; and ideal levels of body mass index, physical activity, diet, blood pressure, fasting blood glucose, and total cholesterol), participants with 0 to 2, 3 to 4, and 5 to 7 ideal metrics were categorized as having low, moderate, and high cardiovascular health. Change in cardiovascular health over 2 years between 2005 and 2006 was considered. Results The study population included 162,149 participants without prior CVD or malignancy (median age at baseline, 69 [IQR 66–73] years; 91,408 [56.2%] women), of whom 59,887 had data about cardiovascular health change. Over a median follow-up of 5.8 (5.5–8.0) years, 5346 incident CVD events and 6035 death occurred. In multivariable analysis and compared with individuals with persistently low cardiovascular health (consistently low group, 7.9% of participants; CVD incident rate per 1000 person-years, 21.1 [95% CI, 19.4–23.0]), a lower CVD risk was observed in the consistently moderate group (38.7% of participants; absolute rate difference per 1000 person-years, −4.8 [95% CI, −5.5 to −4.1]; HR, 0.77 [95% CI, 0.70–0.85]), the moderate to high group (11.6% of participants; absolute rate difference per 1000 person-years, −7.7 [95% CI, −8.8 to −5.5]; HR, 0.62 [95% CI, 0.55–0.70]), the high to moderate group (11.2% of participants; absolute rate difference per 1000 person-years, −7.2 [95% CI, −8.3 to −5.9]; HR, 0.64 [95% CI, 0.56–0.72]), and the consistently high group (11.3% of participants; absolute rate difference per 1000 person-years, −10.2 [95% CI, −11.2 to −9.1]; HR, 0.51 [95% CI, 0.44–0.58]). A lower mortality risk was observed in the consistently moderate group, the moderate to high group, and the high to moderate or high groups. Conclusion Among a group of elderly participants without CVD, there was benefit of moderate or high cardiovascular health for incident cardiovascular events and mortality. Funding Acknowledgement Type of funding source: None

Background Predictors are not well known for long-lasting sinus rhythm after atrial fibrillation catheter ablation (AFCA). Purpose We investigated the pre-procedural clinical factors associated with the patients with 5-year long-term atrial fibrillation (AF) free after AFCA. Methods Among 2,085 patients who underwent de novo AFCA, 934 patients (58±11 years, 73.1% male, 66.0% paroxysmal AF), who underwent guidelines-based rhythm follow-up longer than 5-years, were included in this study. We compared 340 patients who never showed AF recurrence for 5-years and 594 patients with AF/ atrial tachycardia (AT) recurrence at least a single episode. Cut-off values of pericardial fat volume and electrocardiogram (ECG) parameters were obtained by Youden index. Results 1. The patients with AF-free for 5-years (AF-Free-5yrs) had higher proportion of paroxysmal AF (p Conclusions Pericardial fat volume ( Funding Acknowledgement Type of funding source: None

Patients with glioblastoma have poor overall survival and experience significant burden from neurologic decline and adverse treatment effects. Despite the well-known benefits of early palliative care integration with oncology care, utilization of palliative care is low. The purpose of this quality improvement (QI) project is to investigate the feasibility, value, and effectiveness of using an adapted palliative care screening tool to improve outpatient palliative care screening and referral of glioblastoma patients. This QI project was conducted over a 10-week period. A glioma palliative care screening tool was developed and integrated into outpatient visits. Providers were required to use the screening tool during each patient visit. Patients 18 years or older who were diagnosed with a World Health Organization grade IV glioma and returning to the neuro-oncology clinic for a brain MRI evaluation were targeted. Screening, palliative care discussion, and referral rates were evaluated. Among 530 eligible patients who returned to the clinic over a 10-week period, the tool was available for 433 patients. Fifty-six percent (n = 294/530) of the patients were screened. Nine percent (n = 27) of screened patients were identified as candidates for a palliative care referral (score ≥ 5 on the screening tool). Of these 27 patients, the proportion of patients who had a palliative care discussion was 63% (n = 17). Overall, 71% (n = 12) of patients who had a palliative care discussion were referred to a palliative care provider. Integrating a glioma palliative care screening tool with outpatient visits can draw attention to palliative care needs and lead to a referral to palliative care.

We report a phase I pharmacological study of an oral formulation of CKD‐516, a vascular‐disrupting agent, in patients with refractory solid tumors. Twenty‐seven patients (16 in the dose‐escalation cohort and 11 in the expansion cohort) received a single daily dose (5‐25 mg) of CKD‐516 five days per week. Nausea (67%) and diarrhea (63%) were the most common treatment‐related adverse events. The recommended phase II dose of oral CKD‐516 was 20 mg/d (15 mg/d with a body surface area (BSA)

Isocitrate dehydrogenase 1 (IDH1) is commonly mutated in grade II-III gliomas, and the mutant enzyme leads to the production of the oncometabolite 2-hydroxyglutarate (2-HG). 2-HG is responsible for the gliomagenesis associated with these tumors and the promotion of seizures via glutamate receptors. Ivosidenib, a small molecule oral mIDH1 inhibitor, has shown promise in clinical trials to treat IDH1 mutant gliomas, and providers can utilize this agent in IDH1 mutant glioma patients. We evaluated our IDH1 mutant glioma patients treated off-label with ivosidenib and described the radiographic response and seizure control in this cohort when ivosidenib was initiated between October 2020 to February 2021. Radiographic response was determined using RANO criteria, and seizure control was determined by comparing seizures per month before and after initiation of ivosidenib. All patients represented received single-agent ivosidenib dosed at 500 mg orally once a day. One patient required a dose reduction to 250 mg orally once a day because of drug-induced diarrhea. In our cohort of six patients, patient age range was 31 to 74 years with four female patients and two male patients. Diagnoses represented were astrocytoma, IDH1 mutant (n=3) oligodendroglioma (WHO), IDH1 mutant, 1p19q co-deleted (n=2), and anaplastic astrocytoma IDH1 mutant (n=1). Three patients experienced a reduction of seizure frequency, two patients did not have seizures before or after therapy, and one patient remained with the same level of seizures (1 seizure/month). Radiographic responses recorded included three patients with stable disease, two patients with minor responses, and one patient with a partial response. Treatment with ivosidenib is ongoing for this cohort of mIDH1 glioma patients. Updated information on prolonged disease control and seizure control in this cohort of IDH1 mutant glioma patients will be presented. Therapeutics, such as ivosidenib, can lead to improved seizure control and radiographic outcomes in IDH1 mutant glioma patients.

INTRODUCTION There is increasing recognition that palliative care (PC) can benefit patients with advanced cancers. However, early referral to PC is not yet a reality for patients diagnosed with a primary brain tumor. We hypothesize that lack of knowledge and/or misperceptions regarding PC by patients, caregivers, or their providers remain barriers. METHODS This is an IRB-exempt, one-time QR-accessible REDcap questionnaire administered to patients, caregivers, and providers at the Preston Robert Tisch Brain Tumor Center between September 2020 and May 2021. We administered 9 questions regarding knowledge and beliefs about PC from the Health Information National Trends Survey 5, Cycle 2: results of this nationally representative U.S. sample are publicly available and used for comparison. RESULTS We had 141 survey respondents: 25 providers, 59 patients, and 57 caregivers. The median patient and caregiver ages were 49 (21-74) and 50 years (24-73), respectively. Caregivers were more likely female (55.2 %) and identified as a spouse or domestic partner (58.2%). Providers, were equally distributed by years of experience. Compared to patients and caregivers, providers reported more baseline knowledge of PC (p< 0.0001, p< 0.0001) and better understood the role of PC in pain/symptom management (p=0.0038, p=0.0087) and social/emotional support (p=0.0044, p=0.0279). Interestingly, most providers (76.0%) disagreed with the statement “the goal of palliative care is to give patients more time at the end of life.” Compared to a general U.S. sample (n=1,162) our patients (n=39) were better informed in only 2 of 9 questions. Whereas, caregivers (n=48) were better informed in 6 of 9 questions. CONCLUSION Neuro-oncology providers were knowledgeable, but a minor gap in understanding the goal of PC was identified. Caregivers were overall more knowledgeable than patients. However, Neuro-oncology patients, had similar knowledge and beliefs compared to a nationally representative sample. PC interventions should prioritize filling knowledge gaps for Neuro-oncology patients.

PURPOSE/OBJECTIVE(S) Radiographic density changes in normal lung parenchyma are a function of radiation dose, are associated with inflammation, and vary among patients. The purpose of this study is to evaluate these radiation-induced changes quantitatively in different patient cohorts treated with PD-1 Immune Checkpoint Inhibitors (ICI) and investigate them as possible RT-related imaging biomarker for outcome. MATERIALS/METHODS We looked at two groups of non-small cell lung cancer (NSCLC) patients drawn from two institutions: patients with metastatic disease treated with non-curative intent and normal lung in the radiation field, and patients receiving definitive chemo-radiation (CRT) followed by adjuvant PD-L1 blockade (durvalumab), some of which received durvalumab also concurrently. Normal lung parenchyma on the first post-treatment chest computer tomography (CT) scans (median time 3 months post RT) was deformably registered to the treatment plan to analyze lung density changes as function of dose, normalized to 2Gy-equivalent, and quantified as Hounsfield Unit (HU)/Gy. Differences between groups were assessed using Wilcoxon's rank sum test, correlation to progression-free and overall survival using Cox regression. RESULTS We analyzed a total of 26 patients treated with non-curative intent RT and 60 patients who received CRT. For metastatic patients, RT delivered concurrently with ICI (n = 16) led to significantly larger changes compared to patients receiving RT before initiation of ICI (median 2.21 vs 0.27 HU/Gy, P = 0.02), even though the former received significantly lower doses to the normal lung (median 27.6 vs 55.8 Gy, P = 0.02). Fraction sizes were smaller when RT was delivered concurrently with ICI (median 3.3 vs 5.5 Gy/fraction). Number of patients and events in metastatic patients were too low for survival analysis. During CRT, patients receiving concurrent durvalumab (n = 20) did not show significant lung density changes compared to those that did not (median 1.39 vs 1.28 HU/Gy, P = 0.99). All CRT patients received 1.8-2.2 Gy/fraction. The amount of change in each patient did not correlate with progression-free or overall survival (HR = 0.91, 95% CI [0.71-1.16] and HR = 0.92, [0.72-1.17] respectively). CONCLUSION RT delivered concurrently with PD-1 ICI leads to significantly increased normal lung density changes in metastatic patients but not in locally advanced patients treated with CRT, possibly related to the different fraction size. For CRT patients treated with adjuvant durvalumab, normal lung changes after CRT do not correlate with outcome. The correlation of lung density changes to oncologic outcomes in metastatic patients' needs to be studied in larger cohorts.

OBJECTIVE There is no validated model for delivering palliative care (PC) in the glioblastoma (GBM) population. The primary objectives were to assess the feasibility and determine the acceptability of a time-based model of integrated specialty PC to patients and providers. Secondary objectives were to estimate the impact on healthcare utilization and quality of life (QoL) compared to historical controls. METHODS We consented and referred patients to PC at their initial Neuro-Oncology consultation between 4/2018 and 5/2019. We conducted QoL assessments (NCCN Distress Tool; Functional Assessment of Cancer Therapy-Brain (FACT-BR); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); Epworth Sleepiness Scale (ESS)) at (1) baseline (2) immediately after chemoradiation, and (3) 6 months following chemoradiation. Ongoing PC follow-up was at the discretion of the PC provider. We administered the Edmonton Symptom Assessment System (ESAS) before and after PC visits. We measured patient and referring provider satisfaction using FAMCARE-16 and a PC departmental survey, respectively. RESULTS We did not meet our goal enrollment of 50 patients. 32 were offered participation, 12 consented and 8 attended at least one PC visit. The mean number of PC visits was 1.6. Mean age was 62 (42–79). 75% had a KPS ≥80. Of those that did not complete the study, 2 died and 5 either withdrew consent or declined further visits. At baseline, 91.7 % had a NCCN distress score ≥4. Patients were overall satisfied with the intervention. CONCLUSION Introduction of specialty PC at the time of GBM diagnosis is challenging. Participants reported their experience as overall positive. Results from referring providers are pending. Due to low-enrollment we did not pursue further statistical comparisons regarding healthcare utilization compared to historical controls.

Background There are limited and conflicting data regarding the prognostic implication of guideline-directed therapy, especially in heart failure (HF) patients with atrial fibrillation (AF). Thus, this study evaluated the relationship between guideline adherence to recommended therapy at discharge and relevant 60-day clinical outcomes in acute HF patients with AF having reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). Methods and results Of 5,625 acute HF patients in the Korean Acute Heart Failure Registry, 2,071 with documented AF (HFrEF, n=986; HFpEF, n=1,085) were separately analysed. A guideline adherence score was calculated for the prescription of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, mineralocorticoid receptor antagonists, and anticoagulants. In HFrEF patients with AF, there was significant trend of increase in mortality (p for trend Conclusion Better adherence to guidelines was associated with a better 60-day prognosis in both HFrEF and HFpEF patients with AF. However, the beneficial effect of guideline adherence was more pronounced in HFrEF patients with AF.

Background Overall survival (OS) in glioblastoma (GBM) is poor at an average of 14 to 18 months, and long-term survivors (LTS) of GBM are rare. LTS of GBM, defined as surviving >5 years postdiagnosis, represent only 2% to 10% of all GBM patients. LTS of cancer are at high risk of developing second primary neoplasms. This study looks at occurrences of second primary neoplasms in LTS of GBM. Methods Records from adult patients newly diagnosed with GBM between January 1, 1998 and February 8, 2010, were retrospectively reviewed to identify LTS, defined as patients who survived ≥5 years. We focused on the identification of a new diagnosis of cancer occurring at least 2 years after the initial GBM diagnosis. Results We identified 155 LTS of GBM, with a median OS of 11.0 years (95% CI: 9.0 to 13.1 years) and a median follow-up of 9.6 years (95% CI: 8.7 to 10.7 years). In this cohort of patients, 13 (8.4%) LTS of GBM developed 17 secondary cancers. Eight could potentially be attributed to previous radiation and chemotherapy (skin cancer in radiation field [n = 4], leukemia [n = 2], low-grade glioma [n = 1], and sarcoma of the scalp [n = 1]). The other 9 cases included melanoma (n = 2), prostate cancer (n = 2), bladder cancer (n = 1), endometrioid adenocarcinoma (n = 1), basal cell carcinoma (n = 1), and renal cell carcinoma (n = 1). Conclusions Although second primary cancers are rare in GBM LTS, providers should continue close monitoring with appropriate oncologic care. Moreover, this highlights the need for survivorship care of patients with GBM.

To obtain an additional pharmacological agent for the diagnosis of inflammation, we investigated the medical use of (89)Zr-oxalate as a positron emission tomography (PET) probe for the in vivo imaging of inflammation and compared its efficacy to that of 2-deoxy-2-[(18)F]fluoro-d-glucose ([(18)F]FDG) and sodium [(18)F]fluoride. (89)Zr-oxalate exhibited observable higher uptake in a macrophage cell line than in tumor cells. The inflammatory lesions and tumors were clearly visualized by PET imaging and autoradiography using (89)Zr-oxalate. Compared to [(18)F]FDG and sodium [(18)F]fluoride, (89)Zr-oxalate demonstrated a high selectivity index to the tumor at an early time point after injection and to inflammation at a delayed time point after injection (24 h). Through histological examination, large numbers of macrophages and neutrophils were observed in the tumor lesions with the highest (89)Zr-oxalate uptake. In a rheumatoid arthritis (RA) mouse model, (89)Zr-oxalate demonstrated a high level of accumulation in inflammatory lesions. (89)Zr-oxalate is a new strategic tool for tumor imaging and inflammatory processes.

INTRODUCTION Malignant glioma (MG) patients often experience chemotherapy-induced nausea and vomiting (CINV). Olanzapine has recently been added to national anti-emesis guidelines for patients on moderately/highly emetogenic chemotherapy. In this retrospective study, we investigated the use of olanzapine for refractory-CINV (R-CINV) in MG patients. METHODS In this chart review, we queried adult MG patients with KPS ≥ 70 who received olanzapine from January 2019-March 2020. Patients were included if they were prescribed olanzapine for CINV. Data on nausea/vomiting improvement, olanzapine dosing/schedule, number of refractory anti-emetic trials, concomitant corticosteroid use, and demographics were collected. RESULTS We identified 21 MG patients who were prescribed olanzapine, with 9 of those patients receiving olanzapine specifically for CINV. Seven patients had WHO grade IV glioma, and 2 patients had anaplastic astrocytoma (WHO grade III). Five of 9 patients (55.6%) were male, all were Caucasian and median age was 54 years. Patients tried an average of 3 anti-emetics prior to initiating olanzapine for R-CINV. Only one patient was taking concomitant corticosteroids; which is not in concordance with national anti-emesis guidelines. Four of 9 patients (44.4%) achieved control of R-CINV with olanzapine. The olanzapine dose and key biomarkers (IDH-status, MGMT promoter methylation) were similar between those experiencing R-CINV and those without symptoms. CONCLUSIONS In this study, we find that approximately half of patients with R-CINV achieved improved nausea and vomiting control with the addition of olanzapine. The lack of corticosteroid use for anti-emesis in MG continues to make this population challenging to manage. The relatively high success rate in patients that had failed, on average, 3 anti-emetics, suggests that olanzapine may be a potent addition to the anti-emetic toolkit for MG patients. These results inspire further large-scale research to validate this observation and define the optimal role for olanzapine in treating R-CINV in MG patients.

BACKGROUND From the time of diagnosis to end of life, patients with primary brain tumors experience challenges to maintain quality of life. While traditional research focuses on clinical trials that involve directly treating cancer, we have designed a specific research committee at our institution that promotes supportive care research to improve patients’ and caregivers’ quality of life. Past research has shown that issues key to patients and caregivers often differ from what researchers and providers might appreciate as important. Incorporating input from brain tumor patients and caregivers is vital to direct the most relevant and necessary supportive care research. METHODS As part of an IRB-approved quality improvement project, we sought the opinions of our supportive care research committee about what are the essential quality of life issues for brain tumor patients and caregivers. We polled our committee before and after a session with patients and caregivers discussing factors relevant to their quality of life. After this patient/caregiver intervention, we used a group discussion and note comparison technique to distill down key elements to advance supportive care research for this population. RESULTS Engagement of the committee included members that were neuro-oncology providers, biostatisticians, and data/regulatory/clinical trial staff. Before the intervention, common themes about key issues for patients and caregivers were comfort, pain management, counteracting side effects, cognitive issues, and financial toxicity. While similar themes emerged after the patient/caregiver intervention, the committee gleaned that aspects of communicating outcomes and support of caregivers were consistently mentioned from the discussion session with patients and caregivers. CONCLUSIONS Opinions of brain tumor patients and caregivers are crucial in driving future direction and relevance of supportive care research in neuro-oncology. Our supportive care research committee will continue to engage patients and caregivers and are planning interventions to improve communication and support for caregivers.

Objectives To identify the tumors included in the WHO classification of low-grade gliomas, and review the importance of molecular biomarkers and their implication for treatment, prognosis, and outcomes. Data Sources Published research, clinical guidelines, educational articles in oncology journals, and Web-based resources. Conclusion Molecular neuropathology has influenced the reclassification of low-grade gliomas and, as such, has provided patient-specific treatments with improving outcomes. Implications for Nursing Practice Nurses play a key role in patient education and communication with the patient's interdisciplinary care team. Understanding the molecular neuropathology that determine treatment recommendations and in turn recognizing and identifying complications provides improved patient/caregiver satisfaction and outcomes.

Glioblastoma multiforme (GBM), the most common malignant brain tumor, is characterized by aggressive proliferation and invasive potential. Xenograft animal models of GBM have critically contributed to evaluation of novel therapeutic agents, drug delivery system, and diagnostic tools. To mimic intrinsic behavior of GBM, orthotopic transplantation of cancer cells and continuous observation of cell growth should be conducted in animal study. Here, we generated xenograft model mouse of GBM in which U-87 MG human glioblastoma cells were intracranially implanted for live imaging. Introducing luciferase gene into U-87 MG cell line enabled real-time observation and quantification of tumor survival and propagation by detecting photon emission derived from luciferase. Our GBM model mouse has potentials to bring great advantages in pharmacological and mechanistic investigation on brain tumors.

The thymidine analogue 3′-deoxy-3′-[18F]fluorothymidine, or [18F]fluorothymidine ([18F]FLT), is used to measure tumor cell proliferation with positron emission tomography (PET) imaging technology in nuclear medicine. FLT is phosphorylated by thymidine kinase 1 (TK1) and then trapped inside cells; it is not incorporated into DNA. Imaging with18F-radiolabeled FLT is a noninvasive technique to visualize cellular proliferation in tumors. However, it is difficult to distinguish between [18F]FLT and its metabolites by PET imaging, and quantification has not been attempted using current imaging methods. In this study, we successfully acquiredin vivoF19spectra of natural or nonradioactive 3′-deoxy-3′-fluorothymidine ([19F]FLT) and its monophosphate metabolite (FLT-MP) in a tumor xenograft mouse model using 9.4T magnetic resonance imaging (MRI). This preliminary result demonstrates that19F magnetic resonance spectroscopy (MRS) with FLT is suitable for thein vivoassessment of tumor aggressiveness and for early prediction of treatment response.

Objective: Temporomandibular disorder (TMD) includes a number of clinical conditions involving the masticatory musculature or the temporomandibular joint (TMJ) and associated structures. Previous studies have shown the presence of high-affinity estrogen receptors in the TMJ articular cartilage. The aim of this study was to evaluate the developmental changes in mouse TMJ under estrogen deficiency. Materials and methods: Four-month-old ovariectomized mice were killed after certain weeks. We examined the significant alterations of the expression patterns of bone morphogenetic protein (BMP)-4, Runx2, and bone sialoprotein (BSP) after ovariectomy. Results: In the control group, BMP-4, Runx2, and BSP expressions showed no definite difference at any stage. In the ovariectomy group, the intensity of BMP-4 and Runx2 expression increased after ovariectomy. BSP immunoreactivity, however, increased slightly at 2 weeks but then decreased gradually. Conclusions: Estrogen plays important roles in the metabolism and maintenance of TMJ via regulations of signaling molecules such as BMP-4, Runx2, and BSP. Our results suggest that estrogen deficiency is a candidate cause of TMD. This study revealed further osteogenetic properties of estrogen that may be useful in the clinical treatment and prevention of TMD.

START psychological intervention versus treatment as usual with outcome HADS (hospital anxiety and depression scale) total, anxiety and depression subscales, HADS caseness and quality of life (HSQ). Costs were measured using the CSRI (Client Services Receipt Inventory).Results:At twoyears, the follow-up rate was over 80%. We will report in the results of the intervention at two years according to both pre-specified primary analysis and sensitivity analysis in depression, depressive and anxiety symptoms and quality of life and on costs for people with dementia. Conclusions: Family carers for dementia require tailored affordable interventions to enable them to cope without becoming depressed. The intervention was manual based, standardised and supervised. The high fidelity ratings and lack of therapist clustering suggest the intervention can be delivered consistently. This manual based intervention can be taught to psychology graduates rapidly and delivered relatively cheaply. 1 Livingston G, Barber J, Rapaport P, Knapp M, Griffin M, King D et al.. BMJ 2013;347:f6276. 2 Knapp M, KingD, RomeoR, Schehl B, Barber J, GriffinM et al. BMJ 2013;347:f6342.

Recently, natural plant-derived products have been recognized as one of the main sources for drug discovery and development in human disease. 9-Hydroxy-6,7-dimethoxydalbergiquinol (HDDQ) isolated from the heart wood of Dalbergia odorifera is widely used in oriental medicine, however, the pharmacological effect of HDDQ in osteoclast-associated diseases remains unknown. In this study, HDDQ dose-dependently inhibited the early stage of RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) without cytotoxicity. HDDQ strongly inhibited Akt phosphorylation in RANKL-stimulated BMMs and did not show any effects on p38, JNK, and IκB phosphorylation and IκB degradation. Interestingly, we found that HDDQ down-regulated the induction by RANKL of c-Fos protein by suppressing its translation. Also, ectopic overexpression of c-Fos and NFATc1 rescued the inhibition of osteoclast differentiation by HDDQ. Furthermore, the Akt/c-Fos/NFATc1-regulated expression of genes required for osteoclastogenesis, such as OSCAR and TRAP, was inhibited by HDDQ. These findings suggest that HDDQ prevents osteoclast differentiation via down-regulation of Akt, c-Fos, and NFATc1 signaling molecules, suggesting a potential therapeutic value of HDDQ for bone disorders associated with increased bone resorption.

Summary Background. Type I interferon (IFN) has been reported to have an important role in the development of cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE). A new subset of CD4+ T cells, T helper (Th)17 cells, also plays a role in the development of autoimmunity. Aim. To investigate expression of interleukin (IL)-17 and IFN-α in different CLE subsets, and their associations with the pathogenesis of LE. Methods. Skin tissue samples from 33 cases, including chronic discoid LE (n = 24), acute (A)CLE (n = 4), subacute CLE (n = 1) and lupus panniculitis (n = 4) were collected for immunohistochemistry. Expression of IL-6, IL-17A, IFN-α, IFN-γ, myxovirus protein (Mx)A and transforming growth factor (TGF)-β was assessed in these samples. Results. All LE specimens had staining for IL-6 and TGF-β in the infiltrated inflammatory cells. IL-17A staining was seen in 84.8% of specimens, and IFN-α or MxA was seen in 93.9%. TGF-β expression in ACLE was significantly greater than that in both chronic cutaneous (CC)LE and in lupus panniculitis (P = 0.02 for both). Expression of IL-17A was positively associated with expression of IFN-α and MxA (Spearman’s ρ = 0.56 and 0.39, respectively). In addition, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) correlated positively with expression of IFN-α and MxA (ρ = 0.40 for both), whereas there was no correlation with IL-17A expression. Conclusions. Two major cytokines, IL-17A and IFN-α, may play roles in the pathogenesis of CLE. Their patterns of expression positively correlated with each other.

Background We designed a hypoxia-imaging modality to detect ischemia of the gastric conduit after esophagectomy. Materials and Methods A rat esophagectomy model was created using 12-16-week-old, 300-350 g male Sprague-Dawley rats. In the operation group (n=6), partial gastric devascularization was performed by ligating the left gastric artery and the short gastric arteries and an esophagogastric anastomosis was performed. In the control group (n=6), the esophageal-gastric junction was incised and suturing was performed without gastric devascularization. Positron emission tomography (PET) images were taken using a microPET rodent model scanner, 24 h after the initial operation, after injection of 200 μCi 64Cu-diacetyl-bis (N4-methylsemicarbazone) (64Cu-ATSM) and pimonidazole 120 mg/kg. After microPET imaging, autoradiography and immunohistochemistry were performed. Results The PET image revealed 64Cu-ATSM uptake at the fundus in the operation group 3 h after 64Cu-ATSM injection. The maximum percentage of the injected dose per gram of tissue was higher in the operation group (0.047±0.015 vs. 0.026±0.006, p=0.021). The fundus/liver ratio was also higher in the operation group (0.541±0.126 vs. 0.278±0.049, p=0.002). Upon autoradiography, 64Cu-ATSM uptake was observed in the fundus in the operation group, and was well-correlated to that observed on the PET image. Upon immunohistochemistry, expression of hypoxia-inducible factor 1a and pimonidazole were significantly increased at the fundus and lesser curvature compared to the greater curvature in the operation group. Conclusion Hypoxia PET imaging with 64Cu-ATSM can detect ischemia in a rat esophagectomy model. Further clinical studies are needed to verify whether hypoxia imaging may be useful in humans.

e20616 Background: Overall survival in primary glioblastoma (GBM) has been poor with 5% at 2 years, but recent advances have improved overall survival in this population. Long-term survivors (LTS),...

Portal vein aneurysm is believed to be a rare vascular anomaly. However, it is being found increasingly more frequently due to the wide use of ultrasonography and computed tomography. When a portal vein aneurysm is patent, it can be easily diagnosed with duplex or colour Doppler sonography. However, when an acute thrombosis develops in the aneurysm, it may mimic a pancreatic pseudocyst or a cystic tumour. Complications of such an aneurysm include upper gastrointestinal bleeding, portal hypertension, and acute thrombosis may require bypass surgery or an aneurysmorrhaphy. Patients without significant symptoms or signs of portal hypertension may be treated conservatively. However, to our knowledge, there is no report describing the morphological changes in a portal vein aneurysm associated with an acute thrombosis after conservative management. We report a case of portal vein aneurysm with an acute thrombosis and subsequent portal cavernous transformation on the follow-up study.

Objectives: Polycystic ovary syndrome (PCOS) presents a high risk of developing type 2 diabetes mellitus. We studied a group of women with PCOS and evaluated this defect in insulin action. Methods: The study population consisted of nine PCOS women, six obese type 2 diabetic patients, and five controls whose body mass index (BMI) was similar to that of the nine PCOS women. The 75-g oral glucose tolerance test (OGTT) and the hyperinsulinemic euglycemic glucose clamp test were performed. Clinical characteristics and the metabolic profiles, including the insulin sensitivity index (ISI), were compared. Results: PCOS women showed significantly elevated insulin responses during OGTT, but their blood glucose levels were comparable with the controls. The subjects with PCOS had more insulin resistance than the other groups. There was no difference among the groups in terms of clinical characteristics and metabolic profiles, except age, luteinzing hormone (LH), testosterone, and sex hormone binding globulin (SHBG). Conclusion: We conclude that PCOS women have significant insulin resistance which is independent of adiposity.

2074^ Background: Prognosis of recurrent MG remains poor with a median survival of 3-9 months. Few evidence based treatments are available and response rates have been < 20% with 6 month progression–free survival (PFS) of < 9-16%. Poor prognosis is linked to the MG’s ability to induce vascular proliferation and invasion. MG’s have an abundance of neo-vascularization and high levels of vascular endothelial growth factor (VEGF). BEV, an antibody to VEGF, is the most active agent tested for recurrent MG with an overall response rate of 21.2%. Rilotumumab is a human monoclonal antibody that blocks human hepatocyte growth factor (HGF) and its receptor c-Met. HGF/c-Met signaling plays a role in MG tumorigenicity inducing angiogenesis and expression of additional angiogenic autocrine factors such as VEGF. The novel combination of rilotumumab (C-Met inhibitor) with an anti-VEGF drug (BEV) to block vascular invasion and tumor proliferation may demonstrate synergistic tumor growth inhibition. Methods: A two-stage design is used to assess radiographic response rate with > 3 responses required for the first stage. Secondary endpoints were PFS, overall survival (OS) and toxicity. Subjects with recurrent BEV-naïve MGs received rilotumumab at 20 mg/kg in combination with BEV at 10 mg/kg every two weeks ≥ 28 days after the last surgical procedure. A brain MRI was obtained after each 6-week cycle. Results: 15 of the 19 patients required for the first stage have been accrued. 10(67%) were male and ≥ 50 years. 73% received ≥ 2 prior regimens and 46% had ≥ 2 prior progressions. Best tumor response included 1(7%) complete response, 2 (13%) partial responses, 8 (53%) stable disease, 1 (7%) progressive disease with 20% (3/15) non-evaluable due to early termination secondary to toxicity. Median PFS was 3.9 months (95% CI: 1, 7.1) with a 6-month PFS of 25.4% (95% CI: 6.4, 50.5) and 6-month OS of 68.3% (95% CI: 34, 87.1). Toxicities are listed below. Maximum average weight increase over all cycles was 6.3 % (SD ± 6.09). Conclusions: Rilotumumab in combination with BEV is an active regimen in MG. Toxicity will need to be closely monitored. [Table: see text]

Purpose:To assess the incidence of neonatal hearing loss in a neonatal intensive care unit and the relative importance of risk factors for hearing imparement in a neonatal intensive care unit which the Joint Committee on Infant Hearing(JCIH) had recommended. Methods:One thousand, two hundred and one newborns admitted to the Good Moonhwa Intensive Care Unit from May 2003 to December 2005 were assesed using the automated auditory brainstem response(AABR). The screening was performed on those aged more than 36 weeks and weighing more than 2,200 g. We divided the infants into two groups, ‘pass’ and ‘refer’. The ‘refer’ group were retested one month later, and if classified as ‘refer’ during the retest, were referred to a hearing impairment clinic. Results:From the 1,201 neonates, 1,187(98.8 percent) passed the test and 14(1.2 percent) failed. 293(24.4 percent) of the 1,201 neonates had a risk factor for hearing impairment; 282(96.2 percent) passed the test and 11(3.8 percent) failed. The group with risk factors were shown to have a higher incidence of hearing loss(P