Search

We assessed the role of [18F]FDG-PET/CT in identifying and managing cancer of unknown primary site (CUP syndrome). We reviewed [18F]FDG-PET/CT scans of individuals with CUP syndrome recorded in clinical referral letters from 2012 to 2019. We evaluated the identification of primary tumor (PT) by [18F]FDG-PET/CT, according to histological subtype, and the impact on clinical management. The median age was 65 years, 36/64 males (56%). PTs were detected in 28/64 (44%) patients. Detection was significantly lower in patients with squamous cell carcinoma (SCC) than with other histologies combined, p = 0.034. Mean age, mean SUVmax (10.6 ± 6.0) and organ involvement were similar between patients with and without discovered PTs; and between patients with SCC and with other histologies combined. However, those with SCC were less likely than the others to present with multi-lesion involvement, p

Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that the metabolic stress induced by a KD combined with metformin would enhance radiation’s efficacy. We sought to assess the tolerability and feasibility of this approach. A single-institution phase I clinical trial. Radiotherapy was either 60 or 35 Gy over 6 or 2 weeks, for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a Modified Atkins Diet (ModAD) supplemented with medium chain triglycerides (MCT). There were three cohorts: Dietary intervention alone, and dietary intervention combined with low-dose or high-dose metformin; all patients received radiotherapy. Factors associated with blood ketone levels were investigated using a mixed-model analysis. A total of 13 patients were accrued, median age 61 years, of whom six had newly diagnosed and seven with recurrent disease. All completed radiation therapy; five patients stopped the metabolic intervention early. Metformin 850 mg three-times daily was poorly tolerated. There were no serious adverse events. Ketone levels were associated with dietary factors (ketogenic ratio, p

Background: Fatigue is thought of as a leading cause of iatrogenic accidents. A significant deterioration in qualitative balance function has been shown in sleep deprived individuals. Aim/Objectives: To quantify the degree to which balance is impaired by sleep deprivation (SD) in post-call medical residents. Methods: Medical residents voluntarily underwent computed dynamic posturography (CDP) before and after an on-call night, at an identical time of the day. Order of test performance was random to avoid behavioral learning. Each participant served as his or her own control. Results: Seventeen residents were enrolled (median age 32years). Average sleeping duration the night before and during the night shift was 6.5 and 1 hour, respectively. The average response times difference between alert and fatigued was 10.15 milliseconds (95% CI: 6.81-13.49 milliseconds), yielding a significantly prolonged response times from 120 milliseconds before to 130 milliseconds after the night shift ( P < .001). Comparison of additional measurements of CDP performance did not differ between test conditions. Conclusion: Medical residents are fatigued due to the effect of on-call nights. Sleep deprivation prolongs response times to vestibular stimuli. This finding probably has an effect on execution of manual skills and may reflect a more generalized slowing of responses and overall performance impairment. Significance: The vestibular system is susceptible to SD.

Background Advances in imaging, biomaterials and precision radiotherapy provide new opportunities to salvage locally recurrent prostate cancer (PC). This study evaluates the efficacy and safety of re-irradiation using stereotactic body radiation therapy (SBRT). We hypothesized that patients with castrate-resistant PC (CRPC) would benefit less from local salvage. Methods A prospective clinical database was reviewed to extract 30 consecutive patients treated with prostate re-irradiation. Gallium prostate specific membrane antigen (PSMA) ligand positron emission tomography was performed following prostate-specific antigen failure in all patients and biopsy was obtained in 18 patients (60%). Re-irradiation was either focal (n = 13) or whole-gland (n = 17). Endo-rectal balloons were used in twenty-two patients and hydrogel spacers in eight patients. The median prescription dose was 5 fractions of 6.5 (range: 6–8) Gray (Gy). Results Median follow-up was 28 months. Failure occurred in 10 (out of 11) CRPC patients versus 6 (out of 19) castrate-sensitive patients (91% vs. 32%, p = 0.008) after a median of 13 and 23 months, respectively. Metastases occurred in 64% (n = 7) of CRPC patients versus 16% (n = 3) of castrate-sensitive patients (p = 0.007). Two patients experienced local in-field recurrence, thus local control was 93%. The 2 and 3-year recurrence-free survival were 84% and 79% for castrate-sensitive patients versus 18% and 9% for CRPC patients (p p Conclusions Early delivery of salvage SBRT for local recurrence is associated with excellent 3-year disease control and acceptable toxicity in the castrate-sensitive phenotype. PSMA imaging for detection of local recurrence and the use of precision radiotherapy with rectal protective devices should be further investigated as a novel salvage strategy for radio-recurrent PC.

Background: In the current study we evaluated 68Ga PSMA PET/ CT to measure local control of bone metastasis in oligometastatic prostate cancer patients treated with SBRT. Materials and methods: After the institutional review board approval, a retrospective review of medical records of consecutive prostate cancer patients treated between 2014 and 2018 was conducted. Only medical records of patients that were treated with SBRT for bone metastasis and had pre-and post-SBRT 68Ga PSMA PET/CT scans were included in our study. Data extracted from the medical files included patient-related (age), disease-related (Gleason score, site of metastasis), and treatment-related factors and outcomes. Results: During the study period, a total of 12 patients (15 lesions) were included, with a median age of 73 years. The median follow-up was 26.5 months (range 13–45 months). Median time of 68Ga PSMA PET/ CT follow up was 17.0 months (range 3–39 months). The median pre-treatment PSA was 2 ng/mL (range 0.56–44 ng/mL) vs. post treatment PSA nadir of 0.01 ng/mL (0.01–4.32) with a median time to nadir of 7 months (range, 2–12). Local control was 93% during the follow up period and there was correlation with PSMA avidity on PET. None patients developed recurrences in the treated bone. None of the patients had grade 3 or more toxicities during follow-up. Conclusions: SBRT is a highly effective and safe method for treatment of prostate cancer bone metastases. More studies are required to determine if SBRT provides greater clinical benefit than standard fractionation for oligometastatic prostate cancer patients. 68Ga PSMA PET/CT should be further investigated for delineation and follow-up.

PURPOSE: Neutropenia is a serious complication of chemotherapy in patients with solid tumors. The influence of hospital volume on outcomes in patients with neutropenia has been little investigated. We hypothesized that large-volume hospitals would have reduced mortality rates for neutropenic patients compared with small-volume institutions. METHODS: We used the Nationwide Inpatient Sample database of the Healthcare Cost and Utilization Project, for the years 2007-2011. All adult inpatient episodes with a diagnosis of both neutropenia and solid-tumor malignancy were included. Hospital volume was defined as the number of neutropenic cancer episodes per institution per year. Mortality was defined as death during admission. A multilevel mixed-effects logistic regression model was applied. RESULTS: Twenty thousand three hundred and ten hospitalizations were included in the study, from 1,869 different institutions. Median age was 62 years. The overall inpatient mortality was 2.3%, and was dependent on age (age 50-59 years—1.6% and age 80-89 years—5.3%). The median number of neutropenic inpatient episodes in each institution per year was 14 (range, 1-168). Mortality was 3.3%, 2.7%, 2.2%, 2.2%, and 1.2% for each quintile of hospital volume (from lowest to highest volume, P < .001). Likewise, the proportion discharged home was 85.7%, 90.3%, 91.5%, 92.7%, and 95.4% ( P < .001). The association between hospital volume and mortality remained significant after adjustment for patient-level and hospital-level variables. DISCUSSION: Patients with neutropenia hospitalized in large-volume institutions have a substantially lower mortality compared with those hospitalized at low-volume institutions. Further study is required to validate our findings or overcome potential biases, understand mechanism, and investigate how smaller institutions can improve outcomes.

Objective. Novel therapeutics and supportive care improved outcomes for metastatic non-small-cell lung cancer (mNSCLC) patients. Major advances over the past five decades include the introduction of combination chemotherapy, small molecules targeting mutant proteins, especially EGFR, and more recently immunotherapy. We aim to document real-world long-term survival over the past five decades. Methods. Survival statistics were extracted from the Survival, Epidemiology, and End Results (SEER) database for mNSCLC patients during 1973–2015. Two- and five-year survival (2yS and 5yS) were analyzed using Kaplan–Meier and proportional hazard models. Results. The study population consisted of 280,655mNSCLC patients diagnosed during 1973–2015. Longer survival was seen in younger, female, married, Asian/Pacific Islander race, adenocarcinoma, lower grade, more recent diagnosis, higher income, and chemotherapy-treated patients. 2yS increased during the study period from 2.6% to 12.9%, and 5yS increased from 0.7% to 3.2%. 2yS of patients

Restricted mouth opening or trismus is often encountered in patients with head and neck cancer. The restriction may be the presenting sign of malignancy, a sequela of tumor site or growth, an adverse effect of oncologic treatment, or a first sign of tumoral recurrence. In general, any insult to the temporomandibular joint, masticatory muscles, or their neural innervation may cause limitation in mouth opening. The etiologies leading to trismus are as follows: myospasm secondary to tumor infiltration; reflectory myospasm; radiation-induced myositis and myofibrosis; temporomandibular joint involvement with tumor; unfavorable postsurgical scarring; muscle and joint atrophy secondary to immobilization; pain; jaw fracture and hardware failure; and infection. Preventive measures should be implemented before, during, and after treatment. These measures include identification of high-risk patients, utilization of dose-sculpting radiation techniques whenever possible, performing reconstruction at the same time of resective surgery whenever feasible, and initiating mobilization exercises as early as possible. When trismus develops, treatments are often challenging and disappointing. These include physical therapy, mouth opening appliances, drug therapy, and release surgery. All medical specialties dealing with head and neck cancer should be familiar with the diagnosis and prevention of trismus and make an effort to ensure patients are referred to the appropriate care when needed. Trismus should not be considered a trivial sequela of head and neck cancer.

Objectives The purpose of this study was to evaluate the use of Gallium-68 prostatic-specific membrane antigen (PSMA) PET-computerized tomography (CT) in patients with prostate cancer undergoing imaging for initial staging, biochemical failure or the evaluation of metastatic disease. Methods This is a single institution retrospective study of 95 patients with prostate cancer who were referred for PSMA PET-CT scans. The National Comprehensive Cancer Network guidelines were used to generate treatment recommendations. Univariate and multivariate statistical analyses were performed to identify parameters associated with positive findings on a PET-CT PSMA scan. Results Mean age, Gleason score, and median prostate serum antigen (PSA) were: 72 years, 7.6 and 4 ng/ml, respectively. PSMA PET-CT was positive in 75.5% of the patients. A maximum standardized uptake value was 10.7 ± 8.8. PSMA avidity increased with rising PSA level: PSA ≤ 1 ng/ml: 5/15 patients (33%); PSA 1-5 ng/ml: 18/27 patients (67%), and PSA ≥ 5 ng/ml: 33/34 patients (97%). Following imaging in nine high-risk patients referred for staging, changes in treatment occurred in 6 (67%). Treatment recommendations changed in 27/35 (65%) patients referred due to biochemical failure; these included recurrences suitable for salvage therapy (n = 14), metastatic disease not suitable for salvage therapy (n = 10), and no lesion (n = 17). No changes in treatment occurred in any of the 35 patients referred to evaluate metastatic disease. Discussion PSMA PET-CT imaging may have a substantial impact on clinical management in prostate cancer patients at the time of initial staging or with biochemical failure; yet this modality does not appear useful in the management of patients with known metastatic disease.

Objective Androgen deprivation therapy (ADT) is beneficial for unfavorable intermediate-risk (IR) prostate cancer patients receiving curative radiotherapy (RT). However, for favorable IR patients the latest NCCN guidelines recommends RT alone. We retrospectively studied treatment patterns and outcomes of patients with IR prostate cancer in our institution over the past two decades. Materials and methods Three hundred seventy-three IR prostate cancer patients treated with definitive RT between 5/2002–5/2016 were identified in an institutional review board approved database. All patients received conformal RT to the prostate while the vast majority did not receive nodal radiation. ADT was commenced 2 months prior to RT and was continued for 4 months after RT. Results Compared to RT alone, patients receiving combined RT+ ADT had more positive biopsy cores, higher pre-radiation PSA, more IR factors, and were more likely to receive pelvic lymph node radiation. However, there were no differences in failure either biochemical, local or distal, nor on survival between the favorable RT alone and the unfavorable RT+ ADT cohorts, suggesting a beneficial role for ADT. On multivariate analysis, patients 70 years or younger receiving RT alone were at increased risk for biochemical failure during a 6-year follow-up (HR 3.06, P = 0.025). Biochemical relapse free survival in patients ≤70 years who received RT alone was 82.1% vs 94.0% for RT + ADT (P = 0.030). There was no difference for combined treatment modality in patients > 70 years (P = 0.87). Conclusions Men 70 years or younger with favorable IR prostate cancer treated with RT alone to 78 Gy are at increased risk of biochemical failure. Short term ADT should be considered in this cohort of men. Electronic supplementary material The online version of this article (10.1186/s13014-019-1298-9) contains supplementary material, which is available to authorized users.

Background Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that metabolic stress (moderate hypoglycemia) would enhance the anti-tumor efficacy of concurrent DNA damage. We further hypothesized that concurrent metformin would decrease insulin resistance and consequently elevate ketone blood level. We performed a formal prospective phase I dose-escalation trial to assess the tolerability and feasibility of this approach. Methods A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin (850mg twice-daily) combined with dietary intervention and 3) high-dose metformin (850mg three-times daily) combined with dietary intervention. Statistics: The prediction of blood ketones levels was performed using a mixed-model univariate analysis methodology. Clinicaltrials.gov NCT02149459. Results A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4/5 adverse events. Median levels of β-hydroxybutyrate increased from 0.09 mmol/l at baseline to 0.59 mmol/l during the trial (p=0.006). Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0.02) and low insulin levels (p = 0.002). Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease.Conclusions The intervention was fairly well tolerated. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a KD combined with 850mg metformin twice daily. The trial was supported by the EU FP7 Marie Curie program FP7-MC-CIG 303795, and the Rosetrees Trust. The MCT oil was provided by Nutricia, Netherlands. Citation Format: Yaacov R. Lawrence, Keren Porper, Yael Shpatz, Luba Plotkin, Ronit Pechthold, Alisa Talianski, Zvi Symon, uri Amit, Zvi Cohen, Hili Gnessin, Yair Anikster, Yael Mardor, Leor Zach. A Phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma [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 CT142.

Background Animal brain-tumor models have demonstrated a synergistic interaction between radiation therapy and a ketogenic diet (KD). Metformin has in-vitro anti-cancer activity, through AMPK activation and mTOR inhibition. We hypothesized that metabolic stress (moderate hypoglycemia) would enhance the anti-tumor efficacy of concurrent DNA damage. We further hypothesized that concurrent metformin would decrease insulin resistance and consequently elevate ketone blood level. We performed a formal prospective phase I dose-escalation trial to assess the tolerability and feasibility of this approach. Methods A prospective single-institution phase I clinical trial of combined metabolic therapy and radiotherapy. Radiotherapy was either 60Gy over six weeks or 35Gy over two weeks for newly diagnosed and recurrent gliomas, respectively. The dietary intervention consisted of a KD supplemented with medium chain triglycerides (MCT). There were three cohorts 1) dietary intervention alone, 2) low-dose metformin (850mg twice-daily) combined with dietary intervention and 3) high-dose metformin (850mg three-times daily) combined with dietary intervention. Statistics: The prediction of blood ketones levels was performed using a mixed-model univariate analysis methodology. Clinicaltrials.gov NCT02149459. Results A total of 13 patients were accrued, median age 61 years, of whom 6 had newly diagnosed and 7 with recurrent disease. All completed radiation therapy; 5 patients stopped the metabolic intervention early. Metformin 850mg three-times daily was poorly tolerated. There were no grade 4/5 adverse events. Median levels of β-hydroxybutyrate increased from 0.09 mmol/l at baseline to 0.59 mmol/l during the trial (p=0.006). Ketone levels were associated with dietary factors (ketogenic ratio, p < 0.001), use of metformin (p = 0.02) and low insulin levels (p = 0.002). Median progression free survival was 10 months for newly diagnosed disease and 4 months for recurrent disease. Conclusions The intervention was fairly well tolerated. Metformin use and dietary intake were associated with higher serum ketone levels. The recommended phase II dose is the 8 weeks of a KD combined with 850mg metformin twice daily. The trial was supported by the EU FP7 Marie Curie program FP7-MC-CIG 303795, and the Rosetrees Trust. The MCT oil was provided by Nutricia, Netherlands. Citation Format: Yaacov Lawrence, Keren Porper, Yael Shpatz, Uri Amit, Zvi Symon, Leor Zach. A phase I clinical trial of dose-escalated metabolic therapy combined with concomitant radiation therapy in high-grade glioma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-004.

Endothelial activation with up-regulation of E-selectin adhesion molecules mediates leukocyte rolling along the vascular wall and controls inflammation in many diseases including atherosclerosis and heart failure. Therefore, we aimed to test the hypothesis that inhibition of E-selectin-mediated interactions by a new E-selectin-targeted copolymer could inhibit the progression of atherosclerosis. To target E-selectin on activated endothelium, we developed a new N-(2-hydroxypropyl)methacrylamide (HPMA)-based E-selectin binding copolymer with or without dexamethasone (Dex) (designated P-(Esbp)-Dex and P-Esbp, respectively). To determine the effect of P-(Esbp)-Dex and P-Esbp on atherosclerosis, we allocated ApoE (−/−) mice on a high fat diet, to weekly intra-peritoneal injections of either 1) P-Esbp; 2) P-(Esbp)-Dex; 3) free Dex (1 mg/kg) or 4) saline, for four weeks. Aortic atherosclerosis and left ventricular (LV) remodeling and function were assessed by serial ultrasound studies and histology. Monocytes and macrophages were characterized by flow cytometry. After four weeks of treatment, P-Esbp effectively targeted aortic atherosclerotic lesions. Both P-Esbp and P-(Esbp)-Dex reduced wall thickening of the ascending aortas. However, only the drug-free copolymer (P-Esbp) significantly decreased the areas of necrotic core in the plaques and switched spleen macrophages toward an anti-inflammatory (M2) phenotype. Furthermore, P-Esbp attenuated adverse LV remodeling and dysfunction in ApoE (−/−) mice. In summary, P-Esbp copolymer targets activated endothelial cells, regresses and stabilizes atherosclerotic plaques, and prevents adverse LV remodeling and dysfunction in ApoE (−/−) mice. Our results suggest a new, drug-free macromolecular therapy to treat vascular inflammation.

Background The immune system plays a pivotal role in myocardial homeostasis and response to injury. Interleukins‐4 and ‐13 are anti‐inflammatory type‐2 cytokines, signaling via the common interleukin‐13 receptor α1 chain and the type‐2 interleukin‐4 receptor. The role of interleukin‐13 receptor α1 in the heart is unknown. Methods and Results We analyzed myocardial samples from human donors (n=136) and patients with end‐stage heart failure (n=177). We found that the interleukin‐13 receptor α1 is present in the myocardium and, together with the complementary type‐2 interleukin‐4 receptor chain Il4ra , is significantly downregulated in the hearts of patients with heart failure. Next, we showed that Il13ra1 ‐deficient mice develop severe myocardial dysfunction and dyssynchrony compared to wild‐type mice (left ventricular ejection fraction 29.7±9.9 versus 45.0±8.0; P =0.004, left ventricular end‐diastolic diameter 4.2±0.2 versus 3.92±0.3; P =0.03). A bioinformatic analysis of mouse hearts indicated that interleukin‐13 receptor α1 regulates critical pathways in the heart other than the immune system, such as extracellular matrix (normalized enrichment score=1.90; false discovery rate q=0.005) and glucose metabolism (normalized enrichment score=−2.36; false discovery rate q=0). Deficiency of Il13ra1 was associated with reduced collagen deposition under normal and pressure‐overload conditions. Conclusions The results of our studies in humans and mice indicate, for the first time, a role of interleukin‐13 receptor α1 in myocardial homeostasis and heart failure and suggests a new therapeutic target to treat heart disease.

722 Background: Surgical resection is the only curative modality in pancreatic cancer, yet the vast majority of patients undergoing surgery succumb of their disease. No randomized studies have been performed to assess the survival impact of the procedure. We hypothesized that in the era of effective systemic treatments, the survival advantage of surgical resection would be lessened. Methods: A meta-analysis of published phase III clinical trials in pancreatic cancer in both the post resection adjuvant setting and the locally advanced metastatic setting, based upon indirect aggregate data. Data was stratified based upon the systemic agents used. Patients from trials arms for which there were not complementary data sets with/without surgical resection were excluded. Primary endpoint was 3 year overall survival (OS). Results: Trials were published between 1997 and 2018. A total of 2722 patients were included in the data analysis, of whom 1645 underwent tumor resection and 814 were metastatic. Median follow-up was 40 months. Analyses were performed of five systemic options with / without tumor resection. Across the trials averaged 3 yr OS was 0%, 0.8%, 0%, and 3.8% for 5FU, gemcitabine, gemcitabine + capecitabine, & FOLFIRINOX respectively; and 18.1%, 30.0%, 37.9%, 42.5%, and 62.5% for the same systemic treatments delivered following surgical resection. Hence the additive impact of surgical resection on absolute 3 yr OS was only 18.1% in the absence of systemic treatment, but 30.0%, 37.1%, 42.5% and 58.8% in the presence of 5FU, gemcitabine, gemcitabine + capecitabine, FOLFIRINOX respectively. Conclusions: Within the limitations of this analysis, it appears that our hypothesis was incorrect, and that the opposite is true. The introduction of effective systemic therapies has greatly increased the impact of pancreatic surgery on long-term survival in pancreatic cancer. Consequently, every effort should be made to bring patients to curative resection.

Background: Significantly increased rate of hospitalizations in current smokers is a major smoking-related problem which is associated with a heavy economic burden, whereas car­diovascular disease accounted for nearly half of hospitalizations. The effect of bezafibrate on the rate of re-hospitalization in smokers already treated with statin immediately post-acute coronary syndrome (ACS) is unknown. The aim of this study was to investigate 30-day rate of re-hospitalization in current smokers participating in the ACS Israeli Surveys (ACSIS) and who were treated on discharge with a bezafibrate/statin combination vs. statin alone. Methods: The study population comprised 3392 patients with confirmed current smoking status from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 3189 (94%) were discharged with statin alone, 203 (6%) with a combination of a statin and bezafibrate. Results: Thirty-day re-hospitalization rate was significantly lower in patients from the com­bination group than in their counterparts from the statin monotherapy group: 12.8% vs. 19%, p = 0.028. Multivariable analysis identified the combined bezafibrate/statin treatment as an independent predictor of reduced risk of 30-day re-hospitalization rate with odds ratio (OR) 0.53 (95% confidence interval [CI] 0.31–0.91), and it corresponded to 47% risk reduction. Other significant variables in our model associated with independent risk of 30-day re-hospi­talization rate during the follow-up were female gender (OR 1.43, CI 1.05–1.95, p = 0.03) and age > 65 years (OR 1.49, CI 1.13–1.95, p = 0.004). Conclusions: Adding bezafibrate to statin in smokers was associated with a significantly reduced 30-day rate of re-hospitalization after ACS.

Background: Many patients with upper-abdominal malignancies suffer from severe low back / epigastric pain caused by infiltration of the celiac plexus. The celiac plexus is a network of nociceptive nerves, located along the aorta. Contemporary approaches (opioids, celiac plexus chemical neurolysis, systemic chemotherapy) are often inadequate. The celiac plexus has not previously been targeted using radiation. We hypothesized that ablative radiation targeted to the celiac plexus would alleviate pain and improve quality of life (QOL). Methods: We conducted a single arm prospective clinical trial. Eligible patients had celiac-pain > 4/10 on Numerical Rating Scale (NRS) and completed treatment per protocol with at least one post-treatment visit. The celiac plexus was irradiated from D12 to L2. Radiation was given as either five fractions of 9 Gy or a single-fraction 25 Gy. The primary endpoint was NRS pain 3 weeks post-treatment. Secondary endpoints were toxicity, pain at 6w, analgesic use, and pain interference with daily activities as evaluated by ‘Brief pain assessment short-form’. Analgesic use was not restricted. Here we report results from those who received single fraction treatment. Results: 19 patients were evaluable. The median age of the study population was 67 yr with a median ECOG of 2, 89% had pancreatic cancer. Patients were a median 8 months from diagnosis, and had received a median of one systemic treatment. Toxicity was limited to grade 1-2. Average pain decreased from 5.9/10 at baseline, to 3.1/10 at 3w, and to 1.8/10 (both p < 0.0001) at 6w post-treatment. Number of rescue analgesic doses decreased from 3.6 (baseline) to 1.9 at 3w and 1.7 at 6w (both p Conclusions: Single fraction celiac plexus radiosurgery alleviates pain, and improves quality of life among patients with advanced upper-GI cancer. An international phase II trial is accruing. Pain interference measuresdomainweek 0 (baseline)week 3p (w0 vs v3)week 6p (w0 vs v6)General Activity7.93.4 Citation Format: Yaacov R. Lawrence, Liat Hammer, Ofir Morag, Maoz Ben-Ailan, Dror Alezra, Ofer Margalit, Naama Halpern, Ben Boursi, Einat Shacham Shmueli, Galia Jacobson, Uri Amit, Tamar Katzman, Kinneret Shefer, Ilana Weiss, Inessa Yanovsky, Adam P. Dicker, Talia Golan, Zvi Symon, David Hausner. Celiac plexus radiosurgery a new palliative modality for upper gastrointestinal malignancies - final quality of life results from a proof-of-concept clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT147.

Acute coronary syndromes (ACS) in patients with diabetes mellitus (DM) are associated with a high risk for major adverse cardiovascular events (MACEs) despite statin treatment. The impact of combined bezafibrate and statin therapy in patients with DM and ACS has not been specifically investigated. The aim of this study was to evaluate the association of combined therapy with 30-day MACEs in patients with DM participating in the nationwide Acute Coronary Syndrome Israeli Surveys (ACSIS). The study population comprised 3,063 patients with DM from the ACSIS 2000, 2002, 2004, 2006, 2008, and 2010 enrollment waves who were alive at discharge and received statins. Of these, 225 (7.3%) received on discharge combined bezafibrate and statin therapy, and 2,838 (92.7%) were treated with statins alone. MACEs were defined as a composite measure of death, recurrent myocardial infarction, recurrent ischemia, stent thrombosis, ischemic stroke, and urgent revascularization. The development of 30-day MACEs was recorded in 8% patients receiving combination therapy and 14.2% of those receiving statins alone (p = 0.01). Crude 1-year mortality and 30-day rehospitalization rates were also significantly lower in patients receiving combination therapy: 4.0% versus 8.1% (p = 0.03) and 13.3% versus 21.6% (p = 0.003), respectively. Multivariate analysis identified combined therapy as an independent predictor of reduced risk for 30-day MACEs, with an odds ratio of 0.56 (95% confidence interval 0.34 to 0.92), corresponding to a 44% relative risk reduction. In conclusion, a significantly lower risk for 30-day MACEs was observed in statin-treated patients with DM who also received bezafibrate after ACS. Signals regarding improvement of 30-day rehospitalization and 1-year mortality rates emerged as well.

Objective Our objective was to determine the utility of point-of-care ultrasound (POCUS) to identify and guide treatment of tamponade or clinically significant pericardial effusions in the emergency department (ED). Methods This was a retrospective cohort study of non-trauma patients who were diagnosed with large pericardial effusions or tamponade by the ED physician using POCUS. The control group was composed of those patients later diagnosed on the medical wards or incidentally in the ED by other means such as a computed tomography. The following data were abstracted from the patient's file: demographics, medical background, electrocardiogram results, chest radiograph readings, echocardiogram results, and patient outcomes. Results There were 18 patients in the POCUS arm and 55 in the control group. The POCUS arm had a decreased time to pericardiocentesis (11.3 vs. 70.2 hours, P=0.055) as well as a shorter length of stay (5.1 vs. 7.0 days, P=0.222). A decreased volume of pericardial fluid was drained (661 vs. 826 mL, P=0.139) in the group diagnosed by POCUS. Conclusion This study suggests that POCUS may effectively identify pericardial effusions and guide appropriate treatment, leading to a decreased time to pericardiocentesis and decreased length of hospital stay. Pericardial tamponade or a large pericardial effusion should be considered in all patients presenting to the ED with clinical, radiographic, or electrocardiographic signs of cardiovascular compromise.

Background: Little is known about the potentially unfavorable effects of mesenchymal stromal cell (MSC) activation on the heart. MSCs can respond to tissue injury by anti- or proinflammatory activation. We aimed to study the potential negative interaction between left ventricular dysfunction (LVD) and MSC activation. Methods: We isolated MSCs from cardiac and subcutaneous fat tissues of mice with LVD 28 days after myocardial infarction or sham operation. To evaluate the effect of LVD on MSCs, we characterized cardiac MSCs and subcutaneous MSCs in vitro. Subsequently, we injected MSCs or saline into the infarcted myocardium of mice and evaluated LV remodeling and function 28 days after myocardial infarction. To test the hypothesis that toll-like receptor 4 ( TLR4 ) mediates proinflammatory polarization of MSCs, we characterized cardiac MSCs from TLR4 -/- and wild-type (WT) mice after inflammatory stimulation in vitro. Next, we transplanted cardiac MSCs from TLR4 -/- and WT male mice into the infarcted myocardium of female WT mice and evaluated infarct size, MSC retention, inflammation, remodeling, and function after 7 days. Results: LVD switched cardiac MSCs toward an inflammatory phenotype, with increased secretion of inflammatory cytokines as well as chemokines. The effect of LVD on subcutaneous MSCs was less remarkable. Although transplantation of cardiac MSCs and subcutaneous MSCs from LVD and sham hearts did not improve LV remodeling and function, cardiac MSCs from LVD exacerbated anterior wall thinning 28 days after myocardial infarction. The inflammatory polarization of cardiac MSCs by LVD was mediated by TLR4 , as we found less secretion of inflammatory cytokines and higher secretion of anti-inflammatory cytokines from activated cardiac MSCs of TLR4 -deficient mice, compared with WT cardiac MSCs. Significantly, TLR4 deficiency preserved the expression of CD47 (don’t eat me signal) on cardiac MSCs after both TLR4 stimulation in vitro and transplantation into the infarcted heart. Compared with WT cardiac MSCs and saline, TLR4 -/- cardiac MSCs survived in the cardiac tissue and maintained their reparative properties, reduced infarct size, increased scar thickness, and attenuated LV dilatation 7 days after myocardial infarction. Conclusions: The environment of the failing and infarcted myocardium drives resident and transplanted MSCs toward a proinflammatory phenotype and restricts their survival and reparative effects in a mechanism mediated by TLR4 .

Inflammation has been implicated in the initiation, progression and manifestation of hypertensive heart disease. We sought to determine the role of monocytes/macrophages in hypertension and pressure overload induced left ventricular (LV) remodeling.We used two models of LV hypertrophy (LVH). First, to induce hypertension and LVH, we fed Sabra salt-sensitive rats with a high-salt diet. The number of macrophages increased in the hypertensive hearts, peaking at 10 weeks after a high-salt diet. Surprisingly, macrophage depletion, by IV clodronate (CL) liposomes, inhibited the development of hypertension. Moreover, macrophage depletion reduced LVH by 17% (p0.05), and reduced cardiac fibrosis by 75%, compared with controls (p=0.001). Second, to determine the role of macrophages in the development and progression of LVH, independent of high-salt diet, we depleted macrophages in mice subjected to transverse aortic constriction and pressure overload. Significantly, macrophage depletion, for 3 weeks, attenuated LVH: a 12% decrease in diastolic and 20% in systolic wall thickness (p0.05), and a 13% in LV mass (p=0.04), compared with controls. Additionally, macrophage depletion reduced cardiac fibrosis by 80% (p=0.006). Finally, macrophage depletion down-regulated the expression of genes associated with cardiac remodeling and fibrosis: transforming growth factor beta-1 (by 80%) collagen type III alpha-1 (by 71%) and atrial natriuretic factor (by 86%).Macrophages mediate the development of hypertension, LVH, adverse cardiac remodeling, and fibrosis. Macrophages, therefore, should be considered as a therapeutic target to reduce the adverse consequences of hypertensive heart disease.

Introduction and Hypothesis: Mesenchymal stem/stromal cells (MSCs) are appealing candidates for cardiac cell therapy due to their ease of preparation, immunoprivilege properties, reparative potential and safety. We aimed to test the hypothesis that the inflammatory environment following myocardial infarction (MI) and left ventricular (LV) dysfunction could modulate the reparative properties of resident and transplanted MSCs. Methods and Results: To test this hypothesis, we isolated and cultured resident cardiac and subcutaneous (SC) fat tissue MSCs from mice, 28 days after MI (LVEF: 27.9%±3.8) or sham operation (LVEF: 54.9%±3.8). Proliferation rate was highest in cardiac MSCs after MI, compared with other groups (pTLR4 ) deficient and wild-type mice, with the secretome of LPS-activated macrophages. Significantly, there was less inflammatory cytokine secretion in TLR4-deficient MSCs, compared with control suggesting that cardiac MSC polarization is mediated by TLR4 activation. Conclusions: Post MI inflammatory environment switches resident cardiac and implanted MSCs toward a pro-inflammatory phenotype and impair their reparative properties. This effect is mediated by TLR4 . Our findings are relevant to the pathogenesis and progression of LV remodeling, and could guide the selection and engineering of MSCs for heart repair.

232 Background: Over the previous two decades several new agents have been approved for the treatment of metastatic pancreatic cancer (mPDAC). Their efficacy was demonstrated amongst highly selected patients that participate in randomized phase III trials, hence it is not clear to what extent these advances are reflected within the broader mPDAC population. We performed a population-based survival analysis of newly diagnosed patients who presented with mPDAC. Methods: Survival statistics were extracted from the Survival, Epidemiology and End Results (SEER) Database for patients diagnosed with mPDAC between 1993-2013. Demographic variables collected included age, gender, race, and marital status. Tumor characteristics collected included location and grade. Survival was analyzed using the Kaplan-Meier method and proportional hazard models as appropriate. Exclusion criteria included diagnosis at autopsy, unknown histology and pancreatic neuroendocrine tumors. Results: The study population consisted of 57,263 patients diagnosed with mPDAC from 1993-2013, 52% male, median age 69 years (range 15-104). Prognosis correlated with age, gender, race, marital status, tumor location, grade and year of diagnosis. Median overall survival (OS) stayed stable at 2 months between 1993 and 2013. Improvements in OS were seen for all patients, but especially for younger patients ( < 50 years of age) and more recent year of diagnosis group (2009-2013). The percentage of patients who died within two months of initial diagnosis decreased between 1993 and 2013 (from 63.5% to 50.6%, p < 0.0001). The subgroup of patients achieving longer-term survival has increased, with 12-month survival improving from 4.9 % to 12.7% (p < 0.0001) between 1993 and 2013. Conclusions: There has been a continuous but modest improvement in OS of patients diagnosed with mPDAC between 1993 and 2013. The percentage of patients living beyond one year has significantly increased over time; however the percentage of patients dying within 2 months has only slightly decreased.

The extension in human lifespan in the last century results in a significant increase in incidence of age related diseases. It is therefore crucial to identify key factors that control elderly healthspan. Similar to dietary restriction, mice overexpressing the NAD+ dependent protein deacylase SIRT6 (MOSES) live longer and have reduced IGF-1 levels. However, it is as yet unknown whether SIRT6 also affects various healthspan parameters. Here, a range of age related phenotypes was evaluated in MOSES mice. In comparison to their wild-type (WT) littermates, old MOSES mice showed amelioration of a variety of age-related disorders, including: improved glucose tolerance, younger hormonal profile, reduced age-related adipose inflammation and increased physical activity. The increased activity was accompanied with increased muscle AMP-activated protein kinase (AMPK) activity. Altogether, these results indicate that overexpression of SIRT6 in mice retards important aspects of the aging process and suggest SIRT6 to be a potential therapeutic target for the treatment of a set of age-related disorders.

6600Background: Hospital Volume is associated with improved outcomes in cancer surgery, and some aspects of cancer care. The influence of hospital volume on outcomes in neutropenic patients is unkn...

In a longitudinal study, Kingella kingae carriage rate was nil below 6 months of age, 1.5% at 6 months, 9.6% at 12 months, remained stable between 10.4% and 12.0% during the second year of life, and decreased significantly to 5.3% at 30 months. Replacement of carried strains occurred over time.

The annual incidence of invasive Kingella kingae infection in children younger than 4 years of age was significantly higher in westernized Jews than in indigent Bedouins living side by side in southern Israel (12.21/100,000 and 5.83/100,000, respectively, (P < 0.05). One K. kingae clone was overrepresented among isolates from Jewish children, suggesting that differences in bacterial pathogenicity may contribute to the morbidity excess detected in this population group.