High-dose Bolus Research Articles

Schisandrin B: A Double-Edged Sword in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of liver lesions ranging from hepatic steatosis, nonalcoholic steatohepatitis, hepatic cirrhosis, and hepatocellular carcinoma. The high global prevalence of NAFLD has underlined the important public health implications of this disease. The pathogenesis of NAFLD involves the abnormal accumulation of free fatty acids, oxidative stress, endoplasmic reticulum (ER) stress, and a proinflammatory state in the liver. Schisandrin B (Sch B), an active dibenzooctadiene lignan isolated from the fruit of Schisandra chinensis (a traditional Chinese herb), was found to possess antihyperlipidemic, antioxidant, anti-ER stress, and anti-inflammatory activities in cultured hepatocytes in vitro and in rodent livers in vivo. Whereas a long-term, low dose regimen of Sch B induces an antihyperlipidemic response in obese mice fed a high fat diet, a single bolus high dose of Sch B increases serum/hepatic lipid levels in mice. This differential action of Sch B is likely related to a dose/time-dependent biphasic response on lipid metabolism in mice. The hepatoprotection afforded by Sch B against oxidative stress, ER stress, and inflammation has been widely reported. The ensemble of results suggests that Sch B may offer potential as a therapeutic agent for NAFLD. The optimal dose and duration of Sch B treatment need to be established in order to ensure maximal efficacy and safety when used in humans.

Driving Up the Dose: Implications for High-Dose Vitamin D Therapy

Driving Up the Dose: Implications for High-Dose Vitamin D Therapy

Acute and subacute pulmonary toxicity and mortality in mice after intratracheal instillation of ZnO nanoparticles in three laboratories

Inhalation is the main pathway of ZnO exposure in the occupational environment but only few studies have addressed toxic effects after pulmonary exposure to ZnO nanoparticles (NP). Here we present results from three studies of pulmonary exposure and toxicity of ZnO NP in mice. The studies were prematurely terminated because interim results unexpectedly showed severe pulmonary toxicity. High bolus doses of ZnO NP (25 up to 100 μg; ≥1.4 mg/kg) were clearly associated with a dose dependent mortality in the mice. Lower doses (≥6 μg; ≥0.3 mg/kg) elicited acute toxicity in terms of reduced weight gain, desquamation of epithelial cells with concomitantly increased barrier permeability of the alveolar/blood as well as DNA damage. Oxidative stress was shown via a strong increase in lipid peroxidation and reduced glutathione in the pulmonary tissue. Two months post-exposure revealed no obvious toxicity for 12.5 and 25 μg on a range of parameters. However, mice that survived a high dose (50 μg; 2.7 mg/kg) had an increased pulmonary collagen accumulation (fibrosis) at a similar level as a high bolus dose of crystalline silica. The recovery from these toxicological effects appeared dose-dependent. The results indicate that alveolar deposition of ZnO NP may cause significant adverse health effects.

Abstract 4127: Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks

Abstract Preclinical and clinical studies have suggested that stopping antiangiogenic therapy may lead to rapid revascularization and rebound tumor growth in certain instances. However, the implications for these findings remain unclear. It is possible that treatment rebounds may impact disease progression following neoadjuvant therapy, where drugs are administered for short periods and then halted prior to surgical removal of a primary tumor. Indeed, recent retrospective clinical studies have suggested that neoadjuvant antiangiogenic treatment discontinuation increases vascular proliferation and, in turn, might increase post-surgical disease progression and metastasis. However, this hypothesis has not been studied experimentally in clinically relevant mouse models of metastatic disease. We examined the effect of treatment discontinuation in the neoadjuvant setting using approved vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) such as sunitinib. Our studies utilized models of spontaneous metastatic breast, melanoma, and kidney cancer following surgical removal of orthotopically grown primary tumors. Neoadjuvant sunitinib treatment periods were 14 days in duration (60 mg/kg) with treatment breaks of 0, 3, 7, and 11 days compared. Pre-surgical molecular and cellular biomarkers were investigated as potential surrogates for post-surgical metastatic disease progression. These included tumor and vascular cell Ki67 and CD31 expression, as well as circulating tumor cells (CTCs) and myeloid derived suppressor cells (MDSCs). Our results show that VEGF RTKI neoadjuvant treatment benefits observed pre-surgically (such as reduction in primary tumor growth) did not consistently correlate with post-surgical survival and reduced metastatic recurrence. The addition of treatment breaks prior to surgery had positive or negative impact on post-surgical survival depending on the tumor model used. Interestingly, high-dose bolus (3 day) neoadjuvant sunitinib (120 mg/kg) treatment consistently improved post-surgical benefits when compared to sustained treatments, despite gaps in therapy. Finally, our results show that tumoral CD31+/Ki67+ cells, CTCs, and MDSCs may serve as surrogate markers of metastatic potential and predict the impact of treatment cessation on disease recurrence. Citation Format: Michalis Mastri, Amanda Tracz, Li Shen, Roberto Pili, John M.L. Ebos. Bolus high-dose neoadjuvant sunitinib treatment overcomes potential for rebound growth during pre-surgical treatment breaks. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4127. doi:10.1158/1538-7445.AM2015-4127

Severe opioid withdrawal syndrome after a single dose of nalmefene

Case 1 A 43-year-old man was brought by ambulance to the emergency department (ED) with severe agitation and clinical signs of severe opioid withdrawal approximately 2 h after a single dose of nalmefene (Selincro®, Lundbeck (Switzerland)) for his alcohol dependence. His medical history included paranoid schizophrenia, depression, and alcohol and codeine dependence. He consumed up to two bottles of Makatussin®Hustentropfen (GebropharmaAG, Liestal, Switzerland), a codeine-containing cough medicine, per day (equivalent to 636 mg codeine base per day). The psychiatrist who prescribed the nalmefene was unaware of the extent of the patient’s codeine abuse. The patient needed high bolus doses of midazolam (cumulative dose 25 mg, commenced in the community prior to transfer to the ED), morphine (10 mg), and propofol (40 mg) to treat the agitation. He was transferred to the intensive care unit (ICU) for further monitoring and treatment, where he received midazolam, propofol, morphine, and clonidine by continuous intravenous infusion. After the first 12 h, it was possible to withdraw clonidine and propofol; however, midazolam and morphine were continued for a further 48 h. Attempts to stop the medication before this point resulted in reemergence of the opioid withdrawal symptoms. After 3 days of ICU treatment, we were able to transfer the patient to psychiatric inpatient services.

Spinal Metastases and Steroid Treatment: A Systematic Review

Introduction Early and effective management of the neurologic sequelae of metastatic spinal cord compression (MSCC) is critical as the potential for return to function is directly related to severity of symptoms. Systemic corticosteroids have been used as a first-line agent to limit disease progression; however, the data supporting this practice are limited. Currently, there is no defined protocol for the role of steroids in the acute management of MSCC. Materials and Methods A systematic review of the literature was conducted utilizing the key concepts of MSCC, steroids, and outcome measures to answer the following questions: (1) What is the effect of steroid administration on the ambulatory status, bowel and bladder function, and survival in cases of MSCC? (2) What steroid dosing regimens are associated with the best outcome considering neurologic symptoms and complication prevention in cases of MSCC? Results Of 327 articles retrieved, 57 abstracts were reviewed and 29 full-text articles were evaluated. Of these, a total of 12 articles detailing the use of steroid administration in MSCC were found. Basic science studies showed that steroids were effective in reducing vasogenic edema of the spinal cord as quantified by the water content of compressed versus control segments of the spinal cord ( p < 0.001), wet to dry weight of the spinal cord ( p < 0.0001) as well as permeability of the blood spinal cord barrier ( p < 0.007). Animal models receiving steroid therapy displayed higher functional outcome scores ( p < 0.001, p < 0.05, and p < 0.0006), delay to onset of paraplegia ( p < 0.05), and an overall lower incidence of paraplegia ( p < 0.05). Clinical studies showed that when compared with a control, patients receiving steroids had a better chance of maintaining ambulatory status at the 6-month follow-up ( p = 0.05); however, this effect was not maintained at the 1-year mark. A case series where patients were given a high dose bolus (100 mg) followed by a high dose regimen (96 mg/d) showed that along with radiotherapy, steroid administration was able to provide substantial pain relief with minimal incidence of side effects. However, a subsequent cohort study of patients receiving either high dose or low dose steroid protocols (96 vs. 16 mg/d) showed no significant differences between treatment groups regarding ambulation rate, and demonstrated a significantly greater number of both serious and total side effects in the high dose group ( p = 0.0429 and p = 0.0284, respectively). Another case series using the same dosing regimen revealed that patients who started treatment later than 12 hours after the onset of symptoms were 6.22 times more likely to remain nonambulatory ( p < 0.001). Conclusion The use of steroids in cases of MSCC is widespread, likely because of extrapolation of data from basic science investigations, studies of metastases to the brain, and the NASCIS trials. Based on the available literature, the use of steroids in MSCC is most effective in patients when administered within 12 hours of symptom onset and before the onset of paralysis or bowel and bladder symptoms. Use of a high dose protocol likely does not confer a better functional outcome while exposing the patient to a significantly greater risk of potentially serious complications.

(450) Identification of inappropriate patient-controlled analgesia (PCA) prescribing patterns to improve patient safety

Recent reports suggest the occurrence of PCA-related adverse events may be increasing, possibly due to inappropriately high bolus doses and use of basal rates in opioid-naïve patients. In 2011, the FDA decreased the recommended initial intravenous hydromorphone dose, but prescribers may be unaware of this change. In 2013, equianalgesic opioid conversion information was added to the institution’s PCA order form. This study aims to (1) determine if the frequency of inappropriate morphine and hydromorphone PCA orders has changed since 2012 and (2) identify factors associated with prescribing of inappropriate PCA orders. An institutional review board-approved retrospective, single-center review of morphine and hydromorphone PCA orders in post-operative, opioid-naïve adult inpatients identified through pharmacy records from 1/2012-2/2012 and 7/2013-1/2014 was conducted. Patient demographics, surgery types, prescribers, and initial PCA order components were recorded. 332 PCA orders met the inclusion criteria, 111 (56 morphine, 55 hydromorphone) in 2012 and 221 (64 morphine, 157 hydromorphone) in 2013. There was no significant difference in the overall frequency of inappropriate PCA orders (23.4% vs. 24.9%, p=0.90, Fisher’s exact) between 2012 and 2013. However, prescribing of PCA basal rates increased from 14.4% to 24.4% (p=0.05, Fisher’s exact), and inappropriate PCA bolus doses decreased from 9% to 0.5% (p=0.0001, Fisher’s exact). There was also a statistically significant decrease in the mean bolus dose of hydromorphone PCA from 2012 to 2013 (mean difference=0.13mg, p=0.0002, T-test). Logistic regression did not identify factors associated with an increased likelihood of PCA basal rate prescribing. Although prescribing of inappropriately high hydromorphone PCA bolus doses decreased from 2012 to 2013 after changes in the PCA order form, the prescribing of PCA basal rates increased. Prescriber education and modification of the PCA order form may help reduce the frequency of inappropriate PCA orders in the future. Recent reports suggest the occurrence of PCA-related adverse events may be increasing, possibly due to inappropriately high bolus doses and use of basal rates in opioid-naïve patients. In 2011, the FDA decreased the recommended initial intravenous hydromorphone dose, but prescribers may be unaware of this change. In 2013, equianalgesic opioid conversion information was added to the institution’s PCA order form. This study aims to (1) determine if the frequency of inappropriate morphine and hydromorphone PCA orders has changed since 2012 and (2) identify factors associated with prescribing of inappropriate PCA orders. An institutional review board-approved retrospective, single-center review of morphine and hydromorphone PCA orders in post-operative, opioid-naïve adult inpatients identified through pharmacy records from 1/2012-2/2012 and 7/2013-1/2014 was conducted. Patient demographics, surgery types, prescribers, and initial PCA order components were recorded. 332 PCA orders met the inclusion criteria, 111 (56 morphine, 55 hydromorphone) in 2012 and 221 (64 morphine, 157 hydromorphone) in 2013. There was no significant difference in the overall frequency of inappropriate PCA orders (23.4% vs. 24.9%, p=0.90, Fisher’s exact) between 2012 and 2013. However, prescribing of PCA basal rates increased from 14.4% to 24.4% (p=0.05, Fisher’s exact), and inappropriate PCA bolus doses decreased from 9% to 0.5% (p=0.0001, Fisher’s exact). There was also a statistically significant decrease in the mean bolus dose of hydromorphone PCA from 2012 to 2013 (mean difference=0.13mg, p=0.0002, T-test). Logistic regression did not identify factors associated with an increased likelihood of PCA basal rate prescribing. Although prescribing of inappropriately high hydromorphone PCA bolus doses decreased from 2012 to 2013 after changes in the PCA order form, the prescribing of PCA basal rates increased. Prescriber education and modification of the PCA order form may help reduce the frequency of inappropriate PCA orders in the future.

Dietary pretreatment with green tea polyphenol, (−)-epigallocatechin-3-gallate reduces the bioavailability and hepatotoxicity of subsequent oral bolus doses of (−)-epigallocatechin-3-gallate

Human case-studies have reported an association between green tea-based dietary supplements and hepatotoxicity. Studies have demonstrated the hepatotoxicity of high-dose oral bolus dosing with the tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) in mice and dogs. We examined the effect of pretreatment with dietary EGCG on the hepatotoxicity and bioavailability of acute oral bolus dosing with EGCG in CF-1 mice. EGCG (750 mg/kg, i.g., once daily for 3 days) increased plasma alanine aminotransferase by 80-fold, decreased both reduced (by 59%) and total (by 33%) hepatic glutathione, and increased hepatic levels of phosphorylated histone 2AX. Pretreatment with dietary EGCG (3.2 mg/g diet) for 2 weeks mitigated hepatotoxicity. Acute oral EGCG also decreased mRNA expression of glutathione reductase. Dietary pretreatment prevented these decreased and increased glutathione peroxidase (Gpx)2, Gpx3, Gpx5, and Gpx7 expression. We found that dietary EGCG reduced the plasma (57% reduction) and hepatic (71% reduction) EGCG exposure following oral bolus dosing compared to mice that were not pre-treated. Overall, it appears that EGCG can modulate its own bioavailability and that dietary treatment may reduce the toxic potential of acute high oral bolus doses of EGCG. These data may partly explain the observed variation in hepatotoxic response to green tea-containing dietary supplements.

Adenosine, lidocaine and Mg2+improves cardiac and pulmonary function, induces reversible hypotension and exerts anti-inflammatory effects in an endotoxemic porcine model

IntroductionThe combination of Adenosine (A), lidocaine (L) and Mg2+ (M) (ALM) has demonstrated cardioprotective and resuscitative properties in models of cardiac arrest and hemorrhagic shock. This study evaluates whether ALM also demonstrates organ protective properties in an endotoxemic porcine model.MethodsPigs (37 to 42 kg) were randomized into: 1) Control (n = 8) or 2) ALM (n = 8) followed by lipopolysaccharide infusion (1 μg∙kg-1∙h-1) for five hours. ALM treatment consisted of 1) a high dose bolus (A (0.82 mg/kg), L (1.76 mg/kg), M (0.92 mg/kg)), 2) one hour continuous infusion (A (300 μg∙kg-1 ∙min-1), L (600 μg∙kg-1 ∙min-1), M (336 μg∙kg-1 ∙min-1)) and three hours at a lower dose (A (240∙kg-1∙min-1), L (480 μg∙kg-1∙min-1), M (268 μg∙kg-1 ∙min-1)); controls received normal saline. Hemodynamic, cardiac, pulmonary, metabolic and renal functions were evaluated.ResultsALM lowered mean arterial pressure (Mean value during infusion period: ALM: 47 (95% confidence interval (CI): 44 to 50) mmHg versus control: 79 (95% CI: 75 to 85) mmHg, P <0.0001). After cessation of ALM, mean arterial pressure immediately increased (end of study: ALM: 88 (95% CI: 81 to 96) mmHg versus control: 86 (95% CI: 79 to 94) mmHg, P = 0.72). Whole body oxygen consumption was significantly reduced during ALM infusion (ALM: 205 (95% CI: 192 to 217) ml oxygen/min versus control: 231 (95% CI: 219 to 243) ml oxygen/min, P = 0.016). ALM treatment reduced pulmonary injury evaluated by PaO2/FiO2 ratio (ALM: 388 (95% CI: 349 to 427) versus control: 260 (95% CI: 221 to 299), P = 0.0005). ALM infusion led to an increase in heart rate while preserving preload recruitable stroke work. Creatinine clearance was significantly lower during ALM infusion but reversed after cessation of infusion. ALM reduced tumor necrosis factor-α peak levels (ALM 7121 (95% CI: 5069 to 10004) pg/ml versus control 11596 (95% CI: 9083 to 14805) pg/ml, P = 0.02).ConclusionALM infusion induces a reversible hypotensive and hypometabolic state, attenuates tumor necrosis factor-α levels and improves cardiac and pulmonary function, and led to a transient drop in renal function that was reversed after the treatment was stopped.

Abstract 15957: A Simple Ablation Strategy Targeting Exclusively AF Triggers is Equally Effective for Paroxysmal and Persistent Atrial Fibrillation: Single Center Large Series

Backgrounds: Recent studies reported that the ablation strategies including ganglionated plexi ablation, linear ablation and ablation of complex and fractionated electrograms and atrial fibrillation (AF) rotors in conjunction with pulmonary vein isolation (PVI) were superior to the conventional ablation strategy aimed to eliminate AF triggers in terms of post-ablation clinical outcomes. It is controversial whether addition of above-mentioned supplementary ablation to PVI improves post-ablation clinical outcomes in persistent AF (PeAF). Purposes: To test the post-ablation clinical outcomes of our ablation strategy exclusively targeting AF triggers in paroxysmal (PAF) and PeAF, and to compare the post-ablation clinical outcomes between PAF and PeAF in a single center large series. Methods: Consecutive 1183 patients (pts) (age: 64±11 years, LA diameter: 40±6mm) with PAF (988 pts (84%)) or PeAF (195 pts (16%), AF duration: 5±3 months (range: 1-11)) who received ablation procedures in our institution were included. Irrespective of AF types, the procedure consisted of encircling PVI (EPVI) and SVC isolation (SVCI) in all pts, and additional ablation targeting non-PV, non-SVC AF triggers if spontaneous AF initiation was observed by high dose (100-400μg/hr) isoproterenol (ISP) infusion and bolus administration of 40mg of adenosine triphosphate (ATP) during ISP infusion. Procedure end point was complete elimination of spontaneous AF initiation on by ISP infusion and ATP boluses. Results: Total of 1949 procedures were performed in all 1183 pts (1.3±0.5/pt, range: 1-4). EPVI and SVCI were successful in all pts. Non-PV, non-SVC AF triggers were identified in 50 pts (4%) and eliminated by focal ablation in 42 (84%). Kaplan-Meier analysis revealed similarly favorable recurrence-free survivals after the last ablation procedure without antiarrhythmic drugs (blanking period of 1 month) in both PAF and PeAF groups (945 (96%)/988 vs. 190 (97%)/195; p&gt;0.05, follow-up period: 414±245 days (median: 395)). Conclusions: This study exhibited that post-ablation recurrence-free survivals were similar between PAF and PeAF, even if only AF triggers were targeted. An ablation strategy targeting only AF triggers may be sufficient in both PAF and PeAF.

Abstract 15975: Atrial Fibrillation Triggers From Non-PV, Non-SVC Foci: Assessment of Incidence, Characteristics and Efficacy of Catheter Ablation in a Single Center, High Volume Series

Backgrounds: The electrical isolation of the thoracic veins to eliminate triggers of atrial fibrillation (AF) is the mainstay of catheter ablation (CA) for AF. AF is sometimes triggered by repetitive firings from the non-PV, non-SVC (nPVnSVC) foci, and their characteristics have not been fully elucidated. Purposes: To elucidate the incidence, characteristics and efficacy of CA of the nPVnSVC foci in AF patients (pts). Methods: Consecutive 1491 pts who received CA for AF (1080 males, age: 64±10 years, paroxysmal: 995, non-paroxysmal: 496) were included in this study. In index procedures, PV and SVC isolation were performed in all pts without subsequent provocation of nPVnSVC triggers. In repeat procedures, high dose isoproterenol (up to 400μg/hr) and boluses of adenosine triphosphate were given to provoke AF initiation by nPVnSVC triggers and focal ablation of all AF triggers was performed. Results: Among 2097 procedures in all 1491 pts, 58 AF triggers from nPVnSVC foci were provoked in 55 pts (3.7%; 30 paroxysmal and 25 non-paroxysmal AF pts) during 57 procedures (12 index and 45 repeat procedures). The pts with nPVnSVC triggers were significantly more likely to be females (42 vs 28%; P=0.03). The trigger foci were localized in the RA (20 foci; CS os in 8, crista terminalis in 7, IVC os in 3 and tricuspid annulus in 2), LA (24 foci; anterior (6), inferior (3) and posterior wall (3), roof in 3, mitral annulus in 3, Marshall vein in 5 and appendage in 1) and septum (14 foci; left (7) and right side (2) of fossa ovalis, high right septum in 4 and non-coronary cusp of the aortic sinus in 1). All AF triggers were eliminated in 46 pts (84%), while in the others they were not. During follow-up after the last procedure (284±218 days), recurrence-free survival was similar in those with and without nPVnSVC triggers (91 vs 95%; P=0.05), although mean procedure number was significantly larger in those with nPVnSVC triggers than in those without (2.1±0.6 vs 1.4±0.6 times/pt; P&lt;0.0001). Conclusions: The nPVnSVC triggers were observed in 3.7% of all AF pts. The location of the triggers could be clustered to the several anatomical regions. Successful elimination of nPVnSVC triggers contributed to high post-ablation recurrence-free survival that was similar to that in those without nPVnSVC triggers.

44IN - Immunotherapy: Myth or Reality?

ABSTRACT An improved understanding of kidney cancer (KC) tumor biology has led to major advancements in the treatment of patients with metastatic disease. While agents that target the VEGF and mTOR pathways prolong survival, resistance develops for most patients within the first year of therapy. Agents that lead to durable remissions are of urgent need to patients living with this disease. For two decades, the clinical experience with high-dose bolus IL-2 has served as proof of principle that immunotherapy can produce durable responses in a small percentage of KC patients. Basic and translational investigation to elucidate the molecular mechanisms that govern the interaction between a tumor and its host immune response has helped to explain why immunotherapies too often fail to achieve satisfactory results. In KC, obstacles to effective immunotherapy may include the physiological down-modulation of the immune response through the expression of programmed death ligand-1 (PD-L1) on tumor cells and cytotoxic T-lymphocyte antigen-4 (CTLA-4) on activated T cells, which serve to restrict the cytolytic function of tumor-infiltrating T lymphocytes, the proliferation of regulatory (CD4+ CD25+) T cells (T-regs) in response to nonspecific cytokine administration, and the immunosuppressive effects of elevated circulating VEGF levels and myeloid-derived suppressor cells (MDSC). These insights have encouraged investigators to pursue agents that block T-cell regulation (e.g., PD-1 and CTLA-4 antibodies), inhibit tumor-induced immunosuppression (e.g. PD-L1 antibody) and more specifically activate T-cells (eg, CD-137 antibody, IL-21), and dendritic cells (e.g. AGS-003). Several of these approaches have shown encouraging efficacy in early trials both as single agents and in combination with standard therapies. However, for “targeted immunotherapy” to reach its full potential, significant work will need to be done to improve patient selection by refining proposed predictive biomarkers and overcome resistance mechanisms through the development of combination regimens. Disclosure: D.F. McDermott: BMS, Merck, Genentech - Scientific Advosry Board Partiicpation, compensated.

Influence of Diuretic Dose and Route of Administration on Loop Diuretic Efficiency: Insights from the Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE-AHF) Trial

Diuretic resistance is common in acute decompensated heart failure (ADHF) and portends a poor prognosis. Loop diuretic efficiency (DE), defined as milliliters of net urine output per 40 mg of furosemide, appears to be more closely associated with mortality than raw diuretic dose or fluid/weight loss. The DOSE-AHF trial was a randomized 2X2 trial of high vs low dose and infusion vs bolus loop diuretic therapy in patients with ADHF. The influence of these diuretic strategies on DE and the poor prognosis associated with DE is unknown.

HPV-targeted tumor-infiltrating lymphocytes for cervical cancer.

LBA3008 Background: Adoptive T-cell therapy (ACT) is a promising cancer treatment modality with potentially broad application. It is not known if ACT can mediate regression of carcinomas, the most common solid tumors in humans. We studied carcinoma of the uterine cervix, a virally induced malignancy that constitutively expresses the HPV E6 and E7 oncoproteins, as a model cancer to test if ACT can mediate regression of an epithelial malignancy. Methods: We initiated a clinical trial to treat metastatic HPV+ cancers with tumor-infiltrating lymphocytes (TIL) selected for HPV E6- and E7-reactivity (HPV-TIL). Patients from the cervical cancer cohort are reported here. HPV-TIL infusion was preceded b y non-myeloablative conditioning and followed by high-dose bolus aldesleukin. HPV-reactivity was assessed by ELISPOT, IFN-gamma production, and CD137 expression assays. Results: Nine patients were treated on the study. They received a median of 81 x 109 T cells (range 33 to 159 x 109) as a single infusion. The infused cells possessed reactivity against high-risk HPV E6 and/or E7 in 6/8 patients. The two patients with no HPV reactivity did not respond to treatment. 3/6 patients with HPV reactivity demonstrated objective tumor responses by RECIST (1 PR and 2 CR). One patient had a 39% best response. Two patients with widespread metastases had complete tumor responses that are ongoing 18 and 11 months after treatment. One patient with a complete response had a chemotherapy-refractory HPV-16+ squamous cell carcinoma and the other a chemoradiation-refractory HPV-18+ adenocarcinoma. Both patients demonstrated prolonged repopulation with HPV-reactive T cells following treatment. Increased frequencies of HPV-specific T cells were detectable after 13 months in one patient and 6 months in the other. Two patients with HPV-reactive TIL that did not respond to treatment did not display repopulation with HPV-reactive T cells. Conclusions: HPV-TIL can mediate durable, complete regression of metastatic cervical cancer. Continued investigation of HPV-TIL for cervical cancer, and possibly other HPV+ malignancies, is warranted. Cellular therapy can mediate complete regression of an epithelial malignancy. Clinical trial information: NCT01585428.

The effect of atrazine administered by gavage or in diet on the LH surge and reproductive performance in intact female Sprague-Dawley and Long Evans rats.

Atrazine (ATR) blunts the hormone-induced luteinizing hormone (LH) surge, when administered by gavage (50–100 mg/kg/day for 4 days), in ovariectomized rats. In this study, we determined if comparable doses delivered either by gavage (bolus dose) or distributed in diet would reduce the LH surge and subsequently affect fertility in the intact female rat. ATR was administered daily to intact female Sprague-Dawley (SD) or Long Evans (LE) rats by gavage (0, 0.75 1.5, 3, 6, 10, 12, 50, or 100 mg/kg/day) or diet (0, 30, 100, 160, 500, 660, or 1460 ppm) during one complete 4-day estrous cycle, starting on day of estrus. Estrous status, corpora lutea, ova, and LH plasma concentrations were evaluated. A second cohort of animals was mated on the fourth treatment day. Fertility metrics were assessed on gestational day 20. A higher portion of LE rats had asynchronous estrous cycles when compared to SD rats both during pretreatment and in response to ATR (≥50 mg/kg). In contrast, bolus doses of ATR (≥50 mg/kg) inhibited the peak and area under the curve for the preovulatory LH surge in SD but not LE animals. Likewise, only bolus-treated SD, not LE, rats displayed reduced mean number of corpora lutea and ova. There were no effects of ATR administered by gavage on mating, gravid number, or fetus number. Dietary administration had no effect on any reproductive parameter measured. These findings indicate that short duration, high-bolus doses of ATR can inhibit the LH surge and reduce the number of follicles ovulated; however, dietary administration has no effect on any endocrine or reproductive outcomes

The effect of ketamine on optical and electrical characteristics of spreading depolarizations in gyrencephalic swine cortex

Spreading depolarization (SD) is a wave of mass neuronal and glial depolarization that propagates across the cerebral cortex and has been implicated in the pathophysiology of brain injury states and migraine with aura. Analgesics and sedatives seem to have a significant effect on SD modulation. Studies have shown that ketamine, an NMDA receptor blocker, has the capacity to influence SD occurrence. The aim of this study was to analyze the dose-dependent effect of ketamine on SD susceptibility through electrocorticography (ECoG) and intrinsic optical signal (IOS) imaging in a gyrencephalic brain. Ketamine in a low-dose infusion (2 mg/kg/h) decreases SD spread and had an effect on the amplitude of SD deflections, as well as on duration, and speed. Moreover, during ketamine infusion at this dose, there was a sustained decrease in the hyperemic response following SD. However, a high-dose infusion (4 mg/kg/h) of ketamine inhibited SD induction and expansion. Furthermore, a high-dose bolus (4 mg/kg), 1 min after stimulation, blocked SD propagation abruptly within 1–2 min, and hindered SD induction and expansion for the following 15–30 min. The results suggest that ketamine may be therapeutically beneficial in preventing SDs. Nonetheless, an adequate dosage and way of administration should be considered and established for human use.

A comparison of bolus injection of landiolol versus oral administration of propranolol before cardiac computed tomography

Heart rate (HR) reduction is essential to achieve good image quality for cardiac computed tomography (CCT). We evaluated the efficacy of a bolus injection of landiolol, an ultra-short acting β-blocker, without the administration of oral β-blocker to reduce HR prior to CCT. We enrolled 678 consecutive patients who underwent CCT from December 2011 to March 2012 and divided them into three groups, which were a propranolol group (n = 277), a low-dose landiolol group (n = 188), and a high-dose landiolol group (n = 213). Patients in the propranolol group received oral propranolol (10–20 mg) prior to CCT. Patients in the low-dose and high-dose landiolol groups were administered a bolus injection of landiolol (0.125 mg/kg), while the high-dose group received an additional 3.75 mg of landiolol if the baseline HR was ≥75/min. Although the average HR was significantly lower in the propranolol group (61.6 ± 8.0/min) than in the low-dose landiolol group (64.1 ± 7.4/min, P < 0.001), there was no significant difference in the image quality (P = 0.91). Among patients with baseline HR ≥75/min, the average HR tended to be lower in the high-dose landiolol group (67.2 ± 6.9/min) compared with the low-dose landiolol group (69.0 ± 6.9/min, P = 0.10), and there was a corresponding difference in image quality between these two groups (P = 0.02). In conclusion, Although the decrease of HR was significantly larger in the propranolol group than in the landiolol groups, the image quality was similar. Among the patients who received landiolol, a higher dose was associated with a lower HR and better image quality. Further investigation to assess higher-dose bolus injection of landiolol or bolus injection following oral administration of a β-blocker would be needed.

Recombinant interleukin‐2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: Results from Cancer and Leukemia Group B 19808

Recombinant interleukin-2 (rIL-2) induces cellular cytotoxicity against leukemia blasts. Patients with acute myeloid leukemia (AML) in first complete remission (CR) may harbor minimal residual disease that is susceptible to rIL-2-activated effector cells. In the Cancer and Leukemia Group B (CALGB) 19808 study, patients with AML in first CR were randomly assigned after all planned chemotherapy to receive a 90-day course of subcutaneously administered rIL-2 or no further therapy. The primary objective was to compare disease-free survival (DFS) between the 2 treatment arms. A total of 534 patients achieved a CR, 214 of whom were randomized. Six courses of low-dose daily rIL-2 were given for the expansion of cytotoxic effector cells, each followed by 3-day high-dose boluses given to trigger cytotoxicity against minimal residual disease. On the protocol-specified intention-to-treat analysis, the hazards ratio for DFS was 0.75 (95% confidence interval, 0.52-1.09; P = .13); the 5-year DFS rate was 42% in the observation arm and 53% in the rIL-2 treatment arm. The hazards ratio for overall survival (OS) was 0.88 (95% confidence interval, 0.54-1.23; P = .34); the 5-year OS rate was 58% for the observation arm and 63% for the rIL-2 treatment arm. Twenty-five of the 107 patients randomized to treatment with rIL-2 either refused or were unable to initiate therapy and 30 patients did not complete their assigned therapy. However, significant toxicities were not commonly observed. The trial design did not anticipate the difficulties patients would encounter with protocol compliance. The efficacy of immunotherapy with rIL-2 administered after intensive postremission treatment was not assessed as planned because of unexpected refusals by patients and/or their physicians to comply with protocol-directed therapy. Neither DFS nor OS was found to be significantly improved.

Optical coherence tomography criteria for defining functional severity of intermediate lesions: a comparative study with FFR

Fractional flow reserve (FFR) is the gold standard in the assessment of severity of the coronary stenosis. The aim of the study was to compare optical coherence tomography (OCT) obtained intermediate coronary lesions lumen areas measurements with FFR assessments, with the goal to develop an OCT threshold to identify significant coronary stenosis. 48 patients (mean age 65 ± 10 years) was enrolled for the study. Within this population, 71 intermediate coronary lesions were investigated using both FFR and OCT. High dose bolus of Adenosine (120 μg) was used to obtain coronary hyperemia. OCT imaging was performed using non-occlusive technique to assess minimal lumen area (MLA) and diameter. The OCT cut-off value that showed the best correlation with the FFR cut-off of 0.80 was the MLA less than 2.05 mm2 (accuracy 87%, sensitivity 75%, specificity 90%, p < 0.001). The study did not disclose any relationship between FFR value and the lesion length. Vessel size influenced the OCT cut-off values, with greater values being found in presence of arteries with a reference diameter greater than 3.0 mm. OCT derived minimal lumen area might be complementary to FFR measurement in identifying ischemia related lesions. Further studies are warranted to assess threshold values in relation to vessel size and location.

Antibody Gene Therapy: Getting Closer to Clinical Application?

Monoclonal antibodies are successfully used in the clinic. However, repeated high-dose bolus injections imply high costs. As an alternative to recombinant protein administration, gene therapy may provide a novel mean for systemic delivery of monoclonal antibodies. This strategy has been used in preclinical studies of a wide variety of pathological conditions, including cancer, infectious diseases, drug addiction, retinal neovascularisation and Alzheimer's disease. The two main gene therapy approaches are based on direct gene delivery (using viral or non-viral vectors) or on inoculation of ex vivo genetically modified cells (autologous or allogenic). Viral vectors are highly efficient as gene delivery vehicles and have been tested in numerous clinical trials, but still raise concerns about safety and limitation of the therapeutic effect due to immune responses against viral antigens. On the other hand, use of standard non-viral vectors has been limited by their low transduction efficiency. Practical application of ex vivo genetically modified cells would imply the availability of stocks of "ready-to-use" gene-modified allogenic cells that should be protected from the host immune system. Actually, this field did not meet the expectation raised initially, mainly because of difficulties with obtaining sustained therapeutic plasma levels in animal models. However, this situation is changing rapidly and the therapeutic potential of these approaches is getting closer to clinical applications. This review focuses on the current achievements in preclinical studies, as well as the challenges and future prospects of antibody gene therapy.