IT Treatment Research Articles

Phenolic Acids and Their Relationship to Nutritional and Technological Grain Parameters of Durum Wheat Under Variable Treatment Intensity in Central European Conditions

The objective of this two-year study was primarily the evaluation of the free and the bound forms of phenolic acids and phenolic aldehydes (PAAs) in grains of four selected cultivars of spring durum wheat subjected to three treatment intensities (GD—Green Deal, BT—Basic and IT—Intensive). All treatments included a common basic level and different spring production levels of nitrogen fertilisation (0 kg N in the case of GD; 30 kg N in the case of BT; and 60 kg N in the case of IT). Pesticide applications included herbicides and insecticides in both the BT and IT treatments, which were supplemented by combinations of fungicide and morphoregulator in the IT treatment. The GD treatment included only basic nitrogen, herbicide protection, and the application of a biostimulator (ExelGrow). The spring durum wheat cultivars subjected to testing were cultivated under Central European conditions, specifically in the Czech Republic’s central Bohemian region. UHPLC-ESI-MS/MS was used for the detection and accurate quantification of PAAs. In parallel, 12 other nutritional and basic technological parameters of the cereal were evaluated. Nine bound and seven free forms of PAAs were quantified in the analysed cereal samples. Bound forms of PAAs were dominant, accounting for 99.4% of total PAAs. Considering single PAAs, ferulic acid was the most abundant, accounting for 87% of the total bound PAAs. Interestingly, year and treatment intensity were the key factors in the variability of both free and bound PAAs, but these factors had different effects on bound PAAs. Under low nitrogen conditions, plants responded with an increase in free PAAs in particular, as well as in three bound PAAs. Unfavourable weather conditions, combined with the presence of biotic factors (e.g., Fusarium infections), significantly influenced the increase in both PAA groups, with the exception of free p-coumaric acid. PCA analysis confirmed close relationships between PAAs within both categories (free and bound). Subsequent correlation analysis further revealed that the immunoreactive gluten component (G12) exhibited a high negative correlation with the dominant ferulic acid (r = −0.70) and sinapic acid (r = −0.68). Additionally, moderate negative correlations were observed between four bound phenolic acids and grain hardness (r = −0.48–−0.60).

Abstract A005: Synergistically Engaging a b-Selective IL-2 Agonist with PD1/PDL-1 Blockade in a Bifunctional Superkine, MDNA223

Abstract Introduction: Combination treatment with a long-acting IL-2 superkine (MDNA109FEAA-Fc; aka MDNA19) and anti-PD1 or anti-CTLA4 has shown clear evidence of synergy in blunting tumor growth. To further leverage this synergism, we designed MDNA223, a BiSKIT (Bifunctional SuperKine for ImmunoTherapy) comprising MDNA109FEAA with enhanced affinity for IL-2Rb and no binding to IL-2Ra, fused to either human or mouse anti-PD1. We present in vitro and in vivo characterization of MDNA223 and demonstrate its enhanced IL-2R agonism and effective PD1/PDL-1 blockade in multiple “hot” and “cold” syngeneic tumor models. Experimental Procedure: In vitro studies included human PBMCs and cell-based reporter assays. In vivo studies were conducted in CT26, B16F10, E0771 and TRAMP-C1 tumor models by intraperiotonneal (IP) administration. Intratumoral treatment was performed in a CT26 bilateral tumor model with or without a STING agonist. Analysis of tumor infiltrating lymphocytes (TILs) was performed using flow cytometry. Results: In studies with human PBMCs, MDNA223 showed increased p-STAT5 signaling in CD8+ T cells and reduced activity in Tregs compared to rhIL-2, consistent with its enhanced receptor selectivity. MDNA223 and anti-PD1 were similarly potent at PD1/PDL-1 blockade in a cell-based reporter assay. In mice, MDNA223 induced proliferation (based on Ki67 expression) and expansion of peripheral CD8+ T cells for over 7 days. IP treatment with MDNA223 resulted in significantly greater inhibition of CT26, B16F10, E0771 and TRAMP-C1 tumor growth when compared to combination of MDNA19 with anti-PD1 at equimolar dosage. This observation is consistent with the proposed cis-binding mechanism of MDNA223 to both, IL-2R and PD1 on the same effector immune cell. In a bilateral CT26 tumor model, IT treatment with MDNA223 not only inhibited the treated tumor but also exhibited an abscopal effect by slowing growth of the untreated tumor implanted on the opposite flank. TILs analysis of B16F10 melanoma following a single dose of MDNA223 showed increased infiltration of CD8+ T cells over Tregs compared to single agent treatment with MDNA19 or anti-PD1 as well as their combination. Treatment with MDNA223 also resulted in a larger population of functional effector CD8+ T cells expressing low levels of the Tim-3 exhaustion marker and high levels of the cytotoxic Granzyme-B protease. Conclusion: MDNA223 demonstrated superior therapeutic activity over the combination of MDNA19 and anti-PD1 in both immunologically ‘hot’ (CT26) and ‘cold’ (B16F10, E0771 and TRAMP-C1) tumor models. Additional studies with variants of MDNA223 capable of tumor selective targeting and/or conditional activation within the tumor micro-environment are in progress to maximize activity at the tumor site with tunable peripheral stimulation. Citation Format: Aanchal Sharma, Minh D To, Hardeep Kataria, Qian Liu, Rosemina Merchant, Fahar Merchant. Synergistically Engaging a b-Selective IL-2 Agonist with PD1/PDL-1 Blockade in a Bifunctional Superkine, MDNA223 [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr A005.

Poor Outcome of Patients with Acute Myeloid Leukemia in First Relapse Underscores the Need for Effective Initial Treatment

Introduction: The incorporation of novel targeted agents into combination regimens used in the treatment of patients with acute myeloid leukemia (AML) has improved their outcomes. However, disease relapse is still challenging and associated with a poor response rate, limited therapeutic options and poor outcome. Predictors of outcome for patients in first relapse include the duration of first remission, cytogenetic risk at diagnosis, age and whether they underwent an allogeneic stem cell transplantation (alloSCT) in first remission. The incorporation of genetic aberrations detectable at diagnosis has been useful in further stratifying prognosis, but their predictive value at the time of relapse is not well established. Herein we analyze a large cohort of frontline-treated AML patients, focusing on the outcomes of patients presenting a first disease relapse. Methods: This is a retrospective single-center study including patients diagnosed with AML from April 2017 to October 2022. Risk assessment and response to treatment were defined according to the ELN 2022 guidelines. Mutations were assessed using an 81-gene NGS panel. Survival analyses were estimated with the Kaplan-Meier method, using the log-rank test for comparison. Univariate and multivariate analysis were performed using Cox proportional hazards regression. Results: A total of 875 patients with AML were included in the study, with a median age of 65 years old (range,18-95). According to the ELN risk category, 171 (20%) patients had favorable disease, 200 (23%) patients intermediate and 473 (54%) adverse. Patients received intensive treatment (IT; 40% of patients, 41% of whom with the addition of venetoclax) or low intensity treatments (LIT; 60% of patients, 72% with venetoclax). The overall response rate including complete remission (CR)/CR with incomplete hematologic recovery (CRi) was 73%. Among responding patients, 201 (32%) underwent alloSCT in first remission. After a median follow-up of 25 months, the median OS was 53 months for patients receiving IT and 11 months for patients receiving LIT (Figure 1). The median OS for favorable, intermediate and adverse risk patients was not achieved, 24 and 11 months, respectively. During this follow up time, 337 patients were alive and maintaining CR. 197 patients have relapsed after having achieved CR/CRi, 36 of them after undergoing alloSCT. Available data for analysis was available in 164 of these patients. The median age at relapse was 67 (21-95) and 57 (35%) received prior IT whereas 107 (65%) received LIT. At diagnosis, 15%, 16% and 69% were favorable, intermediate and adverse risk, respectively. The median time from best response to relapse was 7.5 (range,1-35) and 6.3 (range, 1-49) months for patients treated with IT and LIT, respectively. At the time of relapse, 36% of patients had a complex karyotype, 4% had MECOM gene rearrangement and 3% had KMT2A gene rearrangement. The most common mutations at time of relapse were TP53 (34%), DNMT3A (34%), TET2 (23%) and RUNX1 (19%). After relapse, 32 (20%) and 132 (80%) received salvage IT and LIT treatment, respectively. The CR/CRi rate for IT and LIT were 31% and 27%, respectively. The mOS from relapse was 3.4 and 5.5 months for patients with salvage IT and LIT, respectively (p=0.6). Age at relapse (mOS of 6.5 vs 5.1 months for patients age <60 and ≥60, respectively [p=0.1]), type of induction therapy (mOS of 6.6 vs 4.9 for patients receiving IT and LIT, respectively [p=0.07]), or risk classification at relapse (mOS of 4.9, 6.3 and 5.1 months for favorable, intermediate and adverse risk, respectively [p=0.7]) did not stratify patients. Duration of first remission longer than 12 months was associated with a better OS (mOS 8.1 vs 4.3 months, p=0.008). Univariate and multivariate analysis was performed, including clinical and biological variables at diagnosis and relapse (Table 1). Importantly, high white blood cell count at relapse (HR 2.1), short first remission (HR 1.6), complex karyotype at relapse (HR 1.7) and KMT2A rearrangement at relapse (HR 3.8) were independent predictors of outcome after relapse. Conclusion: Although outcomes of patients with AML have improved, disease relapse remains a major obstacle with poor outcomes despite the availability of new salvage strategies. Highly effective induction and maintenance regimens are needed to reduce the risk of relapse.

Intratympanic Steroid Use for Sudden Sensorineural Hearing Loss: Current Otolaryngology Practice in the Kingdom of Saudi Arabia

Abstract Objectives: Sudden sensorineural hearing loss (SSNHL) is commonly defined as a hearing loss of more than 30 decibels in three consecutive frequencies that occurs within 72 h. In most cases, it is considered idiopathic, and an evidence-based strategy to treat it is still debated. We aim to analyze the current practice of intratympanic steroid injection (ITSI) for SSNHL in the Kingdom of Saudi Arabia (KSA) and compare it to the published data from the United Kingdom (UK), the United States (US), and continental Europe. Methodology: A survey of 28 questions was distributed among Otolaryngology Consultants and Specialists of KSA. It includes questions about demographics, indications for IT treatment, procedure, follow-up, and outcomes. Results: We received 75 responses. Around 66% of them indicated that they use ITSI to treat idiopathic SSNHL (ISSNHL). Forty-six percent (n = 23) did not use ITSI as a primary therapy. Forty percent (n = 20) used it in combination with other treatments, including oral steroids, and 14% (n = 7) used it as a primary monotherapy. The majority (36%, n = 18) considered using ITSI for up to 1 month. The commonly used course of treatment for our ear, nose, and throat (ENT) doctors was three injections (50% n = 25), with a weekly dose being the most frequent interval (42% n = 21). Conclusion: This study showed wide variability in practice among Saudi ENT clinicians. This variation has been found across countries, in the UK, US, and continental Europe, which tells us that this is a global issue and there is not yet one unified protocol to be followed in the treatment of ISSNHL.

Abstract A019: Targeting STAT3 for lung cancer prevention

Abstract Former smokers have an elevated risk of lung cancer and account for a large proportion of newly diagnosed lung cancer. Former smokers with airway dysplasia have received modest benefit in randomized chemoprevention trials, while active smokers have not. More effective chemoprevention agents for former smokers at risk for lung cancer are needed. We previously reported that a cyclic double-stranded DNA oligonucleotide STAT3 decoy (CS3D) administered intravenously (IV) had strong anti-tumor effects in lung cancer xenograft models and was also effective as a chemoprevention agent using a tobacco carcinogen (NNK)-induced lung cancer mouse model that mimics “ex-smokers”. CS3D prevents the binding of activated STAT3 dimers to the promoter of target genes and induces p-STAT3 degradation. Our goal was to develop a clinically applicable direct delivery method of CS3D to the lungs. Using fluorescently tagged CS3D, we evaluated the feasibility and determined the optimal dosing schedule of CS3D administered intratracheally (IT, a mimic of human inhalation) compared to IV in mice. IT delivery 3 times/week provided a high initial drug level that was cleared from the lungs within a few hours, while IV dosing provided lower initial drug levels but persisted up to 8 hrs, with CS3D accumulation over time in the lungs. While the pharmacodynamic effect was also greater with systemic dosing, IT delivery produced inhibition of the STAT3 pathway. Phosphorylated STAT3, VEGF, IL6 and Ki67 expression in NNK-induced lung preneoplasias was down-modulated by IT CS3D delivery after 4 weeks of treatment compared to the mutant oligonucleotide (CS3M), confirming our previous findings with IV delivery. We also demonstrated that CS3D delivered IT altered the pulmonary environment by promoting a pro-inflammatory, anti-tumor response in myeloid cells of the lung directly, or by acting on tumor and stromal components to establish an immune-reactive tumor-microenvironment. No toxicities were found during IT or IV treatment and no organ abnormalities were detected by either regimen. A long-term chemoprevention study of CS3D delivered IT in the ex-smoker lung cancer murine model is underway. Our findings suggest that blocking STAT3 may be a useful strategy for lung cancer prevention, and may involve both inhibition of oncogenic signaling and enhanced anti-tumor immunity. Citation Format: Jill M. Siegfried, Adam C. Soloff, Autumn Gaither Davis, Amy A. Powers, Seth H. Eisenberg, Laura P. Stabile. Targeting STAT3 for lung cancer prevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A019.

How does temperature affect aggression during and after dominance hierarchy formation in Nile tilapia?

Social animals commonly establish dominance relationships by means of aggressive interaction, leading to hierarchical stability and priority of access to limited resources by high-ranked individuals. In poikilothermic animals, temperature is a major abiotic factor influencing social and non-social behaviors, including aggression. Here, we investigated the effect of cold temperature on aggression in dominance hierarchies of the commercially important tropical fish Nile tilapia (Oreochromis niloticus). Aggression components were examined in fish shoals during hierarchy formation (T1) and after hierarchy establishment (T2) under optimal (26 °C) or cold (14 °C) temperatures, and 24 h afterwards (T3) following gradual temperature increase (14–26 °C, IT treatment), decrease (26–14 °C, DT treatment) or constant optimal conditions (26 °C, CT control). During dominance hierarchy formation, fish in cold water showed reduced aggressive interactions involving lower-intensity behaviors whereas fish under warm temperature exhibited high aggression involving escalated fighting. Following temperature alterations, at T3, aggression levels increased in the IT groups, decreased in the DT groups and remained similarly high in the CT groups. However, despite the drop of temperature in the DT treatment, aggression level at T3 in cold temperature in this treatment was similar to that in the IT treatment and CT control in warm temperature. Likewise, despite the increase of temperature, aggression level in the IT treatment at T3 was lower than that observed under the same warm temperature conditions in the DT and CT groups. Our results demonstrate that in addition to the acute effect of the current temperature on aggression in dominance hierarchies, there is a significant carryover effect of prior thermal conditions under which dominance hierarchy has been formed. Thus, cold temperature can possibly be applied during hierarchy formation for mitigating adverse social effects arising from fish grouping under captive conditions.

Prognostic Factors Other Than Age Drive the Risk of Disease Progression in Adults with Burkitt Lymphoma Treated with DA-EPOCH-R

Prognostic Factors Other Than Age Drive the Risk of Disease Progression in Adults with Burkitt Lymphoma Treated with DA-EPOCH-R

EXTH-04. INTRATHECAL (IT) DELIVERY OF TYPE I POLARIZED DENDRITIC CELL VACCINE (DC1) ERADICATES TUMOR GROWTH IN BREAST CANCER (BC) XENOGRAFT MODEL WITH BRAIN METASTASES (BM) AND LEPTOMENINGEAL DISEASE (LMD)

Abstract BACKGROUND Approx. 5% of BM will also develop LMD. Currently there is no effective treatment for BC-associated BM/LMD. As systemic therapies do not prevent the disease recurrence and eventual death, the better option would be direct-targeted approach. We have shown that there is a loss of the anti-HER2 and anti-HER3 CD4 Th1 immune response in BC patients (pts). In a clinical setting, administration of class II HER2 peptide-pulsed Type I polarized dendritic cell vaccine (HER2-DC1) partially restored anti-HER2 Th1 immune responses with pathologic complete response in HER2+ BC patients. In this study, we examined the IT delivery of HER2/HER3- DC1 in BC-LMD model. METHODS Luciferase-labeled HER2+ TUBO BC cell line was injected into the cisterna magna of BALB/c mice to develop BM/LMD. We developed a technique, coined the “Top Hat” (TH) for mouse model that mimics the Ommaya reservoir in BC-pts. The TH essentially allows us to administer IT treatment directly into CSF. BC-BM/LMD bearing mice were given HER2- and Her3 peptide-pulsed Type I polarized DC1 through the TH. RESULTS AND DISCUSSION BM/LMD mice were randomized into following groups: 1) systemic Her2-DC1 2) IT Her2-DC1 3) IT Her2-/Her3-DC1. The median survival (MS) of control mice was 10 days and systemically treated mice was 19 days. IT Her2-DC1 animals did significantly better than both control and systemic treated groups (MS: 63 days; p< 0.0001) and overall survival (OS): 44%. Interestingly, mice given IT Her2-/Her3-DC1 had the best OS (78%). Surviving animals were eventually disease free. Mice that had complete tumor regression were immune to subsequent rechallenge with TUBO cells. Immune cell infiltration in the of CSF, spinal cord and tissues of experimental mice are currently ongoing. CONCLUSIONS Our preclinical data supports the clinical relevance of using intrathecal delivery of DC1 vaccine as a potential treatment for BM and LMD of BC-pts.

Efficacy of radiotherapy vs. The combination of radio- and immunotherapy: a systematic review and meta-analysis

Introduction and objectives. The combination of radiotherapy and immune checkpoint inhibitors has demonstrated antitumor activity in numerous preclinical studies and is currently being investigated in the clinical setting. This study aims to compare the efficacy of radiotherapy alone (RT) vs. the combination of radio- and immunotherapy (IT-RT) and identify the treatment regimen associated with maximal efficacy by using a meta-analysis.
 Materials and methods. A systematic literature search was performed using the PubMed database and materials of the key oncology congresses. Studies reporting 1-year overall survival (OS) of patients with brain metastases undergoing IT-RT treatment were included in the analysis. Information about 1-year OS, individual patients characteristics, and treatment regimens for both IT-RT and control RT arms was extracted. Identification of the optimal treatment regimen was performed using a mixed meta-regression modeling approach. Analysis was performed using the R statistical environment (metafoR package).
 Results. In total, 30 studies were identified, of which 13 reported outcomes for the control RT groups. The analysis revealed that IT inclusion into RT is associated with a significant increase in 1-year OS; given simultaneously, IT and RT demonstrated the highest efficacy with a 1-year OS of 68% (95% confidence interval (CI): 60%75%), followed by a sequential regimen: 1-year OS = 54% (95% CI: 47%61%) and RT alone: 1-year OS = 32% (95% CI: 2539%).
 Conclusion. The current study demonstrates the superiority of combined IT-RT over RT alone; simultaneous IT and RT treatment is associated with the highest efficacy.

Usefulness of Imaging for Intrathecal Drug Delivery Systems: An update

Intrathecal Drug Delivery Systems are invasive pain treatment techniques that require bypassing the blood-brain barrier in order to implant a catheter inside the CSF. Imaging is a key element before and during implantation as well as in the diagnosis of complications. The understanding of delivery mechanisms has been greatly improved using MRI. Drug diffusion can now be modeled according to infusion level and flow rate for each individual patient. MRI and CT are useful in diagnosing the patient, targeting spinal level, and accurately evaluating implantation concerns or contraindications. Imaging is a key tool during the implantation of the device. Catheter positioning is essential as the treatment diffusion is limited, and the tip of the catheter must be set behind the spinal cord. Currently, fluoroscopy is the gold standard for catheter placement. Biplane Interventional Imaging and surgical CT scan will soon be able to help with more accurate positioning. An ultrasound-guided technique is helpful to localize a recessed septum in challenging pump refill procedures where pumps are deeply situated. Imaging is also essential for device malfunction diagnosis. Plain radiology is currently limited as new catheters have a poor opacity, but it remains useful for confirming motor stall of the peristaltic pump and is appropriate for the diagnosis of pump rotation. High-resolution three-dimensional Computer Tomography reconstruction allows accurate control of catheter positioning and the diagnosis of dislodgment, kinking, and breaking. MRI is the most accurate imagery to diagnose spinal cord injuries following implantation or as an adverse effect of IT treatment such as granuloma. Diffusion control requires dynamic imaging which can be performed by TC99 scintigraphy. This allows for the visualization of drug diffusion and velocity. In the near future, novel techniques such as PET- CT scan could be useful for testing the distribution of intrathecal drugs

Therapeutic strategies in the treatment of Menière's disease: the Italian experience.

Ménière's disease (MD) is an inner ear disorder of unknown etiology, whose pathological substrate is the endolymphatic hydrops. Different treatments have been proposed; however, evidence of their effectiveness is lacking. The aim of this study was to evaluate by a questionnaire which medical and surgical treatments are used in Italy for the treatment of MD and to compare them with those proposed in other countries. An electronic questionnaire of 40 questions was formulated and sent to Italian otolaryngologist (ENT) divided into two groups: Group 1 ("generalists" 60.8%) and Group 2 ("neurotologist- NO" 39.2%). One hundred and twenty five ENT replied. Treatment of the acute phase, apart from symptomatics, was based on diuretics that are prescribed by 83.5% of respondents, steroids, prescribed by 66.7%, and vasodilators, prescribed by 22%. In the intercritical phase, 87.2% of respondents recommended low-salt diet, 78.4% of respondents prescribed betahistine, and 52.8% diuretics. Statistical analysis did not show correlation neither with the declared specialization nor with the number of patients treated. In case of failure of medical treatment, IT gentamicin was suggested by 48.8% of the respondents and IT steroids by 40.8%. Statistical analysis showed that generalists prefer IT steroids and NO IT gentamicin (p 0.019). In case of failure of both medical treatment and IT treatment, vestibular neurectomy was indicated by 58.4% of the respondents, 6.4% indicated endolymphatic sac surgery, and 2.4% surgical labyrinthectomy. In Italy, the treatment of MD stand on a gradual approach that starts from the dietary-behavioral changes and a pharmacological therapy based on betahistine. In refractory cases, IT treatment initially with steroids and, therefore, with gentamicin allows the control in vertigo in the majority of cases. In case of failure of IT treatment, VNS is the surgery of choice.

Transcriptome analysis of Spodoptera frugiperda 9 (Sf9) cells infected with baculovirus, AcMNPV or AcMNPV-BmK IT.

To analyze the transcriptome of Spodoptera frugiperda 9 (Sf9) cells infected with AcMNPV or AcMNPV-BmK IT. A comprehensive transcriptome profile for Sf9 cells infected with AcMNPV or AcMNPV-BmK IT is shown. 43127572, 46529744 and 47235310 RNA-Seq profiles permitted the quantification of expression levels for control (C), AcMNPV-BmK IT treatment (ABT) and AcMNPV treatment (AT) groups. There were 997 up-regulated or down-regulated candidate genes with significant different expression level in these treatment groups. These results provide a broad spectrum of candidate genes that are critically involved in the molecular regulation mechanism of Sf9 cells infected with AcMNPV-BmK IT.

An International Collaborative Study of Outcome and Prognostic Factors in Patients with Secondary CNS Involvement By Diffuse Large B-Cell Lymphoma

Background: Secondary CNS involvement (SCNS) is a detrimental complication seen in ~5% of patients with diffuse large B-cell lymphoma (DLBCL) treated with modern immunochemotherapy. Data from older series report short survival following SCNS, typically Aims: The aims of this study were to i) describe the natural history of SCNS in a large cohort of patients treated with immunochemotherapy, and ii) determine prognostic factors after SCNS. Patients and methods: We performed a retrospective study of patients diagnosed with SCNS during or after frontline immunochemotherapy (R-CHOP or equivalently effective regimens). SCNS was defined as new involvement of the CNS (parenchymal, leptomeningeal, and/or eye) in patients without known CNS involvement at the time of first pathologic diagnosis of DLBCL. Patients were identified from local databases and/or regional/national registries in Denmark, Canada (British Columbia), Australia, Israel, US (University of Iowa/Mayo Clinic SPORE), and England (Guy9s and St. Thomas9 Hospital, London). Clinico-pathologic and treatment characteristics at the time of SCNS were collected from medical records. Results: In total, 281 patients with SCNS diagnosed between 2001 and 2016 were included. Median age at SCNS was 64 (range 20-93) years and male:female ratio was 1.3. SCNS occurred as part of first relapse in 244 (87%) patients and 112 (40%) had documented concurrent systemic disease at the time of SCNS. The median time from initial DLBCL diagnosis to SCNS was 9 months, which was similar for patients treated with (N=76, 27%) or without upfront CNS prophylaxis (N=205, 73%) (10 vs 9 Mo; P=0.3). The median post-SCNS OS was 4 months (interquartile range 2-13) and the 2yr survival rate was 20% (95% CI 15-25) for the entire cohort. Associations between clinicopathologic features, management strategy, and post-SCNS survival are shown in Table 1, which excludes patients who did not receive any treatment against SCNS, patients treated with steroids alone, and a patient with unavailable treatment information (n=43, 15%). In multivariable analysis, performance status >1, concurrent leptomeningeal and parenchymal involvement, SCNS developing before completion of 1st line treatment, and combined systemic and CNS involvement by DLBCL were associated with inferior outcomes. Upfront CNS prophylaxis did not influence post-SCNS OS. High-dose methotrexate (HDMTX) and/or platinum based treatment regimens (i.e. ICE, DHAP, or GDP [+/- IT treatment and/or radiotherapy], N=163) for SCNS were associated with reduced risk of death (HR 0.45 [0.32-0.62, P Conclusions: Outcomes for patients with SCNS remain poor in this large international cohort of patients from the immunochemotherapy era. Combined parenchymal and leptomeningeal disease, presence of systemic disease concurrent with SCNS, performance status >1, and SCNS developing during first line treatment were independently associated with inferior OS. However, a significant fraction of patients with isolated SCNS after first line DLBCL treatment and with good performance status may achieve long-term remissions after intensive regimens for SCNS. Disclosures El-Galaly:Roche: Consultancy, Other: travel funding. Cheah:Bristol Myers Squibb: Membership on an entity9s Board of Directors or advisory committees; Gilead Sciences: Membership on an entity9s Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity9s Board of Directors or advisory committees, Other: Speaker9s Bureau. Kansara:Celgene: Honoraria. Connors:Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Seymour:Genentech: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Villa:Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria, Research Funding.

Multimodal intrathecal analgesia in refractory cancer pain

Background and aimsCancer pain treatment has improved over the last decades. The majority of this population can be treated effectively with analgesics following the Guidelines of the original World Health Organisation (WHO). Unfortunately 10–15% of these patients still suffer from severe and refractory cancer pain, especially in the terminal phases of disease and require additional pain management modalities. Therefore, end-stage clinical interventions are particularly needed to minimize the perception of pain. With intrathecal therapy (ITT), drugs are delivered close to their site of action in the central nervous system avoiding first-pass metabolism and blood–brain barrier. It may improve analgesia with a smaller dose and possibly achieve a reduction in systemic or cerebral side effects compared to oral supplied medication alone. Multimodal analgesia enables further dose reduction with improved analgesia and fewer side effects. MethodsIn this retrospective research we investigated the effectiveness and side-effect profile of intrathecal morphine, bupivacaine and clonidine. Patients were followed until death occurred. Pain scores and side effects were recorded before initiating ITT (T0), just after initiating ITT (T1), at hospital discharge (T2), in the ambulant setting (T3) and the last obtained scores before death occurred (T4). ResultsNine patients were included who suffered from severe and refractory cancer pain, not reacting to conventional pain management or had intolerable side effects. Primary tumour location was pancreatic (4), urothelial (3) and prostate (2). Primary pain was considered neuropathic or mixed neuropathic-nociceptive. The treatment team consisted of an anaesthetist, specialized nurse in coordination with primary physician, treating oncologist and specialized home care.All patients were free of pain after initiation of the intrathecal therapy. The average follow-up period was 11 weeks in which there was a slight increase in NRS-score. In the last days before death occurred, half the patients were still free of pain. There were no problems during insertion of the catheter, device malfunction or infection. No severe adverse events defined as hypotension requiring inotropes, respiratory depression or neurological deficits were observed. Three patients experienced mild hypotension which gradually decreased after clonidine dose adjustment. Lower extremity weakness occurred in three patients as well. After bupivacaine dose adjustment the weakness disappeared in two patients and in one patient the lower extremity weakness persisted as a result of conus compression by tumour. Conclusion and implicationsMultimodal IT treatment with morphine, bupivacaine and clonidine is effective and safe for treating refractory cancer pain in the terminal phase of disease.The study offers an important contribution to literature where there is still lack of convincing evidence about the benefits and harms of this type of pain management in patients with otherwise refractory cancer pain.

Simultaneous Determination of Sufentanil and Ziconotide in Combination for Intrathecal Analgesia by UPLC-UV

AbstractIntrathecal analgesia has increased over the past two decades based on high level proof of efficacy in patients with cancer. Morphine and Ziconotide remains the reference. Polyanalgesic Consensus Conference IT treatment algorithm recommends as the second line therapy opioids/ziconotide combination. Sufentanil and ziconotide combination can be used. The implantable pumps development helped to improve the comfort of the patient. The refills were prepared under a laminar airflow hood under strictly aseptic conditions, by the hospital pharmacist. In order to secure the process, a new analytical method by simple liquid chromatography ultraviolet spectrometry method was developed for the simultaneous quantification of two analgesic drugs (sufentanil, ziconotide). The method was validated according to the recommendation of the US Food and Drug Administration (FDA). The method was linear between 0.1 to 4 μg/mL for ziconotide and 3.125 to 50 µg/mL for sufentanil. This routine quality control analysis secures the production process.

Effect of different tumbling marination treatments on the quality characteristics of prepared pork chops.

The effect of different tumbling marination treatments (control group, CG; conventional static marination, SM; vacuum continuous tumbling marination, CT; vacuum intermittent tumbling marination, IT) on the quality characteristics of prepared pork chops was investigated under simulated commercial conditions. The CT treatment increased (p<0.05) the pH value, b* value, product yield, tenderness, overall flavor, sensory juiciness and overall acceptability in comparison to other treatments for prepared boneless pork chops. The CT treatment decreased (p<0.05) cooking loss, shear force value, hardness, gumminess and chewiness compared with other treatments. In addition, CT treatment effectively improved springiness and sensory color more than other treatments. However, IT treatment achieved the numerically highest (p<0.05) L* and a* values. These results suggested that CT treatment obtained the best quality characteristics of prepared pork chops and should be adopted as the optimal commercial processing method for this prepared boneless pork chops.

Effect of different tumbling marinade treatments on the water status and protein properties of prepared pork chops.

Recently, in consideration of the rapidly increasing demand for meat products and the trend towards fast food consumption, the prepared boneless pork chop, as a new style of value-added product, is cut from pork loins and welcomed by consumers after marinating or further cooking. The effect of different tumbling marinade treatments (control group, CG; conventional static marinade, SM; vacuum continuous tumbling marinade, CT; vacuum intermittent tumbling marinade, IT) on the water status and protein properties of prepared pork chops was investigated. The CT treatment significantly increased T22 peak area ratio compared with other treatments (P < 0.05). Histological microstructure results showed that CT treatment significantly increased solubility of salt-soluble proteins and decreased muscle fiber diameter compared with other treatments (P < 0.05). The net enthalpy (ΔH) of IT treatment was significantly lower than SM treatment (P < 0.05), whereas the protein denaturation temperature (Tm3 ) and ΔH3 of CT treatment were lower than IT treatment. These results suggest that CT treatment was more effective in improving the water mobility and distribution, promoting the denaturation of muscle protein and accelerating the marinade efficiency of pork chops compared with other treatments. Thus CT treatment should be adopted.

Improving agronomic practices to reduce nitrate leaching from the rice–wheat rotation system

Winter wheat–summer rice rotation with unique dry–wet cycle water regime is one of the most general cropping systems in the Yangtze Delta, which might favor NO3−-N leaching into shallow groundwater due to high fertilizer-N input with low N use efficiency. To alleviate the detrimental impacts caused by N leaching, it is necessary to apply improved management practices. Therefore, the objectives of the present study are to investigate characteristics of N leaching under drained upland crop-flooded rice rotation and illustrate the effectiveness of an improved agronomic practice for mitigating NO3−-N leaching. N leaching measured in situ for the control (CK), conventional (CT), and improved (IT) treatments for one rice–wheat rotation. Improved fertilization and crop cultivation managements have been applied to the IT treatment in an integrated manner, including low N fertilization rate, high fertilization frequency, and dense planting. During the rice-growing season, NO3–-N and dissolved organic N (DON) were the predominant forms of N in percolation water, and contributed over 25% and 59% to TN, respectively. NO3–-N and TN concentrations in percolation water and leaching losses did not differ significantly (p>0.05) between treatments. N leaching occurred mainly during the early stage of rice seedling transplanting. During the wheat-growing season, N in percolation water was predominantly in the form of NO3–-N, and accounted for over 64.5–82.9% of TN. N fertilization significantly increased NO3–-N and TN concentrations in percolation water. Nitrate and TN leaching losses from the IT treatment (1.15 and 1.38kg Nha−1, respectively) were smaller than the CT treatment (1.34 and 1.76kg Nha−1, respectively). The majority of N leaching losses for wheat occurred during the period from late February to final harvest. The IT treatment exhibited no significant effect on wheat yield, but significantly (p<0.05) increased rice yield (8.60Mgha−1 compared to 8.06Mgha−1) relative to the CT treatment. Compared with the conventional management practice, the improved management practice appeared to be effective in reducing N leaching and increasing grain yield under the rice–wheat rotation.

MO‐A‐16A‐01: QA Procedures and Metrics: In Search of QA Usability

Radiation therapy has undergone considerable changes in the past two decades with a surge of new technology and treatment delivery methods. The complexity of radiation therapy treatments has increased and there has been increased awareness and publicity about the associated risks. In response, there has been proliferation of guidelines for medical physicists to adopt to ensure that treatments are delivered safely. Task Group recommendations are copious, and clinical physicists' hours are longer, stretched to various degrees between site planning and management, IT support, physics QA, and treatment planning responsibilities.Radiation oncology has many quality control practices in place to ensure the delivery of high‐quality, safe treatments. Incident reporting systems have been developed to collect statistics about near miss events at many radiation oncology centers. However, tools are lacking to assess the impact of these various control measures. A recent effort to address this shortcoming is the work of Ford et al (2012) who recently published a methodology enumerating quality control quantification for measuring the effectiveness of safety barriers. Over 4000 near‐miss incidents reported from 2 academic radiation oncology clinics were analyzed using quality control quantification, and a profile of the most effective quality control measures (metrics) was identified. There is a critical need to identify a QA metric to help the busy clinical physicists to focus their limited time and resources most effectively in order to minimize or eliminate errors in the radiation treatment delivery processes. In this symposium the usefulness of workflows and QA metrics to assure safe and high quality patient care will be explored. Two presentations will be given:Quality Metrics and Risk Management with High Risk Radiation Oncology ProceduresStrategies and metrics for quality management in the TG‐100 EraLearning Objectives: Provide an overview and the need for QA usability metrics: Different cultures/practices affecting the effectiveness of methods &amp; metrics. Show examples of quality assurance workflows, Statistical process control, that monitor the treatment planning and delivery process to identify errors. To learn to identify and prioritize risks and QA procedures in radiation oncology. Try to answer the question: Can a quality assurance program aided by quality assurance metrics help minimize errors and ensure safe treatment delivery. Should such metrics be institution specific.

휴대용 멀티 전동 부항 시스템에 관한 연구

Recently oriental medicine has become a new issue in the global medical field because of increasing demands for the treatment of old people. Western medical equipment is becoming popular with big companies related to IT, communication and medical treatment. But globalization of oriental medicine techniques is inadequate due to lack of knowledge about oriental medicine. The cupping equipment has great growth potential because it is easy for old people to use the equipment. The purpose of this paper is to promote the portable multi electrical cupping system. The system may be used by patients themselves without any help from others. By using many cupping cups at the same time and regulating the timer and vacuum pressure. The patient can decrease itching and relax the hardened muscles. The system is expected to grow in the future as oriental medicine will be in high demand in aging society with IT convergence industry.