Single Grade Research Articles

Detection of agriculturally relevant lime concentrations in soil using mid-infrared spectroscopy

Globally, surface and subsurface soil acidity pose a serious threat to crop production and require effective management to prevent yield losses. The application of lime (calcium carbonate, CaCO3) is a well-recognised remediation technique for surface soil acidity. However, for subsurface acidity, improved application and detection methods are required to manage acidity due to the stratification of acidic layers. Mid infrared (MIR) spectroscopy has potential as a rapid, cost effective and accurate method of CaCO3 detection in soils. However, for this technology to be valuable in an agricultural context, there is a need to develop MIR spectroscopy methods for the detection of CaCO3 at agriculturally relevant concentrations of <1%, which was the aim of this study. MIR Partial Least Square Regression (PLSR) carbonate prediction models were developed using carbonate-specific spectral regions to predict CaCO3 concentrations in soil. Prediction models were initially developed using a single soil type spiked with reagent grade CaCO3 and were tested further with soils collected from field trials that had been treated with various rates and sources of lime. Prediction models using specific carbonate peak regions were established and compared with models using the entire MIR spectrum to assess the model performance. Models built using a single peak range at 2560–2460 cm−1 gave the best results (highest R2 values and lowest RMSE values) followed by the single peak range at 1840–1760 cm−1. Specifically, model performance was improved when developed with a single soil type and reagent grade CaCO3 in the 2560–2460 cm−1 spectral region, with PLSR R2 of 0.834 and RMSE of 0.030. Performance was reduced but still satisfactory (R2 of 0.735 and RMSE of 0.069) when applied to field trial soils using a range of different lime sources, including dolomitic lime. The MIR method enabled accurate prediction of carbonate concentrations and had a detection limit of 0.05% CaCO3, similar to what can be achieved using a pressure calcimeter. Findings suggest that MIR spectroscopy measurements of agriculturally applied CaCO3 in soils may provide valuable insights into monitoring the movement and efficacy of lime treatments and will enable more informed lime applications in the future. The method may also be used to detect naturally-occurring carbonates at low concentrations and may be useful for rapid isolation of inorganic carbon from organic carbon in soil carbon measurements and carbon accounting.

DETERMINATION OF VARIANCE OF TIME TO RECRUITMENT WITH INTER-DECISION TIME AS GEOMETRIC PROCESS WHEN THE THRESHOLD HAS THREE COMPONENTS

In this paper, the problem of time to recruitment is analyzed for a single grade manpower system using an univariate CUM policy of recruitment. Assuming policy decisions and exits occur at different epochs, wastage of manpower due to exits form a sequence of independent and identically distributed exponential random variables, the inter-decision times form a geometric process and inter-exist time form an independent and identically distributed random variable. The breakdown threshold for the cumulative wastage of manpower in the system has three components which are independent exponential random variables. Employing a different probabilistic analysis, analytical results in closed form for system characteristics are derived

STOCHASTIC MODEL FOR TIME TO RECRUITMENT IN A SINGLE GRADE MANPOWER SYSTEM WITH TWO TYPES OF INTERDECISION TIMES WHEN THE BREAKDOWN THRESHOLD HAS THREE COMPONENTS

In this paper, the problem of time to recruitment is analyzed for a single grade manpower system in which attrition takes place due to two types of policy decisions where this classification is done according to intensity of attrition, it form an ordinary renewal process. Assuming (i) policy decisions and exits occur at different epochs (ii) wastage of manpower due to exits and wastage due to frequent breaks taken by the personnel working in the manpower system separately form a sequence of independent and identically distributed exponential random variables with different means and (iii) breakdown threshold for the cumulative wastage of manpower in the system has three components which are independent exponential random variables. A stochastic model is constructed and the variance of the time to recruitment is obtained using an univariate CUM policy of recruitment. Employing a different probabilistic analysis, analytical results in closed form for system characteristics are derived.

CTIM-26. PHASE I/II STUDY OF THE COMBINATION OF PEMBROLIZUMAB (MK-3475) AND LASER INTERSTITIAL THERMAL THERAPY (LITT) IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND The blood brain barrier (BBB) remains a potential barrier to central nervous system (CNS) penetration of novel immunotherapies in recurrent glioblastoma (rGBM). Laser interstitial thermal therapy (LITT) was recently demonstrated to induce BBB disruption. When combined with anti-PD1 blockade, LITT may therefore potentiate host T-cell mediated cytotoxicity. This phase I/II study aims to evaluate the safety and efficacy of combining LITT and the PD-1 inhibitor pembrolizumab for rGBM. METHODS Phase I treated eligible bevacizumab-naïve high grade glioma patients with LITT and the anti-PD1 inhibitor pembrolizumab at 3 dose levels (100, 150, and 200 mg IV Q3W; 3 patients at each level), while phase II was restricted to rGBM patients only with the recommended phase II dose (RP2D) of pembrolizumab. Phase II was initially designed to randomize rGBM to either pembrolizumab or pembrolizumab+LITT but was later amended to receive only pembrolizumab+LITT after 16 patients were randomized (10 pembrolizumab+LITT arm, 6 pembrolizumab-alone arm). Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan Meier method, and adverse events (AE) documented. RESULTS Phase I enrolled 9 patients (7 rGBM and 2 anaplastic astrocytomas, 33% IDH-mut, 44% MGMTp-methylated) with no dose limiting toxicities (DLT), prompting selection of 200mg Q3W as the RP2D. Phase II interim analysis included 34 rGBM patients (9% IDH-mut, 50% MGMTp-methylated; 6 receiving pembrolizumab alone and 28 pembrolizumab+LITT) plus two Phase I rGBM patients who received RP2D. On per-protocol analysis, pembrolizumab+LITT cohort had improved PFS (median PFS 10.5 months vs 2.1 months) and OS (median OS 11.4 months vs 5.2 months) than pembrolizumab alone. A single treatment-related grade 3 AE was noted (respiratory infection). CONCLUSION: LITT may be safely combined with pembrolizumab for rGBM with promising clinical outcomes on interim analysis. Enrollment for Phase II, correlative studies, and continued AE documentation are ongoing. Clinical Trial ID NCT02311582.

Isatuximab Rescue for Inadequate Response to Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: Interim Analysis of the Phase II Iril Study of the Australian Myeloma Research Consortium (AMaRC 18-02)

Isatuximab Rescue for Inadequate Response to Lenalidomide and Dexamethasone in Transplant Ineligible Patients with Newly Diagnosed Multiple Myeloma: Interim Analysis of the Phase II Iril Study of the Australian Myeloma Research Consortium (AMaRC 18-02)

Bleeding Outcomes in People with Von Willebrand Disease Receiving Antithrombotic Therapy

▪Aging brings additional challenges in the management of people with von Willebrand Disease (VWD). Plasma von Willebrand Factor (VWF) levels may increase but the impact on bleeding phenotype is unclear. With the development of age-related comorbidities, the use of antiplatelet (AP) or anticoagulant (AC) therapies may be warranted. As highlighted in the 2021 international VWD guidelines, limited evidence exists regarding the bleeding risk and safety of AP/AC use in people with VWD. 1 We sought to address this knowledge gap through a retrospective review of a large cohort of people with VWD attending a tertiary referral center.The records of all patients aged >50 years (y) attending our center registered with VWD were retrospectively reviewed. We identified all individuals treated with AP and/or AC, recording the indication for and duration of therapy. We also recorded disease subtype, baseline and most recent plasma VWF levels and bleeding on AP and/or AC. Bleeding episodes were stratified according to the World Health Organization (WHO) Bleeding Scale.From 255 eligible patients, 18 patients (7 male, 11 female) were identified who received AP and/or AC over a period of 22y. The median age at commencement was 60.2 years (range 40.0-74.5). 15 patients had Type 1 with baseline levels 30-50 IU/dL, (median VWF antigen, VWF:Ag, 57.5, range 39-87 IU/dL; median VWF ristocetin cofactor levels, VWF:RCo, 43, range 35-54 IU/dL). 3 patients had type 2 VWD (median VWF:Ag 64, range 27-90 IU/dL; median VWF:RCo of 16, range 10-66 IU/dL). The type of AP/AC used and indications for treatment are outlined in Table 1.Overall, 12 patients were treated with AP and 7 with AC therapy (19 therapies in total as one patient received first aspirin then warfarin therapy). The cumulative exposure to AP therapy was 61.9y with a median exposure time of 3.2y/patient (range 0.3-14.1y). Duration of AC therapy was shorter, with a cumulative exposure of 17.6y and a median of 1.5 y/patient (range 0.3-6.3y).Overall, 85.7% of patients on AC therapy had at least one episode of bleeding (6/7; 10 episodes total) in contrast to 58.3% of patients on AP (7/12; 12 episodes total). Of these 22 episodes, 5 (22.7%) were grade 1 bleeding. Grade 2 bleeding (iron deficiency or gastrointestinal (GI), gynecological or genitourinary bleeding) occurred in 5 patients (41.7%) treated with AP and 4 patients (57.1%) on AC (total of 14 episodes). 1 episode of grade 3 bleeding occurred in both the AP (8.3%) and AC (14.3%) group (GI bleeding requiring transfusion and abdominal hematoma respectively). The single grade 4 bleed was an intracranial hemorrhage (ICH) and occurred in a patient with type 2 VWD (VWF:RCo 10 IU/dL) on warfarin for atrial fibrillation; this required prothrombin complex concentrate, VWF concentrate, neurosurgical intervention and cessation of AC.Bleeding complications resulted in discontinuation of therapy in 2 patients (11.1%) treated; the individual with ICH and a patient with type 1 VWD on warfarin (baseline VWF:RCo 43 IU/dL) due to recurrent GI bleeding. No patients treated with AP therapy required discontinuation of use. The overall rate of major bleeding (WHO grade >/=3) in our study was 11.4 events/100 patient-years in VWD patients receiving AC therapy, in comparison to the rate of bleeding in the general population using AC of 7.2 events per 100 patient-years. 2For patients with type 1 VWD, plasma VWF levels were seen to increase during follow up (median 8.5y, VWF:Ag median +13 IU/dL, VWF:RCo +18 IU/dL), resulting in plasma VWF levels >50 IU/dL for 66.6% of patients in this cohort. Despite this, bleeding while on AP and/or AC was still experienced in 8/10 patients whose levels had normalized, necessitating cessation in one instance.In conclusion, this study provides important insights into the use of AP and/or AC in patients with VWD. Bleeding rates were higher in patients treated with AC therapy than AP resulting in cessation of therapy in 28.6% of those on AC. Bleeding events still occurred despite normalization of plasma VWF levels in patients with type 1 VWD. These data highlight the need for close follow up of patients with VWD whilst on antithrombotic therapy, particularly AC.1. Connell NT et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021;5(1):301-325.2. Shoeb M, Fang M. Assessing Bleeding Risk in Patients Taking Anticoagulants. J Thromb Thrombolysis 2013;35(3):312-319. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Immunicy-1: Targeting BCMA with Cyad-211 to Establish Proof of Concept of an shRNA-Based Allogeneic CAR T Cell Therapy Platform

Off-the-shelf allogeneic CAR T cells derived from healthy donor cells have the potential to overcome many of the issues associated with the time-consuming manufacturing of autologous CAR T cells. However, adoptive transfer of allogeneic T cells carries the risk of graft-versus-host disease (GvHD). Most of the clinical experience with allogeneic CAR T cells is based on gene editing to eliminate T cell receptor (TCR) to mitigate the risk of GvHD. While clearly effective, the downsides of gene editing include multiple manufacturing steps requiring multiple clinical grade reagents, thus extending culture times, which can be associated with T cell exhaustion.As an alternative, we have explored short hairpin RNA (shRNA) as a means to knockdown TCR expression at the mRNA level. This shRNA is co-expressed along with the CAR in a single clinical grade vector, therefore requiring just one step of genetic modification.CYAD-211 is an allogeneic anti-BCMA CAR T that co-expresses a shRNA targeting CD3z which results in reduction of cell surface TCR expression. IMMUNICY-1 is an ongoing open-label Phase 1 trial (NCT04613557) designed to evaluate CYAD-211 in adult patients with refractory or relapsed multiple myeloma (MM) following at least two prior MM regimens. Patients receive non-myeloablative preconditioning (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, for 3 days) followed by a single CYAD-211 infusion in a 3+3 dose escalation design evaluating three dose-levels (DL): 30x10 6, 100x10 6 and 300x10 6 cells/infusion.As of July 29, 2021, nine patients were enrolled across the 3 DLs. Patients had received a median of four prior lines of treatment. Seventy-eight percent of patients were previously exposed to all three major MM drug classes (proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibody therapy). Eight patients had prior autologous stem cell transplantation.CYAD-211 was well tolerated. One patient developed grade 1 cytokine release syndrome. Two patients had Grade ≥ 3 hematologic toxicities possibly related to the experimental treatment. Two patients experienced infectious adverse events (1 grade 1 rhinitis and 1 grade 2 upper respiratory infection). There was no neurologic toxicity and no GvHD. There was no dose-limiting toxicity.Eight patients were evaluated for activity per IMWG criteria. Two patients achieved partial response at dose-levels 1 and 2 while 5 patients had stable disease (SD). One patient with an ongoing SD (3 months +) showed evidence of reduction in size of plasmacytomas.Analysis of peripheral blood samples by molecular methods confirmed the engraftment of CYAD-211. All patients had detectable CAR T cells. However, the engraftment was short lasting (3-4 weeks). There was a correlation between the depth of lymphodepletion and engraftment. There was also a dose-response in terms of CYAD-211 kinetics with a level neighboring 8,000 copies of CAR T per microgram of input DNA in patients at DL3.These early data indicate that CYAD-211 is well tolerated with a good safety profile. While further study is required to fully understand the anti-BCMA potency of the CAR used in this trial, the lack of observed GvHD despite engraftment of CYAD-211 provides proof of concept of the safe administration of CAR T using a shRNA-allogeneic platform. The lack of sustained engraftment of CYAD-211 can be explained by rejection of the allogeneic cells by the recovering immune system of the recipient and calls for exploring the role of augmented lymphodepletion. Furthermore, given the ability to include multiple shRNA within the single CAR vector, future strategies will also examine knocking down other molecules that are important in driving immune rejection. DisclosuresAl-Homsi: BMS: Other: Independent Medical Education Grant; Daichii Sankyo: Consultancy; Celyad Oncology: Other: Advisory Board. Deeren: Alexion: Consultancy; BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Sanofi: Consultancy, Research Funding; Sobi: Consultancy; Takeda: Consultancy. Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Meuleman: iTeos Therapeutics: Consultancy. Abdul-Hay: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Abbvie: Consultancy; Jazz: Other: Advisory Board, Speakers Bureau; Servier: Other: Advisory Board, Speakers Bureau. Braun: Celyad Oncology: Current Employment. Lonez: Celyad Oncology: Current Employment. Dheur: Celyad Oncology: Current Employment. Alcantar-Orozco: Celyad Oncology: Current Employment. Gilham: Celyad Oncology: Current Employment. Flament: Celyad Oncology: Current Employment. Lehmann: Celyad Oncology: Current Employment.

SCRI-CAR19x22v2 T Cell Product Demonstrates Bispecific Activity in B-ALL

Introduction: CAR T cells in B-ALL have recently focused on the dual targeting of CD19 and CD22 to enhance long term remissions and prevent antigen negative recurrence that is frequently encountered with single antigen targeting. However, a barrier to this approach has been the retention of dual specificity killing and ongoing persistence. PLAT-05 is a multisite phase 1 trial (NCT03330691) that was undertaken to evaluate the safety and feasibility of SCRI-CAR19x22v1, a dual transduced patient-derived product with lentiviral vectors encoding for either a CD19- or CD22-specific CAR, both with 4-1BB co-stimulation. Early results of the first 27 subjects infused demonstrated feasibility and a favorable safety profile with encouraging CR rates. Products were fractionated evenly between CD19 CAR, CD19+CD22 CAR and CD22 CAR. However, engraftment was predominated by the single CD19 CAR population, leading to unsuccessful eradication of CD19-CD22+ leukemia. This finding led to re-engineering the CD22 CAR construct for enhanced CD22 targeting, and re-initiation of dose finding with the new product, SCRI-CAR19v2.Methods: After enrollment, subjects undergo apheresis followed by a combined CD4/CD8 positive immunomagnetic selection and seeded at a prescribed ratio for co-culture in a closed-system G-Rex bioreactor. Following anti-CD3xCD28 bead stimulation, T cells are transduced with two lentiviral vectors that encode for either a CD19- or CD22-specific CAR. After flu/cy lymphodepletion, CAR T cells are infused at one of three dose levels: 0.5, 1 or 3 X 10 6 CAR T cells/kg. Toxicity is graded according to CTCAEv5 except for CRS and ICANS which are graded per ASTCT criteria. Leukemic response and CAR T cell persistence are evaluated by flow cytometry.Results: 14 subjects enrolled onto PLAT-05 for the SCRI-CAR19x22v2 dose escalation and products were successfully manufactured in all subjects with an average of 8.9 days in culture (range 7-12 days). In contrast to v1 products, the CAR composition of v2 products was skewed in favor of CD22 CAR expression, with median expression of each population as follows: 42% CD22 only, 33% CD19 and CD22, 3.2% CD19 only. Twelve subjects were infused (0.5x10 6/kg n=3, 1x10 6/kg n=3, 3x10 6/kg n=6), 11 of whom had prior exposure to CD19 or CD22 targeted therapies with diverse expression of CD19 and CD22 on the leukemic blasts. No dose limiting toxicities occurred in the 11 fully evaluable subjects (1 subject is pending) and the recommended phase 2 dose was determined as 3x10 6 CAR + cells/kg. CRS was present in 45% of subjects, all grade 1. Neurotoxicity occurred in 45% of subjects, all grade 1 except a single self-limited grade 3 ICANS event (due to a single time point CAPD score). 91% of infused subjects obtained a CR, of which 100% were MRD negative. The non-responder had persistent disease that was CD19-CD22-. The in vivo engraftment of CAR T cells peaked most frequently between day +7 and +14 and was predominated by the CD22 CAR T cells, with some minimal contribution of dual and CD19 CAR T cells. Of the 4 subjects who had previously received an FMC63 based CD19 CAR, expansion was due to solely to the CD22 CARs in all 4 subjects, with apparent rejection of the T cells expressing CD19 CAR.Conclusions: We demonstrate enhanced activity of SCRI-CAR19x22v2 compared to v1, now with dual activity against both CD19 and CD22 demonstrated by elimination of ALL with single antigen expression. We maintained encouraging CR rates with a favorable toxicity profile. Interestingly, the product is predominated by CD22 CAR and CD19/CD22 CAR populations, while in vivo engraftment is predominated by single CD22 CAR expressing T cells. Subjects exposed to prior CD19 murine based CAR rejected the CD19 CAR but engrafted the CD22 CAR with demonstratable activity, a potential advantage of a dual transduced product. The impact of lower CD19 CAR engraftment on durable remissions is unknown. While limited expansion of the CD19 CAR population could be protective against exhaustion, the uneven engraftment of the CAR populations may ultimately lead to single antigen targeting. Optimization of transduction may be required for a more balanced product to maintain dual targeting and give further insight into the behavior of dual-expressing CAR T cells. An expansion cohort is currently underway to further characterize engraftment kinetics and in vivo performance to best inform future development of this product. [Display omitted] DisclosuresPulsipher: Jasper Therapeutics: Honoraria; Adaptive: Research Funding; Equillium: Membership on an entity's Board of Directors or advisory committees. Li: Novartis Canada: Membership on an entity's Board of Directors or advisory committees. Jensen: Bluebird Bio: Research Funding; Umoja Biopharma: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Patents & Royalties. Gardner: Novartis: Consultancy; BMS: Patents & Royalties. OffLabel Disclosure:investigational use of SCRI-CAR19x22 will be discussed

A Phase II Trial of Escalated Dose Proton Radiotherapy With Elective Nodal Irradiation and Concomitant Chemotherapy for Patients with Unresectable, Borderline Resectable or Medically Inoperable Pancreatic Adenocarcinoma

To report outcomes of a phase II single-institution trial of escalated dose proton therapy with elective nodal irradiation and concomitant chemotherapy for patients with unresectable, borderline resectable, or medically inoperable pancreatic adenocarcinoma.Patients were treated to 40.5 GyE in 18 fractions to gross disease and elective nodal volumes with a 22.5 GyE in a 10-fraction boost to gross disease, for a total of 63 GyE. Oral capecitabine (1000mg orally twice a day) was given on radiation treatment days. The primary objective of this study was to achieve a 1-year overall survival rate of 75%. Secondary objectives included assessing gastrointestinal toxicity and patient quality of life during treatment, as well as evaluating the safety of subsequent surgical resection. The single-institution study was closed to accrual once opened as the multicenter PAN009-18 trial by the Proton Collaborative Group.At enrollment, 10 (67%) of patients were unresectable, 3 (20%) were borderline, and 2 (13%) refused surgery. Thirteen patients (87%) had previously received chemotherapy. All 15 patients successfully completed radiation therapy as prescribed. With regard to toxicity, a single patient experienced grade 3 nausea requiring cessation of capecitabine, which ultimately resolved at treatment completion. All other patients received concurrent capecitabine for the duration of their radiotherapy treatment. Radiation did not result in any other significant gastrointestinal toxicity during or after treatment. Median percentage weight loss during treatment was -3.0% (-9.6% - +12.0%). Two (13%) initially borderline patients ultimately underwent resection. Their total operating room times were 267 and 410 minutes; blood loss was 700mL and 400mL. Neither patient experienced intraoperative or postoperative complications. Both patients were discharged on postoperative day six. Median follow-up was 0.93 years (0.21-2.14). The 1-year overall survival rate was 47%. Three enrolled patients are currently alive: 2 with no evidence of disease and 1 with stable disease. One patient died of intercurrent disease. Of the remaining 11 patients who died following tumor recurrence, only 3 failed locally, with the remaining 8 failing distantly.Protocol therapy was well-tolerated. Patients undergoing surgery did not experience operative or perioperative complications - suggesting that patients with borderline resectable or even resectable disease may benefit from this regimen as neoadjuvant therapy. The Proton Collaborative Group will test this premise as patients accrue to the multicenter PAN009-18 trial.

Multi-objective optimization of process parameters in TIG-MIG welded AISI 1008 steel for improved structural integrity

This study investigates a parametric multi-objective optimization of the Tungsten Inert Gas-Metal Inert Gas (TIG-MIG) hybrid welding of AISI 1008 mild steel joints. A combined grey relational system theory and the Taguchi method was used for process optimization towards achieving a set of process parameter that maximizes both ultimate tensile strength and 0.2% yield strength for structural applications. An L-9 orthogonal array based on the Taguchi method was adopted for the experimental design matrix. Grey relational grading system was used to establish a single grade for the responses. Mathematical models for first- and second-order regressions were developed and optimum process parameter combination that optimizes the response was obtained. From the results, the gas flow rate had the most significant influence on the responses with a percentage contribution of 39.77%. Also, the second-order regression models had a higher coefficient of determination (R2) compared to the first-order regression for the two responses and, thus, represents the best fit for the process. The grey relational grade was improved by 0.0489 through process optimization. The interactive effects of process parameters and their effects on the responses are also illustrated by response surface plots. This study shows the effectiveness of the grey relational grading system in achieving a multi-objective optimization for the TIG-MIG welding process.

Sistem Pendukung Keputusan Penentuan Uang Kuliah Tunggal Universitas XYZ Menggunakan Algoritma Backpropagation

The determination of the student's single tuition fee grade at XYZ University still faces problems, one of which is the inconsistency of supporting variables which change each year based on the number of students and the level of student welfare. Determination of the class of student's single tuition fee based on the web that applies the backpropagation algorithm is designed to produce an adaptive decision-making system for changing variable determinants so that every year it is not necessary to adjust the weight in determining the student's single tuition fee group. In building a decision support system to determine the student's single tuition fee group, there are several stages including data collection, data processing, backpropagation implementation, evaluation and presentation of the model, and implementation of a web-based decision support system. During the evaluation and presentation of the model, several experiments were carried out by considering various parameters to get the best accuracy results. The accuracy of the best model produced in this study reached 86% with output in the form of a web-based decision support system that is ready to be managed by the Center for Information and Computer Technology (PUSTIKOM) of XYZ University for use by new students.

Phase I Trial of Stereotactic MRI-Guided Online Adaptive Radiation Therapy (SMART) for the Treatment of Oligometastatic Ovarian Cancer

Stereotactic body radiation therapy is increasingly used to treat a variety of oligometastatic histologies, but few data exist for ovarian cancer. Ablative stereotactic body radiation therapy dosing is challenging in sites like the abdomen, pelvis, and central thorax due to proximity and motion of organs at risk. A novel radiation delivery method, stereotactic magnetic-resonance-guided online-adaptive radiation therapy (SMART), may improve the therapeutic index of stereotactic body radiation therapy through enhanced soft-tissue visualization, real-time nonionizing imaging, and ability to adapt to the anatomy-of-the-day, with the goal of producing systemic-therapy-free intervals. This phase I trial assessed feasibility, safety, and dosimetric advantage of SMART to treat ovarian oligometastases. Ten patients with recurrent oligometastatic ovarian cancer underwent SMART for oligometastasis ablation. Initial plans prescribed 35 Gy/5 fractions with goal 95% planning target volume coverage by 95% of prescription, with dose escalation permitted, subject to strict organ-at-risk dose constraints. Daily adaptive planning was used to protect organs-at-risk and/or increase target dose. Feasibility (successful delivery of >80% of fractions in the first on-table attempt) and safety of this approach was evaluated, in addition to efficacy, survival metrics, quality-of-life, prospective timing and dosimetric outcomes. Ten women with seventeen ovarian oligometastases were treated with SMART, and 100% of treatment fractions were successfully delivered. Online adaptive plans were selected at time of treatment for 58% of fractions, due to initial plan violation of organs-at-risk constraints (84% of adapted fractions) or observed opportunity for planning target volume dose escalation (16% of adapted fractions), with a median on-table time of 64 minutes. A single Grade ≥3 acute (within 6 months of SMART) treatment-related toxicity (duodenal ulcer) was observed. Local control at 3 months was 94%; median progression-free survival was 10.9 months. Median Kaplan-Meier estimated systemic-therapy-free survival after radiation completion was 11.5 months, with concomitant quality-of-life improvements. SMART is feasible and safe for high-dose radiation therapy ablation of ovarian oligometastases of the abdomen, pelvis, and central thorax with minimal toxicity, high rates of local control, and prolonged systemic-therapy-free survival translating into improved quality-of-life.

P–200 To transfer or to discard: A retrospective analysis of ploidy, implantation and birthweight outcomes of grade “C” blastocysts following preimplantation genetic testing for aneuploidy (PGT-A)

Abstract Study question What’s the ploidy status of grade “C” blastocysts and what are their implantation potential and birthweight outcomes when tested euploid? Summary answer Grade “C” blastocysts were less likely to be euploid compared to grades “A/B”. Euploid “C”s led to reduced but reasonable implantation potential with similar birthweights. What is known already In contrast to grade “A” or “B”, grade “C” blastocysts are generally considered borderline quality in most in vitro fertilization programs, with inconsistent policies between clinics. Little evidence has been reported regarding their euploidy rate, implantation potential, and birthweight outcomes. Study design, size, duration This retrospective cohort study included 426 consecutive autologous-oocyte patients undergoing PGT-A (biopsy at day 5/6) at two associated private clinics between January 2013 and August 2020. A total of 1418 resulting blastocysts (tested either euploid or aneuploid) were analysed. Implantation outcomes were assessed in a subset of 520 singly transferred euploid blastocysts. Birthweight outcomes were evaluated in 209 singleton newborns using a gestation-adjusted Z score taking into account gestational age and baby gender. Participants/materials, setting, methods Blastocysts were graded “A/B/C” according to a combination of inner cell mass and trophectoderm morphology. Endpoints included ploidy, implantation and birthweight outcomes. Multiple regression (logistic or linear) was performed to investigate relative prognosis of grade “C” blastocysts using different endpoints in reference to grade “A/B” blastocysts, expressed as either adjusted odds ratio (aOR) or coefficients (β) with 95% confidence intervals (CI). Maternal age and biopsy day (5/6) were included as potential confounders at regression analysis. Main results and the role of chance Grade “C” blastocysts (n = 466) were associated with a lower euploidy rate in reference to either grade “A” (n = 179, aOR=0.412, 95% CI: 0.278–0.611, P = 0.000) or “B” blastocysts (n = 773, aOR=0.535, 95% CI: 0.418–0.685, P = 0.000). Euploid “C” grade blastocysts (n = 128) led to significantly reduced chance to implant when compared to either grade “A” (n = 90, aOR=0.387, 95% CI: 0.215–0.696, P = 0.002) or “B” blastocysts (n = 302, aOR=0.617, 95% CI: 0.404–0.944, P = 0.026); although implantation rate was still considered at a reasonable level (44.5%) as opposed to grades “A” (66.7%) or “B” (57.6%). However, no significant difference was observed in the birthweight (g, mean ± standard deviation) following the transfer of a single euploid grade “C” blastocyst (n = 42, 3310.8±704.1) in comparison to a single euploid grade “A” (n = 48, 3367.8±519.3, P &amp;gt; 0.05) or “B” blastocyst (n = 119, 3284.5±535.5, P &amp;gt; 0.05). Taking into account maternal age, biopsy day, gestational age and baby gender; further multiple linear regression analysis also showed similar results using either birthweight itself (C vs A, β=–52.395, 95% CI: –148.83–43.893, P = 0.282; C vs B, β=–104.338, 95% CI: –272.653–63.977, P = 0.223), or the gestation-adjusted Z score as an endpoint (C vs A, β = 0.101, 95% CI: –0.001–0.164, P = 0.052; C vs B, β = 0.084, 95% CI: -–0.073 – 0.241, P = 0.290). Limitations, reasons for caution The retrospective design of this study does not allow control for unknown confounders. Inner cell mass or trophectoderm was not graded separately making it difficult to further break down the “C” grade blastocysts. Only blastocysts suitable for biopsy were included for analysis, so results may not extrapolate to untested blastocysts. Wider implications of the findings: Grade “C” blastocysts may still hold its clinical value despite reduced euploidy rate. PGT-A may be considered as a potential approach to utilize grade “C” blastocysts more effectively, without affecting birthweight outcomes. This is also potentially useful in patient counselling. Trial registration number Not applicable

Wear Resistance of Experimental Hard Alloys Grades with Co-Mo-Ti Binders upon Conditions of Friction without Lubricant on Stainless Steel

The results of studies of wear resistance and tribological properties of experimental single carbide hard alloys grades with modified Co-Mo-Ti binders upon conditions of friction without lubricant on stainless steel are presented. All the data obtained were compared with similar parameters for the basic alloy VK8 (Co-Mo), on the basis of which the experimental grades were developed. Tribological tests were performed on tribometer which implemented a scheme of friction "pin on disk" at constant sliding speed and normal load values with artificially heated tribo contact zone. Studies have found that partial substitution of cobalt in a binder by Mo and Ti has led to a decrease in average friction rates. It was established that the greatest wear resistance and the best tribological characteristics were obtained for specimens of experimental grade 2.22 (5,65%Co+1,8%Mo+0,6%Ti). The process of friction for this pin material was characterized by the formation of secondary structures with high shielding properties, reducing of the adhesive interaction of materials, low volume wear intensity, minimal friction coefficient, as well as the least roughness of friction tracks on the counter body (disk). An increase in the proportion of molybdenum in the binder of more than 5% reduced the wear resistance of the experimental grades in comparison with the basic alloy VK8.

Evaluation of pharmacodynamic (PD) and biologic activity in a preoperative window-of-opportunity (WOO) study of giredestrant (GDC-9545) in postmenopausal patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2–) operable breast cancer (BC).

577 Background: Modulation of ER activity and/or estrogen synthesis is the mainstay therapeutic strategy in ER+ BC treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER degrader (SERD) that achieves robust ER occupancy and is effective regardless of ESR1 mutation status. The first short-term preoperative WOO study (NCT03916744) of giredestrant in ER+/HER2– operable BC was designed for dose selection, while providing an early readout of PD as measured by traditional immunohistochemistry (IHC) and transcriptional profiling by assessing treatment effects in paired tumor tissue pre/posttreatment. We present an interim analysis. Methods: Pts were assigned to 14 days’ preoperative treatment with 10, 30, or 100 mg PO giredestrant QD. Pts had newly diagnosed, stage I–III operable, ER+/HER2– untreated BC ≥1.5 cm in diameter (by ultrasound). Modulation of ER signaling and cell proliferation were assessed using paired formalin-fixed paraffin-embedded tumor specimens collected before and after ̃14 days of study treatment. ER, progesterone receptor (PR), and Ki67 protein levels were analyzed by IHC. Change from baseline in tumor cell proliferation by Ki67 was the primary endpoint. Gene expression analysis was performed using the Illumina TruSeq RNA Access method. Results: From Jul 26, 2019 to Oct 15, 2020, 46/75 biomarker-evaluable pts were enrolled across three dose cohorts (10 mg: n = 15; 30 mg: n = 18; 100 mg: n = 13). Pt demographics and tumor characteristics were similar across cohorts. Baseline PAM50 analysis classified tumors as Luminal A (77%) or B (23%). Giredestrant treatment resulted in robust and indistinguishable PD and biologic activity at all doses. Geometric mean posttreatment proportional reduction of Ki67 was 79% (95% CI: 69–89; 10 mg: 80%; 30 mg: 76%; 100 mg: 80%), and 51% of tumors exhibited complete cell cycle arrest, defined as Ki67 ≤2.7%. Mean posttreatment proportional reductions of ER and PR H-scores were 71% (95% CI: 67–75) and 60% (95% CI: 51–70), respectively. An analysis of a predefined, experimentally derived set of 38 ER target genes (the ‘ER activity signature’), was completed for 42 paired tumor specimens. Forty-one of 42 pts (98%) showed a posttreatment reduction in ER activity with a mean proportional decrease of 79% (95% CI: 70–88). A wide range of baseline ER activity was observed with no correlation to baseline ER or PR H-score, or Ki67. There were no discontinuations due to adverse events (AEs). A single grade 3 serious AE was reported in each cohort (all assessed as unrelated to giredestrant). No grade 4 or 5 AEs were reported. Conclusions: Giredestrant was well tolerated in the preoperative setting in ER+/HER2– operable BC, and PDs were consistent with the 30 mg dose achieving maximal ER inhibition. Clinical trial information: NCT03916744.

The effect of post-consumer recycled polyethylene (PCRPE) on the properties of polyethylene blends of different densities

Polyethylene (PE), a versatile polymer present nearly everywhere, poses many challenges as more of it becomes terrestrial and marine waste and used for everything from packaging such as plastic bag production (LDPE) to construction pipes (HDPE). As more companies are required to follow government regulations and consumers’ requests to produce more sustainable products, the general interest in PE recycling continues to gain momentum. Several processes have been developed to recycle PE, but current data gaps exist on the impact of adding post-consumer recycled polyethylene (PCRPE) to different virgin feedstocks on final product performance. To better understand this impact, a single source of PCRPE was melt blended with four different virgin PE grades at different concentrations (0, 20, 40, 60, 80, and 100 wt% of PCRPE), and changes in the physical, thermal, and mechanical properties were evaluated. Different trends and behaviors were observed depending on the PE density, however, most properties still followed the Law of Mixtures. For example, low-density PE's mechanical strength improved up to 70% increase in tensile modules and 56% in yield strength. The density was increased by ~5%, and no toxic heavy metals (Cd, Cr, Hg, Pb) were found, with less than 4 ppm of Al, Fe, and Ti detected. The insights obtained when mixing polyethylene of different densities with a single recycled grade PE allows plastic manufacturers and recyclers to gain a more comprehensive view of possibilities associated with PCRPE. The results presented herein and previously from our group suggest most physical properties of PCRPE blends follow the Law of Mixtures, enabling the possibility for performance property predictive modeling of different compositions by understanding properties from the virgin and PCR materials alone. The introduction of PCRPE blends also reduces costs by tailoring products to optimal performance and maximum recycled content.

Multi-objectives robust optimization based on Grey-Taguchi method for the electric vehicle frame collision

The proportion of electric vehicles in vehicle manufacturing is increasing, but with the endurance mileage of the battery improved, the collision safety problem of electric vehicles is becoming more prominent. To solve a multi-objective robust design problem with discrete variables for vehicle collision design, we propose the Grey-Taguchi robust optimization method. The Grey-Taguchi method transforms the multi-objective functions into a single grey relation grade sequence instead of the signal-noises ratio used in Taguchi and selects the optimal combination of design variables predicted by the minimum design of experimental and the analysis of means. For the vehicle crashworthiness problem, the Grey-Taguchi method can converge to the Pareto front with several iterations. The mass of frame, maximum lateral intrusion, and peak deceleration after the optimization are decreased 14.5 %, 32.3 %, and 17.8 %, respectively. The Grey-Taguchi robust optimization method can not only enhance the robustness of the optimization design but also improve the lightweight design performance and crashworthiness. The proposed method is considered promising for complex engineering design problems with multi-objectives and discrete design variables.

The Role of Patient-reported Outcomes and Medication Adherence Assessment in Patient-focused Drug Development for Solid Organ Transplantation.

The Role of Patient-reported Outcomes and Medication Adherence Assessment in Patient-focused Drug Development for Solid Organ Transplantation.

Hydronephrosis Classifications: Has UTD Overtaken APD and SFU? A Worldwide Survey.

Objective: To collect baseline information on the ultrasonographic reporting preferences.Method: A 13-multiple choice questionnaire was designed and distributed worldwide among pediatric urologists, pediatric surgeons, and urologists. The statistical analysis of the survey data consisted of 3 steps: a univariate analysis, a bivariate and a multivariate analysis.Results: Three hundred eighty participants responded from all the continents. The bivariate analysis showed the significant differences in the geographical area, the years of experience and the volume of cases. Most of the physicians prefer the SFU and APD systems because of familiarity and simplicity (37 and 34%, respectively). Respondents noted that their imaging providers most often report findings utilizing the mild-moderate-severe system or the APD measurements (28 and 39%, respectively) except for North America (SFU in 50%). Multivariate analysis did not provide significant differences.Conclusion: Our study evaluates the opinions regarding the various pediatric hydronephrosis classification systems from a large number of specialists and demonstrates that there is no single preferred grading system. The greatest reported shortcoming of all the systems was the lack of universal utilization. The observations taken from this study may serve as basis for the construction of a common worldwide system. As APD and SFU are the preferred systems and the UTD a newer combination of both, it is possible that with time, UTD may become the universal language for reporting hydronephrosis. This time, based on the result of this survey, seems not arrived yet.

Efficacy of modified bevacizumab-XELOX therapy in Japanese patients with stage IV recurrent or non-resectable colorectal cancer.

Neoadjuvant chemotherapy (NAC) has been conducted for patients with non-resectable colorectal cancer; however, few reports of a systematic approach to NAC exist. At our hospital, bevacizumab with capecitabine and oxaliplatin (B-mab XELOX) has been used as chemotherapy for Stage IV colorectal cancer since 2014. We aimed to evaluate the efficacy and safety of NAC with a molecular-targeting agent for Stage IV colorectal cancer. A retrospective, single-institute analysis was performed including 27 patients with advanced recurrent cancer following primary tumor resection and 43 patients with non-resectable tumors and remote metastasis. At the time of resection, 17 were receiving chemotherapy. All 70 patients received at least 3 cycles of B-mab XELOX (total: 920 cycles). We determined the 1-year progression-free survival (1Y-PFS), 1-year overall survival (1Y-OS), 3Y-PFS, 3Y-OS, and number of treatment cycles. The objective response rate, clinical benefit rate, and adverse events were assessed. The number of chemotherapy cycles, survival time, and R0 surgery rate were determined for patients who underwent RO conversion surgery. The 1Y-PFS was 28.5% [median survival time (MST): 7.4 months], 1Y-OS was 76.6% (MST not reached), 3Y-PFS was 5.5% (MST: 7.4 months), and 3Y-OS was 26.4% (MST: 25.2 months). The mean and median number of cycles of B-mab XELOX was 13.1 and 10.5, respectively. The objective response rate was 28.6%, and the clinical benefit rate was 58.6%. Grade 1 or Grade 2 adverse events occurred in 60 patients (85.7%); however, they all resolved without intervention. A single Grade 4 event (perforation of the primary tumor) occurred in 1 patient (1.4%). RO conversion surgery was performed in 7 patients (10.0%; primary + liver in 2 patients, primary + lung in 1 patient, liver in 3 patients, and primary in 1 patient). These patients received 3 to 10 cycles preoperatively (mean: 7.3; median: 6.5). R0 surgery was achieved in 5 of the 7 patients (71.4%). Postoperative survival ranged from 1 to 26 months (MST: 8 months). This modified regimen was safe and effective in Japanese patients, and a high quality of life/quality-adjusted life-year was achieved. To further evaluate PFS and OS, more patients are being investigated.