Standard GEM Research Articles

Abstract 1059: Paricalcitol, hydroxychloroquine and gemcitabine promote antitumor effects and modulate immune profile in pancreatic ductal adenocarcinoma

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) has low (<5%) five-year survival. We hypothesized combined Vitamin D3 (Paricalcitol; Par) and hydroxychloroquine (HCQ) impacts stroma, anti-tumor immunity, and autophagy, thereby sensitizing PDAC to gemcitabine (Gem). Methods For subcutaneous efficacy, 5-6-week-old female nude mice (n=5/group) were injected with KPC-Luc cells and randomized to: 1) vehicle (PBS), 2) Gem plus HCQ, 3) Gem plus Par, and 4) Gem, HCQ, and Par once tumors were palpable. Gem and Par (twice weekly) were administered via intraperitoneal injection. HCQ was given orally (daily). For orthotropic efficacy and single cell analysis, female C57BL/6J mice (n=6/group) were injected with 2×105 KPC-Luc cells into the pancreas tail. On day 5, animals were randomized to 1) PBS and 2) combined Gem/HCQ/Par as above. Tumors were analyzed via bioluminescent imaging. After 15 days, animals were euthanized, tumors were weighed and dissociated into single cells. High viability samples were used to generate scRNA-Seq libraries using 10X genomics droplet approach. Results Gem, HCQ, and Par significantly (p<0.001) reduced tumor growth/weight versus controls in both models. Single cell transcriptome profiles of 11,188 cells (controls) and 7,624 cells (Gem/HCQ/Par) were obtained. Split UMAP plots of samples were generated with cell clusters annotated from established gene markers. Eight clusters expressing PDAC-associated genes were designated as PDAC cells. The tumor microenvironment (TME) showed dramatic post-treatment changes with significant decreases in PDAC cells (p=0.007) and increases in B cells, monocytes/macrophages (p=0.0006, 0.03 respectively), and increased T/NK cells in treated versus control mice. Supervised analysis among T cells showed more activation (Cd44, Tnfrsf4/9) and exhaustion (Ctla4, Lag3, Pdcd1) associated gene expression post-treatment, indicating robust T cell response. ssGSEA analysis showed significant (p<.001) activation of Th1/Th2/Th17 pathways. Monocyte/macrophages clusters analysis revealed greater expression of M1 genes and M2 genes in treated and control samples, respectively. Modified EMT was observed in stromal cells with enhanced MHC1 expression. Conclusion HCQ and Par enhance the efficacy of Gem in two mice PDAC models. Single cell transcriptome analyses revealed the combination treatment promoted immune shifts in the PDAC TME. Effects of Par and HCQ and standard chemotherapy drugs, Gem and nab-paclitaxel are being studied in an ongoing clinical trial (NCT04524702). Citation Format: Purnachandra Nagaraju Ganji, Beena Elizabeth Thomas, Maggie Phillips, Cameron Herting, Amanda Ruggieri, Jessica Millian Keilson, Michael Kim Turgeon, Sisira Saraswatula, William Pilcher, Gregory B. Lesinski, Manoj Bhasin, Bassel F. El-Rayes. Paricalcitol, hydroxychloroquine and gemcitabine promote antitumor effects and modulate immune profile in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1059.

Investigation on the performance of a thick ceramic gas electron multiplier

We report the performance of a THick Gas Electron Multiplier (THGEM) fabricated by drilling holes in a gold-clad ceramic substrate using the standard PCB (Printed Circuit Board) technology and etching rims. The THGEM has a total thickness of 200μm with a hole diameter and rim size of 200μm and 80μm, respectively. In order to carry out a performance study, a detector was assembled by putting the THGEM inside a versatile chamber and irradiating it with a 55Fe X-ray source (5.9 keV). An Ar/CO2 gas mixture was flushed inside the chamber at a pressure of about 1 atm, with volume ratios varying between 70/30 and 90/10. Pulse height spectra of the detector were recorded by a multichannel analyzer to investigate the gain and energy resolution at different drift and induction electric fields. The variations in the gain and energy resolution were also interpreted using simulations. The gain and resolution data of the THGEM were compared with those of a standard GEM which was measured using the same experimental setup.

Interpretation of effective gain variations with the drift electric field for a ceramic thick gas electron multiplier

The effective gain variations as a function of the drift electric field strength (Ed) are measured in a ceramic thick gas electron multiplier (THGEM) and a standard GEM using the same experimental setup. Significant differences in the variations are observed between the THGEM and the standard GEM. The effective gain variations with Ed are quantitatively reproduced by calculations via investigating the respective influence of Ed change on the electron collection efficiency and the gain. The differences in the effective gain variation with Ed between the THGEM and standard GEM are thus explained.

Abstract B60: Optimization of biologic scheduling of gemcitabine and abraxane improves treatment response compared to the standard concurrent regimen in preclinical models of pancreatic cancer

Abstract Introduction: Gemcitabine (gem) and Abraxane (albumin-bound paclitaxel, abx) combination chemotherapy delivered on the same day is now one of the preferred chemotherapy regimens for metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC) based on results of the phase III MPACT clinical trial that showed improved overall survival of gem+abx compared to gem alone in the metastatic/advanced setting. Our previous published works revealed that caveolin-1 (Cav-1), the principal structural component of caveolae and mediator of endocytosis, is highly expressed in PDAC cells and associated with enhanced tumor progression and resistance to gem in PDAC preclinical models. We also found that loss of Cav-1 through genetic knockdown inhibited both PDAC cell uptake of albumin and response to albumin-based chemotherapies, i.e., abx. In addition, gem treatment resulted in a time-dependent increase in Cav-1 protein expression. Taken together, we hypothesized pretreatment with gem would increase the efficacy of the gem/abx combination via increased Cav-1 dependent albumin-bound chemotherapy uptake. Results: ASPC1 and HPAFII PDAC cell lines were exposed to gem (25-100nM) for 24-48 hours followed by a 1-hour albumin pulse and displayed a time-dependent increase in intracellular albumin via Western blotting. We next tested PDAC cell proliferation and cell survival via alamarBlue and colony formation assays with various different gem/abx scheduling combinations. HPAFII and ASPC1 cells were treated for 24 hours with the following schedules: (1) vehicle, (2) gem alone, (3) abx alone, (4) gem+abx on same day (d1gem+abx), (5) gem on day 1 and abx day 2 (d1gem_d2abx), or (6) gem on day 1, no drug on day 2 and abx on day 3 (d1gem_d3abx). Both alternative schedules of d1gem_d2abx and d1gem_d3abx had greater inhibition of proliferation and colony formation compared to the current standard of care d1gem+abx, and of all the combinations, d1gem_d3abx was the most efficacious (p<0.01). Genetic knockdown of Cav-1 through short-hairpin loop RNA (shRNA) in Mia-Paca2 cells resulted in reversal of the observed altered scheduling effect on cell proliferation and survival. In vivo, we compared tumor growth rates with altering gem-abx scheduling following subcutaneous injection into athymic nude mice of ASPC1 or HPAFII cells. Similar to our in vitro studies, mice were treated with either the control-vehicle or three cycles delivered over 9 days of the following gem-abx combinations: 1) d1gem+abx, 2) d1gem_d2abx, or 3) d1gem_d3abx. The d1gem_d3abx scheduling had the most significant delay in tumor growth and tumor doubling time compared to the other gem-abx schedules (p<0.001). Conclusion: We found 24- to 48-hour gem treatment increased albumin uptake, leading to maximal treatment efficacy with an optimized schedule of gem delivered on day 1 and abx on day 3 compared to the standard gem+abx administered on the same day. These findings support further testing of an altered and biologically optimized scheduling of gemcitabine and Abraxane. Citation Format: Adam R. Wolfe, Ryan Robb, Ahmad Hegazi, Duan-Liang Shyu, Laith Abushahin, Terence M. Williams. Optimization of biologic scheduling of gemcitabine and abraxane improves treatment response compared to the standard concurrent regimen in preclinical models of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B60.

Feasibility of gem identification using reflectance spectra coupled with artificial intelligence

Standard traditional gem identification requires expert supervision, while sophisticated modern methods are time-consuming and expensive. In contrast, reflectance spectroscopy coupled with artificial intelligence is economical and convenient and does not require specialist supervision. This study established an artificial neural network model that consists of standard multilayered, feed-forward, and back-propagation neural networks, and obtained reflectance spectra of a transparent gem (almandine), an opaque gem (turquoise), several almandine imitations (agate, plastic, and glass), and several treated turquoise samples (dyed, impregnated, and Zachery treated) using an Analytical Spectral Devices spectrometer. The acquired spectra were used to train and test the artificial neural network model. The results show that the model can effectively discriminate between genuine and imitation gems of different classes. However, discrimination between natural and treated gems of same class is not as effective as discrimination of gems of different classes. The results suggest that an artificial neural network based on reflectance spectroscopy could serve as a useful tool for preliminary gem identification, and the advanced identification needs further training and investigation.

Recent advances in bubble-assisted Liquid Hole-Multipliers in liquid xenon

We report on recent advances in the operation of bubble-assisted Liquid Hole-Multipliers (LHM). By confining a vapor bubble under or adjacent to a perforated electrode immersed in liquid xenon, we could record both radiation-induced ionization electrons and primary scintillation photons in the noble liquid. Four types of LHM electrodes were investigated: a THGEM, standard double-conical GEM, 50 μm-thick single-conical GEM (SC-GEM) and 125 μm-thick SC-GEM—all coated with CsI photocathodes. The 125 μm-thick SC-GEM provided the highest electroluminescence (EL) yields, up to ∼ 400 photons per electron over 4π , with an RMS pulse-height resolution reaching 5.5% for events comprising ∼ 7000 primary electrons. Applying a high transfer field across the bubble, the EL yield was further increased by a factor of ∼ 5. The feasibility of a vertical-mode LHM, with the bubble confined between two vertical electrodes, and the operation of a two-stage LHM configuration were demonstrated for the first time. We combine electrostatic simulations with observed signals to draw conclusions regarding the location of the liquid-gas interface and suggest an explanation for the observed differences in EL yield between the investigated electrodes.

Spatial resolution properties of krypton-based mixtures using a 100 μm thick Gas Electron Multiplier

A gaseous imaging detector based on a cascade of two non-standard gas electron multipliers 100 μm thick GEM) was operated in five different krypton-based mixtures and the achievable position resolution was determined. The micropattern gaseous detector (MPGD) has an active area of 10 × 10cm2. The GEM foils are twice as thick as a standard GEM, being more robust to electric discharges and less prone to sparking-caused damage. Krypton, being the noble gas with the lowest value of intrinsic position resolution in the range 14– 34 keV, is a good candidate for imaging applications based on gaseous detectors. Our measurements have confirmed that krypton-CO2 mixtures showed an improvement in position resolution above 18 keV and up to 30 keV relatively to Ar-CO2 mixtures. The MTF value at 10% in the energy range 22–24 keV was evaluated, being 0.5876(342)lp/cm for Ar-CO2 (70:30) and a maximum of 3.2702(15)lp/cm for the Kr-CO2 (90:10) mixture.

Ion mobility measurements in Ar-CO[formula omitted], Ne-CO[formula omitted], and Ne-CO[formula omitted]-N[formula omitted] mixtures, and the effect of water contents

A detector has been constructed for measuring ion mobilities of gas mixtures at atmospheric pressure and room temperature. The detector consists of a standard triple GEM amplification region and a drift region where ions drift. A method has been developed to measure the ions’ arrival time at a cathode wire-grid by differentiating the recorded signals on this electrode. Simulations prove that this method is accurate and robust. The ion mobility in different gas mixtures is measured while applying different drift field values ranging from 200Vcm−1 to 1100Vcm−1. From an extrapolation of a Blanc’s law fit to measurements in Ar-CO2 mixtures we find the reduced mobility of the drifting (cluster) ion species in pure argon to be 1.94±0.01 cm2V−1s−1 and in pure carbon-dioxide to be 1.10±0.01 cm2V−1s−1. Applying the same procedure to our measurements in Ne-CO2 yields 4.06±0.07 cm2V−1s−1 and 1.09±0.01 cm2V−1s−1 for the reduced mobilities in pure neon and carbon-dioxide, respectively. Admixtures of N2 to Ne-CO2 (90-10) reduce somewhat the mobility. For the baseline gas mixture of the future ALICE Time Projection Chamber, Ne-CO2-N2 (90-10-5), the measured reduced mobility of the drifting ions is 2.92±0.04 cm2V−1s−1. Ion mobilities are examined for different water content ranging from 70ppm to about 2000ppm in the gas using Ar-CO2 (90-10) and Ne-CO2 (90-10). A slight decrease of ion mobility is observed for the addition of several hundred ppm of water.

Application of GEM-based detectors in full-field XRF imaging

X-ray fluorescence spectroscopy (XRF) is a commonly used technique for non-destructive elemental analysis of cultural heritage objects. It can be applied to investigations of provenance of historical objects as well as to studies of art techniques. While the XRF analysis can be easily performed locally using standard available equipment there is a growing interest in imaging of spatial distribution of specific elements. Spatial imaging of elemental distrbutions is usually realised by scanning an object with a narrow focused X-ray excitation beam and measuring characteristic fluorescence radiation using a high energy resolution detector, usually a silicon drift detector. Such a technique, called macro-XRF imaging, is suitable for investigation of flat surfaces but it is time consuming because the spatial resolution is basically determined by the spot size of the beam. Another approach is the full-field XRF, which is based on simultaneous irradiation and imaging of large area of an object. The image of the investigated area is projected by a pinhole camera on a position-sensitive and energy dispersive detector. The infinite depth of field of the pinhole camera allows one, in principle, investigation of non-flat surfaces. One of possible detectors to be employed in full-field XRF imaging is a GEM based detector with 2-dimensional readout. In the paper we report on development of an imaging system equipped with a standard 3-stage GEM detector of 10 × 10 cm2 equipped with readout electronics based on dedicated full-custom ASICs and DAQ system. With a demonstrator system we have obtained 2-D spatial resolution of the order of 100 μm and energy resolution at a level of 20% FWHM for 5.9 keV . Limitations of such a detector due to copper fluorescence radiation excited in the copper-clad drift electrode and GEM foils is discussed and performance of the detector using chromium-clad electrodes is reported.

A robust large area x-ray imaging system based on 100 μ m thick Gas Electron Multiplier

We have developed an imaging detector based on a non-standard GEM, made from a 100 μ m thick kapton foil (2-fold thicker than standard GEM's). The 100 micron thick GEM is produced using the same wet etching technique as the standard GEM and is less prone to the damage caused by discharges, creating a robust detector that can safely operate at high gain.In this work we present the results obtained with a cascaded gaseous electron multiplier composed by two 100 micron thick GEM and a 10× 10 cm2 bi-dimensional readout electrode with resistive charge division. We have recorded energy resolution of 21% and charge gains above 104 when the detector was irradiated with 5.9 keV X-rays emitted by a 55Fe radioactive source. We also present 10× 10 cm2 images acquired with the detector when irradiated with X-rays. The minimum position resolution recorded was 1.7 mm.

Optical quality assurance of GEM foils

An analysis software was developed for the high aspect ratio optical scanning system in the Detector Laboratory of the University of Helsinki and the Helsinki Institute of Physics. The system is used e.g. in the quality assurance of the GEM-TPC detectors being developed for the beam diagnostics system of the SuperFRS at future FAIR facility. The software was tested by analyzing five CERN standard GEM foils scanned with the optical scanning system. The measurement uncertainty of the diameter of the GEM holes and the pitch of the hole pattern was found to be 0.5μm and 0.3μm, respectively. The software design and the performance are discussed. The correlation between the GEM hole size distribution and the corresponding gain variation was studied by comparing them against a detailed gain mapping of a foil and a set of six lower precision control measurements. It can be seen that a qualitative estimation of the behavior of the local variation in gain across the GEM foil can be made based on the measured sizes of the outer and inner holes.

747TiP - Scheduling Nab-Paclitaxel with Gemcitabine (Siege): Randomised Phase Ii Trial to Investigate Two Different Schedules of Nab-Paclitaxel (Abx) Combined with Gemcitabine (Gem) As First Line Treatment for Metastatic Pancreatic Adenocarcinoma (Pdac)

ABSTRACT Background: PDAC carries a poor prognosis. Recently ABX combined with GEM was shown to improve overall survival compared with standard single agent GEM. The mechanism by which ABX and GEM interact is not fully understood, but limited preclinical and clinical data has led to two hypotheses: 1: ABX may act to deplete the tumour stroma by binding to the protein, SPARC (secreted protein acidic and rich in cysteine), facilitating GEM penetration of and access to the tumour; 2: ABX may increase intratumoural levels of the active GEM triphosphate by decreasing cytidine deaminase (CDA) activity, thus enhancing GEM cytotoxicity. Mouse models of PDAC suggest that delivery of ABX 24 hours prior to GEM might result in even higher intratumoural GEM concentrations. Thus, scheduling of these 2 agents may be critical to optimising clinical benefit. Optimal scheduling of ABX + GEM and effect on quality of life is the subject of the SIEGE clinical trial. Trial design: Patients with previously untreated, histologically or cytologically confirmed metastatic PDAC are randomised to receive a 4-weekly cycle of ABX + GEM until disease progression, administered either concomitantly (IV ABX 125mg/m2 d1, d8 and d15 immediately followed by IV GEM 1000mg/m2 d1, d8 and d15) or sequentially (the same regimen with GEM given 24hr after ABX). Prior to randomisation, tumour tissue and blood is obtained for analysis of the tumour stroma, SPARC and CDA activity. Blood is collected prior to each treatment cycle and on disease progression. Tumour biopsies are collected prior to starting cycle 3 and at disease progression. The clinical primary endpoint is progression-free survival. Tumour assessments are performed using RECIST every 8 weeks until progression. Recruitment started in January 2014 and a total of 120 patients will be recruited over 2 years at 20 UK sites. Biological samples will be used to determine the mechanism of action of ABX + GEM. Biomarker analyses may identify whether a particular patient subgroup is likely to benefit more than others. The trial is registered as EudraCT 2013-001868-40. Disclosure: P. Corrie: I have received funds from Celgene Ltd for: 1. Work in a consultant/advisory role 2. As research funding 3. To fund travel to conferences/meetings; D.I. Jodrell and B. Basu: I have been awarded funds by Celgene Ltd for: 1. To fund aspects of my research. 2. To fund travel to conferences/meetings; J.W. Valle: I have received funds from Celgene Ltd for: 1. Work in a consultant/advisory role 2. As research funding 3. To fund travel to conferences/meetings. All other authors have declared no conflicts of interest.

725P - A Phase I Study of Gemcitabine (Gem), Cisplatin (Cddp), and S-1 Combination in Untreated Patients (Pts) with Advanced Biliary Tract Cancer (Abtc)

ABSTRACT Aim: GEM plus CDDP has been established as standard first-line chemotherapy based on the results of the phase III study (ABC-02) in ABTC. An oral FU derivative, S-1 showed a similar activity to GEM in a phase II study and is mainly used in GEM-refractory pts in Japan. To develop a triplet regimen, GEM + CDDP + S-1 (GPS), we assessed its safety in this phase I study. Methods: The main eligibility criteria were; histologically or cytologically confirmed ABTC, ECOG Performance Status (PS) 0-2, no prior chemotherapy, and written informed consent. Dose limiting toxicities (DLT) were evaluated in following 2 dose levels; GEM (1000 mg/m2 at level 1 and 1200 mg/m2 at level 2 on day 1) + CDDP (fixed dose of 30 mg/m2 on day 1) + S-1 (fixed dose of 40—60 mg/day bid for 7 days), repeated every 2 weeks until progression. The relative dose intensity of GEM and CDDP at level 2 corresponded to 90% of standard GEM plus CDDP regimen. In each level, 6-10 pts were enrolled and assessed. DLTs were evaluated during the first 2 cycles. Results: Between Oct 2011 and Oct 2013, 18 pts were enrolled and 16 pts were evaluated (median age: 71 years, ECOG PS 0/1: 10/6, intrahepatic/extrahepatic/gallbladder: 7/3/6). DLTs (grade 3 nausea to stop S-1 in cycle 1 and treatment delay due to grade 3 neutropenia in cycle 2) at level 1 were observed in 2 of the first 6 pts. Additional 4 pts enrolled at this dose level experienced no DLTs. A DLT (G3 anorexia) at level 2 was observed in 1 of 6 pts. Grade 3 or 4 treatment-related adverse events within the first 2 cycles were leukocytopenia (38%), neutropenia (50%), thrombocytopenia (0.6%), nausea (0.6%), and anorexia (0.6%). Of 14 pts with measurable lesions, 7 (50%) pts had partial response and 6 (43%) patients had stable disease. Median progression free survival was 9.2 months (95%CI 6.8-11.6, event in 63%) and overall survival did not reach the median value (event in 38%). Conclusions: GPS of dose level 2 (GEM 1200 mg/m2 and 30 mg/m2 on day 1 plus S-1 for 1-7 days, given bi-weekly) was well tolerated, and showed preliminary anti-tumor activity. Further study is warranted. Clinical trial information: UMI06123. Disclosure: T. Moriwaki: Research funding for other study and honoraria from Taiho Pharmaceutical; I. Hyodo: Research funding for other study from Taiho Pharmaceutical and Lilly. Honoraria from Taiho Pharmaceutical. All other authors have declared no conflicts of interest.

Investigation of GEM-Micromegas detector on X-ray beam of synchrotron radiation

To reduce the discharge of the standard bulk Micromegas and GEM detectors, a GEM-Micromegas detector was developed at the Institute of High Energy Physics. Taking into account the advantages of the two detectors, one GEM foil was set as a preamplifier on the mesh of Micromegas in the structure and the GEM preamplification decreased the working voltage of Micromegas to significantly reduce the effect of the discharge. At the same gain, the spark probability of the GEM-Micromegas detector can be reduced to a factor 0.01 compared to the standard Micromegas detector, and an even higher gain could be obtained. This paper describes the performance of the X-ray beam detector that was studied at 1W2B Laboratory of Beijing Synchrotron Radiation Facility. Finally, the result of the energy resolution under various X-ray energies was given in different working gases. This indicates that the GEM-Micromegas detector has an energy response capability in an energy range from 6 keV to 20 keV and it could work better than the standard bulk-Micromegas.

Study of Ion Back Flow suppression with thick COBRA GEM

Ion Back Flow (IBF) suppression is essential to avoid a space-charge distortion of the electric field under a high rate condition in the Time Projection Chamber (TPC). A GEM technology is one possible solution to achieve a small IBF and to keep a good performance in terms of particle tracking and particle identification at high rates in TPC. We developed Thick COBRA GEMs to investigate the capability of further IBF suppression. It was found that the COBRA GEM can suppress IBF more effectively compared to a standard GEM. IBF reaches about 0.1–0.5% with a stack configuration consisting of one standard GEM facing to the drift field and two COBRA GEMs. In this paper, the current status of development of COBRA GEM is described.

Development of a Novel Standard Type of Gel Engineering Materials via Simple Bulk Polymerization

Abstract Gels are soft and wet materials, which have unique properties such as low surface friction, material permeability, and biocompatibility. These superior properties of gels can possibly be applied to develop novel artificial blood vessels and can also be used at knee joints. However, the mechanical properties of the gels have not been clarified and controlled so far due to the lack of standard type of gels for mechanical engineering research. Here we try to develop a novel type of gel named the standard gel engineering materials (standard GEM) via simple bulk polymerization, i.e. dry synthesis without any solvent. In the numerous previous studies of gels, almost all gels have been prepared by solution polymerization, i.e. wet synthesis with various solvents. The mechanical properties of the wet-synthesized gels, however, strongly depend on the concentrations of the monomer, crosslinker, initiator, and accelerator in pre-gel solutions. Therefore, it is difficult to control the mechanical properties of gels causing rough reproducibility of mechanical experiments. In the present paper, the simple bulk polymerization is proposed as another candidate to create a standard GEM. The key point of the present work is to use the liquid type of highly reactive monomer, which plays the role of solvent in preparation, and thus we do not have to consider both the ratio concentrations of the monomer and the accelerator to the solvent in preparation. In this case we can focus only on the ratio concentration of the crosslinker to the monomer. This ratio concentration is directly related to the contour length of the polymer chain between the crosslinking points. We have found that the mechanical properties of the dry-synthesized GEM depend hardly on the ratio concentration of the initiator to the monomer, but mainly on that of the crosslinker. The Young’s modulus is simply, well described as a power function of the crosslinker concentration. We hope this dry-synthesized GEM will be useful as another novel standard sample for mechanical engineering research.

Development of Resistive Electrode Gas Electron Multiplier (RE-GEM)

We successfully produced Resistive-Electrode Gas Electron Multiplier (RE-GEM) which has resistive electrodes instead of the metal ones which are employed for the standard GEM foils. RE-GEM has a resistive electrode of 25 μm-thick and an insulator layer of 100 μm-thick. The hole structure of RE-GEM is a single conical with the wider and narrower hole diameters of 80 μm and 60 μm, respectively. A hole pitch of RE-GEM is 140 μm. We obtained the maximum gain of about 600 and the typical energy resolution of about 20% (FWHM) at an applied voltage between the resistive electrodes of 620 V, using a collimated 8 keV X-rays from a generator in a gas mixture of 70% Ar and 30% CO2 by volume at the atmospheric pressure. We measured the effective gain as a function of the electric field of the drift region and obtained the maximum gain at an drift field of 0.5 kV/cm.

GEM-MIGAS Gain Optimisation for High Pressure Operation in CF$_{4}$ and He/CF$_{4}$ Mixtures

In this work, the GEM-MIGAS configuration was investigated to evaluate its gain properties at elevated gas pressures using CF <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex Notation="TeX">$_{4}$</tex></formula> and He/CF <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex Notation="TeX">$_{4}$</tex></formula> mixtures. The experimental work consisted of gain optimization as a function of the induction region thickness (20 to 300 <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$\mu$</tex></formula> m) using a standard GEM (50 <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$\mu$</tex> </formula> m hole diameter) and an investigation on the influence of the GEM hole diameter on gain at various CF <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$_{4}$</tex> </formula> pressures. As expected, GEMs with narrower holes achieved higher gains, with the advantage of a lower operational voltage. For the GEM-MIGAS using a standard GEM, with 50 <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$\mu$</tex> </formula> m hole diameter, the gain decrease rapidly with pressure, from <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$1.5 \times 10^{4}$</tex></formula> to 400 at 1 and 2.6 bar CF <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$_{4}$</tex> </formula> , respectively. In contrast, the GEM-MIGAS gain drop with pressure is less steep when using a GEM with 30 <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$\mu$</tex></formula> m hole diameter, decreasing from <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$3.0 \times 10^{4}$</tex></formula> to <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$6.0 \times 10^{3}$</tex></formula> for 1 and 2.6 bar CF <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$_{4}$</tex> </formula> , respectively. A GEM-MIGAS configuration with 50 <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex Notation="TeX">$\mu$</tex></formula> m induction gap and a GEM with 30 <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$\mu$</tex></formula> m hole diameter was used in He/CF <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$_{4}$</tex> </formula> mixtures and yielded maximum gains of <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex Notation="TeX">$3 \times 10^{3}$</tex></formula> and <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex Notation="TeX">$2 \times 10^{3}$</tex></formula> for a mixture of 2.6 CF <formula formulatype="inline" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex Notation="TeX">$_{4}$</tex></formula> with 1 and 2 bar He, respectively.

Activity of fractionated radioimmunotherapy with clivatuzumab tetraxetan combined with low-dose gemcitabine (Gem) in advanced pancreatic cancer (APC).

240 Background: The90Y-labeled anti-mucin humanized mAb, clivatuzumab tetraxetan (90Y-hPAM4), is in clinical development in APC. A phase I/II trial of 90Y-hPAM4 with low-dose radiosensitizing Gem has now concluded 90Y-dose escalation. Methods: Pts with untreated, inoperable, stage 3-4 APC received 200 mg/m2 Gem once-weekly x 4 with 90Y-hPAM4 on wks 2-4, and with 90Y escalated in cohorts by 3+3 design. Tumor responses were assessed by CT, FDG/PET and serum CA19.9, with cycles repeated until progression or unacceptable toxicity. Results: Of 42 pts (40-87 yrs, ECOG PS 0-1, 36 stage 4), 4 withdrew early while 38 received weekly x 3 90Y doses of 6.5 (N=4), 9 (N=12), 12 (N=17) and 15 (N=5) mCi/m2. Treatment was well-tolerated with few non-hematologic side-effects, including 13 pts retreated with 1-3 additional cycles. CTCv3 grade 3-4 plts or ANC developed in 21/38 (55%) pts after cycle 1 and all (100%) retreated pts after last cycle. Escalation reached limits on radiation doses to the marrow, but hematologic suppression was reversible without major infections or bleeding events, except for 3 pts after repeated cycles, one with extensive marrow tumor infiltration. By CT, the overall disease control rate was 55%, including 6 pts (16%) with partial responses (PRs) by RECIST criteria and 15 pts (39%) with stabilization as best response. After cycle 1, 43% (10/23) improved by PET studies (negative or &gt;25% reduced uptake), and 36% (9/25) with elevated CA19.9 levels had &gt;50 decreases. With 26% (10/38) of pts still in follow-up, 55% (21/38) have now achieved survival of ≥ 6 months [18% (7/38) ≥ 1 yr]. Treatment outcome may increase with 90Y dose, since pts treated at 3 x ≥12 mCi/m2 vs ≤9 mCi/m2 had 19% vs 6% PRs by CT, 47% vs 22% CA19.9 decreases, 63% vs 25% PET improvement, and 64% vs. 44% survival ≥ 6 months. Anecdotally, PS and pain level improved, which needs validation. Updated survival will be presented at the meeting. Conclusions: Fractionated 90Y-hPAM4 plus low-dose Gem showed encouraging therapeutic activity with manageable hematological toxicity. The 12-mCi/m2 dose level was selected for continued dose exploration now underway, involving standard Gem doses and adding maintenance Gem. [Table: see text]

Gas-gain study of standard CERN GEM and [formula omitted] Thick GEM in low-pressure He/CO 2 mixed gas

We have evaluated and compared the performances of a 50 ‐ μ m -thick CERN GEM and a 400 ‐ μ m -thick Thick GEM in low-pressure He/CO 2 (90%/10%) mixed gas. In particular, the empirical gas gains of the standard CERN GEM and the Thick GEM have been measured and investigated.