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Pastusiak, Tadeusz. "Nautical electronic maps of S-411 standard and their suitability in navigation for assessment of ice cover condition of the Arctic Ocean." Polish Cartographical Review 48, no. 1 (March 1, 2016): 17–28. http://dx.doi.org/10.1515/pcr-2016-0002.
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Abstract The research on the ice cover of waterways, rivers, lakes, seas and oceans by satellite remote sensing methods began at the end of the twentieth century. There was a lot of data sources in diverse file formats. It has not yet carried out a comparative assessment of their usefulness. A synthetic indicator of the quality of data sources binding maps resolution, file publication, time delay and the functionality for the user was developed in the research process. It reflects well a usefulness of maps and allows to compare them. Qualitative differences of map content have relatively little impact on the overall assessment of the data sources. Resolution of map is generally acceptable. Actuality has the greatest impact on the map content quality for the current vessel’s voyage planning in ice. The highest quality of all studied sources have the regional maps in GIF format issued by the NWS / NOAA, general maps of the Arctic Ocean in NetCDF format issued by the OSI SAF and the general maps of the Arctic Ocean in GRIB-2 format issued by the NCEP / NOAA. Among them are maps containing information on the quality of presented parameter. The leader among the map containing all three of the basic characteristics of ice cover (ice concentration, ice thickness and ice floe size) are vector maps in GML format. They are the new standard of electronic vector maps for the navigation of ships in ice. Publishing of ice cover maps in the standard electronic map format S-411 for navigation of vessels in ice adopted by the International Hydrographic Organization is advisable in case is planned to launch commercial navigation on the lagoons, rivers and canals. The wide availability of and exchange of information on the state of ice cover on rivers, lakes, estuaries and bays, which are used exclusively for water sports, ice sports and ice fishing is possible using handheld mobile phones, smartphones and tablets.
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Neelima, S., and R. Brinda. "Implementation of various data encryption methods for medical information transmission." International Journal of Engineering & Technology 7, no. 2.31 (May 29, 2018): 219. http://dx.doi.org/10.14419/ijet.v7i2.31.13446.
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Encryption is the process of converting the data from readable format into unreadable format with help of any mathematical expression or sometimes with the help of key. On the other hand decryption is the reverse process of encryption with help of same key used at encryption or with the help of some other key. The paper presents the different methodology used for encryption and decryption. Several methods presented in the literature are reviewed. The methods- Rivest-Shamir-Adlemen algorithm, Data Encryption Standard, Advanced Encryption Standard and three different Secure Hash Algorithm are reviewed and implemented using various FPGA devices. The power consumption, delay and area are analyzed and compared. From the analyses it is been found that the performance of AES and SHA3 are better when compared to other algorithms. These algorithms provide high security when compared to rest of the methods.
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Kurniawan, Ahmad, Krisna Widatama, and Ike Yunia Pasa. "Bridging Data Pasien Rawat Inap Dengan INA-CBG’s (Indonesian Case Base Groups’s)." Jurnal Sistem Cerdas 5, no. 3 (December 14, 2022): 195–207. http://dx.doi.org/10.37396/jsc.v5i3.249.
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Abstract— Integration and acceleration of data transactions is a very important issue to be discussed in the era of integrated information technology development. This problem is the reason for making the system interact with each other quickly. Indonesian Case Base Groups (INA-CBG's) is an application used to process claims for National Health Insurance (JKN) participants from the Hospital. Every hospital is required to send patient data through INACBG's. However, current data claims for inpatients are still done manually. This manual process will make officers enter patient data into the main system and INACBG's. This results in the efficiency of work performed by hospital staff. In addition, the data entered is not automatic because there is a delay when entering data into the main system and INACBG's. Development of an Inpatient Information System that is integrated with INA-CBG's using JavaScript Object Notation (JSON). This format can send inpatient claim data to the INACBG's application in the form of an array. The JSON format does not have a standard format for writing, so it can be faster and more flexible in sending data. With an integrated system between the main system and INACBG's, it can increase the efficiency of processing data claims to INACBG's.
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Kawka, László, Gergely Juhász, Máté Papp, Tibor Nagy, István Gy Zsély, and Tamás Turányi. "Comparison of detailed reaction mechanisms for homogeneous ammonia combustion." Zeitschrift für Physikalische Chemie 234, no. 7-9 (August 27, 2020): 1329–57. http://dx.doi.org/10.1515/zpch-2020-1649.
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AbstractAmmonia is a potential fuel for the storage of thermal energy. Experimental data were collected for homogeneous ammonia combustion: ignition delay times measured in shock tubes (247 data points in 28 datasets from four publications) and species concentration measurements from flow reactors (194/22/4). The measurements cover wide ranges of temperature T, pressure p, equivalence ratio φ and dilution. The experimental data were encoded in ReSpecTh Kinetics Data Format version 2.2 XML files. The standard deviations of the experimental datasets used were determined based on the experimental errors reported in the publications and also on error estimations obtained using program MinimalSplineFit. Simulations were carried out with eight recently published mechanisms at the conditions of these experiments using the Optima++ framework code, and the FlameMaster and OpenSmoke++ solver packages. The performance of the mechanisms was compared using a sum-of-square error function to quantify the agreement between the simulations and the experimental data. Ignition delay times were well reproduced by five mechanisms, the best ones were Glarborg-2018 and Shrestha-2018. None of the mechanisms were able to reproduce well the profiles of NO, N2O and NH3 concentrations measured in flow reactors.
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Krietemeyer, Andreas, Hans van der Marel, Nick van de Giesen, and Marie-Claire ten Veldhuis. "High Quality Zenith Tropospheric Delay Estimation Using a Low-Cost Dual-Frequency Receiver and Relative Antenna Calibration." Remote Sensing 12, no. 9 (April 28, 2020): 1393. http://dx.doi.org/10.3390/rs12091393.
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The recent release of consumer-grade dual-frequency receivers sparked scientific interest into use of these cost-efficient devices for high precision positioning and tropospheric delay estimations. Previous analyses with low-cost single-frequency receivers showed promising results for the estimation of Zenith Tropospheric Delays (ZTDs). However, their application is limited by the need to account for the ionospheric delay. In this paper we investigate the potential of a low-cost dual-frequency receiver (U-blox ZED-F9P) in combination with a range of different quality antennas. We show that the receiver itself is very well capable of achieving high-quality ZTD estimations. The limiting factor is the quality of the receiving antenna. To improve the applicability of mass-market antennas, a relative antenna calibration is performed, and new absolute Antenna Exchange Format (ANTEX) entries are created using a geodetic antenna as base. The performance of ZTD estimation with the tested antennas is evaluated, with and without antenna Phase Center Variation (PCV) corrections, using Precise Point Positioning (PPP). Without applying PCVs for the low-cost antennas, the Root Mean Square Errors (RMSE) of the estimated ZTDs are between 15 mm and 24 mm. Using the newly generated PCVs, the RMSE is reduced significantly to about 4 mm, a level that is excellent for meteorological applications. The standard U-blox ANN-MB-00 patch antenna, with a circular ground plane, after correcting the phase pattern yields comparable results (0.47 mm bias and 4.02 mm RMSE) to those from geodetic quality antennas, providing an all-round low-cost solution. The relative antenna calibration method presented in this paper opens the way for wide-spread application of low-cost receiver and antennas.
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IVANYTSKA, Olga, Tetiana KOSHCHUK, and Liudmyla OLEYNIKOVA. "Organizational principles of automatic exchange of information in tax matters according to CRS standard." Fìnansi Ukraïni 2022, no. 6 (July 22, 2022): 54–69. http://dx.doi.org/10.33763/finukr2022.06.054.
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Introduction. The urgency of countering the base erosion and profit shifting is only increasing. Problem Statement. Scientific justification for the introduction of automatic exchange of financial account information in tax matters according to the CRS standard. Purpose. The article is devoted to the analysis of organizational bases of automatic exchange of financial account information in tax matters according to the CRS standard and development of recommendations on introduction of such exchange in Ukraine. Materials and Methods. In the course of the research, the following methods were used: abstract-logical, systematization, dialectical and formal logic, expert evaluations. Results. The requirements of the OECD for the implementation of the following steps are analyzed: 1) adaptation of national legislation to the requirements of the CRS standard (amendments to legislation, adoption of bylaws); 2) selection of partner countries and signing of the Multilateral competent authority agreement on automatic exchange of financial account information, deposit of notifications and reservations with the OECD Secretariat; 3) ensuring compliance with the requirements of confidentiality and protection of personal data; 4) automation and technical support of information collection and exchange processes: coordination of the format of data collection and transmission, installation of non-necessary software. The peculiarities of presenting information for reporting according to the CRS standard are revealed, the experience of one of the financial institutions of Poland on self-certification of CRS of its clients is given. Conclusions. It is concluded that the process of establishing CRS reporting and automatic exchange of relevant information is complex, requires increased attention to many details and considerable time and financial resources of both the state and financial institutions and other businesses. The latter cannot be carried out during a period of significant economic and financial upheavals, such as the full-scale invasion of the Russian Federation into Ukraine and further massive hostilities on a large territory of our state with significant destruction. The process of introducing the exchange of information according to the CRS standard should be continued after the end of the war (with a possible significant delay in the calendar schedule of implementation of planned activities).
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Yelleswarapu, Venkata, Joshua R. Buser, Margalit Haber, Jonathan Baron, Eshwar Inapuri, and David Issadore. "Mobile platform for rapid sub–picogram-per-milliliter, multiplexed, digital droplet detection of proteins." Proceedings of the National Academy of Sciences 116, no. 10 (February 14, 2019): 4489–95. http://dx.doi.org/10.1073/pnas.1814110116.
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Digital droplet assays—in which biological samples are compartmentalized into millions of femtoliter-volume droplets and interrogated individually—have generated enormous enthusiasm for their ability to detect biomarkers with single-molecule sensitivity. These assays have untapped potential for point-of-care diagnostics but are currently mainly confined to laboratory settings, due to the instrumentation necessary to serially generate, control, and measure tens of millions of droplets/compartments. To address this challenge, we developed an optofluidic platform that miniaturizes digital assays into a mobile format by parallelizing their operation. This technology is based on three key innovations: (i) the integration and parallel operation of a hundred droplet generators onto a single chip that operates >100× faster than a single droplet generator, (ii) the fluorescence detection of droplets at >100× faster than conventional in-flow detection using time domain-encoded mobile phone imaging, and (iii) the integration of on-chip delay lines and sample processing to allow serum-to-answer device operation. To demonstrate the power of this approach, we performed a duplex digital ELISA. We characterized the performance of this assay by first using spiked recombinant proteins in a complex media (FBS) and measured a limit of detection, 0.004 pg/mL (300 aM), a 1,000× improvement over standard ELISA and matching that of the existing laboratory-based gold standard digital ELISA system. We additionally measured endogenous GM-CSF and IL6 in human serum fromn= 14 human subjects using our mobile duplex assay, and showed excellent agreement with the gold standard system (R2=0.96).
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Babamahmoodi, Farhang, Ahmad Alikhani, Jamshid Yazdani Charati, Amir Ghovvati, Fatemeh Ahangarkani, Leila Delavarian, and Abdolreza Babamahmoodi. "Clinical Epidemiology and Paraclinical Findings in Tuberculosis Patients in North of Iran." BioMed Research International 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/381572.
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Background. Mycobacterium tuberculosis (M.TB) causes a wide spectrum of clinical diseases. The prevalence of TB is different in various parts of Iran and throughout the world. The present study aimed to determine the clinical epidemiology and paraclinical findings of TB. Methods. A cross-sectional study was conducted from 2008 to 2013. Patient demographic, clinical, and radiologic characteristics, picked up from the TB patient’s files, were collected using a standard questionnaire format. Data was entered and analyzed using the SPSS version 16 statistical software and P value < 0.05 was considered statistically significant. Results. Out of 212 patients enrolled in this study 62% were male and the mean age was about 50 years old. 98.6% were Iranian, and 46.2% were rural. Prevalence of smear-positive TB was 66.4%. Prevalence of positive PPD was 50.7% with no significant difference between HIV-positive and -negative patients (P = 0.8). Prevalence of diabetes mellitus was 17%. 36% of the patients had history of smoking and about 29.3% were addicted to narcotics. Cough was the most common symptom (94.5%) and 84% had sputum. 15 cases (7%) had extrapulmonary TB. The mean time between the onset of symptoms and admission was 46.5 days. The delay for admission between urban and rural populations was not significantly different (P = 0.68); but for those who were in prison, the delay was significant (P = 0.02). About 46% of the patients had cavitary lesions in CXRs. Conclusion. Timely diagnosis of TB especially in prisoners by understanding its most important epidemiologic characteristics and clinical features can help to make an early treatment and prevent spread of mycobacteria and their complications.
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Peters, Sönke, Friederike Gärtner, Friederike Austein, Fritz Wodarg, Olav Jansen, and Johannes Hensler. "Evaluation of an Ultra-Short MRI Protocol for Cerebral Staging Examinations in Melanoma Patients." RöFo - Fortschritte auf dem Gebiet der Röntgenstrahlen und der bildgebenden Verfahren 194, no. 04 (November 18, 2021): 409–15. http://dx.doi.org/10.1055/a-1669-9408.
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Purpose Due to its high sensitivity and lack of radiation, MRI is often used to stage cerebral tumors in patients. In contrast, the relatively long examination times and the limited availability of MRI slots at the clinic might delay these examinations. The aim of this study was to compare an ultra-short MRI protocol with the routinely used standard protocol. Materials and Methods Cerebral MRI of 147 patients with malignant melanoma were evaluated retrospectively, whereby only two sequences (FLAIR images and contrast-enhanced T1 MPR images) were evaluated in one group and images from the whole examination were available for the second group, including five sequences (DWI, T2 TSE, FLAIR, native and contrast-enhanced T1 TSE, and contrast-enhanced T1 MPR). The results of the two groups were compared and tested to determine whether the ultra-short approach was inferior to the full examination. Results 13.6 % of the patients had cerebral metastases. Overall, 73 metastases were detected: 60 were located supratentorially and 13 infratentorially. Concerning the detection of cerebral metastases, the ultra-short MRI examination, involving only a FLAIR and a contrast-enhanced T1 MPR sequence, was not inferior to the full MRI protocol in general (p = 0.017) and separated by location for supratentorial (p = 0.026) and infratentorial (p = 0.001) metastases. Conclusion For staging purposes, a focused, ultra-short MRI protocol is not inferior to a standard MRI examination. This might open up opportunities for faster staging processes and a more efficient use of the often-restricted MRI capacities. Key Points Citation Format
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Fukase, Masa-aki, and Tomoaki Sato. "Compact FPU Design and Embedding in a Ubiquitous Processor for Multimedia Performance Enhancement." ECTI Transactions on Electrical Engineering, Electronics, and Communications 6, no. 2 (December 27, 2007): 170–76. http://dx.doi.org/10.37936/ecti-eec.200862.171786.
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The key to protect huge amount of multimedia data in ubiquitous networks is to introduce safety aware high-performed single VLSI processor systems embedded with cipher process. Thus, we exploited the architecture of a hardware cryptography embedded multimedia mobile processor named HC-gorilla by sophisticatedly unifying up-to-date processor techniques. Although it was provided with carefully selected Java bytecodes and cipher codes, FP (floating point) expression was omitted due to the restriction of hardware resource. Considering recent trend of embedded applications like voice recognition, 3D graphics, and image/vision processing, FP hardware is crucial for further enhancing HCgorillafs Java functions. We focus in this article the development of a compact FPU (Floating point number Processing Unit). A compact FP format speci¯c for HCgorilla is IEEE 754 compatible except the bit width representation of FP data. Prioritizing the latency of FPU, it has only 5 stages. The compact FPU is built in HCgorilla by adding 16 FP arithmetic codes and improving the decode stage of the previous HCgorilla. By using a 0.18-¹m standard cell CMOS technology supported by VDEC, we have so far accomplished the logic synthesis and behavior simulation. The 400MHz of clock frequency is justified from delay analysis.
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Liu, Sheng, Di Wu, and Lanyong Zhang. "CGAN BeiDou Satellite Short-Message-Encryption Scheme Using Ship PVT." Remote Sensing 15, no. 1 (December 28, 2022): 171. http://dx.doi.org/10.3390/rs15010171.
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The transmission standard and format of short-message communication in the BeiDou satellite-navigation-system are open, the civilian channel adopts a direct-transmission plaintext mechanism, and the content of short messages is at risk of data leaks. Aiming at addressing the problem of safely transmitting BeiDou short messages, this study proposes a CGAN BeiDou satellite short-message-encryption scheme, using ship PVT (position, speed, and time). Various BeiDou commands with ship position, speed, or time are employed as the input. The two communicating parties use the CGAN (conditional generative adversarial network) confrontation mechanism to encrypt and decrypt the ship-PVT information and generate a symmetrically encrypted key, while the receiver parses only the sender data within the specified PVT-range. Additionally, because the BeiDou system has a positioning error and transmission delay, and considering the ship mobility, the concept of a dynamic tolerance region is introduced at the receiver, to improve the scheme’s decryption success-rate. Finally, the proposed scheme is verified, using simulation and experiments. The proposed algorithm achieves good security, with acceptable efficiency. Furthermore, the experimental platform built by this study is used to prove the feasibility of the scheme applied to BeiDou short-message encryption and decryption.
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Desai, Pujan, Maithili Rairkar, Nela Pawlowska, Scott Thomas, and Pamela N. Munster. "Abstract 5261: Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5261. http://dx.doi.org/10.1158/1538-7445.am2023-5261.
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Abstract Prostate cancer is the most common cancer in men. Commensurate with risk, current approaches to localized prostate cancer include prostatectomy, prostate radiation with or without radiation therapy or active surveillance. Recent data suggest that systemic anti-androgen therapy with enzalutamide reduced the risk of prostate cancer progression in men on active surveillance but was associated with considerable side effects. We developed a novel polymer-based drug delivery method to provide sustained localized drug administration of anti-androgens selectively to the prostate. In vitro and in vivo mouse and canine studies show that this drug eluting implant delivers sustained high prostate to plasma therapeutic anti-androgen levels for an anticipated range of 2 years while preventing accumulation of anti-androgens in the liver, lungs, heart and brain. We performed a proof of concept study in a canine prostate model implanting an 15mm x 1mm bicalutamide eluting implant into each lobe of the prostate. Bicalutamide levels in the prostate measured near the implant at 6 months were 3250 ± 1622 ng/g, n = 3 compared to 3809 ± 638 ng/g, n = 3 to those achieved at steady-state oral administration. Plasma and other off target levels were over 1000-fold lower in the implant cohort compared to oral administration: Plasma: 5.9 ± 0.2 ng/ml, liver: 11.3 ±4.3 ng/g, and brain: 5.4 ±0.8 ng/g versus plasma: 18170 ± 3820 ng/ml, liver: 35407 ±8510 ng/g, and brain: 8870 ±1797 ng/g. The implants were well tolerated without local toxicity and imaged easily with ultrasound. The design characteristics of the implant facilitates minimally invasive surgical implantation under standard image guidance and withstands the concomitant use of prostate radiation. This novel technology warrants future clinical exploration of prostate specific anti-androgen therapy for (neo)adjuvant therapy or in active surveillance. Tissue Bicalutamide oral (2m)(ng/g) Bicalutamide implant (6m)(ng/g) Plasma 18,170 (3820) 5.9 (0.2) Prostate 3,809 (638) 3,250 (1622) Liver 35,407 (8510) 11.3 (4.3) Cerebrum 8,870 (1797) 5.4 (0.8) Cerebellum 8,737 (1550) 6.2 (1.3) Spleen 7,727 (1288) 4.2 (0.9) Lung 27,013 (2896) 11.3 (4.3) Heart 11,737 (3491) 10.0 (1.9) Kidneys 17,413 (6581) 8.5 (2.0) Citation Format: Pujan Desai, Maithili Rairkar, Nela Pawlowska, Scott Thomas, Pamela N. Munster. Prostate specific sustained anti androgen delivery to delay early stage prostate cancer progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5261.
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Tola, Assefa, Lemma Demissie Regassa, and Yohanes Ayele. "Prevalence and associated factors of diabetic foot ulcers among type 2 diabetic patients attending chronic follow-up clinics at governmental hospitals of Harari Region, Eastern Ethiopia: A 5-year (2013–2017) retrospective study." SAGE Open Medicine 9 (January 2021): 205031212098738. http://dx.doi.org/10.1177/2050312120987385.
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Introduction: Diabetic foot disease is a growing major public health problem and the leading cause of prolonged hospital admission, health-related costs, and reduced quality of life for diabetes patients. This study aimed to determine the prevalence of diabetic foot ulcers (DFU) and its associated factors among type 2 diabetes patients in Harari Region, East Ethiopia. Methods: An institution-based retrospective study was conducted from 28 March to 30 April 2018, among type 2 diabetes patients diagnosed between 1 January 2013 and 31 December 2017, at three government hospitals of Harari Region. Data were collected using a standard checklist format. Data were entered into Epi Info Version 7 and analyzed using SPSS 24. Binary and multiple logistic regression models were used to determine the associated factors. Odds ratio with 95% confidence intervals was used to determine level of association. Result: A document of 502 type 2 diabetes patients was reviewed and included in the final analysis in this study. The prevalence of DFU among type 2 diabetes patients was 21.1%. Being currently married decreased the odds of DFU by 60% (adjusted odds ratio = 0.40; 95% confidence interval: 0.17–0.96). Factors associated with increased diabetes ulcers chance were physical inactivity 2.29 (adjusted odds ratio = 2.29; 95% confidence interval: 1.17–4.48), starting treatment with insulin 4.43 times (adjusted odds ratio = 4.43; 95% confidence interval: 1.84–10.67), obesity 27.76 (adjusted odds ratio = 27.76; 95% confidence interval: 13.96–55.23), delay to start follow-up 2.22 (adjusted odds ratio = 2.22; 95% confidence interval: 1.03–4.82), history of infection 3.50 (adjusted odds ratio= 3.50; 95% confidence interval: 1.83–6.69), and hypertension 3.99 (adjusted odds ratio = 3.99; 95% confidence interval: 2.08–7.65). Conclusion: The prevalence of DFU among type 2 diabetes is substantially high as more than one in five patients have this complication. Moreover, marital status, physical activity, baseline medication, obesity, delay for follow-up, infection history, and hypertension were significantly associated with the development of DFU.
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Formenti, Laura, Alessandra Decio, Valentina Dematteis, Giulia Dellavedova, Maria Rosa Bani, Raffaella Giavazzi, and Carmen Ghilardi. "Abstract 4838: Exploiting mitochondrial metabolism to enhance the response to standard of care treatments in ovarian cancer." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4838. http://dx.doi.org/10.1158/1538-7445.am2023-4838.
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Abstract Ovarian cancer best practice consists of debulking surgery followed by platinum/taxane based chemotherapy combined with the angiogenesis inhibitor bevacizumab, and the PARP inhibitor olaparib for HRD positive tumors. However, despite significant improvements in its treatment, the 5-year survival rate remains low due to disease recurrence and resistance to therapy. Emerging evidence suggests that the metabolic requirements of cancer cells change after exposure to chemotherapy or targeted therapies, generating a potential Achilles’ heel. Here, we focused on exploiting the intrinsic or therapy-induced metabolic vulnerabilities of ovarian cancer to improve its response to the standard medical care. To this aim, ovarian cancer patient-derived xenografts (OC-PDX), injected orthotopically in nude mice, were used to assess i) the association between the metabolic profile of OC-PDXs and their responsiveness to treatments (i.e. cisplatin, bevacizumab, olaparib), ii) the metabolic changes induced by the treatments and iii) the therapeutic benefit of combining an OXPHOS inhibitor with the above-stated therapies. The effect on tumor progression was evaluated as increase of survival of OC-PDX bearing mice. First, we characterized the metabolic profile of OC-PDXs and divided them into high- and low-OXPHOS according to their dependence on mitochondrial metabolism. Then, we evaluated their response to the standard of care treatments and found that 75% of high-OXPHOS OC-PDXs were sensitive to cisplatin and olaparib, while 100% of low-OXPHOS OC-PDXs were poorly responsive. Response to bevacizumab varied in the two OC-PDX subsets. Further, we demonstrated that cisplatin or bevacizumab treatment induced the emergence of a sub-population of cells from malignant ascites with higher mitochondrial content and tricarboxylic acid cycle (TCA) intermediates and reduced expression of glycolysis-related genes, thus suggesting a shift toward oxidative metabolism in the residual cancer cells after treatment. Targeting these OXPHOS-dependent cells with the respiratory chain complex I inhibitor IACS-010759 improved the survival of mice. These results indicate that the metabolic profile of ovarian cancer cells is associated with the response to cisplatin and olaparib and lay the ground for the rational combination with OXPHOS inhibition to prolong therapies efficacy and eventually delay the development of recurrent disease. Supported by AIRC IG2019 ID 23520 to RG. Citation Format: Laura Formenti, Alessandra Decio, Valentina Dematteis, Giulia Dellavedova, Maria Rosa Bani, Raffaella Giavazzi, Carmen Ghilardi. Exploiting mitochondrial metabolism to enhance the response to standard of care treatments in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4838.
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Oswald, Eva, Dorothee Lenhard, Kanstantsin Lashuk, Stefan Pfister, Louis Stancato, and Julia Schueler. "Abstract 3524: Pharmacological characterization of pediatric brain tumor PDX models in a single mouse trial format." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3524. http://dx.doi.org/10.1158/1538-7445.am2023-3524.
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Abstract Cancer remains the leading cause of disease-related death in children. Preclinical drug testing to identify promising treatment options for relapsed patients or those with poor prognosis is hindered by the lack of well characterized and annotated preclinical models. In the framework of the ITCCP4 consortium (www.ITCCP4.eu) our group determined the pharmacological profile of 47 orthotopically implanted pediatric brain PDX models. The panel comprised 21 high grade glioma (HGG), 13 medulloblastoma (MB), eight ependymoma (EP), three non-classified brain tumors (XT), one atypical teratoid/rhabdoid tumor (AT/RT) and one neuroblastoma (NB).. Depending on the tumor type the models were screened in an eleven or twelve arms single mouse trial study layout. Three treatment arms comprised standard of care cytotoxic compounds and radiation, whereas the other arms covered targeted therapies, mostly small molecules. Tumor load was determined using a fluorescent based in vivo imaging technology based on the lentiviral transient transduction of the PDX cells with iRFP713 prior to implantation into the brain. In addition, body weight and neurological scoring was applied to determine the overall condition of the animals. At the end of the study brain tissue was harvested and tumor load confirmed by immunohistochemistry. The mean overall survival of the orthotopic implanted animals on study was 48 days with a minimum of 7 days and a maximum of 132 days. Overall, the treatment was well tolerated in the tumor bearing animals as determined by body weight measurement. However, the combination of two cytotoxic drugs in some of the arms needed dose adjustments due to increased toxicity. Across all tumor types at least one of the cytotoxic arms improved overall survival of the tumor bearing animals markedly: Temozolomide and Lomustine for HGG (43d and 50d, respectively vs 28d in the control arm), Lomustine and Endoxan for MB (99d and 73d, respectively vs 61d in the control arm), and Actinomycin D for EP (64d vs 52d). However, several of the targeted agents showed a distinct efficacy profile: Cobimetinib was efficacious in 50% of the HGG (47d vs 28d in the sensitive subset) and Idanasutlin in 80% of the EP models (79d in the sensitive subset vs 52d). The optical imaging signal over time confirmed tumor engraftment at the start of treatment. The most efficacious treatment arms induced growth delay or partial remission. This preclinical validation set gains even more importance using the accompanying molecular profiling data that are available not only for the PDX but also for the donor patient. Together with the breadth and depth of the still growing PDX collection, a unique preclinical platform for the development of drugs as well as companion diagnostics specifically for pediatric brain cancers is now available to the scientific community. Citation Format: Eva Oswald, Dorothee Lenhard, Kanstantsin Lashuk, Stefan Pfister, Louis Stancato, Julia Schueler. Pharmacological characterization of pediatric brain tumor PDX models in a single mouse trial format. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3524.
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El Shafie, Ali M., Zein A. L. Omar, Mai M. Bashir, Sorour F. Mahmoud, Elsayedamr M. Basma, Ahmed E. Hussein, Alaa Mosad Mostafa, and Wael A. Bahbah. "Development and validation of Egyptian developmental screening chart for children from birth up to 30 months." PeerJ 8 (November 11, 2020): e10301. http://dx.doi.org/10.7717/peerj.10301.
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Background Detecting developmental delay in children is an ongoing world commitment, especially for those below three years. To accurately assess the development of children; a culturally appropriate screening tool must be used. Egypt lacks such tool and multiple studies have shown that western tools are not suitable in other cultures. Objectives To develop and validate an easy, rapid, culturally appropriate and applicable screening chart for early detection of developmental delay among Egyptian children from birth up to 30 months and develop a Z-score chart for motor and mental development follow up based on our Egyptian screening chart. Methods A cross sectional randomized study was carried out on 1503 Egyptian children of both genders aged from birth up to 30 months assumed to have normal development according to the inclusion and exclusion criteria. They were selected from vaccination centers and well-baby clinics. Developmental milestones from Baroda development screening test (BDST) were applied on them after items were translated and adapted to Egyptian culture. Egyptian children developmental milestones scores were analyzed and carefully prepared in tables and charts. A 97% pass level of developmental achievements represents the threshold below which children are considered delayed. A Z-score chart for motor and mental development follow up was designed by calculating each age group achievement. The developed Egyptian developmental screening chart (EDSC) was validated against Ages and Stages Questionnaires (ASQ-3) as a reference standard in another different sample of 337 children in different age groups. Results The developed EDSC is represented in a chart format with two curves 50% and 97% pass level. Children considered delayed when the score below 97% pass level. Results revealed a statistically significant difference between EDSC and BDST at 50% and 97% pass levels. A Z-score chart for motor and mental development follow up was designed by calculating each age group achievement. EDSC sensitivity and specificity were calculated 84.38 (95% CI [67.21%–94.72%]) and 98.36 (95% CI [96.22%–99.47%]) respectively with an overall test accuracy 97.03 (95% CI [94.61%–98.57%]) (p ≤ .001). Agreement between EDSC and ASQ-3 was high (kappa score was 0.827) with negative and positive agreement 98.36 and 84.38, respectively. Conclusions Extensive revision of the BDST was needed in order to create and validate a more culturally appropriate Egyptian screening chart. This is the first study to create and validate an Egyptian-specific screening tool, to be rapid and easy to use in Egypt for early detection of developmental delay and enabling early intervention practices. A Z-score curve is reliable for follow up motor and mental development by calculating each age group achievement.
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Pisarev, Alexander D., Alexander N. Busygin, Abdulla Kh A. Ibrahim, and Sergey Yu Udovichenko. "Simulation of information decoding processes in the output device of the biomorphic neuroprocessor." Tyumen State University Herald. Physical and Mathematical Modeling. Oil, Gas, Energy 6, no. 4 (2020): 179–93. http://dx.doi.org/10.21684/2411-7978-2020-6-4-179-193.
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This publication is the series of articles continuation on the creation of neuroprocessor nodes based on a composite memristor-diode crossbar. The authors have determined the principles of modifying the pulse information into a binary code in the output device of the neuroprocessor, implemented in a logical matrix based on a new electronic element — a combined memristor-diode crossbar. The processing of pulse signals is possible in the logical matrix, since one layer of the matrix is a set of logical AND or OR gates with arbitrarily connected inputs. The authors have proposed two solutions to the problem of decoding pulses from a population of neurons in the output device, coming from the hardware neural network of the neuroprocessor, into standard binary signals. The first solution involves the two layers use of a logical matrix and a pulse generator. The compactness of the second solution is achieved due to the presence of a binary number generator, which allows to get rid of one layer of the logical matrix. This article presents the SPICE modeling results of the decoding pulsed information process signals into binary format and confirms the operability of the output device electrical circuit. The originality of the device operation lies in the switching of the generator signals by the logical matrix to the neuroprocessor output based on the time delay of the input pulse from the hardware neural network. The use of the memristor logical matrix in all nodes of the neuroprocessor, including the input device, makes it possible to unify the element base of the neuroprocessor complete electrical circuit, as well as its power supplies.
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Jain, Vinesh Kumar, Arka Prokash Mazumdar, and Mahesh Chandra Govil. "Congestion Prediction in Internet of Things Network using Temporal Convolutional Network A Centralized Approach." Defence Science Journal 72, no. 6 (December 6, 2022): 810–23. http://dx.doi.org/10.14429/dsj.72.17447.
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The unprecedented ballooning of network traffic flow, specifically, Internet of Things (IoT) network traffic, has big stressed of congestion on todays Internet. Non-recurring network traffic flow may be caused by temporary disruptions, such as packet drop, poor quality of services, delay, etc. Hence, the network traffic flow estimation is important in IoT networks to predict congestion. As the data in IoT networks is collected from a large number of diversified devices which have unlike format of data and also manifest complex correlations, so the generated data is heterogeneous and nonlinear in nature. Conventional machine learning approaches unable to deal with nonlinear datasets and suffer from misclassification of real network traffic due to overfitting. Therefore, it also becomes really hard for conventional machine learning tools like shallow neural networks to predict the congestion accurately. Accuracy of congestion prediction algorithms play an important role to control the congestion by regulating the send rate of the source. Various deeplearning methods (LSTM, CNN, GRU, etc.) are considered in designing network traffic flow predictors, which have shown promising results. In this work, we propose a novel congestion predictor for IoT, that uses Temporal Convolutional Network (TCN). Furthermore, we use Taguchi method to optimize the TCN model that reduces the number of runs of the experiments. We compare TCN with other four deep learning-based models concerning Mean Absolute Error (MAE) and Mean Relative Error (MRE). The experimental results show that TCN based deep learning framework achieves improved performance with 95.52% accuracy in predicting network congestion. Further, we design the Home IoT network testbed to capture the real network traffic flows as no standard dataset is available.
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Rosli, Nor Marina, Nur Emma Mustaffa, and Hamizah Liyana Tajul Arifin. "The Crucial Conditions and Attributes of Domestic Subcontract in Malaysian Construction Industry." IOP Conference Series: Earth and Environmental Science 1067, no. 1 (October 1, 2022): 012054. http://dx.doi.org/10.1088/1755-1315/1067/1/012054.
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Abstract The duties and responsibilities of the parties signing a contract are governed by the previously agreed terms of the contract. General conditions are a standardized form of pre-printed contract which specifies the general project rules and relevant commercial terms. The contracts are developed and published by various associations and professional bodies and are widely used in the construction industry. In the Malaysian construction industry, there are several standard forms of main contracts and nominated subcontracts. However, for a domestic subcontract, the main contractor prefers to use a bespoke contract, which results in contract disputes. Drafting a complex contract can be time-consuming and expensive. It also requires the involvement of the legal team to provide legal opinions and advice on its content. Hence, this study intends to identify domestic subcontract attributes and critical conditions to overcome the major issue of unclear terms and conditions for the domestic subcontract. A set of attributes and critical conditions have been established through a detailed review and analysis of twenty-two (22) bespoke contracts collected from the industry and an extensive literature review from published articles. Content analysis was done on leading academic journals in construction engineering and management. Clarity, consistency, parties, risk, language, and format of the domestic subcontract are some of the attributes. Meanwhile, payment, liquidated damages, delay, subcontract sum, termination, variation order, practical completion and defect liability period, commencement and completion, and safety provision are the most crucial conditions discovered through extensive review and content analysis of the bespoke contracts. The advantage of establishing these characteristics and critical conditions is that they serve as a prerequisite for the development of a domestic subcontract framework
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Ivanković, Igor, Ksenija Žubrinić-Kostović, Ana Kekelj, Zoran Bunčeć, Per Andersson, and Jan Eric Larsson. "Advanced and Rapid Tool in Control Room to Determine the Cause and Location of Events in Transmission Network." Journal of Energy - Energija 69, no. 4 (December 30, 2020): 25–29. http://dx.doi.org/10.37798/202069449.
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Operating personnel in control room act on SCADA alarm generated on data from station computer. Using new technologies and advanced technical solutions assistance tool can be designed. This tool provides quick help in busy situations for operator. For this new tool with three types of case studies insight will be given in this paper. Introduction part has short information about numbers of alarms and events in Control centre, and their distribution during one month period. Basic principles for alarm handling in SCADA system is given with all limitations. New tool, Intelligent Alarm Processing system is designed and implemented in control room. It has connection to SCADA system with standard data exchange format CIM/XML and run in real time, with only few seconds delay. This system based on Multilevel Flow Model has root cause analyses implemented for power system. Detail fault location algorithm description with block scheme for this Intelligent Alarm Processing system is part of third chapter. Special attention must be paid for modelling protection data in SCADA system which are sent to this new tool. Demonstration of Intelligent Alarm Processing system operation is reported in fourth chapter. Three characteristic disturbances in transmission network were elaborated. Most complex and challenging disturbances for operator in control room is cascading event. This case study is presented in detail in four sequences through graphical user interface. Second case study is also challenging for operators, heavy winter storm with numerous isolated events. In this case study very effective graphical presentation and alarm list with three types, primary event, consequences and detail list for this events were demonstrated. This list pointed out exactly and clearly what happened in the network. Last case study presents common disturbances which appears on daily basis, where this tool is of great assistance because it points on transmission elements very fast.
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Havlik, Ivo, Sascha Beutel, Thomas Scheper, and Kenneth F. Reardon. "On-Line Monitoring of Biological Parameters in Microalgal Bioprocesses Using Optical Methods." Energies 15, no. 3 (January 25, 2022): 875. http://dx.doi.org/10.3390/en15030875.
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Microalgae are promising sources of fuels and other chemicals. To operate microalgal cultivations efficiently, process control based on monitoring of process variables is needed. On-line sensing has important advantages over off-line and other analytical and sensing methods in minimizing the measurement delay. Consequently, on-line, in-situ sensors are preferred. In this respect, optical sensors occupy a central position since they are versatile and readily implemented in an on-line format. In biotechnological processes, measurements are performed in three phases (gaseous, liquid and solid (biomass)), and monitored process variables can be classified as physical, chemical and biological. On-line sensing technologies that rely on standard industrial sensors employed in chemical processes are already well-established for monitoring the physical and chemical environment of an algal cultivation. In contrast, on-line sensors for the process variables of the biological phase, whether biomass, intracellular or extracellular products, or the physiological state of living cells, are at an earlier developmental stage and are the focus of this review. On-line monitoring of biological process variables is much more difficult and sometimes impossible and must rely on indirect measurement and extensive data processing. In contrast to other recent reviews, this review concentrates on current methods and technologies for monitoring of biological parameters in microalgal cultivations that are suitable for the on-line and in-situ implementation. These parameters include cell concentration, chlorophyll content, irradiance, and lipid and pigment concentration and are measured using NMR, IR spectrophotometry, dielectric scattering, and multispectral methods. An important part of the review is the computer-aided monitoring of microalgal cultivations in the form of software sensors, the use of multi-parameter measurements in mathematical process models, fuzzy logic and artificial neural networks. In the future, software sensors will play an increasing role in the real-time estimation of biological variables because of their flexibility and extendibility.
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Ibrahim, Idris Skloul, Peter J. B. King, and Hans-Wolfgang Loidl. "NsGTFA: A GUI Tool to Easily Measure Network Performance through the Ns2 Trace File." Journal of Intelligent Systems 24, no. 4 (December 1, 2015): 467–77. http://dx.doi.org/10.1515/jisys-2014-0153.
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AbstractNs2 is an open-source communications network simulator primarily used in research and teaching. Ns2 provides substantial support for simulation of TCP, routing, and multicast protocols over wired and wireless networks. Although Ns2 is a widely used powerful simulator, it lacks a way to measure networks that are used to assess reliability and performance metrics (e.g., the number of packets transferred from source to destination, delay in packets, packet loss, etc.) and it does not analyse the trace files it produces. The data obtained from the simulations are not straightforward to analyse. Ns2 is still unable to provide any data analysis statistics or graphics as requested. Moreover, the analysis of the Ns2 trace file using any software scripts requires further steps by a developer to do data processing and then produce graphical outputs. Lack of standardisation of tools means that results from different users may not be strictly comparable. There are alternative tools; however, most of them are not standalone applications, requiring some additional libraries. Also, they lack a user-friendly interface. This article presents the architecture and development considerations for the NsGTFA (Ns2 GUI Trace File Analyser) tool, which intends to simplify the management and enable the statistical analysis of trace files generated during network simulations. NsGTFA runs under Windows and has a friendly graphical user interface. This tool is a very fast standalone application implemented in VC++, taking as input an Ns2 trace file. It can output two-dimensional (2D) and 3D graphs (points, lines, and bar charts) or data sets, whatever the trace file format (Tagged, Old, or New). It is also possible to specify the output of standard network performance metrics. NsGTFA satisfies most user needs. There is no complex installation process, and no external libraries are needed.
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Wang, Yijia, Yuqing Yang, Changjiao Yan, Jixin Yang, Hongliang Wei, Wen Ma, and Nanlin Li. "Abstract P6-05-13: The Psychological Impacts of COVID-19 on Breast Cancer Patients in China." Cancer Research 83, no. 5_Supplement (March 1, 2023): P6–05–13—P6–05–13. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-05-13.
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Abstract Background: Approximately 30% to 50% of breast cancer patients experienced mental distress prior to the advent of COVID.The delayed access to cancer treatment due to the outbreak of COVID -19 pandemic posed a unique challenge to breast cancer patients and caused a significant level of mental distress among them. In the current research, we examined the psychological impacts of COVID on breast cancer patients in China using Symptom Checklist-90-R (SCL-90-R). Method: Participants were breast cancer patients at the outpatient clinic of Xijing hospital. The study was conducted virtually, and the questionnaires were distributed via Wenjuanxing, the Chinese alternative of Qualtrics. The researchers were healthcare workers affiliated with Xijing hospital, and the survey was sent to a breast cancer patient support group which included 1399 cancer patients and 6 healthcare workers. The initial sample consisted of 199 participants who signed an informed consent form to participate in the study. The inclusion criteria were as follows: 1) diagnosed with breast cancer, 2) aged 18 years or above, and 3) had no history of cognitive impairment or previous diagnosis of psychiatric disorders. The validated Mandarin version of the SCL-90-R (Wang, 1984) was then given to the participants to evaluate their psychological status.Categorical variables were summarized as numbers and percentages; continuous variables were described as mean (M) ± standard deviation (SD). Data were analyzed using IBM SPSS Statistics Version 26. Results: Participants (N = 195) filled out the SCL-90 questionnaire in February, 2020. All participants were female breast cancer patients treated at Xijing hospital, among which 16.41%, 36.41%, 19.49%, and 28.21% had respectively received treatment for less than a year, 1-3 years, 3-5 years, and 5 years or more. 64.62% of the patients were at stage I; 0.77% were at stage II and III; 4.62% were at stage IV according to TNM classification. The molecular type of participants is as follows: 47.2% of ER+ HER2-, 31.8% of HER2+, and 21.0% of Triple negative.Participants whose treatments continued to be delayed, on average, reported an elevated general psychopathology score (M = 1.48, SD = 0.47) compared to participants whose treatments were resumed (M = 1.30, SD = 0.34), and the difference was statistically significant, t(193) = 2.96, p = .003, d = 0.44, 95%Cl [0.06, 0.30]. The one-way ANOVA revealed a marginally significant effect of length of treatment delay on general psychopathology score, F(4, 190) = 2.09, p = .08, η^2 = .04. Follow-up multiple comparison analysis showed that participants who had their treatment delayed for 3 weeks to 1 month (M = 1.70, SD = 0.70) reported significantly higher general psychopathology scores than participants whose delay in treatment was less than 1 week (M = 1.34, SD = 0.40), p = .05. General health status (p < .001) and current treatment status (p = .02) are the only two variables that were statistically associated with general psychopathology score.Poorer perceived health status and current delay in treatment were associated with higher general psychopathology score, Additionally, younger age was associated with higher interpersonal sensitivity (p = .01) and hostility (p = .006). Conclusions: We found that breast cancer patients at an advanced stage were more likely to experience psychological symptoms with longer treatment delay, and whose treatments continued to be delayed reported elevated psychological symptoms than individuals whose treatment were resumed, regardless of treatment type. Additionally, a treatment delay of more than three weeks might have exacerbated breast cancer patients’ psychological symptoms, whereas a short-term delay of less than three weeks was less likely to have a significant effect on one’s mental well-being. Table 1. Demographic Characteristics and Health Status of The Participants. Table 2A: Multiple Regression analysis for SCL-90 dimensions. Table 2B: Multiple Regression analysis for SCL-90 dimensions. Citation Format: Yijia Wang, Yuqing Yang, Changjiao Yan, Jixin Yang, Hongliang Wei, Wen Ma, Nanlin Li. The Psychological Impacts of COVID-19 on Breast Cancer Patients in China [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-13.
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Jones, Clark, and Lori Hazlehurst. "Abstract 2412: Emergence of resistance to MTI-101 selects for favorable MET phenotype in lung cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2412. http://dx.doi.org/10.1158/1538-7445.am2022-2412.
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Abstract Lung cancer remains the most-deadly of all cancers, and thus clinical evidence indicates novel treatment strategies are needed to improve patient outcomes. Our laboratory has been developing a novel cyclic peptide coined MTI-101, which induces cell death via calcium overload, a finding dependent on the TRPC1/TRPC5/TRPC4 complex. To better understand determinants of sensitivity and resistance to MTI-101, we developed drug resistant isogenic lung cancer cell lines. Two isogenic drug resistant cell lines were generated with chronic exposure to MTI-101 in PC-9 (NSCLC EGFR Driven) and H446 (SCLC PTEN Deleted and c-MYC amplified). Drug resistance was confirmed in both cell lines with over two-fold increases in IC50 values upon treatment with MTI-101 in MTT assays. Interestingly, pushing the resistant levels beyond a two-fold increase was not obtained as cultures did not sustain growth with increased selection pressure. Using the isogenic systems coupled with RNA-SEQ, the top enriched GSEA hallmark was downregulation of genes that contribute to EMT in both MTI-101 resistant lines. The RNA-SEQ data correlated with changes in the phenotype which included a significant decreased invasion in Matrigel and changes of MET markers (E-Cadherin, Vimentin) at the protein level. Furthermore, in the EGFR driven PC-9 cell line, selection for resistance towards MTI-101 resulted in collateral sensitivity to EGFR inhibitors. To determine the stability of the MET phenotype, cells were removed from drug, then tested for invasion and drug resistance every month. Our data indicated that the MET phenotype and genotype was stable for a minimum of six months. RNA-SEQ data continued to demonstrate decreased expression of EMT in cells removed from drug compared to the parental cell line. MTI-101 treatment in PC-9 and H446 cells showed synergistic activity with standard of cares Erlotinib, Osimertinib, and Cisplatin when used in combination on the wildtype cells as well. Finally, in vivo data indicates that MTI-101 treatment selects for increased E-Cadherin and decreased Vimentin. Similar to the cell line model, this finding correlated with decreased incidence of bone metastasis in the PC-9 in vivo model. Together our data indicate that MTI-101 treatment could be used as a tool to delay the emergence of resistance and potentially inhibit or delay the emergence of metastatic disease for the treatment of lung cancer. Citation Format: Clark Jones, Lori Hazlehurst. Emergence of resistance to MTI-101 selects for favorable MET phenotype in lung cancer [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 2412.
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Nnakenyi, Ifeyinwa, Tonia Onyeka, Ngozi Idemili-Aronu1, Justus Onu, and Echezona Ezeanolue. "Abstract 38: External Quality Assessment for Prostate Specific Antigen Test Accuracy: A Needs Assessment of Nigerian Tertiary Hospitals." Cancer Epidemiology, Biomarkers & Prevention 32, no. 6_Supplement (June 1, 2023): 38. http://dx.doi.org/10.1158/1538-7755.asgcr23-abstract-38.
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Abstract Purpose: Prostate cancer is a major cause of death in African men, and the accuracy of prostate specific antigen (PSA) test results is important to ensure patients have access to accurate early diagnosis and treatment. External Quality Assessment (EQA) is an established framework to improve the quality of PSA results. We aimed to determine the need for implementing an EQA program for PSA in Nigeria. Methods: We used mixed-method design to collect data from 6 tertiary hospitals across the six regions in Nigeria. We conducted an online survey using a structured questionnaire developed from the International Standard Organization (ISO) 15189 checklist for accreditation of diagnostic laboratories. Responses were analyzed to obtain descriptive categorical data that was analyzed on Microsoft Excel. Using an in-depth interview guide, 12 respondents (6 Urologists and 6 Chemical Pathologists) from sampled hospitals were interviewed virtually. Responses were recorded and transcribed and relevant themes were identified and generated from the transcribed data. Results: Five of six laboratories sampled (83%) reported conducting repeat PSA testing. No sampled lab (0%) was enrolled in an EQA program for PSA. Eleven of the twelve respondents confirmed occasional disparities between PSA results and patient’s clinical status. They gave the impact of an erroneous PSA result on patient care as: extra unnecessary cost to the patient due to repeat testing; delay in decision making and initiating appropriate treatment; unnecessary invasive procedures. Training of lab staff, adoption of standard operating procedures and quality measures for EQA were considered opportunities to encourage PSA EQA practice while lack of funds for EQA programs, weak logistics for distribution of EQA samples and results, poor staff motivation and commitment were mentioned as barriers to effective practice uptake. Conclusion: There is a clear need for the implementation of an EQA program for PSA in Nigeria. This will reduce the incidence of incongruous PSA results, thus promoting better clinician approach to disease treatment and better patient outcomes especially in resource-constrained environments. Citation Format: Ifeyinwa Nnakenyi, Tonia Onyeka, Ngozi Idemili-Aronu1, Justus Onu, Echezona Ezeanolue. External Quality Assessment for Prostate Specific Antigen Test Accuracy: A Needs Assessment of Nigerian Tertiary Hospitals [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 38.
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Check, Jerome H. "Abstract 1033: Adult B-cell lymphocytic leukemia associated with osteolysis but normocalcemia and normal hematologic parameters - rare case or influenced by mifepristone treatment." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1033. http://dx.doi.org/10.1158/1538-7445.am2022-1033.
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Abstract Acute B-cell lymphoblastic leukemia (All) is much less common in adults than children and is much less common to present with bone pain. Extremely rare, but precedented, is the absence of hematologic abnormalities or lymphadenopathy. In some of the rare cases early diagnosis was achieved because hypercalcemia and bone pain were related to ectopic production of parathyroid-related peptide with consequent hypercalcemia and bone pain from hyperparathyroidism. However, there has been a case report in a 37-year-old male with B-cell lymphoblastic leukemia with osteolytic lesions, normal parathyroid hormone levels, and normal hematologic parameters despite >80% of the bone marrow replaced with blast cells. We present another case of a 55-year-old woman presenting with B cell ALL, bone pain and perfectly normal hematologic parameters despite 95% of the marrow replaced with blast cells. Her pain began 2 ½ months prior to the bone biopsy which was done because of the finding of osteolytic lesions on MRI. Her first bone marrow evaluation was performed 1 ½ months later. Related to further delays in even getting an appointment with the proper oncologist she was started on mifepristone 200mg daily to hopefully help delay a hematologic ALL crisis in view of 95% blast cells on biopsy. After 1 month of mifepristone therapy her CBC was still perfectly normal before standard chemotherapy was started. Mifepristone was started because of its effectiveness in improving length and quality of life in patients with a variety of advanced cancers without any more treatment options coupled with its beneficial effect in controlled studies with spontaneous leukemia in mice. Furthermore, the target for mifepristone, the immunomodulatory protein known as the progesterone induced blocking factor (PIBF), was found to be highly expressed by multiple human leukemia cell lines and was suppressed by mifepristone. The most common clinical state found in patients with advanced cancers following treatment with mifepristone is to stabilize the disease and inhibit further spread. The possibility exists that the failure to progress to typical pancytopenia after 95% of the bone marrow was replaced by blast cells was related to the mifepristone treatment. However, the possibility also exists that some unknown factor inhibiting this progression was operative as in some other very rare reported cases. With the possibility of a beneficial effect of treatment, mifepristone, an extremely well tolerated oral agent, could be considered for treating ALL when no other reasonable treatment options are available, e.g., a patient not likely to survive standard therapy or failure to respond to traditional chemotherapy. Even in this patient, if it takes more than 1 month to induce remission, her 40% 5-year survival will even be lower so one could consider maintenance therapy with mifepristone. Citation Format: Jerome H. Check. Adult B-cell lymphocytic leukemia associated with osteolysis but normocalcemia and normal hematologic parameters - rare case or influenced by mifepristone treatment [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 1033.
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Knoerzer, Deborah, Anupama Reddy, Adnan Derti, and Caroline M. Emery. "Abstract 4022: ERK1/2 inhibitor ulixertinib demonstrates activity in atypical (non-V600) BRAF mutant models." Cancer Research 82, no. 12_Supplement (June 15, 2022): 4022. http://dx.doi.org/10.1158/1538-7445.am2022-4022.
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Abstract Atypical BRAF (non-V600) alterations comprise approximately half of all BRAF mutations in cancer and can be categorized according to characteristics of molecular signaling (either Class II or III). Atypical BRAF alterations are rare (approximately 3% across all human cancers) and there are currently no approved therapies for this indication. As next-generation sequencing becomes standard clinical practice, oncologists are frequently identifying atypical BRAF alterations in their patients’ tumors. The efficacy of the first-in-class ERK1/2 inhibitor, ulixertinib (BVD-523), was assessed across 10 patient-derived xenograft (PDX) models, which harbored class II or III BRAF alterations (5 models with type II alterations, 4 models with class III, and 1 model with both class II and III). Responses ranging from robust regression to moderate tumor growth delay were observed in 9/10 models. RNA sequencing was performed on tumors from the vehicle-treated and ulixertinib-treated groups with three replicates per PDX model. The samples were collected 2 hours after the last dose of treatment. Expression of the mutant BRAF alleles was readily confirmed from RNA-seq data in all PDX models. In addition, gene expression analysis showed differential expression of MAPK pathway genes in responders compared to the non-responders. In summary, ulixertinib has exhibited strong pre-clinical activity in a variety of patient-derived xenograft models with atypical BRAF alterations. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, harboring specific BRAF mutations (G469A, L485W, or L597Q) and is currently under clinical evaluation in patients with tumors harboring any atypical BRAF alteration (NCT04488003). Citation Format: Deborah Knoerzer, Anupama Reddy, Adnan Derti, Caroline M. Emery. ERK1/2 inhibitor ulixertinib demonstrates activity in atypical (non-V600) BRAF mutant models [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 4022.
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Kojima, Yuki, Shigehiro Yagishita, Kazuki Sudo, Tatsunori Shimoi, Shintaro Iwata, Shun-ichi Watanabe, Chitose Ogawa, et al. "Abstract 3995: Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, effectively inhibits growth of patient-derived xenograft model with CIC-rearranged sarcoma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3995. http://dx.doi.org/10.1158/1538-7445.am2023-3995.
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Abstract Background: Capicua-double homeobox 4 (CIC-DUX4)-rearranged sarcomas (CDS) are extremely rare and highly aggressive sarcomas. There is no standard therapy for the patients with advanced CDS, and therapeutic development is needed. We evaluated preclinical efficacy of trastuzumab deruxtecan (T-DXd), a humanized monoclonal HER2-targeting antibody conjugated to a topoisomerase 1 inhibitor, DXd, in patient-derived xenograft (PDX) models with CDS. Methods: Patient-derived tumor tissue was transplanted into subcutaneous around the flank of female NOG mice, which were treated with vehicle or T-DXd (3 mg/kg, intravenous, Day0) when the mean tumor volume reached 200 mm3. Tumor volume was assessed twice weekly for 3 weeks to assess the efficacy of T-DXd. Results: This study included 3 CDS-derived PDXs. HER2 expression was low in one PDX and not expressed in two PDXs. One PDX was established from a specimen at initial diagnosis, two were established from specimens after prior-chemotherapy. T-DXd demonstrated significant tumor growth delay compared to vehicle in all PDX models investigated. One PDX with no efficacy was HER2-negative and had a treatment history of topoisomerase I inhibitor. In contrast, PDX of HER2-negative topoisomerase I inhibitor-resistant Ewing sarcoma was also administered T-DXd under the same conditions and was found to be refractory. Conclusion: The present study showed that a therapeutic potential of T-DXd in CDS patients, including HER2-negative. Citation Format: Yuki Kojima, Shigehiro Yagishita, Kazuki Sudo, Tatsunori Shimoi, Shintaro Iwata, Shun-ichi Watanabe, Chitose Ogawa, Akihiko Yoshida, Yasushi Yatabe, Kan Yonemori, Akinobu Hamada. Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, effectively inhibits growth of patient-derived xenograft model with CIC-rearranged sarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3995.
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Onono, Maricianah Atieno, Samuel Wahome, Pauline Wekesa, Catherine Kidiga Adhu, Lawrence Wandei Waguma, Titus Serem, Mildred Anyango Owenga, and Patricia Ong'wen. "Effects of an expanded Uber-like transport system on access to and use of maternal and newborn health services: findings of a prospective cohort study in Homa Bay, Kenya." BMJ Global Health 4, no. 3 (May 2019): e001254. http://dx.doi.org/10.1136/bmjgh-2018-001254.
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IntroductionKenya’s progress towards reducing maternal and neonatal deaths is at present ‘insufficient’. These deaths could be prevented if the three delays, that is, in deciding to seek healthcare (delay 1), in accessing formal healthcare (delay 2) and in receiving quality healthcare (delay 3), are comprehensively addressed. We designed a mobile phone enhanced 24 hours Uber-like transport navigation system coupled with personalised and interactive gestation-based text messages to address these delays. Our main objective was to evaluate the impact of this intervention on women’s adherence to recommended antenatal (ANC) and postnatal care (PNC) regimes and facility birth.MethodsWe conducted a prospective cohort study. Women were eligible to participate in the study if they were 15 years or older and less than 28 weeks gestation. We defined cases as those who received the standard of care plus the intervention and the control group as those who received the standard of care only. For analysis, we used logistic regression analysis and report crude and adjusted OR (aOR) and 95 % CI.ResultsCases (women who received the intervention) had five times higher odds of having four or more ANC visits (aOR=4.7, 95% CI 3.20 to 7.09), three times higher odds of taking between 30 and 60 min to reach a health facility for delivery (aOR=3.14, 95% CI 2.37 to 4.15) and four times higher odds of undergoing at least four PNC visits (aOR=4.10, 95% CI 3.11 to 5.36).ConclusionAn enhanced community-based Uber-like transport navigation system coupled with personalised and interactive gestation-based text messages significantly increased the utilisation of ANC and PNC services as well as shortened the time taken to reach an appropriate facility for delivery compared with standard care.
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Kolberg, Hans-Christian, Carmen Röhm, Angrit Stachs, Florian Schütz, Jens-Uwe Blohmer, Sarah Wetzig, Steffi Hartmann, Jörg Heil, and Markus Hahn. "Abstract P2-14-01: MOLECULAR FLUORESCENCE-GUIDED SURGERY USING BEVA800 FOR THE ASSESSMENT OF TUMOR MARGINS DURING BREAST CONSERVING SURGERY OF PATIENTS WITH PRIMARY BREAST CANCER (MARGIN-II)." Cancer Research 83, no. 5_Supplement (March 1, 2023): P2–14–01—P2–14–01. http://dx.doi.org/10.1158/1538-7445.sabcs22-p2-14-01.
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Abstract Introduction: The goal of breast conserving surgery (BCS) for early breast cancer (EBC) is to remove the tumor in toto and preserving as much of the normal breast tissue as possible. In 20-50% of cases a re-excision is necessary because of involved margins. Repeat surgeries are not only a burden to patients physically but also psychologically and can delay recommended adjuvant therapies. Accurate determination of tumor margins during surgery is therefore a critical need. Breast cancer tissue produces significantly higher amounts of VEGF-A than healthy tissue. VEGF-A stimulates tumor angiogenesis and is therefore a target for molecular imaging techniques. The fluorescence imaging agent bevacizumab-IRDye800CW (Beva800) is a conjugate of bevacizumab and IRDye800CW and binds specifically to VEGF-A. Beva800 provides a potentially efficacious approach to imaging specimen and cavity margins during BCS. We are presenting a phase II study that combined Beva800 with the SurgVision Explorer Air camera for intraoperative margin assessment during BCS for EBC. Methods: MARGIN II is a multicenter open-label single arm prospective clinical trial aimed at evaluating Beva800 for assessment of tumor margins in women with EBC scheduled for BCS. The study was a within-patient comparison of positive tumor margin rates using BCS standard of care margin assessment compared to intraoperative assessment with 4.5 mg Beva800 and fluorescence imaging with the SurgVision Explorer Air camera. All patients received an i.-v. bolus injection of 4.5 mg of Beva800 three days before surgery. The fluorescent signal was visualized during surgery using NIR fluorescence imaging (700–1000 nm). Standard of care margin assessment was defined as visual inspection, palpation and, in cases of pre-operative wire marking, specimen sonography or mammography. Beva800 efficacy was determined as the number of patients in which a pathology-confirmed positive margin was identified by fluorescence-guided surgery using Beva800 but not by standard of care BCS. Results: 49 patients were included in 5 centers. 4 training cases were only included in the safety analysis, 45 patients were evaluable for the efficacy analysis. 8 patients (17.8%) had involved margins after standard of care BCS, 4 of which were detected by molecular fluorescence intraoperatively resulting in the reduction of patients with positive margins by 50% (95% CI: 15.7%, 84.3%). 4 patients (8.9%; 95% CI: 2.5%, 21.1%) needed a re-excision because of involved margins. In 27 patients (60.0%) the additional molecular fluorescence guided cavity shaving did not change the resection status from positive to negative (false positive). Adverse events were reported by 16 of 49 patients (32.7%), but only 3 (6.1%) were related to Beva800 (syncope, hot flush, hypertensive crisis). One patient experienced a treatment related SAE (hypertensive crisis). No anti-Beva800 antibodies were detected. Conclusion: In our analysis the rate of necessary second operations was reduced by 50% using Beva800 and the SurgVision Explorer Air camera. The safety analysis confirmed the positive safety profile of Beva800 found in previous studies. Molecular fluorescence-guided surgery may have the potential to change the practice of breast conserving surgery by reducing unnecessary re-excisions. Future studies will have to address the high false positive rates. Citation Format: Hans-Christian Kolberg, Carmen Röhm, Angrit Stachs, Florian Schütz, Jens-Uwe Blohmer, Sarah Wetzig, Steffi Hartmann, Jörg Heil, Markus Hahn. MOLECULAR FLUORESCENCE-GUIDED SURGERY USING BEVA800 FOR THE ASSESSMENT OF TUMOR MARGINS DURING BREAST CONSERVING SURGERY OF PATIENTS WITH PRIMARY BREAST CANCER (MARGIN-II) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-14-01.
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Rosean, Claire Buchta, Mohan Karkada, David M. Koelle, Paul Nghiem, and Teri Heiland. "Abstract 2052: LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses, tumor inhibition, and provides rationale for first-in-human trial." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2052. http://dx.doi.org/10.1158/1538-7445.am2022-2052.
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Abstract The majority of Merkel cell carcinomas (MCC), a rare and highly aggressive type of neuroendocrine skin cancer, are associated with Merkel cell polyomavirus (MCPyV) infection. MCPyV integrates into the host genome, resulting in expression of a truncated form of the viral large T antigen (LT) in infected cells and thus making LT an attractive target for therapeutic cancer vaccines. We designed a cancer vaccine that promotes potent, antigen-specific CD4+ T cell responses to MCPγV-LT. To activate antigen-specific CD4+ T cells in vivo, we utilized our nucleic acid platform, UNITE࣪ (UNiversal Intracellular Targeted Expression), which fuses a tumor-associated antigen with lysosomal-associated membrane protein 1 (LAMP1). This lysosomal targeting technology results in enhanced antigen presentation and a balanced T cell response. LTS220A, encoding a mutated form of MCPγV-LT that diminishes its pro-oncogenic properties, was introduced into the UNITE࣪ platform. In pre-clinical studies, vaccination with LTS220A-UNITE࣪ (ITI-3000) induced antigen-specific CD4+ T cells that were sufficient to delay tumor growth, and this effect was dependent on their ability to produce IFNγ. Moreover, ITI-3000 induced a favorable tumor microenvironment (TME), including significantly enhanced numbers of CD4+ and CD8+ T cells as well as NK and NKT cells. These findings strongly suggest that in pre-clinical studies, DNA vaccination using the UNITE࣪ platform enhances CD4+ T cell responses to MCPγV-LT that result in significant anti-tumor immune responses. We are planning a first-in-human (FIH) Phase 1 open-label study to evaluate the safety, tolerability, and immunogenicity of ITI-3000 in patients with polyomavirus-positive MCC. Patients will receive up to four intramuscular vaccinations of 4mg of ITI-3000 using the PharmaJet Stratis® needle-free injection system. The primary objectives will be safety and tolerability, observing dose-limiting toxicities, serious adverse events, standard clinical assessments, and safety laboratory parameters. Immunogenicity of the vaccine will be measured by peripheral blood assessments of T cell activation using ELISpot and flow cytometry assays. Citation Format: Claire Buchta Rosean, Mohan Karkada, David M. Koelle, Paul Nghiem, Teri Heiland. LAMP1 targeting of the large T antigen of Merkel cell polyomavirus elicits potent CD4+ T cell responses, tumor inhibition, and provides rationale for first-in-human trial [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 2052.
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Marek, Robert D., Junping Wei, Tao Wang, Xiao-Yi Yang, Gangjun Lei, and Zachary C. Hartman. "Abstract 683: Vaccination against androgen receptor splice variant induces anti-tumor adaptive immune responses." Cancer Research 83, no. 7_Supplement (April 4, 2023): 683. http://dx.doi.org/10.1158/1538-7445.am2023-683.
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Abstract Background: Androgen receptor (AR) signaling has been the central target for standard-of-care prostate cancer therapies, although de novo resistance to these therapies occurs in many metastatic prostate cancer patients within 2-3 years. Resistance to AR targeting agents most often develops through overexpression of AR and expression of truncated, constitutively active RNA splice variants of AR. While clinical use of PD-1/PD-L1 immune checkpoint blockade has failed to demonstrate clinical success in treating resistance prostate cancers, the slower progression of prostate cancer provides an opportunity for immune targeted interventions. Cancer specific vaccines have the potential to enable and enhance tumor specific immune responses by stimulating and directing T cell immunity to important oncologic targets. We hypothesized that a cancer vaccine designed to induce a T cell response against cells expressing high levels of AR would result in an anti-tumor effect and potentially prevent or delay the development of therapeutic resistance. Methods: To evaluate AR and AR variants as potential immunological targets, we produced adenoviral vaccines against AR (Ad-AR) or AR splice variant 7 (Ad-AR-V7). We vaccinated naïve mice and examined AR and AR variant specific immunity in peptide restimulation. We further tested our vaccines in prophylactic and therapeutic regimens using multiple subcutaneous syngeneic tumor models (including prostate tumor lines, such as TrampC2) which were engineered to express AR or AR-V7. Results: Adenoviral vaccines targeting AR or AR-V7 produced robust T-cell responses against the N-terminal domain of AR. Notably, vaccination with both Ad-AR or Ad-AR-V7 induced significant anti-tumor immune responses, inducing complete tumor clearance against tumors expressing AR-V7 and allowing for long-term survival in the majority of vaccinated mice. Conclusions: These data demonstrate the potential of AR and AR splice variants as immunologic targets of prostate cancer vaccines, which elicit AR specific T cell immunity and produce anti-tumor responses in prostate cancers. Citation Format: Robert D. Marek, Junping Wei, Tao Wang, Xiao-Yi Yang, Gangjun Lei, Zachary C. Hartman. Vaccination against androgen receptor splice variant induces anti-tumor adaptive immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 683.
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Soh, Chien Lin, Samantha Muktar, Charles M. Malata, and John R. Benson. "Abstract P6-05-44: REASONS FOR CHOOSING DELAYED RATHER THAN IMMEDIATE CONTRALATERAL PROPHYLACTIC MASTECTOMY IN PATIENTS WITH UNILATERAL BREAST CANCER." Cancer Research 83, no. 5_Supplement (March 1, 2023): P6–05–44—P6–05–44. http://dx.doi.org/10.1158/1538-7445.sabcs22-p6-05-44.
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Abstract Background: Rates of contralateral prophylactic mastectomy (CPM) have more than doubled in the past decade amongst breast cancer patients irrespective of inherited genetic predisposition related to high penetrance genes. Increasing numbers of women with unilateral breast cancer are opting for removal of both the affected ipsilateral and unaffected contralateral ‘normal’ breast even when suitable for breast conserving surgery. Reasons for requesting CPM include prevention of recurrence, peace of mind and moving on after breast cancer. Some women seek CPM as a delayed procedure but factors influencing this are poorly understood. Methods: A retrospective analysis examined patients undergoing CPM as either an immediate or delayed procedure with or without breast reconstruction (BR) at a single tertiary referral centre between January 2009 and December 2019. A cross-sectional survey was undertaken that was compiled and based on validated questionnaires and responses to defined statements generated using a 5-point Likert scale (1 = strongly disagree to 5 = strongly agree) with calculation of mean scores and standard deviation (SD). This questionnaire explored patient’s decision-making process in terms of timing of CPM and any BR and was supported by subjective free-text boxes to gauge qualitative and quantitative aspects of the patient-related decision-making process. Those patients who consented to participate were provided with access to an online questionnaire. Results: Amongst this cohort of 39 delayed CPM patients, there were 6 decliners and therefore questionnaires were issued to the remaining 33 patients. The response rate was 67% (22/33) and the most common reason for seeking delayed CPM was to allow completion of adjuvant treatment recommendations (including radiotherapy/chemotherapy) before surgery on the unaffected breast [mean score 2.91; SD 1.0]. This avoided risk of delay in commencement of adjuvant treatment consequent to potential complications of contralateral surgery (especially with BR). The second most important reason for choosing delayed CPM was unavailability of genetic test results at the time of therapeutic mastectomy [mean score 2.64; SD 1.4]. The third most common reason was a subsequent change in family history cancer history after their personal breast cancer diagnosis that often prompted genetic testing [mean score 2.55; SD 2.7]. Several patients cited a shorter recovery time as a strong reason for requesting delayed CPM. Conclusion: Factors determining delayed CPM are patient-driven and this accords with documented reasons for women seeking CPM in general. Patients tend to make decisions about CPM based on two main themes relating to either ‘fear’ of cancer or a desire to ‘take control’. Temporal factors are important in the context of a delayed procedure and relate to subsequent availability of genetic test results and changes in family history in relatives who were otherwise unaffected at the time of initial diagnosis. Completion of all cancer treatments prior to delayed CPM (with BR) can be advantageous when implant-based BR is planned at the time of an immediate CPM. Radiotherapy can increase capsular contracture rates and surgical complications can delay start of chemotherapy. CPM should be offered as a potentially delayed option with informed discussion of risks and benefits. Citation Format: Chien Lin Soh, Samantha Muktar, Charles M Malata, John R Benson. REASONS FOR CHOOSING DELAYED RATHER THAN IMMEDIATE CONTRALATERAL PROPHYLACTIC MASTECTOMY IN PATIENTS WITH UNILATERAL BREAST CANCER. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-44.
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Meattini, Icro, Giulio Francolini, Vanessa Di Cataldo, Luca Visani, Carlotta Becherini, Erika Scoccimarro, Monica Mangoni, et al. "Abstract PD3-03: Preoperative robotic radiosurgery for early breast cancer: results of the phase II ROCK trial (NCT03520894)." Cancer Research 83, no. 5_Supplement (March 1, 2023): PD3–03—PD3–03. http://dx.doi.org/10.1158/1538-7445.sabcs22-pd3-03.
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Abstract Introduction. Breast-conserving surgery (BCS) followed by postoperative radiotherapy (RT) still represents the standard of care for early breast cancer (BC) patients. Hypofractionated schedules in maximum 15 fractions are currently accepted as the gold standard for external beam whole and partial breast irradiation (PBI). PBI for selected early BC patients allowed a shorter overall treatment duration and an improved patient compliance as compared to old-fashioned RT schedules. Preoperative PBI, due to the advantage of treating a well-defined volume, has been gaining attention in this multidisciplinary scenario. It avoids local treatment delay and might allow tumour downstaging with increased rates of BCS and improved cosmetic outcomes. Since local recurrence might be driven by biological mechanisms of radioresistance rather than geographical miss, higher dose per fraction may overcome repair mechanisms allowing tumoral cells to escape from conventional RT damage. We report the results of the phase II ROCK trial (NCT03520894), enrolling early BC patients treated with preoperative robotic radiosurgery (prRS), in terms of acute and early late toxicity, disease control, and cosmesis. Material and methods. The study recruited between August 2018 and September 2021 at the Radiation Oncology Unit of the University of Florence (Florence, Italy). Eligible patients were women aged 50+ years, with histologically proven invasive early BC, HR+/HER2- disease, without lymph vascular invasion, tumour size up to 25 mm suitable for BCS. Exclusion criteria were clinical node positive disease, multiple foci tumours, and patients with breast lesion limiting within 5 mm from the skin surface. The study aimed to prospectively assess the safety and feasibility of a single Cyberknife® (Accuray Incorporated, Sunnyvale, CA, USA) 21Gy-fraction prRS in preoperative setting, and to identify predictive factors for outcomes based on biologic and clinical features. The primary endpoint was the acute skin toxicity (from the end of prRS to surgery) according to the RTOG and the EORTC scales. Secondary endpoints were the rate of early late skin and non-skin toxicity as measured 90 days from the end of prRS, the rate of pathological complete response (pCR) according to Chevalier score. Cosmetic outcomes were prospectively scored every 6-month using the BCCT.core software. Results. From August 2018 to September 2021, a total of 70 patients were recruited and enrolled. Of those, 41 were excluded due to tumour biology exclusion criteria and 7 due to multiple foci breast disease evidenced at basal MRI. Therefore, 22 patients were successfully treated with pRS. Median age at diagnosis was 68 years (range 50-86), median tumour size was 14 mm (range 7.5-25). Required target dosimetric parameters were met in all patients, as well as normal tissue constraints. Patients received surgery after a median time of 29 days from biopsy, without any delay or postoperative complication. Overall, three G1 adverse events (13.6%) were recorded within 7 days from prRS (1 erythema, 2 breast pain). Three events (13.6%) were recorded between 7 and 30 days from prRS, one G2 breast oedema and two G1 breast pain. No acute toxicity greater than G2 was recorded. Five patients experienced early late G1 toxicity (1 breast pain, 4 breast induration). One patient reported G2 breast induration. No early late toxicity greater than G2 was observed. At a median follow up of 18 months (range 6-29.8), cosmetic results were scored excellent/good and fair in 14 and 5 patients, respectively, while 3 patients experienced a poor cosmetic outcome. Overall, pCR after surgery was reported in 2 patients (9%). Two patients received postoperative whole breast irradiation, according to histopathological results. Conclusions. ROCK trial showed that a single 21 Gy dose prRS represents a feasible technique for selected patients affected by early BC, showing a good safety profile and a promising effectiveness. Citation Format: Icro Meattini, Giulio Francolini, Vanessa Di Cataldo, Luca Visani, Carlotta Becherini, Erika Scoccimarro, Monica Mangoni, Viola Salvestrini, Laura Masi, Chiara Bellini, Raffaela Doro, Federica Di Naro, Marco Bernini, Jacopo Nori, Lorenzo Orzalesi, Simonetta Bianchi, Lorenzo Livi. Preoperative robotic radiosurgery for early breast cancer: results of the phase II ROCK trial (NCT03520894) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD3-03.
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Zanuttini, Roberto, Giovanni Nicolotti, and Corrado Cremonini. "Poplar plywood resistance to wood decay agents: efficacy of some protective treatments in the light of the standard ENV 12038." Annals of Forest Science 60, no. 1 (January 2003): 83–89. http://dx.doi.org/10.1051/forest:2002077.
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Ma, C. "The Precision of J2000.0 Radio Source Positions from Mark III VLBI." Symposium - International Astronomical Union 109 (1986): 157–62. http://dx.doi.org/10.1017/s0074180900076506.
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A celestial coordinate frame defined by extragalactic radio sources has been developed from Mark III VLBI data. 33 000 delay and delay rate pairs acquired between August 1979 and December 1982 have been analyzed to give positions for 82 radio sources. Standard J2000.0 astronomical models were applied. 90% of the formal errors for arc lengths between sources are less than Arc lengths estimated from separate one-year data sets are consistent at the to level.
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Tolaney, Sara M., Romualdo Barroso-Sousa, Zefei Jiang, Yeon Hee Park, Mothaffar Rimawi, Cristina Saura, Andreas Schneeweiss, et al. "Abstract OT1-14-02: Phase 3 study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09." Cancer Research 82, no. 4_Supplement (February 15, 2022): OT1–14–02—OT1–14–02. http://dx.doi.org/10.1158/1538-7445.sabcs21-ot1-14-02.
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Abstract Background: A combination of a taxane, trastuzumab, and pertuzumab (THP) is the standard-of-care (SOC) 1L treatment for patients (pts) with HER2+ mBC; THP demonstrated median progression-free survival (mPFS) of 18.7 mo and overall survival (OS) of 56.5 mo (Swain et al. N Engl J Med. 2015;372:724-734). However, pts eventually develop resistance to treatment. Novel treatment options are necessary in order to delay the emergence of resistance and provide better clinical outcomes, improve quality of life (QOL), and prolong survival in the 1L setting. T-DXd has demonstrated efficacy in pts with heavily pretreated HER2+ mBC, with an objective response rate (ORR) of 61.4%, duration of response (DOR) of 20.8 mo, and mPFS of 19.4 mo (Modi et al. Cancer Res. 2021. Abstract PD3-06). Data from DESTINY-Breast01 supported global approvals of T-DXd in HER2+ mBC. Here we describe a phase 3 trial evaluating the efficacy and safety of T-DXd ± pertuzumab compared with THP in the 1L treatment of HER2+ mBC. Trial design: DESTINY-Breast09 (NCT04784715) is a global, multicenter, randomized, phase 3 trial assessing the efficacy and safety of T-DXd with or without pertuzumab compared with SOC THP as 1L treatment in pts with HER2+ (IHC 3+ or ISH+ assessed locally per ASCO-CAP guidelines and centrally confirmed) advanced or mBC. This study consists of 3 treatment arms: arm A (T-DXd + placebo), arm B (T-DXd + pertuzumab), and arm C (THP). Randomization is 1:1:1 and pts will be stratified by prior treatment status (de novo vs recurrent), hormone receptor status (positive vs negative), and PIK3CA mutation status (detected vs not detected). Pts (N≈1134) must have had no prior chemotherapy or HER2-targeted therapy for advanced or mBC (1 prior line of endocrine therapy is allowed for mBC). The primary endpoint is PFS by blinded independent central review. Secondary endpoints include PFS by investigator assessment, OS, ORR, DOR, PFS2, health-related quality of life (QOL), pharmacokinetics, immunogenicity, and safety. Citation Format: Sara M Tolaney, Romualdo Barroso-Sousa, Zefei Jiang, Yeon Hee Park, Mothaffar Rimawi, Cristina Saura, Andreas Schneeweiss, Masakazu Toi, Tinghui Yu, Jagdish Shetty, Pia Herbolsheimer, Sibylle Loibl. Phase 3 study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-14-02.
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Christensen, Keegan A., Osama Tarabichi, Sei Sho, Hidaly Hernández, Bryce Hunger, Melissa A. Fath, Jeffery Keene, Robert Beardsley, Marlan Hansen, and Douglas R. Spitz. "Abstract 5062: Small molecule superoxide dismutase mimetic avasopasem manganese for the mitigation of cisplatin induced ototoxicity." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5062. http://dx.doi.org/10.1158/1538-7445.am2023-5062.
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Abstract Introduction: Avasopasem manganese (GC4419) is a selective superoxide dismutase mimetic which has recently completed a Phase 3 clinical trial (NCT03689712) demonstrating a significant reduction in the severity of oral mucositis in patients receiving standard cisplatin and radiotherapy for head and neck squamous cell carcinoma (HNSCC). Up to 66% of HNSCC patients experience ototoxicity from platinum-based chemotherapy, resulting in tinnitus and hearing loss. The analysis of clinical trial data also revealed that patients treated with GC4419 in addition to cisplatin (cis) and radiotherapy reported less tinnitus than those treated with standard therapy alone. The generation of reactive oxygen species has long been recognized as an important contributor to cis-induced hearing loss; therefore, we hypothesize that administration of GC4419 with cisplatin can prevent ototoxicity by scavenging superoxide. Results: Organotypic cultures using postnatal day 2 or 3 mouse cochlea were treated with cis 4 µM and 0.5, 2, or 4 µM GC4419 for 24 hours. The explants were then stained for anti-myosin-VIIa. Hair cells were counted, and it was determined that 4 µM cis was sufficient to cause a decrease in hair cell numbers and GC4419 dose as low as 2 µM protected against this biological endpoint. To assess the effects of GC4419 on hearing loss in vivo, CBA/CaJ mice were treated as follows: 5 mice (1 female, 4 males) received 3 mg/kg cis IP, 4 mice (2 males and 2 females) received vehicle, 3 mice (2 females, 1 males) received 10 mg/kg IP GC4419, and 5 mice (2 females, 3 males) were treated with GC4419 10 minutes prior to cisplatin injection. Cis and GC4419 were administered for four consecutive days followed by two days of GC4419. The animals were allowed 8 recovery days, with Normosol SQ and high calorie food administered, prior to a second repetition of the treatment cycle. This protocol for cis dosing was found to be lethal in three mice in the cisplatin only group. Auditory brainstem response testing was performed before and after treatment, revealing elevated hearing thresholds in cis treated mice but not in mice treated with GC4419 and cis. Additionally, the cis treatment group experienced greater weight loss than the mice treated with GC4419 and cis Separately, in an H1299 tumor xenograft model in nu/nu mice, GC4419 5 mg/kg IP BID over 14 days was shown not to interfere with, and in fact somewhat increased, the tumor growth delay with cis 5 mg/kg IP QW x 3. Conclusion: These results support the hypothesis that treatment with the SOD mimetic GC4419 can reduce cis induced ototoxicity by scavenging superoxide and justify further studies to determine if this mechanism based approach can be implemented in cancer therapy. (Supported by a sponsored research agreement between the University of Iowa and Galera Therapeutics, Inc.) Citation Format: Keegan A. Christensen, Osama Tarabichi, Sei Sho, Hidaly Hernández, Bryce Hunger, Melissa A. Fath, Jeffery Keene, Robert Beardsley, Marlan Hansen, Douglas R. Spitz. Small molecule superoxide dismutase mimetic avasopasem manganese for the mitigation of cisplatin induced ototoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5062.
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Ridinger, Maya, Errin Samuelsz, Peter J. Croucher, Mark Erlander, Katherine Ruffner, and David J. Einstein. "Abstract 1236: Biomarkers of response to abiraterone and the polo-like kinase 1 (PLK1) inhibitor onvansertib in metastatic castration resistant prostate cancer (mCRPC) patients." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1236. http://dx.doi.org/10.1158/1538-7445.am2022-1236.
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Abstract Background: Abiraterone (abi), a widely-used standard of care for castration-sensitive and castration-resistant prostate cancers, inhibits the androgen receptor signaling pathway. While abi slows disease progression, extended treatment universally results in acquired resistance. PLK1 is a serine/threonine protein kinase, master regulator of the cell cycle. PLK1 is upregulated in prostate cancer following androgen-deprivation therapy and PLK1 inhibition synergizes with abi in CRPC models, providing a potential means to reverse or delay abi resistance. Onvansertib is an oral highly selective PLK1 inhibitor that showed synergistic anti-tumor activity with abi in in-vitro and in-vivo CRPC models. A phase 2 clinical trial (NCT03414034) is ongoing to assess the efficacy of onvansertib in combination with abi in mCRPC patients with early abi resistance. Genomic and transcriptomic analyses were performed to identify response biomarkers for the onvansertib/abi combination. Methods: Cell-free DNA isolated from patient plasma was analyzed by targeted sequencing using Guardant OMNI® (500-gene panel). RNA expression profiling was performed using archival tissues by Veracyte (formerly Decipher Biosciences). Genomic and transcriptomic profiles of patients who progressed within 12 weeks of treatment (“PD” patients) were compared to patients who had radiographic stable disease at 12 weeks (“SD” patients). Results: Genomic profiles were successfully obtained from 19 PD patients and 31 SD patients. On average, PD patients had more somatic alterations than SD patients (14 vs 7, p=0.017). SD was positively correlated with the presence of alterations affecting signaling pathways such as MTOR, NF1, PTEN and EGFR, and negatively correlated with gene alterations involved in cell migration and invasion such as APC, KDR, PREX2, NF2 and AKT3. Eight (26%) of the 31 SD patients had alterations either in MTOR (n=5) or PTEN (n=3), that were predicted to have functional impacts on the protein, while only 1 PD patient (5%) had an alteration in either of those 2 genes. Moreover, transcriptomic analyses performed on tissue from 8 patients revealed that SD patients (n=5) exhibited a gene expression signature of “PTEN loss” that was absent in PD patients (n=3) (p=0.016). Conclusions: Taken together, these data suggest that alterations in PTEN and MTOR, two key genes of the PI3K signaling pathway, are potential biomarkers for sensitivity to onvansertib/abi combination in mCRPC patients with early abi-resistance. Preclinical studies are underway to assess the activity of onvansertib/abi in combination with PI3K-pathway inhibitors. Citation Format: Maya Ridinger, Errin Samuelsz, Peter J. Croucher, Mark Erlander, Katherine Ruffner, David J. Einstein. Biomarkers of response to abiraterone and the polo-like kinase 1 (PLK1) inhibitor onvansertib in metastatic castration resistant prostate cancer (mCRPC) patients [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 1236.
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Ng, Terry L., Gregory R. Pond, Marta Sienkiewicz, Kednapa Thavorn, and Mark Clemons. "Abstract OT1-06-01: A randomised trial comparing continuation or de-escalation of bone modifying agents (BMA) in patients treated for over 2 years for bone metastases from either breast or castration-resistant prostate cancer (REaCT-HOLD BMA)." Cancer Research 82, no. 4_Supplement (February 15, 2022): OT1–06–01—OT1–06–01. http://dx.doi.org/10.1158/1538-7445.sabcs21-ot1-06-01.
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Abstract Background: Current guidelines recommend bone modifying agents (BMAs), such as bisphosphonates and denosumab, every 4 to 12 weeks to reduce the incidence of and delay the onset of symptomatic skeletal events (SSEs) in patients with bone metastases from breast cancer and castration-resistant prostate cancer (CRPC). Given the absence of level one evidence, the optimal frequency and duration of BMAs after 2 years of treatment is unknown. This is an important clinical question as the risk of SSEs decreases with time, while the risk of treatment-related toxicities increases. Methods: Patients with bone metastases from breast cancer or CRPC who have received ≥ two years of BMA treatment will be approached for this pragmatic, multicenter, open-label RCT. Using the Rethinking Clinical Trials (REaCT) methodology that incorporates the integrated oral consent model, eligible and consented patients will be randomized to either continue standard schedule BMA (every 4 or 12 weeks) or de-escalated BMA (every 24 weeks). This is a non-inferiority study. The co-primary endpoints are the physical functioning subscale of EORTC-QLQ-C30 and functional interference subscale of EORTC-QLQ-BM22. Secondary endpoints include number of patients with ≥ 1 SSE, time to development of SSE, SSE-free survival, skeletal morbidity rate, EORTC-QLQ-C30 and BM22 scores, BMA-related toxicity, and treatment adherence. To achieve 80% power for both co-primary endpoints and assuming a 10% non-compliance and 20% death rate, the planned sample size is 240 patients (120 per arm). Randomization (1:1 ratio) will be stratified by cancer type (breast vs prostate) and treatment schedule prior to randomization (Q4weeks vs. Q12weeks). A subgroup analysis comparing patients with 2-3 years vs. > 3 years of prior BMA treatment will be conducted. Results: The study has been open for enrollment since Oct 2020. As of July 5, 2021, the study has opened at 2 sites, 48 patients have been randomized and 8 are in screening. The study needs 60 patients randomized by September 2021 to continue to receive funding. There is a plan to open the study at two other academic centers in Ontario, Canada. Conclusion: This will be the first RCT providing level one evidence regarding the optimal frequency of BMA treatment that accounts for health-related quality of life after ≥ two years of prior BMA in this patient population. Citation Format: Terry L. Ng, Gregory R. Pond, Marta Sienkiewicz, Kednapa Thavorn, Mark Clemons. A randomised trial comparing continuation or de-escalation of bone modifying agents (BMA) in patients treated for over 2 years for bone metastases from either breast or castration-resistant prostate cancer (REaCT-HOLD BMA) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-06-01.
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Gallaher, Jill, Maximilian Strobl, Jeffrey West, Mark Robertson-Tessi, Robert Gatenby, Jingsong Zhang, and Alexander R. A. Anderson. "Abstract 852: Predicting progression in metastatic castrate-sensitive prostate cancer by coupling PSA and testosterone dynamics to a mechanistic mathematical model." Cancer Research 83, no. 7_Supplement (April 4, 2023): 852. http://dx.doi.org/10.1158/1538-7445.am2023-852.
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Abstract The purpose of this study is to use the dynamics of commonly collected biomarker levels for prostate cancer to identify the underlying cancer cell subtype composition and help predict response to treatment. In castrate-sensitive prostate cancer, the current standard of care is continuous maximum-tolerated dose (MTD) of anti-androgen compounds, which successfully reduces the tumor burden. However, continuous use often leads to treatment resistance. Alternatively, adaptive therapy approaches have been used clinically to delay or prevent resistant outgrowth. In adaptive therapy, a drug is given to maintain a tumor size by killing enough treatment-sensitive cells to shrink the burden but keep enough sensitive cells to suppress the outgrowth of resistant cells. Clinical trials using adaptive therapy approaches have shown longer tumor control compared to MTD for castrate-resistant disease and, more recently, shown feasibility for control in castrate-sensitive disease. This approach relies on using prostate-specific antigen (PSA) as a systemic biomarker as a surrogate for total tumor burden. Because PSA is a product of testosterone metabolism by androgen receptors (AR) in cells, and both testosterone and AR can vary over time and amongst cells, we can use a mathematical model to couple PSA, testosterone, and AR-dependency to dissociate systemic biomarkers from tumor burden and uncover potential mechanisms of resistance. We build a system of ordinary differential equations to investigate the emergence of different resistance mechanisms for metastatic castrate-sensitive prostate cancer patients. We first fit the equations to testosterone dynamics alone. Then, fixing those parameters, we fit to the dynamics of PSA assuming cell subtypes consisting of testosterone-dependent cells, testosterone producers, and AR-overexpressing cells. From the best fits, we can estimate the tumor cell subtype compositions for each patient and test different treatment strategies. We find that patients with tightly correlated testosterone and PSA levels tend to have mostly testosterone-dependent cells and continued robust responses to each round of treatment. Less correlated testosterone and PSA dynamics was usually associated with changes in PSA nadirs, peaks, or rates of return after stopping treatment over subsequent rounds of adaptive therapy. By fitting to both PSA and testosterone dynamics, we can distinguish between tumors that maintain testosterone-dependent cells from those with increasing resistant cell types. This allows for better quantification of the underlying tumor composition to help optimize therapies that target those cell types and better maintain tumor control. Citation Format: Jill Gallaher, Maximilian Strobl, Jeffrey West, Mark Robertson-Tessi, Robert Gatenby, Jingsong Zhang, Alexander R. A. Anderson. Predicting progression in metastatic castrate-sensitive prostate cancer by coupling PSA and testosterone dynamics to a mechanistic mathematical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 852.
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Alcaniz, Joshua, Lars Winkler, Maria Stecklum, Hagen Wieland, Antje Siegert, Michael Becker, Bernadette Brzezicha, Wolfgang Walther, and Jens Hoffmann. "Abstract 4674: Patient-derived xenograft (PDX) and corresponding cell line models from glioblastoma for drug development, immuno-oncology and translational research." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4674. http://dx.doi.org/10.1158/1538-7445.am2023-4674.
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Abstract Background: Glioblastoma (GBM) is the most common malignant brain tumor in adults, with about 90% of tumors developing de novo. Their heterogeneity, aggressiveness and infiltrative growth limit success of current standard of care (SoC) therapy and efficacy of new therapeutic approaches. For drug development a large panel of patient-derived tumor cell models is needed to generate most comparable in vitro and in vivo platform reflecting the complex biology of glioblastoma. Glioblastoma cell lines from patient-derived xenografts (PDX) preserve many patient specific characteristics and to perform the essential steps of pre-clinical drug development from in vitro screening to orthotopic in vivo approaches under conditions, which closely resemble the clinical situation. Further, GBM PDX models are useful for immune oncology research. Methods: A panel of 26 glioblastoma PDX models was established on immunodeficient mice (15 out of these established orthotopically). All models were characterized for drug sensitivity and molecular profile using panel and transcriptome sequencing. From these, three corresponding tumor cell lines were successfully established and characterized. Quality and identity of the models was performed by FACS and PCR analysis. Expression profile, drug sensitivity and growth behavior was determined and compared in vitro and after re-transplantation in vivo with the original PDX glioma model. In addition, we employed GBM PDX models for checkpoint-inhibitor sensitivity in humanized mouse settings. Results: Drug testing was performed in s.c. and orthotopic models revealed, that best treatment responses in s.c. models (tumor growth inhibition > 50%) were observed for SoC temozolomide (TMZ), irinotecan and bevacizumab. Molecular characterization identified all our models as IDH-wt (R132) with frequent mutations in PARP1, EGFR, TP53, FAT1, and within the PI3K/AKT/mTOR pathway. Their expression profiles resemble proposed mesenchymal, proneural and classical GBM molecular subtypes. Further, treatment of GBM PDX with ipilimumab, nivolumab or pembrozolumab generated minor growth delay. Conclusions: In drug sensitivity screening, irinotecan or bevacizumab were identified as alternative treatment options in TMZ resistant GBM PDX models. Our data demonstrate, that the established platform of s.c. and orthotopic GBM PDX is valuable for drug development and can well be complemented by a PDX-derived cell lines for in vitro screens. Furthermore, these models can be used for the evaluation of new immune-oncology therapies. Citation Format: Joshua Alcaniz, Lars Winkler, Maria Stecklum, Hagen Wieland, Antje Siegert, Michael Becker, Bernadette Brzezicha, Wolfgang Walther, Jens Hoffmann. Patient-derived xenograft (PDX) and corresponding cell line models from glioblastoma for drug development, immuno-oncology and translational research. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4674.
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Lazarides, Miltos K., George S. Georgiadis, and Nikolaos Papanas. "Do’s and Don’ts for a Good Reviewer of Scientific Papers: A Beginner’s Brief Decalogue." International Journal of Lower Extremity Wounds 19, no. 3 (June 11, 2020): 227–29. http://dx.doi.org/10.1177/1534734620924349.
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Peer review has been the principal way of evaluating scientific articles, ensuring that publications meet standards of methodology, integrity, and ethics. Occasionally, however, reviews are suboptimal, especially those by inexperienced reviewers. Therefore, this article offers suggestions on how to review a scientific article. Some of the most important suggestions include submitting the review in a timely fashion without undue delay, not breeching confidentiality, focusing mainly on the methodology, following specific format, and avoiding embarrassing comments to the authors.
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Guimarães, Henrique Cerqueira, Thiago Cardoso Vale, Victor Pimentel, Nayara Carvalho de Sá, Rogério Gomes Beato, and Paulo Caramelli. "Analysis of a case series of behavioral variant frontotemporal dementia: Emphasis on diagnostic delay." Dementia & Neuropsychologia 7, no. 1 (March 2013): 55–59. http://dx.doi.org/10.1590/s1980-57642013dn70100009.
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ABSTRACT Introduction: Despite many advances in the characterization of the behavioral variant of frontotemporal dementia (bvFTD), the diagnosis of this syndrome poses a significant challenge, while delays or diagnostic mistakes may impact the proper clinical management of these patients. Objective: To describe the clinical profile at first evaluation of a sample of patients with bvFTD from a specialized outpatient neurological unit, with emphasis on the analysis of the delay between the onset of symptoms and diagnosis. Methods: We selected 31 patients that fulfilled international consensus criteria for possible or probable bvFTD. Patients' medical admission sheets were thoroughly reviewed. Results: Patients' mean age was 67.9±8.2 years; 16 (51.6%) were men. Mean number of years of formal education was 7.7±4.0 years. Mean age at onset was 62.2±7.7 years, indicating a mean of 5.8 years of diagnostic delay. Thirteen patients (41.9%) presented with initial behavioral complaints only, eleven patients (35.5%) had mixed behavioral and memory complaints, five patients (16.1%) presented with memory complaints only, and two patient (6.4%) had behavioral and speech problems. Nine patients (29%) were admitted with alternative diagnoses. Mean and standard deviation scores for the mini-mental state examination, animal category fluency and memory test for drawings (five-minute delayed recall) were 19.3±6.3, 8.3±4.1 and 3.7±2.7, respectively. Conclusion: Most patients from this sample were evaluated almost six years after the onset of symptoms and performed poorly on both cognitive screening tests and functional evaluation measures.
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Alruwaili, Mohammed M., Justin Zonneville, Mohammed A. Alqarni, Priyanka Rajan, Hannah Serio, Robert Straubinger, Christos Fountzilas, and Andrei Bakin. "Abstract 3397: Evaluation of a novel two-drug combination strategy for p53-deficient colorectal and pancreatic cancers." Cancer Research 83, no. 7_Supplement (April 4, 2023): 3397. http://dx.doi.org/10.1158/1538-7445.am2023-3397.
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Abstract Colorectal Cancer (CRC) and Pancreatic Ductal Adenocarcinoma (PDAC) are the most lethal cancers worldwide. Despite initial response to standard-of-care therapy, a significant proportion of CRC/PDAC cancers relapse and progress to metastatic disease with poor overall survival (OS). Thus, better treatment options are urgently needed. Genetic alterations in the tumor suppressor p53 gene (TP53) are found in most CRC and PDAC cases and contribute to cancer relapse, progression, and metastasis. Even though the functional consequences of p53 mutations have been extensively studied, there are no FDA approved drug or their combination targeting p53 mutant (p53mut) cancers. Here we present a novel inducer-amplifier strategy for selective targeting p53-deficient CRC and PDAC. The Cancer Genome Atlas (TCGA) data showed elevated tumor mutational burden (TMB) and high expression levels of Base-Excision Repair (BER) in p53mut CRC and PADC. Assessment of the BER activity in CRC and PADC cells by a new methodology with deoxyuridine analogues ethynyl-deoxyuridine (EdU) and trifluorothymidine (TFT) revealed a significant delay in removal of genomic EdU and TFT in p53-deficient cells compared to isogenic p53 wildtype (p53wt) cells. Notably, p53-deficient cells accumulated in late S/G2 phase. Further, deoxyuridine analogues such as TFT-containing TAS102 induced buildup of DNA damage in p53-deficient cancer cells. Mechanistically, TAS102 did not block DNA replication but rather provoked activation of DNA Damage Response (DDR) resulting in DNA breaks in p53-deficient cells, while p53wt repaired the DNA lesion. This response was further enhanced by poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) leading to elevated cell death selectively in p53-deficient cancer cells, along with accumulation of cells in G2 phase. PARPi alone did not induce DNA damage in cancer cells. In preclinical in vivo models, the TAS102-PARPi combination was far more effective than either drug alone in the p53mut Cell-Derived Xenograft (CDX) and Patient-Derived xenograft (PDX) models. Immunohistochemistry data showed that the two-drug combination increased DNA damage and cell death while decreasing cell proliferation in p53-mutant models. In comparison, the two-drug combination and TAS102 exhibited comparable effectiveness in p53wt PDX model. Notably, the two-drug therapy did not exhibit significant toxicity in mouse models. In summary, this work demonstrates that our novel inducer-amplifier strategy provides effective treatment option for aggressive p53-deficient CRC and PDAC cancers while limiting adverse toxic events and improving the quality of life for cancer patients. Citation Format: Mohammed M. Alruwaili, Justin Zonneville, Mohammed A. Alqarni, Priyanka Rajan, Hannah Serio, Robert Straubinger, Christos Fountzilas, Andrei Bakin. Evaluation of a novel two-drug combination strategy for p53-deficient colorectal and pancreatic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3397.
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Chakraborty, Goutam, Rahim Hirani, Subhiksha Nandakumar, Nabila Zaman, Teja Muralidhar Kalidindi, Sai Harisha Rajanala, Gwo-Shu M. Lee, et al. "Abstract A002: A reciprocal signaling crosstalk between the AR and BCl2-AKT pathways induces castration resistance in castration sensitive prostate cancer." Cancer Research 83, no. 11_Supplement (June 2, 2023): A002. http://dx.doi.org/10.1158/1538-7445.prca2023-a002.
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Abstract Introduction: A leading contributor to the significant mortality burden of prostate cancer (PC) is the resistance to androgen deprivation therapy (ADT). Although most PCs are initially sensitive to ADT, the duration of response is variable, and relapse invariably occurs in the transition to metastatic castration-resistant prostate cancer (mCRPC), the lethal form of the disease. Therefore, it is essential to discover and validate early resistance mechanisms that initially protect castration sensitive prostate cancer (CSPC) cells from ADT and to develop novel combination therapies that can block or delay the ADT-induced shift from CSPC to mCRPC. Overexpression of the hallmark antiapoptotic gene B-cell lymphoma 2 (BCL2) is a potential mechanism of resistance to ADT. Methods: To discover the molecular drivers of castration resistance, we analyzed the tumor transcriptomic profile of a cohort of localized PC patients (N=58) treated with neoadjuvant-intensive ADT (NCT00924469; Taplin et al, 2014, Sowalsky et al, 2018). Experimentally, we treated CSPC cells and genetically engineered mice (GEM) prostate tumors with ADT and analyzed the signaling pathways, which were enriched post-ADT treatment compared untreated samples. Results: We discovered ~10-fold increased mRNA expression of BCL2 (p<0.001) in ADT-treated localized PC patients compared to untreated (standard of care surgery) patients in NCT00924469 samples. Our experimental study showed that treatment with AR inhibitors strongly augments BCL2 expression in human CSPC cell lines and GEM PC model, indicating possible direct negative regulation of BCL2 by the AR-signaling pathway. Mechanistically, our preliminary data reveal a striking induction of cell metabolism pathways (fatty acid and xenobiotic metabolism), including activation of PI3K/AKT signaling in BCL2-overexpressing CSPC cells. We used siRNA-mediated BCL2 knockdown in LNCaP cells and showed that loss of BCL2 strongly suppressed ADT-induced AKT- phosphorylation. We also showed increased Bcl2 mRNA expression in PTEN-knockout mice-derived prostate organoids compared to the wild-type control. Furthermore, we observed that AKT kinase -inhibitor MK2206 strongly inhibits enzalutamide-induced BCL2 expression in LNCaP cells. Conclusion: Together our data indicate a non-canonical role of BCL2 in activating PI3K/AKT signaling in prostate cancer. For the first time, we demonstrate the crucial importance of AR-BCL2-AKT signaling pathway crosstalk in CSPC biology and reveal this complex signaling crosstalk may act as a key driver of CSPC transformation to lethal CRPC. Citation Format: Goutam Chakraborty, Rahim Hirani, Subhiksha Nandakumar, Nabila Zaman, Teja Muralidhar Kalidindi, Sai Harisha Rajanala, Gwo-Shu M. Lee, Konrad H. Stopsack, Naga Vara Kishore Pillarsetty, Lorelei A. Mucci, Daniel C. Danila, Philip W. Kantoff. A reciprocal signaling crosstalk between the AR and BCl2-AKT pathways induces castration resistance in castration sensitive prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A002.
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Massarotti, Claudia, Matteo Lambertini, Sara Stigliani, Fausta Sozzi, Paola Scaruffi, and Paola Anserini. "Abstract P5-18-05: Long-acting GnRH agonist ovulation trigger to avoid ovarian hyperstimulation and to combine oocyte cryopreservation with ovarian suppression during chemotherapy." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–18–05—P5–18–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-18-05.
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Abstract Background: Oocyte cryopreservation and gonadal suppression during chemotherapy with long-acting GnRH agonists (GnRHa) are standard fertility preservation (FP) methods in women with breast cancer. When both strategies are accepted by the patient, the first injection of GnRHa is frequently administered few days after oocyte retrieval in order to start oncological therapies as soon as possible. GnRHa suppress gonadal function after an initial stimulation phase due to a gonadotropins surge. Consequently, some cases of ovarian hyperstimulation (OHSS) have been described following GnRHa administration during the luteal phase of an oocyte cryopreservation cycle, as a consequence of the initial flare-up effect on recently stimulated ovaries. OHSS is associated with specific complications, such as an increased thromboembolic risk and a possible delay in the start of chemotherapy. These risks may discourage physicians from proposing gonadal suppression in combination with oocyte cryopreservation, denying women a FP opportunity with proven efficacy. However, since the same flare up effect of short-acting GnRHa (e.g. Triptorelin 0.2 mg) is commonly used to trigger ovulation in high responding infertile patients, we propose the initiation of long-acting GnRHa administration at triggering. Our hypothesis is that by inducing ovulation with long-acting GnRHa we meet the last requirement for oocytes maturation and create suppression by the time patients start chemotherapy, without the need of a further injection in the luteal phase. Methods From 2016 to 2020, 70 consecutive ovarian stimulation cycles for oocyte cryopreservation in oncological patients before chemotherapy were performed in a single university centre. Cycle outcomes were evaluated accordingly to the trigger method. Maturation rate was defined as number of cryopreserved mature oocytes/total number of oocytes retrieved. When the long-acting GnRHa was used for triggering, luteal phase hormones were assessed. Results After controlled ovarian stimulation (COS) with standard or random start antagonist protocol, ten women received the long-acting GnRHa trigger (Decapeptyl 3.75 mg, Ipsen. Group A) 36 hours before oocyte retrieval, 37 received highly purified Chorionic Gonadotrophin (Gonasi HP 10000 UI, IBSA. Group B) and 23 the short-acting GnRHa (Decapeptyl 0.2 mg, Ipsen. Group C). The groups were comparable in terms of demographic and clinical parameters. Median number of mature cryopreserved oocytes in group A was 14 (range 8-22) with a maturation rate of 81% (68-100), versus 9 (0-24) with a maturation rate of 78% (43-100) in group B, and 9 (3-34), 78% (38-100) in group C. There was no case of OHSS in Group A. Two patients developed OHSS after administration of long-acting GnRH in the luteal phase after COS, one in Group B and one in Group C. Five days after oocyte retrieval (7 days after trigger), serum FSH median level in group A was 1.28 mUI/ml (0.48-2.50) and LH median level was 1.04 mUI/ml (0.26-2.46). Conclusion We report for the first time the efficacy of long-acting GnRHa in obtaining mature oocytes and, at the same time, in guaranteeing complete suppression by chemotherapy initiation. We are aware that our data should be confirmed by more robust studies and higher numbers. Nevertheless, the feasibility of this strategy is an important step in reducing the risk of OHSS after ovarian stimulation while giving the opportunity to combine oocyte cryopreservation and ovarian suppression during chemotherapy, with proven efficacy as options to preserve fertility and ovarian function, respectively. Citation Format: Claudia Massarotti, Matteo Lambertini, Sara Stigliani, Fausta Sozzi, Paola Scaruffi, Paola Anserini. Long-acting GnRH agonist ovulation trigger to avoid ovarian hyperstimulation and to combine oocyte cryopreservation with ovarian suppression during chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-05.
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JASKIERNY, Leszek. "REVIEW OF THE DATA MODELING STANDARDS AND DATA MODEL TRANSFORMATION TECHNIQUES." Applied Computer Science 14, no. 4 (December 30, 2018): 93–108. http://dx.doi.org/10.35784/acs-2018-32.
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Manual data transformations that result in high error rates are a big problem in complex integration and data warehouse projects, resulting in poor quality of data and delays in deployment to production. Automation of data transformations can be easily verified by humans; the ability to learn from past decisions allows the creation of metadata that can be leveraged in future mappings. Significant improvement of the quality of data transformations can be achieved, when at least one of the models used in transformation is already analyzed and understood. Over recent decades, particular industries have defined data models that are widely adopted in commercial and open source solutions. Those models (often industry standards, accepted by ISO or other organizations) can be leveraged to increase reuse in integration projects resulting in a) lower project costs and b) faster delivery to production. The goal of this article is to provide a comprehensive review of the practical applications of standardization of data formats. Using use cases from the Financial Services Industry as examples, the author tries to identify the motivations and common elements of particular data formats, and how they can be leveraged in order to automate process of data transformations between the models.
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Zhang, Jingsong, Joel S. Brown, Jessica Cunningham, Evan Adler, and Robert Gatenby. "Abstract CT159: A phase 2a evolutionarily informed, mathematically guided adaptive abiraterone trial in metastatic castrate resistant prostate cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): CT159. http://dx.doi.org/10.1158/1538-7445.am2022-ct159.
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Abstract Background: To achieve better prostate cancer control and to delay the emergency of treatment resistance, we developed an evolutionary game theory model using Lotka-Volterra equations with three competing prostate cancer "species": T+, Tp, and T-. T+ prostate cancer cells depend on exogenous androgen; Tp cells express CYP17A1, produce and depend on androgen; and T- cells are androgen-independent and abiraterone (abi)-resistant. We applied this model to guide the on and off treatment cycles with abi for metastatic castration resistant prostate cancer (mCRPC). At the first interim analysis with 11 patients, this approach was shown to prolong the time to cancer progression with less than 50% drug usage compared to the conventional continuous abi (Nat Commun. 2017). Here we present the updated data of this phase 2a study with a median follow up of 5.8 years. Methods: Men with asymptomatic or minimal symptomatic mCRPC were enrolled after they achieved > 50% PSA reduction with abi as a frontline therapy for mCRPC. The primary objective is feasibility and is measured by the percentage of abi responsive men who remain to be responsive to abi (defined as > 50% decline of the pre Abi PSA) after completing 2 adaptive treatment cycles. The secondary objective is to assess the clinical benefits by comparing the radiographic progression free survival (rPFS) and overall survival (OS) in men undergoing adaptive Abi therapy to a contemporaneous cohort of patients who met trial eligibility but received continuous abi dosing as standard of care (SOC). Computer simulations of each patient’s clinical course estimated critical evolutionary parameters and then tested alternative strategies for individuals in both cohorts. Result: 17 evaluable patients were enrolled at Moffitt Cancer Center between June 2015 and January 2019. 5 of the 17 patients have completed at least 5 adaptive therapy cycles and 4 remain on study treatment without imaging progression for > 52 months at the data cut off on 1/4/2022. The study is closed for enrollment after demonstrating the feasibility of adaptive therapy. 16 SOC patients treated with continuous abi for mCRPC between 2015 and 2018 were identified through retrospective chart reviewed. Clinical features like Gleason score and metastasis burden are similar between the two groups. Evolution-based application of abiraterone significantly improved (p<0.001) median rPFS (30.4 months) and median OS (58.5 months) in the adaptive group compared to the 14.3 months median rPFS and the 31.3 months median OS in the SOC group. Average cumulative dose in the adaptive cohort was 54% of SOC dosing. Conclusions: Adaptive Abi therapy is feasible in men who responded to Abi as a frontline therapy for mCRPC. The updated data with longer follow up demonstrated OS as well as rPFS benefits of our adaptive therapy approach with less drug usage compared to the conventional continuous Abi. Clinical trial information: NCT02415621 Citation Format: Jingsong Zhang, Joel S. Brown, Jessica Cunningham, Evan Adler, Robert Gatenby. A phase 2a evolutionarily informed, mathematically guided adaptive abiraterone trial in metastatic castrate resistant prostate cancer [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 CT159.
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Javaid, Huma, Ivan Marin, Jessica Montalvan, Logan Healy, Brian Menegaz, Cary Hsu, Eric Silberfein, Elizabeth Bonefas, Stacey A. Carter, and Alastair M. Thompson. "Abstract P3-18-10: Current options and future perspectives for breast margin assessment in clinical practice." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–18–10—P3–18–10. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-18-10.
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Abstract Background: Ensuring negative margins at the time of breast conserving surgery for invasive breast cancer or ductal carcinoma in situ is necessary to minimize the chance of local recurrence and avoid re-excisions that cause patient concern and may delay adjuvant therapy. However, about 25% of women who have lumpectomy have a second surgery to remove residual disease, suggesting an ongoing need for improved methods of intraoperative margin assessment. This study aimed to perform a contemporary review of methods of intraoperative margin assessment during breast conservation surgery. Methods: A review of the scientific literature from 2009 to 2021 comprising 62 manuscripts of the current and proposed. intraoperative techniques for breast margin assessment during breast conservation surgery was conducted via PubMed and Google Scholar. The methods assessed were grouped into 10 categories based on the technology employed: bioimpedance/radiofrequency, high-resolution imaging, optical imaging, mass spectrometry, magnetic-resonance imaging, 2D/3D specimen CT, X-ray, multimodal optical microscopy, pharmacologic and pathological margin assessment. All technologies were reviewed for overall effectiveness in lowering re-excision rates derived from their respective advantages, limitations, sensitivity, and specificity. Results: Overall, 8 current and 7 technologies under development were assessed (Table 1). Frozen section and cytology yielded the highest diagnostic accuracy; however, these can be time-consuming, resource-intensive, and have limited sampling points. Conversely, 2D specimen CT provides rapid results but is limited by relatively low sensitivity. Future technologies such as optical coherence tomography showed promising results in demonstrating higher diagnostic accuracy for lumpectomy and margin shaves, but remain to be proven in clinical practice. Conclusion: Intraoperative margin assessments can lower final positive margins and subsequent re-excisions rates. A number of current and upcoming technologies that assess margin status range in their respective efficacies and limitations. There remains demand for improved margin assessment at the time of breast conserving surgery, but which technologies will become standard of care remains, at present, unclear. Table 1.Methods of intraoperative margin assessmentMethod:Brand:Sensitivity:Specificity:Source:Bioimpedence• ClearEdge™87.3%75.6%Dixon et al. 2016• MarginProbe75.2%70-87%Schanabel et al., 2014Cytology:• Imprint72%97%Esbona & Zhanhai 2012; Qui et al., 2018Frozen Section–83%95%Schmidt et al, 2020; Schwarz & Schmidt, 2020Mass Spectrometry• iKnife93.4-94.7%94.7-96.2%St. John et al., 2017• MasSpec Pen83-95%95-100%Garza et al., 2020Multimodal optical microscopy• fluorescence imaging combination withRCM/OCT subsystemTBDTBDScimone et al., 2021MRI• ClearSight™93%92%Moshe et al., 2016Optical Coherence Tomography (OCT)• OTIS™96%92%Mojahed et al., 2020; Schmidt et al. 2020Pharmacology• Bevacizumab98%79%Koch et al., 2017• Lumicell2-3D specimen CT• Mozart®93%78%Black et al., [poster]• Faxitron78.6-85.6%100%Emmadi & Wiley 2012; Bathla et al. 2011• MicroCT56%100%Qiu et al. 2018X-ray• XPCI83%83%Massimi et al. 2021 Citation Format: Huma Javaid, Ivan Marin, Jessica Montalvan, Logan Healy, Brian Menegaz, Cary Hsu, Eric Silberfein, Elizabeth Bonefas, Stacey A. Carter, Alastair M. Thompson. Current options and future perspectives for breast margin assessment in clinical practice [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-18-10.