Zeitschriftenartikel zum Thema „Human thorax surrogate“

Abstract Background: Invasive lobular carcinoma (ILC) accounts for 15% of all invasive breast cancers (BC) and has a peculiar metastatic spread in comparison to BC of no-special type. Since ILC is less likely to disrupt normal tissue architecture and is usually non-mass forming, imaging of ILC lesions entails many challenges. Insights into pathologic versus radiological metastatic invasion can lead to better diagnostic and monitoring tools for patients with ILC. Here, we compare microscopical findings during autopsy with clinical findings prior to death in patients with metastatic ILC included in our post-mortem tissue donation program UPTIDER (NCT04531696). Methods: UPTIDER was started in November 2020 in University Hospitals Leuven/KU Leuven with inclusion of patients with stage IV BC who were willing to participate. One of the predefined subgroups consisted of patients with primary pure (i.e. not mixed) ILC. Samples were taken from different macroscopically invaded and non-invaded sites. Clinical data on disease progression, imaging, biochemistry and treatment regimens were extracted from patient files. The number of samples that were preregistered as pathological served as a surrogate for lesions that were seen on imaging performed during the treatment of the patient. These samples are compared to microscopical findings of the autopsy. Results: Since the start of UPTIDER, an autopsy has been performed on 6 patients with pure ILC (26.1% of all autopsies). Median age at initial diagnosis was 52 years (range: 37 – 80 years). Three patients (50.0%) had stage IV disease at diagnosis, the others relapsed on average 162.7 months (range: 55 – 358 months) after initial diagnosis. The average time between clinical occurrence of metastases and death was 44.8 months (range: 15 – 83 months). Median number of treatment lines for stage IV disease was 5 (median endocrine lines 2; median chemotherapy regimens 3.5). To follow disease evolution, computed tomography of thorax and abdomen was used for 4 (66.7%) patients and whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) for the remaining 2 (33.3%). Median time between last premortem imaging and death was 5.9 weeks (range: 1.6 – 16.6 weeks). At autopsy, a median of 26 unique metastases (range: 12-36) were sampled per patient. Table 1 gives an overview on the unique microscopically invaded metastases that were sampled per patient. Only 47.3% of the sampled unique metastases was preregistered. Of all unique metastases, 26.7% appeared macroscopically normal during autopsy. Tissues that appeared normal but turned out to be microscopically infiltrated included liver, stomach, adrenal glands, heart, pericardium, visceral and subcutaneous fat tissue. There were 2 patients with normal appearing, microscopically infiltrated livers. In these patients, elevation of γGT and transanimases was seen in the months prior to death. Conclusions: The disease burden of metastatic ILC reported on premortem imaging does not reflect the microscopical findings at autopsy. One of the priorities of metastatic ILC research should be the development of diagnostic tools to better estimate the extent of the disease. Future analyses of the performed postmortem MRIs in our study can aid in improving the interpretation of WB-DWI/MRI for patients with ILC. For now, clinicians should consider that unexplained clinical and/or biochemical findings might indicate progression of ILC. Table 1: patient overview on performed imaging and unique metastases sampled during autopsy CT = computed tomography; ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; pt = patient; WB-DWI MRI = whole-body diffusion-weighted magnetic resonance imaging *exclusion of samples of patient 2012 since no preregistration was performed for this patient due to unexpected death Citation Format: Karen Van Baelen, Gitte Zels, Maxim De Schepper, Marion Maetens, Josephine Van Cauwenberge, Tatjana Geukens, Kristien Borremans, François Richard, Amena Mahdami, Ha-Linh Nguyen, Sophia Leduc, Anirudh Pabba, Ann Smeets, Ines Nevelsteen, Patrick Neven, Hans Wildiers, Vincent Vandecaveye, Wouter Van Den Bogaert, Giuseppe Floris, Christine Desmedt. Underestimation of metastatic spread in patients with lobular breast cancer: results from the post-mortem tissue donation program UPTIDER [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-06.

ABSTRACT Introduction For behind armor blunt trauma (BABT), recent prominent BABT standards for chest plate define a maximum deformation distance of 44 mm in clay. It was developed for soft body armor applications with limited animal, gelatin, and clay tests. The legacy criterion does not account for differing regional thoracoabdominal tolerances to behind armor-induced injury. This study examines the rationale and approaches used in the legacy BABT clay criterion and presents a novel paradigm to develop thoracoabdominal regional injury risk curves. Materials and Methods A review of the original military and law enforcement studies using animals, surrogates, and body armor materials was conducted, and a reanalysis of data was performed. A multiparameter model analysis describes survival–lethality responses using impactor/projectile (mass, diameter, and impact velocity) and specimen (weight and tissue thickness) variables. Binary regression risk curves with ±95% confidence intervals (CIs) and peak deformations from simulant tests are presented. Results Injury risk curves from 74 goat thorax tests showed that peak deflections of 44.7 mm (±95% CI: 17.6 to 55.4 mm) and 49.9 mm (±95% CI: 24.7 to 60.4 mm) were associated with the 10% and 15% probability of lethal outcomes. 20% gelatin and Roma Plastilina #1 clay were stiffer than goat. The clay was stiffer than 20% gelatin. Penetration diameters showed greater variations (on a test-by-test basis, difference 36-53%) than penetration depths (0-12%) across a range of projectiles and velocities. Conclusions While the original authors stressed limitations and the importance of additional tests for refining the 44 mm recommendation, they were not pursued. As live swine tests are effective in developing injury criteria and the responses of different areas of the thoracoabdominal regions are different because of anatomy, structure, and function, a new set of swine and human cadaver tests are necessary to develop scaling relationships. Live swine tests are needed to develop incapacitation/lethal injury risk functions; using scaling relationships, human injury criteria can be developed.

Abstract Tumor mutations giving rise to neoantigens have recently emerged as promising targets for cancer immunotherapy. Vaccines delivering tumor-specific neoantigens have demonstrated favorable efficacy and safety results in numerous preclinical and early clinical studies. However, selecting therapeutically relevant neoantigens amongst the myriad of cancer mutations has proven challenging. To overcome this, we have developed a proprietary AI-based target discovery platform, PIONEER, with enhanced predictive performance and increased precision. The PIONEER top-ranked neoantigens were selected and included in the personalized DNA vaccine candidate EVX-02. To assess the ability of the PIONEER designed neoantigen vaccine candidate to induce neoantigen immunogenicity and anti-tumor effect in preclinical models, mice were immunized with a mouse surrogate EVX-02 molecule, mEVX-02. mEVX-02 vaccination completely prevented establishment of tumors and induced neoantigen-specific, polyfunctional CD4+ and CD8+ T cells in the blood and spleen of immunized mice. An enhanced antitumor effect was obtained when combining mEVX-02 with anti-PD-1 mAb treatment. Encouraged by the preclinical results, we conducted a first-in-human multicenter Phase I clinical study of EVX-02 in combination with nivolumab in patients with resected malignant melanoma. The objectives of the trial were to investigate safety and tolerability, operational and clinical feasibility, and immunogenicity of the applied personal neoantigens. Each patient received a fully personalized drug that was produced in a complex process, from biopsy, through genome sequencing, AI-profiling, vaccine design, manufacturing, quality testing, and drug product release. This was succeeded with every single step for each patient. In all patients, EVX-02 treatment was well tolerated, and only very mild adverse events (AEs) have been observed in relation to immunization with EVX-02. Interim data demonstrated neoantigen-specific T-cell immune responses upon EVX-02 treatment and that the responses were mediated by activated CD4+ and CD8+ T cells. The measured T-cell responses were robust and long lasting. Together, these findings validate the precision and predictive power of our proprietary AI platform, PIONEER, and provide proof of mechanism for the DNA-delivery technology in that the encoded neoantigens gave rise to significant immune reactions. Citation Format: Daniela Kleine-Kohlbrecher, Nadia Viborg Petersen, Michail Angelos Pavlidis, Thomas Trolle, Stine Friis, Jens Kringelum, Anders Bundgaard Soerensen, Thomas Strandet Jepsen, Camilla Højgaard, Anders Jespersen, Erik D. Heegaard, Britt Winding Lauenborg, Birgitte Rønø. A personalized neoantigen vaccine is well tolerated and induces specific T-cell immune response in patients with resected melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB199.

Abstract RNA sequencing has improved our understanding of cellular heterogeneity by providing in-depth transcriptome information at the single cell level. However, this “dataset infodemic” did not translate into an abundance of new validated targets due to the difficulties in performing gene-to-function studies. The main goal of the ENIGMAC™ discovery platform is to support gene-to-function studies and to deliver new validated macrophage targets. ENIGMAC™ combines custom, disease relevant assays and unique genome editing methods supported by multi-omics bioinformatics analyses yielding selected gene sets for interrogation. We use a human Induced Pluripotent Stem Cell (iPSC) line that yields macrophages phenotypically and functionally similar to MDM. By employing this iPSC system, we can produce millions of macrophages per week, which allows multiple high throughput assays to support target validation and drug discovery. Furthermore, we developed several proprietary technologies allowing fast and reliable gene editing of macrophages, including gene Knock In (KI), Knock Out (KO) and Knock Down (KD) with high efficiency both at iPSC and macrophage level while maintaining expression/silencing during macrophage differentiation. Here we report preliminary results of the CRISPRi screen, aiming to identify novel regulators of INFg-mediated PD-L1 upregulation on macrophages, a surrogate readout for a suppressive phenotype. To this aim, we developed a proprietary human iPSC line that constitutively expresses dCAS9-KRAB protein, allowing for a highly gene specific guide RNA (sgRNA)-mediated method of silencing of gene transcription. Notably, our proprietary anti-silencing system allows to maintains dCAS9-KRAB expression throughout the entire macrophage differentiation process. During the screen, 100 million iPSC-derived microphages were transduced with a 6500 gRNAs library targeting 1300 genes selected from disease-relevant macrophage datasets. Macrophages were subsequently stimulated with INFg and sorted for loss of PD-L1 expression using flow cytometry. Sequencing of the PD-L1 low macrophage population successfully identified PD-L1 regulators such as IFNGR1, IFNGR2, JAK1, STAT1 and IRF1 among other hits. The novel hits are being now individually validated, and selected ones will be progressed to drug discovery. Importantly, this macrophage CRISPRi screen provides technical proof of concept for the ENIGMAC™ platform to perform screens at scale and to identify novel hits. In conclusion, the ENIGMAC™ platform represents a unique tool for gene to function studies using human macrophages. Furthermore, it is disease agnostic and can be integrated with a variety of disease-specific conditions and phenotypic readouts. Citation Format: Thomas W. Monteiro Crozier, Martha Lopez-Yrigoyen, Helena Engman, Moritz Haneklaus, Samuel Witham, Krzystof B. Wicher, Steven Myatt, Luca Cassetta, Carola Ries. ENIGMAC platform enables at-scale CRISPRi screenings for macrophage target discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB201.

Abstract We present here a novel therapeutic agent, XMT-2056, that results in robust anti-tumor activity mediated by an immune response through targeted delivery of a STING agonist to the tumor microenvironment. By leveraging an antibody-drug conjugate (ADC) strategy, systemic administration of a STING agonist with tumor-targeted delivery can be achieved, potentially overcoming limitations of either intratumoral or intravenous administrations of unconjugated, small molecule STING agonists. XMT-2056 was generated through conjugation of Immunosynthen, a platform that employs a novel STING agonist payload specifically designed for ADCs, to HT-19, a HER2-targeting antibody which binds to a novel epitope and does not compete for binding with either trastuzumab or pertuzumab. Initial results showed XMT-2056 has target-dependent anti-tumor activity in vivo and is well tolerated in non-human primates at significantly higher exposure levels than those required for anti-tumor activity. To evaluate the impact of HER2 expression level on the activity of XMT-2056, in vivo studies in gastric and breast cancer models with varying HER2 expression levels were conducted, and XMT-2056 showed potent anti-tumor activity in a dose dependent and target dependent manner including in models with very low expression of HER2. Because the antibody employed in XMT-2056 does not compete for binding with trastuzumab or pertuzumab, we hypothesized that there could be benefit in combining with such approved HER2-targeted therapies. This advantage was demonstrated in vivo as the combination of XMT-2056 and trastuzumab or pertuzumab showed greater anti-tumor activity compared to the administration of either agent alone. Further efforts to elucidate the mechanism(s) of the observed benefit of these combinations will be discussed. Given the innate immune activation by XMT-2056, there is also a strong rationale for combination with immune checkpoint inhibitors. To this end, administration of an XMT-2056 surrogate ADC in combination with an anti-PD1 agent improved anti-tumor activity in a ratHER2-engineered EMT-6 syngeneic mouse model. Together these data support the potential of XMT-2056 both as a monotherapy and in combination with other HER2 targeted agents as well as checkpoint inhibitors. Citation Format: Jeremy R. Duvall, Raghida A. Bukhalid, Naniye M. Cetinbas, Kalli C. Catcott, Kelly Lancaster, Keith W. Bentley, Suzanna Clark, Susan Clardy, Scott D. Collins, Anouk Dirksen, Elizabeth Ditty, Bingfan Du, Eugene W. Kelleher, Travis Monnell, Marina Protopopova, Caitlin Routhier, Cheri Stevenson, Elena Ter-Ovanesyan, Joshua D. Thomas, Alex Uttard, Jason Wang, Phonphimon Wongthida, Ling Xu, Annika Yau, Jeffrey Zurita, Dorin Toader, Marc Damelin, Timothy B. Lowinger. XMT-2056, a HER2-targeted Immunosynthen STING-agonist antibody-drug conjugate, binds a novel epitope of HER2 and shows increased anti-tumor activity in combination with trastuzumab and pertuzumab [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 3503.

Abstract CD8+ cytotoxic T cells are key players in anti-cancer immune responses as they destroy MHC class I-dependent tumor cells. Therefore, the spatial distribution of CD8+ cytotoxic T cells might represent an important surrogate for the response to cancer immunotherapy including immune checkpoint inhibitor therapy ICT. The radiolabeled minibody [89Zr]Zr-Df-IAB22M2C is characterized by a high affinity to human CD8 and was already investigated in a phase I study. Here, we present our first experience with the non invasive in vivo assessment of the whole body CD8 T cell distribution in cancer patients using clinical [89Zr]Zr-Df-IAB22M2C PET/MRI. In total 8 patients with metastasized cancers (5 x malignant melanoma; 1 x choroidal melanoma, 1 x NSCLC and 1 x sarcoma) were studied before (n = 3) or during (n = 5) ICT. Multiparametric PET/MRI was performed 24 h after injection of 74.2±17.9 MBq [89Zr]Zr-Df-IAB22M2C (1.1 - 1.8 mg Df-IAB22M2C) on a Siemens Biograph mMR System (SiemensHealthineers, Erlangen, Germany). The whole body distribution of the [89Zr]Zr-Df-IAB22M2C tracer was analyzed with a special focus on tumors/metastases as well as primary and secondary lymphatic organs. The PET tracer [89Zr]Zr-Df-IAB22M2C was well tolerated without any reported side effects. The PET/MRI acquisitions 24h p.i. of [89Zr]Zr-Df-IAB22M2C revealed a comparably low background signal with only a minor blood pool and unspecific tissue retention. Regarding the primary and secondary lymphoid organs we observed a high interpatient variability of the tracer uptake. Four out of five patients with previous ICT exhibited a relatively high [89Zr]Zr-Df-IAB22M2C uptake in the bone marrow. Also a large number of non metastatic lymph nodes yielded a pronounced [89Zr]Zr-Df-IAB22M2C uptake in four patients. Strikingly, a low [89Zr]Zr-Df-IAB22M2C uptake in the spleen compared to the liver (liver/spleen ratio < 10) was observed in 4 out of the 5 patients with cancer progression during ICT. Interestingly, only one metastasis with an intense tracer was detected in this patient cohort. This first clinical experiences revealed the feasibility to assess potential immune-related changes by [89Zr]Zr-Df-IAB22M2C PET/MRI. Considering these results we hypothesize that the whole body distribution of CD8+ cytotoxic T-cells assessed by non-invasive in vivo [89Zr]Zr-Df-IAB22M2C PET/MRI might be associated with the response to cancer immunotherapy which needs to be investigated in subsequent prospective trials. Citation Format: Johannes Schwenck, Dominik Sonanini, Walter Ehrlichmann, Gabriele Kienzle, Gerald Reischl, Pascal Krezer, Ian Wilson, Ron Korn, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Ferdinand Seith, Andrea Forschner, Thomas Eigentler, Lars Zender, Martin Röcken, Bernd Pichler, Lukas Flatz, Manfred Kneilling, Christian la Fougere. Imaging of CD8+ cytotoxic T-cells by Zr-89-Df-IAB22M2C PET/MRI: First clinical experience in patients with metastatic 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 LB058.

Abstract Drug-eluting bead transcatheter arterial chemoembolization (DEB-TACE) is a treatment procedure for liver cancer that involves the selective catheterization and subsequent embolization of tumor-feeding arteries with drug-eluting beads (DEBs). DEB-TACE elicits ischemic cell death in the embolized tumor while simultaneously delivering a local, sustained release of chemotherapy. We hypothesize that the application of DEBs loaded with an immunostimulatory adjuvant in the DEB-TACE procedure will promote local antigen presenting cells to utilize the antigens released by dying tumor cells to generate a systemic, adaptive anti-tumor immune response. This approach represents a novel form of transarterial immunoembolization (TIE). 558 is a highly potent, small molecule Toll-like receptor 7/8 agonist that activates both innate and adaptive immune responses to eliminate tumor cells in various preclinical tumor models. Hydrogel microspheres composed of cross-linked sulfobutylether-β-cyclodextrin (SBE-βCD) were investigated as DEBs for 558 in the current study. SBE-βCD hydrogel microspheres (SBE-βCDMS) of 10 - 300 μm diameter were synthesized via suspension polymerization of SBE-βCD and ethylene glycol diglycidyl ether followed by wet sieving. 558 loading was achieved by incubating blank SBE-βCDMS in aqueous solutions of 558. Under non-saturating conditions, SBE-βCDMS absorbed almost the entirety of 558 from loading solutions in 4 h. The dose of 558 loaded in SBE-βCDMS was tuned by altering the initial amount of 558 in solution, up to a maximum loading of 0.28 mg 558/mg dry SBE-βCDMS determined under saturating conditions. The time to 50% release of 558 from loaded SBE-βCDMS was less than 30 min when phosphate buffered saline was used as release media. However, the release of 558 was negligible when deionized water was used as release media. The released drug was as effective as free 558 in stimulating cytokine response from human peripheral blood mononuclear cells in vitro. As a surrogate for TIE, we evaluated plasma and tumor pharmacokinetics upon intratumoral injection of 558-loaded SBE-βCDMS (50 - 100 μm diameter) or free 558 at a dose of 100 μg in C57BL/6 mice bearing B16F10-OVA flank tumors. The gradual release of 558 from loaded SBE-βCDMS prevented an initial spike in plasma concentration that was observed for mice administered with free 558, and maintained constant tumor concentrations for at least 4 h post-injection. High-resolution MALDI mass spectrometry imaging of 15 μm-thick tumor cryosections indicated that 558 was initially concentrated within SBE-βCDMS after intratumoral injection, and extensively released into the surrounding tumor tissue 24 h post-injection. Taken together, these results suggest that 558-loaded SBE-βCDMS are a promising platform for local drug delivery and immune cell stimulation via TIE. Citation Format: Joel Updyke, Shubhmita Bhatnagar, Nitu Bhaskar, Rachel Parise, Swati Nagar, John Schultz, David Ferguson, Tamara Kucaba, Thomas Griffith, Ronald Siegel, Jayanth Panyam. Sulfobutylether-β-cyclodextrin hydrogel microspheres delivering TLR 7/8 agonist for transarterial immunoembolization [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 1993.

Abstract To assess risk factors that contribute to lung cancer burden in the Abramson Cancer Center (ACC) catchment area, we integrated geospatial data of exposure to pollutants from publicly available EPA and NASA datasets. The study area covers the 421 zip codes that make up the 12 counties of the catchment area from which most of the ACC patients come. The counties include 5 that surround Philadelphia, 6 in New Jersey, and 1 in Delaware. Environmental exposure data, sourced from US-EPA Air Quality System (AQS) Data Mart, were focused on air pollutants since air pollution is recognized by the International Agency on Cancer (IARC) as a Group 1 human carcinogen. Exposomics data included: hourly, daily, and annual (1980 -2018) PM2.5, PM10, NO2; Hazardous Air Pollutants (HAPS); Volatile Organic Compounds (VOCs); (Air Quality Index) AQI; NONOxNOy monitoring; and annual Toxic Release Inventory (TRI) air emissions by chemical classifier and point source (1987 -2017). Annual NASA satellite-derived grids were incorporated for PM2.5 (1998-2016; 1 km resolution) and NOx (1997 - 2012; 10 km resolution). ESRI’s ArcGIS was used to develop programming scripts to automate the process of data integration, geocoding, and classifying chemical parameters by (1) status as a lung carcinogen with sufficient evidence of lung carcinogenesis; (2) status as one of the priority 16 EPA polycyclic aromatic hydrocarbons, as a surrogate marker of exposure to carcinogens; (3) status in the IARC rankings for Cancer Group; (4) status as a component of diesel exhaust; and (5) status as a VOC. 1-km search radius kernel density grids were generated for each air pollutant. We sliced the density estimates into ordinal rankings ranging from “10 = high” to “1 = low.” A hazard index may be generated by summing data layers of cumulative environmental exposomics in a process called map algebra. Spatial sorting and merging of exposome releases by facility, year, chemical and zip code concentration allow for addressing “low-hanging fruit” through summary statistics. Although the focus of this investigation is on lung cancer, the utility of the methodology may be applied to probe exposures related to other cancers. Incorporating more years or larger geographic areas of study may make exploring the risk of exposure possible for less prevalent cancers. In future studies, we are conducting statistical analysis to determine whether geocoded exposure data predict lung cancer risks in those vulnerable zip codes using electronic health record data of geolocations of lung cancer patients. This novel approach will help determine whether geocoded exposomics data are associated with cancer incidence. The hazard index was used to identify zip codes that are the most vulnerable to carcinogen exposure. Zip codes 19720, 19061, 08066, 08027, 19153, and 19145 scored highest on the hazard index based on cumulative exposure. (Supported by P30-CA-016520 and P30-ES013508.) This abstract is also being presented as Poster A08. Citation Format: Thomas P. McKeon, Vicky Tam, Wei-Ting Hwang, Paul Wileyto, Karen Glanz, Trevor M. Penning. Geocoding and integrating multiple environmental exposomics sources: Assessing population hazard to lung carcinogens in 421 zip codes of a cancer center catchment area [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr PR06.

Abstract Background: The predictive and prognostic value of the 21-gene recurrence score (RS) has emphasized the importance of tumor biology and minimized the credence of a limited (1-3 positive) nodal burden. The practice changing results of RxPonder demonstrated that post-menopausal women with 1-3 positive lymph nodes (pN1) and a RS of ≤25 did not necessarily benefit from adjuvant chemotherapy. Given that RS influences adjuvant therapy decision-making more significantly than nodal status, it is unclear whether axillary staging with sentinel lymph node biopsy (SLNB) has a continued role in the surgical care of post-menopausal patients otherwise presenting with early stage, clinically node negative (cN0) hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) invasive breast cancer. In this context, the de-escalation of axillary staging, especially in the presence of a low RS, is an area of active investigation. To help elucidate this further, we sought to estimate the association of RS with pathologic nodal stage. Methods: Using the 2004-2019 National Cancer Database (NCDB) Patient User File (2022 release), we evaluated the association of RS with the incidence of pN0, pN1 and pN2-3 disease. Only female patients diagnosed who were age 50 and older with HR+/HER2- invasive breast cancer were eligible, and only those presenting with cT1-T2N0 who underwent upfront surgery with a SLNB comprised our study population. Those with Oncotype DX testing performed with an available RS were included. Given the limitations within the dataset, age 50 and over was selected as a surrogate for post-menopausal status. Categorical variables were compared between RS groups (≤25 vs. >25) using chi-square tests and continuous variables were compared using t-tests. A logistic regression analysis was performed to estimate the association between RS (≤25 vs. >25) and nodal burden (pN2-3 vs pN0-1). Results: There were 151,447 patients with an invasive breast cancer diagnosis between 2015 and 2019 who met inclusion criteria. The average age at diagnosis was 64.1 (IQR 58-69) and almost 75% of tumors displayed ductal histology. There were 130,568 (86.2%) patients with a RS≤25 and 20,879 (13.8%) with a RS >25. On final pathology, 85.2% were pN0 and 14.8% were pN1-3. For those with a RS ≤25, 84.9% were pN0, 14.8% were pN1 and 0.3% were pN2-3. For those with a RS >25, 86.8% were pN0, 12.9% were pN1 and 0.3% were pN2-3. Overall, 14.5% demonstrated pN1 disease, of which 12.3% yielded a RS >25. Of the 461 patients with pN2-3 disease for whom RS was available, 12.4% (57 patients) had RS >25. After adjustment, RS >25 was associated with reduced incidence of pN2-3 compared to pN0-1 (OR=0.64, 95% CI 0.47-0.87, p=0.004). Conclusion: In this population of post-menopausal patients with cT1-T2N0, HR+/HER2- invasive breast cancer and an available RS, almost 86% displayed pN0 or pN1 disease in conjunction with a RS ≤25. Based on the current available literature, less than 5% of cT1-2N0 patients are thought to harbor >pN1 disease. These data add further support, suggesting that this patient population is unlikely to harbor a higher than limited nodal burden given a clinically negative axilla. Though less than 0.5% of the studied patient population demonstrated pN2-3 disease, an important caveat to make is that these patients would not have met criteria for RS, and it’s likely this low number reflects the absence of testing. Given that RS has not been validated for this higher nodal stage, we cannot make recommendations to omit axillary surgery in this cohort of patients. The data presented here provides further rationale for the two large prospective studies addressing whether SLNB could be eliminated in patients with otherwise small HR+/HER2- tumors which are currently ongoing. Table 1: Pathologic Nodal Staging Based on Recurrence Score Citation Format: Astrid Botty van den Bruele, Morgan Paul, Samantha M. Thomas, Sarah L. Sammons, Maggie L. DiNome, Jennifer K. Plichta, Akiko Chiba, Laura H. Rosenberger, E Shelley Hwang. Low 21-Gene Recurrence Score Is Not Associated with a High Axillary Nodal Burden in Post-Menopausal Women Presenting with a Clinically Negative Axilla [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 P3-05-20.

The first objective of the study was to determine the thorax and abdomen deflection time corridors using the equal stress equal velocity approach from oblique side impact sled tests with postmortem human surrogates fitted with chestbands. The second purpose of the study was to generate deflection time corridors using impulse momentum methods and determine which of these methods best suits the data. An anthropometry-specific load wall was used. Individual surrogate responses were normalized to standard midsize male anthropometry. Corridors from the equal stress equal velocity approach were very similar to those from impulse momentum methods, thus either method can be used for this data. Present mean and plus/minus one standard deviation abdomen and thorax deflection time corridors can be used to evaluate dummies and validate complex human body finite element models.

In the field of biomechanics, numerical procedures can be used to understand complex phenomena that cannot be analyzed with experimental setups. The use of experimental data from human cadavers can present ethical issues that can be avoided by utilizing biofidelic models. Biofidelic models have been shown to have far-reaching benefits, particularly in evaluating the effectiveness of protective devices such as body armors. For instance, numerical twins coupled with a biomechanical model can be used to assess the efficacy of protective devices against intense external forces. Similarly, the use of human body surrogates in experimental studies has allowed for biomechanical studies, as demonstrated by the development of crash test dummies that are commonly used in automotive testing. This study proposes using numerical procedures and simplifying the structure of an existing biofidelic FE model of the human thorax as a preliminary step in building a physical surrogate. A reverse engineering method was used to ensure the use of manufacturable materials, which resulted in a FE model called SurHUByx FEM (Surrogate HUByx Finite Element Model, with HUByx being the original thorax FE model developed previously). This new simplified model was validated against existing experimental data on cadavers in the context of ballistic impact. SurHUByx FEM, with its new material properties of manufacturable materials, demonstrated consistent behavior with the corresponding biomechanical corridors derived from these experiments. The validation process of this new simplified FE model yielded satisfactory results and is the first step towards the development of its physical twin using manufacturable materials.

Abstract Behind Armor Blunt Trauma (BABT), resulting from dynamic deformation of protective ballistic armor into the thorax, is currently assessed assuming a constant threshold of maximum backface deformation (44 mm). Although assessed for multiple impacts on the same armor, testing is focused on armor performance (shot-to-edge and shot-to-shot) without consideration of the underlying location on the thorax. Previous studies identified the importance of impacts over organs of animal surrogates wearing soft armor. However, the effect of impact location was not quantified outside the threshold of 44 mm. In the present study, a validated biofidelic advanced human thorax model (50th percentile male) was utilized to assess the BABT outcome from varying impact location. The thorax model was dynamically loaded using a method developed for re-creating BABT impacts, and BABT events within the range of real-world impact severities and locations were simulated. It was found that thorax injury depended on impact location for the same BFDs. Generally, impacts over high compliance locations (anterolateral rib cage) yielded increased thoracic compression and loading on the lungs leading to pulmonary lung contusion. Impacts at low compliance locations (top of sternum) yielded hard tissue fractures. Injuries to the sternum, ribs, and lungs were predicted at BFDs lower than 44 mm for low compliance locations. Location-based injury risk curves demonstrated greater accuracy in injury prediction. This study quantifies the importance of impact location on BABT injury severity and demonstrates the need for consideration of location in future armor design and assessment.

Abstract The WIAMan anthropomorphic test device (ATD) has been originally developed to predict and prevent injuries for occupants in military vehicles, in an underbody blast environment. However, its crash performance and biofidelity of the thoracic region have not been explored. The aim of this study was to determine and evaluate the WIAMan thoracic responses in a typical frontal sled test. The 40 kph frontal sled tests were conducted to quantify the WIAMan thoracic kinematics, chest deflection, and belt loads. Comparative biofidelities of the WIAMan thorax and other surrogates, including post-mortem human surrogates (PMHS), Hybrid III, and THOR ATDs, were assessed under comparable testing conditions. The similarities and differences between WIAMan and the other surrogates were compared and analyzed, including the motion of bilateral shoulders and T1, time histories of chest deflections, and belt loads. The CORelation and Analysis (CORA) ratings were used to evaluate the correlations of thoracic responses between the ATDs and PMHS. Compared to the PMHS and THOR, the WIAMan experienced a similar level of left shoulder forward excursions. Larger chest deflection was exhibited in WIAMan throughout the whole duration of belt compression. Differences were found in belt loads between subject types. Overall, WIAMan had slightly lower CORA scores but showed comparable overall performance. The overall thoracic responses of WIAMan under the frontal sled test were more compliant than HIII, but still reasonable compared with PMHS and THOR. Comprehensive systematic studies on comparative biofidelity of WIAMan and other surrogates under different impact conditions are expected in future research.

Abstract Aims Fibroblast activation protein (FAP) is upregulated at sites of tissue remodelling including chronic arthritis, solid tumours, and fibrotic hearts. It has also been associated with human coronary atherosclerotic plaques. Yet, the causal role of FAP in atherosclerosis remains unknown. To investigate the cause–effect relationship of endogenous FAP in atherogenesis, we assessed the effects of constitutive Fap deletion on plaque formation in atherosclerosis-prone apolipoprotein E (Apoe) or low-density lipoprotein receptor (Ldlr) knockout mice. Methods and results Using en face analyses of thoraco-abdominal aortae and aortic sinus cross-sections, we demonstrate that Fap deficiency decreased plaque formation in two atherosclerotic mouse models (−46% in Apoe and −34% in Ldlr knockout mice). As a surrogate of plaque vulnerability fibrous cap thickness was used; it was increased in Fap-deficient mice, whereas Sirius red staining demonstrated that total collagen content remained unchanged. Using polarized light, atherosclerotic lesions from Fap-deficient mice displayed increased FAP targets in terms of enhanced collagen birefringence in plaques and increased pre-COL3A1 expression in aortic lysates. Analyses of the Stockholm Atherosclerosis Gene Expression data revealed that FAP expression was increased in human atherosclerotic compared to non-atherosclerotic arteries. Conclusions Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability with decreased collagen breakdown. Thus, inhibition of FAP expression or activity may not only represent a promising therapeutic target in atherosclerosis but appears safe at the experimental level for FAP-targeted cancer therapies.

I was born illegitimate. Born on an existential precipice. My unwed mother was 36 years old when she relinquished me. I was the fourth baby she was required to give away. After I emerged blood stained and blue tinged – abject, liminal – not only did the nurses refuse me my mother’s touch, I also lost the sound of her voice. Her smell. Her heart beat. Her taste. Her gaze. The silence was multi-sensory. When they told her I was dead, I also lost, within her memory and imagination, my life. I was adopted soon after but not told for over four decades. It was too shameful for even me to know. Imprinted at birth with a psychological ‘death’, I fell, as a Late Discovery Adoptee (LDA), into a socio-cultural and psychological abyss, frozen at birth at the bottom of a parturitive void from where, invisible within family, society, and self I was unable to form an undamaged sense of being.Throughout the 20th century (and for centuries before) this kind of ‘social abortion’ was the dominant script. An adoptee was regarded as a bastard, born of sin, the mother blamed, the father exonerated, and silence demanded (Lynch 28-74). My adoptive mother also sinned. She was infertile. But, in taking me on, she assumed the role of a womb worthy woman, good wife, and, in her case, reluctant mother (she secretly didn’t want children and was privately overwhelmed by the task). In this way, my mother, my adoptive mother, and myself are all the daughters of bereavement, all of us sacrificed on the altar of prejudice and fear that infertility, sex outside of marriage, and illegitimacy were unspeakable crimes for which a price must be paid and against which redemptive protection must be arranged. If, as Thomas Keneally (5) writes, “original sin is the mother fluid of history” then perhaps all three of us all lie in its abject waters. Grotevant, Dunbar, Kohler and Lash Esau (379) point out that adoption was used to ‘shield’ children from their illegitimacy, women from their ‘sexual indiscretions’, and adoptive parents from their infertility in the belief that “severing ties with birth family members would promote attachment between adopted children and parents”. For the adoptee in the closed record system, the socio/political/economic vortex that orchestrated their illegitimacy is born out of a deeply, self incriminating primal fear that reaches right back into the recesses of survival – the act of procreation is infested with easily transgressed life and death taboos within the ‘troop’ that require silence and the burial of many bodies (see Amanda Gardiner’s “Sex, Death and Desperation: Infanticide, Neonaticide, and Concealment of Birth in Colonial Western Australia” for a palpable, moving, and comprehensive exposition on the links between 'illegitimacy', the unmarried mother and child murder). As Nancy Verrier (24) states in Coming Home to Self, “what has to be understood is that separation trauma is an insidious experience, because, as a society, we fail to see this experience as a trauma”. Indeed, relinquishment/adoption for the baby and subsequent adult can be acutely and chronically painful. While I was never told the truth of my origins, of course, my body knew. It had been there. Sentient, aware, sane, sensually, organically articulate, it messaged me (and anyone who may have been interested) over the decades via the language of trauma, its lexicon and grammar cellular, hormonal, muscular (Howard & Crandall, 1-17; Pert, 72), the truth of my birth, of who I was an “unthought known” (Bollas 4). I have lived out my secret fatality in a miasmic nebula of what I know now to be the sequelae of adoption psychopathology: nausea, physical and psychological pain, agoraphobia, panic attacks, shame, internalised anger, depression, self-harm, genetic bewilderment, and generalised anxiety (Brodzinsky 25-47; Brodzinsky, Smith, & Brodzinsky 74; Kenny, Higgins, Soloff, & Sweid xiv; Levy-Shiff 97-98; Lifton 210-212; Verrier The Primal Wound 42-44; Wierzbicki 447-451) – including an all pervading sense of unreality experienced as dissociation (the experience of depersonalisation – where the self feels unreal – and derealisation – where the world feels unreal), disembodiment, and existential elision – all characteristics of Post Traumatic Stress Disorder (PTSD). In these ways, my body intervened, acted out, groaned in answer to the social overlay, and from beyond “the dermal veil” tried to procure access, as Vicky Kirby (77) writes, to “the body’s opaque ocean depths” through its illnesses, its eloquent, and incessantly aching and silent verbosities deepened and made impossibly fraught because I was not told. The aim of this paper is to discuss one aspect of how my body tried to channel the trauma of my secret fatality and liminality: my pre-disclosure art work (the cellular memory of my trauma also expressed itself, pre-disclosure, through my writings – poetry, journal entries – and also through post-coital glossolalia, all discussed at length in my Honours research “Womb Tongues” and my Doctoral Dissertation “The Womb Artist – A Novel: Translating Pre-verbal Late Discovery Adoption Trauma into Narrative”). From the age of thirty onwards I spent twelve years in therapy where the cause of my childhood and adult psychopathology remained a mystery. During this time, my embodied grief and memories found their way into my art work, a series of 5’ x 3’ acrylic paintings, some of which I offer now for discussion (figures 1-4). These paintings map and express what my body knew but could not verbalise (without language to express my grief, my body found other ways to vent). They are symptom and sign of my pre-verbal adoption trauma, evidence that my body ‘knew’ and laboured ceaselessly and silently to find creative ways to express the incarcerated trauma. Post disclosure, I have used my paintings as artefacts to inform, underpin, and nourish the writing of a collection of poetry “Womb Tongues” and a literary novel/memoir “The Womb Artist” (TWA) in an ongoing autoethnographical, performative, and critical inquiry. My practice-led research as a now conscious and creative witness, fashions the recontextualisation of my ‘self’ into my ‘self’ and society, this time with cognisant and reparative knowledge and facilitates the translation of my body’s psychopathology and memory (explicit and implicit) into a healing testimony that explores the traumatised body as text and politicizes the issues surrounding LDAs (Riley 205). If I use these paintings as a memoirist, I use them second hand, after the fact, after they have served their initial purpose, as the tangible art works of a baby buried beneath a culture’s prejudice, shame, and judgement and the personal cries from the illegitimate body/self. I use them now to explore and explain my subclinical and subterranean life as a LDA.My pre-disclosure paintings (Figures 1-4) – filled with vaginal, fetal, uterine, and umbilical references – provide some kind of ‘evidence’ that my body knew what had happened to me as if, with the tenacity of a poltergeist, my ‘spectral self’ found ways to communicate. Not simply clues, but the body’s translation of the intra-psychic landscape, a pictorial and artistic séance into the world, as if my amygdala – as quasar and signal, homing device and history lesson (a measure, container, and memoir) – knew how to paint a snap shot or an x-ray of the psyche, of my cellular marrow memories (a term formulated from fellow LDA Sandy McCutcheon’s (76) memoir, The Magician’s Son when he says, “What I really wanted was the history of my marrow”). If, as Salveet Talwar suggests, “trauma is processed from the body up”, then for the LDA pre-discovery, non-verbal somatic signage is one’s ‘mother tongue’(25). Talwar writes, “non-verbal expressive therapies such as art, dance, music, poetry and drama all activate the sub-cortical regions of the brain and access pre-verbal memories” (26). In these paintings, eerily divinatory and pointed traumatic, memories are made visible and access, as Gussie Klorer (213) explains in regard to brain function and art therapy, the limbic (emotional) system and the prefrontal cortex in sensorimotor integration. In this way, as Marie Angel and Anna Gibbs (168) suggest, “the visual image may serve as a kind of transitional mode in thought”. Ruth Skilbeck in her paper First Things: Reflections on Single-lens Reflex Digital Photography with a Wide-angled Lens, also discusses (with reference to her photographic record and artistic expression of her mother’s death) what she calls the “dark matter” – what has been overlooked, “left out”, and/or is inexplicable (55) – and the idea of art work as the “transitional object” as “a means that some artists use, conceptually and yet also viscerally, in response to the extreme ‘separation anxiety’ of losing a loved one, to the void of the Unknown” (57). In my case, non-disclosure prevented my literacy and the evolution of the image into language, prevented me from fully understanding the coded messages left for me in my art work. However, each of my paintings is now, with the benefit of full disclosure, a powerful, penetrating, and comprehensible intra and extra sensory cry from the body in kinaesthetic translation (Lusebrink, 125; Klorer, 217). In Figure 1, ‘Embrace’, the reference to the umbilical is palpable, described in my novel “The Womb Artist” (184) this way; “two ropes tightly entwine as one, like a dark and dirty umbilical cord snaking its way across a nether world of smudged umbers”. There is an ‘abject’ void surrounding it. The cord sapped of its colour, its blood, nutrients – the baby starved of oxygen, breath; the LDA starved of words and conscious understanding. It has two parts entwined that may be seen in many ways (without wanting to reduce these to static binaries): mother/baby; conscious/unconscious; first person/third person; child/adult; semiotic/symbolic – numerous dualities could be spun from this embrace – but in terms of my novel and of the adoptive experience, it reeks of need, life and death, a text choking on the poetic while at the same time nourished by it; a text made ‘available’ to the reader while at the same narrowing, limiting, and obscuring the indefinable nature of pre-verbal trauma. Figure 1. Embrace. 1993. Acrylic on canvas.The painting ‘Womb Tongues’ (Figure 2) is perhaps the last (and, obviously, lasting) memory of the infinite inchoate universe within the womb, the umbilical this time wrapped around in a phallic/clitorial embrace as the baby-self emerges into the constrictions of a Foucauldian world, where the adoptive script smothers the ‘body’ encased beneath the ‘coils’ of Judeo-Christian prejudice and centuries old taboo. In this way, the reassigned adoptee is an acute example of power (authority) controlling and defining the self and what knowledge of the self may be allowed. The baby in this painting is now a suffocated clitoris, a bound subject, a phallic representation, a gagged ‘tongue’ in the shape of the personally absent (but socially imposing) omni-present and punitive patriarchy. Figure 2. Womb Tongues. 1997. Acrylic on canvas.‘Germination’ (Figure 3) depicts an umbilical again, but this time as emerging from a seething underworld and is present in TWA (174) this way, “a colony of night crawlers that writhe and slither on the canvas, moving as one, dozens of them as thin as a finger, as long as a dream”. The rhizomic nature of this painting (and Figure 4), becomes a heaving horde of psychosomatic and psychopathological influences and experiences, a multitude of closely packed, intense, and dendridic compulsions and symptoms, a mass of interconnected (and by nature of the silence and lie) subterranean knowledges that force the germination of a ‘ghost baby/child/adult’ indicated by the pale and ashen seedling that emerges above ground. The umbilical is ghosted, pale and devoid of life. It is in the air now, reaching up, as if in germination to a psychological photosynthesis. There is the knot and swarm within the unconscious; something has, in true alien fashion, been incubated and is now emerging. In some ways, these paintings are hardly cryptic.Figure 3. Germination.1993. Acrylic on canvas.In Figure 4 ‘The Birthing Tree’, the overt symbolism reaches ‘clairvoyant status’. This could be read as the family ‘tree’ with its four faces screaming out of the ‘branches’. Do these represent the four babies relinquished by our mother (the larger of these ‘beings’ as myself, giving birth to the illegitimate, silenced, and abject self)? Are we all depicted in anguish and as wraithlike, grotesquely simplified into pure affect? This illegitimate self is painted as gestating a ‘blue’ baby, near full-term in a meld of tree and ‘self’, a blue umbilical cord, again, devoid of blood, ghosted, lifeless and yet still living, once again suffocated by the representation of the umbilical in the ‘bowels’ of the self, the abject part of the body, where refuse is stored and eliminated: The duodenum of the damned. The Devil may be seen as Christopher Bollas’s “shadow of the object”, or the Jungian archetypal shadow, not simply a Judeo-Christian fear-based spectre and curmudgeon, but a site of unprocessed and, therefore, feared psychological material, material that must be brought to consciousness and integrated. Perhaps the Devil also is the antithesis to ‘God’ as mother. The hell of ‘not mother’, no mother, not the right mother, the reluctant adoptive mother – the Devil as icon for the rich underbelly of the psyche and apophatic to the adopted/artificial/socially scripted self.Figure 4. The Birthing Tree. 1995. Acrylic on canvas.These paintings ache with the trauma of my relinquishment and LDA experience. They ache with my body’s truth, where the cellular and psychological, flesh and blood and feeling, leak from my wounds in unspeakable confluence (the two genital lips as the site of relinquishment, my speaking lips that have been sealed through non-disclosure and shame, the psychological trauma as Verrier’s ‘primal wound’) just as I leaked from my mother (and society) at birth, as blood and muck, and ooze and pus and death (Grosz 195) only to be quickly and silently mopped up and cleansed through adoption and life-long secrecy. Where I, as translator, fluent in both silence and signs, disclose the baby’s trauma, asking for legitimacy. My experience as a LDA sets up an interesting experiment, one that allows an examination of the pre-verbal/pre-disclosure body as a fleshed and breathing Rosetta Stone, as an interface between the language of the body and of the verbalised, painted, and written text. As a constructed body, written upon and invented legally, socially, and psychologically, I am, in Hélène Cixous’s (“To Live the Orange” 83) words, “un-forgetting”, “un-silencing” and “unearthing” my ‘self’ – I am re-writing, re-inventing and, under public scrutiny, legitimising my ‘self’. I am a site of inquiry, discovery, extrapolation, and becoming (Metta 492; Poulus 475) and, as Grosz (vii) suggests, a body with “all the explanatory power” of the mind. I am, as I embroider myself and my LDA experience into literary and critical texts, authoring myself into existence, referencing with particular relevance Peter Carnochan’s (361) suggestion that “analysis...acts as midwife to the birth of being”. I am, as I swim forever amorphous, invisible, and unspoken in my mother’s womb, fashioning a shore, landscaping my mind against the constant wet, my chronic liminality (Rambo 629) providing social landfall for other LDAs and silenced minorities. As Catherine Lynch (3) writes regarding LDAs, “Through the creation of text and theory I can formulate an intimate space for a family of adoptive subjects I might never know via our participation in a new discourse in Australian academia.” I participate through my creative, self-reflexive, process fuelled (Durey 22), practice-led enquiry. I use the intimacy (and also universality and multiplicity) and illegitimacy of my body as an alterative text, as a site of academic and creative augmentation in the understanding of LDA issues. The relinquished and silenced baby and LDA adult needs a voice, a ‘body’, and a ‘tender’ place in the consciousness of society, as Helen Riley (“Confronting the Conspiracy of Silence” 11) suggests, “voice, validation, and vindication”. Judith Herman (3) argues that, “Survivors challenge us to reconnect fragments, to reconstruct history, to make meaning of their present symptoms in the light of past events”. I seek to use the example of my experience – as Judith Durey (31) suggests, in “support of evocative, creative modes of representation as valid forms of research in their own right” – to unfurl the whole, to give impetus and precedence for other researchers into adoption and advocate for future babies who may be bought, sold, arranged, and/or created by various means. The recent controversy over Gammy, the baby boy born with Down Syndrome in Thailand, highlights the urgent and moral need for legislation with regard to surrogacy (see Kajsa Ekis Ekman’s Being and Being Bought: Prostitution, Surrogacy and the Split Self for a comprehensive examination of surrogacy issues). Indeed, Catherine Lynch in her paper Doubting Adoption Legislation links the experiences of LDAs and the children of born of surrogacy, most effectively arguing that, “if the fate that closed record adoptees suffered was a misplaced solution to the question of what to do with children already conceived how can you justify the deliberate conception of a child with the intention even before its creation of cruelly removing that child from their mother?” (6). Cixous (xxii) confesses, “All I want is to illustrate, depict fragments, events of human life and death...each unique and yet at the same time exchangeable. Not the law, the exception”. I, too, am a fragment, an illustration (a painting), and, as every individual always is – paradoxically – a communal and, therefore, deeply recognisable and generally applicable minority and exception. In my illegitimacy, I am some kind of evidence. Evidence of cellular memory. Evidence of embodiment. Evidence that silenced illegitimacies will manifest in symptom and non-verbal narratives, that they will ooze out and await translation, verification, and witness. This paper is offered with reverence and with feminist intention, as a revenant mouthpiece for other LDAs, babies born of surrogacy, and donor assisted offspring (and, indeed, any) who are marginalised, silenced, and obscured. It is also intended to promote discussion in the psychological and psychoanalytic fields and, as Helen Riley (202-207) advocates regarding late discovery offspring, more research within the social sciences and the bio-medical field that may encourage legislators to better understand what the ‘best interests of the child’ are in terms of late discovery of origins and the complexity of adoption/conception practices available today. As I write now (and always) the umbilical from my paintings curve and writhe across my soul, twist and morph into the swollen and throbbing organ of tongues, my throat aching to utter, my hands ready to craft latent affect into language in translation of, and in obedience to, my body’s knowledges. It is the art of mute witness that reverses genesis, that keeps the umbilical fat and supple and full of blood, and allows my conscious conception and creation. 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