Clinical Importance Research Articles

VENOUS THROMBUS STIFFNESS IN COMBINATION OF PULMONARY EMBOLISM AND DEEP VEIN THROMBOSIS OF THE LOWER EXTREMITIES (CLINICAL CASE)

Many aspects of pulmonary embolism pathogenesis are still unclear: for example, what is the probability of pulmonary embolization in venous thrombosis and thrombi formation in the pulmonary artery in situ. The origin and timing of thromboemboli formation in the pulmonary artery are of great clinical importance for effective treatment and prognosis of pulmonary embolism outcome. The aim of the study was as part of clinical observation to compare the results of shear wave ultrasound elastography of a venous thrombus and the histological structure of blood clots in the lower extremity and the pulmonary artery obtained during a pathoanatomical examination. Research results. Patient Sh., 67 years old, was hospitalized with a diagnosis of pulmonary embolism. Ultrasound imaging visualized heterogeneous, predominantly hypoechoic non-occlusive thrombotic masses in the lumen of the posterior tibial vein of the left lower limb, extending into the lumen of the popliteal vein for 2 cm with an uneven "ragged" contour of the proximal part of the thrombus, without clear signs of flotation. Shear wave ultrasound elastography determined stiffness of the proximal part of the venous thrombus with an average Young's modulus of 8.5 kPa, which corresponds to the acute stage of thrombosis. Negative dynamics was observed after thrombolytic therapy. Computed tomography angiography of the cerebral vessels revealed signs of intracerebral hemorrhage. On the third day, the patient was pronounced dead. The pathological examination was supplemented with histological data from a fragment of a venous thrombus of the pulmonary artery and lower leg veins. The morphological characteristics of blood clots from the veins of the lower extremities and the pulmonary artery coincided, indicating their common origin and the time of formation (acute stage). Conclusion. A comparative analysis of ultrasound and pathoanatomical data of the clinical case give us the opportunity to recommend shear wave ultrasound elastography of venous thrombi of the lower extremities to assess the state of thromboembolism in the pulmonary artery.

Expert opinion of the Heart Rhythm Association of the Polish Cardiac Society and the Polish Neurological Society on evidence-driven implementation of implantable loop recorders in Poland.

Implantable loop recorders (ILR) are considered increasingly helpful in diagnosing cardio-neurological conditions, especially if arrhythmic events are of high clinical importance but are unlikely to be captured by standard methods of electrocardiogram recording due to the low frequency of events and short duration of a single event. The compelling evidence from randomized trials and observational studies strongly supports ILR utilization in patients after cryptogenic stroke or transient ischemic attack and in patients with recurrent transient loss of consciousness of unknown origin. These two groups of patients are expected to gain the most from initiating ILR-driven clinically effective management strategies. Stroke or transient ischemic attack survivors with detected subclinical atrial fibrillation can be switched from antiplatelets to anticoagulants, whilst patients with recurrent syncope may avoid severe injuries and/or substantial impairment of their quality of life. This joint opinion of the Heart Rhythm Association of the Polish Cardiac Society and experts from the Polish Neurological Society summarizes the up-to-date rationale for using ILR in everyday clinical practice and describes the road map for implementing this technology in Poland. Special emphasis is placed on the most recent guidelines issued by both cardiological and neurological scientific societies.

In silico analysis of overall survival with YBX1 in male and female solid tumours

The Y-box binding protein-1 (YBX1) gene codes for a multifunctional oncoprotein that is increasingly being linked to the regulations of many aspects of cancer cell biology. Disparities in treatment outcomes between male and female cancer patients are increasingly reported. This study aimed to examine the relationship between YBX1 expression and overall survival in male and female patients with solid tumours. Overall survival and YBX1 expression data for cohorts of male and female cancer patients obtained from freely available databases were analysed with a cox proportional hazard model with covariates of biological sex and YBX1 expression. Kaplan–Meier curves and Violin plots were constructed for segregated male and female cohorts. High YBX1 expression was significantly associated with poor survival in 2 female-only and 4 mixed-sex cancer sites. In female lung cancer patients, better survival and lower YBX1 expression were identified. The clinical importance of YBX1 expression in cancer ought to be evaluated in a sex-specific manner, especially in lung cancer.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update – XII – Recommendations on milk formula supplements with and without probiotics for infants and toddlers with CMA

BackgroundCow's milk allergy (CMA) is the most common food allergy in infants. The replacement with specialized formulas is an established clinical approach to ensure adequate growth and minimize the risk of severe allergic reactions when breastfeeding is not possible. Still, given the availability of multiple options, such as extensively hydrolyzed cow's milk protein formula (eHF-CM), amino acid formula (AAF), hydrolyzed rice formula (HRF) and soy formulas (SF), there is some uncertainty as to the most suitable choice with respect to health outcomes. Furthermore, the addition of probiotics to a formula has been proposed as a potential approach to maximize benefit. ObjectiveThese evidence-based guidelines from the World Allergy Organization (WAO) intend to support patients, clinicians, and others in decisions about the use of milk specialized formulas, with and without probiotics, for individuals with CMA. MethodsWAO formed a multidisciplinary guideline panel balanced to include the views of all stakeholders and to minimize potential biases from competing interests. The McMaster University GRADE Centre supported the guideline-development process, including updating or performing systematic evidence reviews. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used, including GRADE Evidence-to-Decision frameworks, which were subject to review by stakeholders. ResultsAfter reviewing the summarized evidence and thoroughly discussing the different management options, the WAO guideline panel suggests: a) using an extensively hydrolyzed (cow's milk) formula or a hydrolyzed rice formula as the first option for managing infants with immunoglobulin E (IgE) and non-IgE-mediated CMA who are not being breastfed. An amino-acid formula or a soy formula could be regarded as second and third options respectively; b) using either a formula without a probiotic or a casein-based extensively hydrolyzed formula containing Lacticaseibacillus rhamnosus GG (LGG) for infants with either IgE or non-IgE-mediated CMA.The issued recommendations are labeled as “conditional” following the GRADE approach due to the very low certainty about the health effects based on the available evidence. ConclusionsIf breastfeeding is not available, clinicians, patients, and their family members might want to discuss all the potential desirable and undesirable consequences of each formula in infants with CMA, integrating them with the patients' and caregivers’ values and preferences, local availability, and cost, before deciding on a treatment option. We also suggest what research is needed to determine with greater certainty which formulas are likely to be the most beneficial, cost-effective, and equitable.

Association of Placental Cysts with Increased Fetal Anomalies and Growth Restriction: An Observational Cohort Study

Purpose: To investigate the placental cysts in every aspect and evaluate associations with fetal anomalies, fetal growth, accompanying maternal diseases, and obstetric outcomes. Methods: The presented cohort study was conducted with twenty pregnant women diagnosed with placental cysts. Maternal age, obstetrical histories, maternal diseases, ultrasonographic characteristics of cysts, additional ultrasound findings, and fetal anomalies were recorded at the time of diagnosis and each examination. Pregnancy outcomes; birth weight, gestational age at birth, APGAR scores, NICU admissions, amniotic fluid disorders, and fetal growth restriction (FGR) were recorded for all participants. Data were evaluated according to diagnosis time, cyst size at the diagnosis time, delivery time cyst size, fetal anomalies, and obstetric outcomes. Results: All cysts were single. Five of them increased in size with follow-ups. The mean follow-up duration was 12 weeks. There were 9 FGR (64.3%). Six of the FGR patients had cyst sizes >5cm. There were eight fetal anomalies; 5 were heart-associated, and 3 had a single umbilical artery. The frequency of C/S in delivered patients was 78%, and preterm delivery was 35.7%. Conclusion: The presented study showed that placental cysts have clinical importance due to their potential risk for FGR and accompanying fetal anomalies. Appropriate patient follow-ups for cyst size enlargements and anomaly screening, especially for cardiac evaluation, might be important for placental cyst management. Also, uterine artery doppler measurements and prophylactic acetylsalicylic acid use might be under consideration. However, the clinical utility of uterine doppler examination and prophylactic use of acetylsalicylic acid needs further studies.

Measurement of the 12C(p,n)12N reaction cross section below 150 MeV

Objective. Proton therapy currently faces challenges from clinical complications on organs-at-risk due to range uncertainties. To address this issue, positron emission tomography (PET) of the proton-induced 11C and 15O activity has been used to provide feedback on the proton range. However, this approach is not instantaneous due to the relatively long half-lives of these nuclides. An alternative nuclide, 12N (half-life 11 ms), shows promise for real-time in vivo proton range verification. Development of 12N imaging requires better knowledge of its production reaction cross section. Approach. The 12C(p,n)12N reaction cross section was measured by detecting positron activity of graphite targets irradiated with 66.5, 120, and 150 MeV protons. A pulsed beam delivery with 0.7–2 × 108 protons per pulse was used. The positron activity was measured during the beam-off periods using a dual-head Siemens Biograph mCT PET scanner. The 12N production was determined from activity time histograms. Main results. The cross section was calculated for 11 energies, ranging from 23.5 to 147 MeV, using information on the experimental setup and beam delivery. Through a comprehensive uncertainty propagation analysis, a statistical uncertainty of 2.6%–5.8% and a systematic uncertainty of 3.3%–4.6% were achieved. Additionally, a comparison between measured and simulated scanner sensitivity showed a scaling factor of 1.25 (±3%). Despite this, there was an improvement in the precision of the cross section measurement compared to values reported by the only previous study. Significance. Short-lived 12N imaging is promising for real-time in vivo verification of the proton range to reduce clinical complications in proton therapy. The verification procedure requires experimental knowledge of the 12N production cross section for proton energies of clinical importance, to be incorporated in a Monte Carlo framework for 12N imaging prediction. This study is the first to achieve a precise measurement of the 12C(p,n)12N nuclear cross section for such proton energies.

Secondary fracture prevention/Update osteoporosis guidelines 2023 of the Umbrella Organization Osteology

The S3guidelines on the prophylaxis, diagnostics and treatment of osteoporosis 2023 were completely revised and updated between 2021 and 2023 in accordance with the Association of the Scientific Medical Societies of Germany (AWMF) regulations. The guideline committee consisted of delegates from the 20specialist societies of the Umbrella Organization Osteology (Dachverband Osteologie, DVO) as well as delegates from the German Society of General Medicine and Family Medicine (DEGAM), the German Society for Nephrology (DGfN) and the Federal Self-help Association for Osteoporosis (BfO).The guidelines focus on preventive measures, diagnostic procedures and treatment approaches for osteoporosis in men aged50 years and over and postmenopausal women. The main aim is the optimization of care processes, reduction of fracture incidences and maintenance or improvement of the quality of life and functional capacity of patients affected by fractures. Amajor update to the guidelines includes the introduction of anew risk calculator that can take more risk factors (n = 33) into account and that can estimate the risk of vertebral body and proximal femoral fractures for a3-year period (previously 10years). This results in new thresholds for diagnostics and treatment. The programmed app is currently not yet certified as a medical product and apaper version is therefore currently available for patient care with the planned integration of aweb-based version of the risk calculator. From the perspective of trauma surgery, the recommendations and innovations for manifest osteoporosis are of particular clinical importance. The focus of the DVO guidelines update is therefore on the implementation of secondary fracture prevention in trauma surgery, orthopedic and geriatric traumatology in the clinical and practical daily routine.

Patient-specific factors for deformity after upper blepharoplasty in an Asian population.

The success of upper blepharoplasty depends on both surgeon experience and skill as well as patient factors. Therefore, we aimed to identify patient-specific characteristics that may contribute to poor prognoses by analyzing data derived from patients with various deformities after undergoing upper blepharoplasty. This study included 202 patients who underwent revision surgery for upper blepharoplasty. We explored relationships between types of deformities before revisions and relevant patient factors before initial surgery using statistical analyses. Age > 30 years, thick upper lid skin, medial epicanthus, and other patient factors were significantly associated with the deformities. Asymmetrical, disappeared, shallow, and low creases were the most prevalent deformities. For these four most prevalent deformities, the concordance indices and 95% confidence limits of the risk prediction models were 0.654 (0.575-0.734), 0.724 (0.637-0.810), 0.783 (0.702-0.863), and 0.750 (0.655-0.844), respectively. Among the four most prevalent prognostic deformities, significant patient factors included medial epicanthus, thick upper eyelid skin, weak levator palpebrae superioris, age > 30 y, and a short gap between eyes and brows. We also attempted to clarify the clinical importance of these patient factors. Our findings provide a guide and reference for future investigations into upper blepharoplasty.

Anatomy of Maxillary Sinus: Focus on Vascularization and Underwood Septa via 3D Imaging.

The study of the maxillary sinus anatomy should consider the presence of two features of clinical importance. The arterial supply course and the presence of the so-called Underwood septa are two important factors to consider when planning surgical treatment to reduce the risk of surgical complications such as excessive bleeding and Schneiderian membrane perforations. This study aimed to investigate the above-mentioned anatomical structures to improve the management of eventual vascular and surgical complications in this area. This study included a total of 200 cone-beam computed topographies (CBCTs) divided into two groups of 100 CBCTs to evaluate the arterial supply (AAa) course through the lateral sinus wall and Underwood's septa, respectively. The main parameters considered on 3D imaging were the presence of the AAa in the antral wall, the length of the arterial pathway, the height of the maxillary bone crest, the branch sizes of the artery in the first group, and the position of the septa, the length of the septa, and their gender associations in the second group. The CBCT analysis showed the presence of the arterial supply through the bone wall in 100% of the examined patients, with an average size of 1.07 mm. With regard to the septa, 19% of patients presented variations, and no gender difference was found to be statistically significant. The findings add to the current understanding of the clinical structure of the maxillary sinus, equipping medical professionals with vital details for surgical preparation and prevention of possible complications.

Conventional and molecular cytogenetic characterization of a Moroccan patient with WAGR syndrome

BackgroundWAGR syndrome is a rare genetic disorder characterized by a de novo deletion of 11p13 and is usually clinically associated with Wilms’ tumor, aniridia, genitourinary anomalies, and mental retardation (W-A-G-R). Although the genotypic defects in WAGR syndrome have been well established. The congenital aniridia is caused, in nearly 90% of cases by mutations in the gene PAX6. In the face of congenital aniridia, it is imperative to specify whether it falls within the scope of a WAGR syndrome or if it is an isolated congenital aniridia or inherited by performing karyotype, FISH (Fluorescence In Situ Hybridization) or a CGH array for genetic counseling.Case presentationWe report here a case of genetic testing for newborn with aniridia, to detect 11p13 rearrangements, using karyotyping and CGH array to complete picture of the chromosomal deletions and breakpoints in aniridia. Results show either a loss of 3811.196 kb on chromosome 11 delimited by the bands p14.1 and p13 with formula or a loss of a 1867.287 kb on chromosome 18 fragment delimited by q21.33 and q22.1 bands, that has not been detected by karyotype analysis.ConclusionsCytogenetics screening is a good strategy for the genetic diagnosis of aniridia and associated syndromes, allowing for a better identification of breakpoints. Our results underline the clinical importance of performing exhaustive and accurate analysis of chromosomal rearrangements for patients with aniridia, especially newborns to improve survival and quality of life for affected individuals.

Special methods of magnetic resonance in diagnosis of multiple sclerosis.

The article is devoted to the review of the most promising MRI techniques in the diagnosis of multiple sclerosis as part of personalized medicine. A brief description of the current state of the problem is provided. Examples of promising MR research techniques are considered. The issues of clinical importance and expediency of using these techniques are discussed. The existing approaches in the diagnosis of multiple sclerosis are summarized. In conclusion, the prospects and importance of the considered methods in the structure of healthcare are summarized.

Abstract 2452: Clinical importance of nicotinamide nucleotide transhydrogenase in obesity-associated colorectal cancer

Abstract Background: Obesity is increasing worldwide, and many associated diseases are emerging as global health problems. There is a relationship between body mass and the risk of developing colorectal cancer (CRC). However, predictive biomarkers of survival with body mass remain elusive. Therefore, we aimed to identify novel clinically relevant biomarkers for obesity-associated CRC. Methods: We searched for biomarker candidates in The Cancer Genome Atlas CRC cohort. We divided the TCGA CRC cohort (n=268) data into 3 groups (healthy weight CRC group [HT], adjacent normal tissue from the HT group [AN]), and obesity CRC group [OT]). Candidates were validated by survival analysis after immunohistochemistry in an independent cohort of 420 patients. Results: The gene expression levels of NNT, PANK3, PPARGC1B, RTL6, FAM220A, and TMEM9 were associated with survival in overweight and obese patients with CRC from TCGA cohort. These findings were validated using protein expression data from our independent cohort. In our patient cohort, the hazard ratio (HR) of the subgroup of low NNT versus that of high NNT in terms of 5-year event-free survival (EFS) was 2.20 (adjusted for age and sex, 95% CI: 1.01-4.80, p < 0.05) among patients of obesity-associated CRC. When both TNM staging and NNT expression were considered, patients of obesity-associated CRC with low NNT expression and advanced stage III-IV cancer had a HR of 21.20 (adjusted for age and sex, 95% CI: 2.88-156.08, p < 0.01) compared to those with high NNT expression and early stage I-II cancer. However, when patients of obesity-associated CRC with high NNT expression and advanced stage III-IV cancer were compared to those with high NNT expression and early stage I-II cancer, the former subgroup had a HR of 8.39 (adjusted for age and sex, 95% CI: 1.03-68.39, p < 0.05) in terms of the 5-year EFS. Finally, when the 5-year disease-specific survival analysis was performed, the patients of obesity-associated CRC with low NNT expression and advanced stage III-IV cancer were found to have a HR of 14.05 (adjusted for age and sex, 95% CI: 1.89-104.38, P = 0.01) compared to those with high NNT expression and early stage I-II cancer. Furthermore, low NNT expression results in the inactivation of several metabolic pathways, including ROS-related pathways. Conclusions: NNT is a novel and promising CRC prognostic biomarker for overweight and obese patients. It can provide clinicians with early indicators of patient prognosis and aid in appropriate treatment selection. Citation Format: Soyeon Jeong, Sungjin Park, Jungsuk An, Myunghee Kang, Seungyoon Nam, Jung Ho Kim. Clinical importance of nicotinamide nucleotide transhydrogenase in obesity-associated colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2452.

Comparison of the relative diagnostic performance of 68Ga-DOTA-IBA and 18F-NaF for the detection of bone metastasis.

We aimed to compare the relative diagnostic efficacy of 68Ga-Labeled DOTA-ibandronic acid (68Ga-DOTA-IBA) to that of18F-NaF PET/CT as a mean of detecting bone metastases in patients with a range of cancer types. This study retrospectively enrolled patients with bone metastases associated with various underlying malignancies. All patients underwent both 68Ga-DOTA-IBA and 18F-NaF PET/CT scans. Histopathology and follow-up CT or MRI imaging results were used as reference criteria, with a minimum follow-up period of 3 months. The maximum Standardized Uptake Value (SUVmax) and number of bone metastases were recorded. The Target-Background Ratio (TBR) was calculated along with the detection rate, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 68Ga-DOTA-IBA and 18F-NaF PET/CT imaging for overall and partial primary solid tumor bone metastases. Pearson chi-square test, McNemar test, and Kappa test was conducted to assess the correlation and consistency of diagnostic efficiency between the two imaging agents. Receiver Operating Characteristic curve (ROC curve) was performed to compare diagnostic performance and the area under the curve of the two imaging agents, determining optimal critical values for SUVmax and TBR in diagnosing bone metastasis. Differences in SUVmax and TBR values between the two imaging agents for detecting bone metastases were analyzed using the Wilcoxon signed rank test. The difference was statistically significant when P < 0.05. A total of 24 patients (13 women and 11 men) were included in this study, with a mean age of 52 (interquartile range, 49-64 years). The detection rate, sensitivity, specificity, PPV, NPV, accuracy, and AUC of 68Ga-DOTA-IBA and 18F-NaF PET/CT for bone metastases were 81%, 90%, 62%, 95%, 43%, 88%, 0.763, and 89%, 99%, 59%, 95%, 89%, 95%, 0.789, respectively. There was no significant difference between the two imaging methods (P < 0.01), and there was a significant correlation (X2=168.43, P < 0.001) and a strong consistency (Kappa=0.774,P < 0.001) between the diagnostic results of the two imaging agents. The SUVmax values of lesions measured by 68Ga-DOTA-IBA and 18F-NaF imaging in 22 patients with bone metastasis were 5.1 ± 5.4 and 19.6 ± 15.1, respectively, with statistically significant differences (P<0.05). The TBR values of the two imaging methods were 5.0 ± 5.0 and 6.7 ± 6.4, respectively, with statistically significant differences (P<0.05). The AUC of the SUVmax of 68Ga-DOTA-IBA and 18F-NaF curves were 0.824 and 0.862, respectively, with no statistically significant difference (P=0.490). No significant difference was found in the AUC of the TBR of 68Ga-DOTA-IBA and 18F-NaF (0.832 vs 0.890; P=0.248). Subgroup analysis showed significant correlation between the two imaging agents in the diagnosis of bone metastases in lung cancer and breast cancer, with consistent diagnostic results. However, in the diagnosis of bone metastases in prostate cancer, there was a significant difference (P<0.001) and lack of consistency (P=0.109). The diagnostic efficacy of 68Ga-DOTA-IBA for bone metastasis lesions is comparable to that of 18F-NaF. This finding holds significant clinical importance in terms of diagnosis of bone metastasis and selecting treatment plans for patients with malignant tumors.

Radiology diagnostics of neonatal pneumonia.

The article is dedicated to reviewing the role of radiological diagnosis in “Identifying neonatal pneumonia”. It includes a brief historical and terminological overview, as well as a description of the current state of the issue. The article discusses the clinical importance and feasibility of using radiological diagnostic methods, summarizes existing approaches in the diagnosis and treatment of the most significant nosological forms, and concludes with an overview of the prospects and significance of these methods in the healthcare system.

Perceptual Awareness in Human Infants: What is the Evidence?

Perceptual awareness in infants during the first year of life is understudied, despite the philosophical, scientific, and clinical importance of understanding how and when consciousness emerges during human brain development. Although parents are undoubtedly convinced that their infant is conscious, the lack of adequate experimental paradigms to address this question in preverbal infants has been a hindrance to research on this topic. However, recent behavioral and brain imaging studies have shown that infants are engaged in complex learning from an early age and that their brains are more structured than traditionally thought. I will present a rapid overview of these results, which might provide indirect evidence of early perceptual awareness and then describe how a more systematic approach to this question could stand within the framework of global workspace theory, which identifies specific signatures of conscious perception in adults. Relying on these brain signatures as a benchmark for conscious perception, we can deduce that it exists in the second half of the first year, whereas the evidence before the age of 5 months is less solid, mainly because of the paucity of studies. The question of conscious perception before term remains open, with the possibility of short periods of conscious perception, which would facilitate early learning. Advances in brain imaging and growing interest in this subject should enable us to gain a better understanding of this important issue in the years to come.

Abstract 1025: An AI based CT scan classifier for predicting extranodal extension and nodal metastasis of HPV-associated oropharyngeal carcinoma

Abstract Background: Pathologic extranodal extension (ENE) and nodal metastasis (NM) are of prognostic significance in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). The pretreatment identifications of these two factors through computed tomography (CT) imaging are of clinical importance since they could guide treatment de-escalation protocols and select candidates suitable for surgery. In an effort to enhance pretreatment decision making, we developed and validated an AI model (specifically a multi-layer perceptron (MLP)-based deep learning model) to predict radiologic NM and pathologic ENE in HPV-associated OPSCC patients. Methods: Radiographic CT scans for 290 OPSCC patients treated with definitive chemoradiation were acquired from The Cancer Imaging Archive (TCIA) and divided into training (D1) and validation (D2) cohorts for NM prediction. Radiologic NM for D1 and D2 were reviewed by two radiologists. Only nodes with concordant NM judgments from both radiologists were included for analysis. An additional 46 OPSCC patients treated with surgery at Emory Winship Cancer Institute were collected to form the test cohorts (D3) for ENE prediction. The largest metastatic or normal nodes were annotated for D1 and D2 while all visible nodes with pathology confirmation of ENE from D3 were annotated. We present a novel deep-learning model utilizing U-shaped multi-layer perceptron mixer (MLP-Mixer) to capture both global and local feature representations by spatially aggregating image patch information through a procedure called token-mixing. The model was trained for 20 epochs with learning rate of0.0001 and batch size of 64. The diagnostic performance of the AI model was evaluated on D2 and D3 using accuracy and area under the ROC curve (AUROC). Results: There were 121 NM negative and 130 NM positive nodes in D1, 14 NM negative and 25 NM positive nodes in D2 and 46 ENE negative and 20 ENE positive nodes in D3. On D2 for NM prediction, the AI model achieved overall accuracy of 0.77 and AUROC of 0.78. On D3 for ENE prediction, the AI model achieved overall accuracy of 0.71, AUROC of 0.69, positive predictive value of 0.52 and negative predictive value of 0.86. Conclusions: The new AI–based deep learning model was able to identify HPV-associated OPSCC NM and ENE with satisfactory diagnostic performance and shows promise to assist clinicians in treatment decision-making. Additional, multi-site prospective validation of the approach is warranted. Citation Format: Bolin Song, Kailin Yang, Shaoyan Pan, Liping Li, Qiyun Liu, Jonathan Lee, Sarah Stock, Nabil F. Saba, Mehmet Asim Bilen, Mihir R. Patel, Anant Madabhushi. An AI based CT scan classifier for predicting extranodal extension and nodal metastasis of HPV-associated oropharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1025.

Abstract 2884: Resistance to pan-FGFR inhibition is determined by the EMT phenotype associating with clinical outcome in HNSCC

Abstract Receptor tyrosine kinases (RTK) and integrins coalesce at focal adhesions. These cell membrane areas serve as huge signaling hubs critically contributing to central aspects of cancer cell survival and therapy resistance. Despite the fact that these receptors mutually interact, co-dependencies between these receptors and associated therapeutically exploitable vulnerabilities remain largely unclear in HPV-negative head and neck squamous cell carcinoma (HNSCC). Here, we evaluated the cytotoxic and radiochemosensitizing potential of targeting 10 RTK and β1 integrin in up to 20 different 3D matrix grown HNSCC cell models. RNA sequencing and protein-based biochemical assays were performed for molecular and pathway characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts to show clinical relevance. Our observations demonstrate that fibroblast growth factor receptors (FGFR 1-4) present with the strongest cytotoxic and radiosensitizing potential, both as monotherapy and in combination with β1 integrin inhibition, surpassing the efficacy of the other investigated RTK. Pharmacological pan-FGFR inhibition elicited a variable response spectrum ranging from cytotoxicity/radiochemosensitization to resistance/radioprotection. Transcriptomic characterization revealed an association of these contrasting responses to FGFR inhibition with a mesenchymal-to-epithelial transition (MET) for sensitive cell models and a partial epithelial-to-mesenchymal transition (EMT) for resistant cell models. Accordingly, deactivation of EMT associated kinases like EGFR, PKC and PAK proved effective in diminishing the adaptive FGFR-driven resistance. Importantly, the translation of the adaptive resistance profiles to HNSCC patient cohorts showed its prognostic value and provided conclusive validation of the presence of EMT-related vulnerabilities that can be strategically used for therapeutic intervention. In conclusion, our study demonstrates that pan-FGFR inhibition induces both a highly beneficial radiochemosensitizing and a detrimental radioprotective effect in HNSCC cell models. Adaptive EMT-associated resistance appears to be of clinical importance, and we provide effective molecular approaches to exploit this therapeutically. Citation Format: Felix Broghammer, Mahesh Gouda, Irina Korovina, Cornelia Brunner, Robert P. Coppes, Olivier Gires, Michael Seifert, Nils Cordes. Resistance to pan-FGFR inhibition is determined by the EMT phenotype associating with clinical outcome in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2884.

Abstract 4136: Tracking metastatic dissemination and tumor growth using longitudinal imaging and ctDNA

Abstract Metastatic lung cancer is a heterogeneous disease, characterized by different patterns of clinical progression and therapy response. The scale of this heterogeneity on a lesion specific level has yet to be quantified but is of clinical importance because it may provide an indication of molecular mechanisms underpinning metastasis growth. Currently, whether metastasis growth patterns can be predicted by the primary tumor or governed by metastasis specific characteristics is not known. Furthermore, circulating tumor DNA (ctDNA) has proven useful to predict disease relapse, but how closely it reflects metastatic growth post relapse is unclear. In 104 patients enrolled in the TRACERx study with disease relapse post-surgical resection of the primary tumor, lesion volumetric dynamics were tracked in 460 metastases. Total volume growth rate (TVGR) was calculated using CT imaging performed between disease relapse and death. All patients had whole exome sequencing (WES) of the primary tumor. For 19 patients enrolled in the PEACE autopsy study WES and RNAseq from 60 metastases visible on imaging prior to death and subsequently sampled at autopsy were analyses. In 29 patients, ctDNA was used to track 200 tumor-specific mutations to assess tumor burden and detect metastatic subclones. High TVGR correlated with poor survival (hazard ratio for death 1st vs 2nd tertile was 0.21, p&amp;lt;0.001; 2nd vs 3rd tertile was 0.51, p=0.04). Primary tumor subclonal whole genome doubling was predictive of high TVGR. There was considerable heterogeneity in the growth rate of metastases within patients. The anatomical location of metastases contributed to this, extrathoracic soft tissue and pleura had the highest growth rates, whilst lymph node and adrenal the lowest (p&amp;lt;0.001). Molecular attributes differed between metastases, with fast growing metastases being enriched for proliferation pathway gene expression. It was observed that the most prevalent population of cells, or clone, in the fastest growing metastasis within a patient was exclusive to that metastasis, suggesting that genomic features that characterize the clone might support rapid growth. ctDNA tracked with tumor burden post relapse and patients with extrathoracic relapse had higher levels of ctDNA. In 9 patients, metastasis specific mutations identified at autopsy and in ctDNA, were used to determine the proportion of ctDNA shed by different metastatic sites. ctDNA subclonal fraction was found to track with changes in lesion volumes during disease progression. This work highlights significant heterogeneity in metastatic growth rates which can potentially be attributed to the presence of distinct genomic features which may dictate tumor growth rate. ctDNA accurately reproduces patterns of radiological disease progression and when combined with longitudinal imaging and tumor DNA sequencing, can accurately reconstruct the natural history of cancer evolution. Citation Format: Wing Kin Liu, Boyue Ding, Hessey Sonya, Carlos Martinez-Ruiz, Cristina Naceur-Lombardelli, Corentin Richard, Hyothaek Lee, Catarina Veiga, Kishen Patel, Ariana Huebner, Allan Hackshaw, Christopher Abbosh, Alexander M. Frankell, Gary Royle, Charles Swanton, Mariam Jamal-Hanjani. Tracking metastatic dissemination and tumor growth using longitudinal imaging and ctDNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4136.

Abstract 5725: Aurkin-A, a TPX2-Aurora A inhibitor disrupts alisertib-induced polyploidy in HG-diffuse large B cell lymphoma

Abstract Chemotherapy induced polyploidy (CIP) is a mechanism of inherited drug resistance resulting in an aggressive disease course in cancer patients. Alisertib, an Aurora Kinase A (AK-A) ATP site inhibitor, induces cell cycle disruption resulting in polyaneuploidy in high-grade (MYC and BCL2 amplified or expressed) Diffuse Large B Cell Lymphoma (HG-DLBCL). Propidium Iodide cycle flow cytometry was utilized to quantify alisertib induced polyploidy in U2932 and VAL cell lines. In U2932 cells, 1µM alisertib generated 8n+ polyploidy in 48% of the total cell population after five days of treatment. Addition of Aurkin A an AK-A/TPX2 site inhibitor, disrupted alisertib induced polyploidy in a dose-dependent manner with associated increased apoptosis in DLBCL cells. Combination of Aurkin A plus alisertib significantly reduced polyploidy and sensitized DLBCL cells to alisertib. The sensitization of alisertib with Aurkin A through complete AK-A inhibition is of high clinical importance as the alisertib dose can be significantly reduced while preventing polyploidy, enhancing efficacy, and significantly reducing toxicity to normal tissue. In clinical trials of alisertib in lymphoma, a maximum tolerated dose of 1.5µM was achieved. In U2932 cells, we found the addition of 100µM Aurkin A reduced the alisertib IC50 from 983nM to 34nM. We generated a stable FUCCI U2932 cell line expressing Geminin-clover (S/G2/M) and cdt1-mKO (G1), to help monitor cell cycle progression in live cells. Using this system, we identified alisertib-induced polyploidy through endomitosis, which was eliminated with Aurkin A treatment. In a VAL cell line mouse xenograft model, we show polyploidy generation in alisertib treated mice versus vehicle control or Aurkin A. Aurkin A plus alisertib significantly reduced polyploidy and tumor growth compared to vehicle control or Aurkin A levels. Finally, we performed Data-Independent Acquisition Mass Spectrometry on alisertib, Aurkin A, and combination alisertib/Aurkin A treated U2932 cells to identify therapy induced proteomic changes. This proteomic analysis has provided insight into the mechanism of alisertib polyploidy induction and the protective mechanism of within the combination therapy. Our in vitro and in vivo studies show that Aurkin A synergizes with alisertib and significantly decreases the alisertib dose needed to disrupt polyploidy while increasing apoptosis in HG-DLBCL cells. Citation Format: Patrick J. Conway, Bárbara De la Peña Avalos, Jonathan Dao, Sebastian Montagnino, Dmytro Kovalskyy, Eloise Dray, Daruka Mahadevan. Aurkin-A, a TPX2-Aurora A inhibitor disrupts alisertib-induced polyploidy in HG-diffuse large B cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5725.

Identification and validation of neutrophils-related subtypes and prognosis model in triple negative breast cancer

BackgroundNeutrophils are considered to be crucial players in the initiation and progression of cancer. However, the complex relationship between neutrophils and cancer prognosis remains elusive, mainly due to the significant plasticity and diversity exhibited by these immune cells.MethodsAs part of our thorough investigation, we examined 38 Neutrophils-Related Genes (NRGs) and the associated copy number variations (CNV), somatic mutations, and gene expression patterns in relation to triple negative breast cancer (TNBC). The interactions between these genes, their biological roles, and their possible prognostic significance were then examined. With the NRGs as our basis, we applied Lasso and Cox regression analyses to create a predictive model for overall survival (OS). Furthermore, TNBC tissue and a public database were used to assess changes in MYO1D expression (MYO1D is characterized as a member of the myosin-I family, a group of motor proteins based on actin), its connection to neutrophil infiltration, and the clinical importance of MYO1D in TNBC.ResultsFour neutrophil-related genes were included in the development of a prognostic model based on neutrophils. The model was further shown to be an independent predicted factor for overall survival by multivariate Cox regression analysis. According to this study, neutrophil subtype B as well as gene subtype B, were associated with activated cancer immunity and poor prognosis of TNBC patients. Furthermore, considering that poor OS was linked to increased MYO1D expression, MYO1D was increased in TNBC tissues and associated with neutrophil infiltration. In vitro experiments also confirmed that MYO1D facilitates breast cancer invasion and metastasis.ConclusionBased on the degree of gene expression linked to neutrophils, a unique prognostic model was created. MYO1D could be a potential prognostic biomarker in TNBC patients and also a prospective target for therapy.