Distinct Clinical Features Research Articles

Diffuse Pleural Mesotheliomas with Genomic Near-Haploidization: A Newly Recognized Subset with Distinct Clinical, Histologic, and Molecular Features.

Diffuse pleural mesotheliomas (DPM) with genomic near-haploidization (GNH) represent a novel subtype first recognized by The Cancer Genome Atlas project; however, its clinicopathologic and molecular features remain poorly defined. We analyzed clinical genomic profiling data from 290 patients with DPM using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. Allele-specific copy number analysis was performed using the Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) algorithm. A total of 210 patients were evaluable for loss of heterozygosity (LOH) analysis using FACETS from MSK-IMPACT tumor:normal sequencing data. In this cohort, GNH, defined as LOH across >80% of the genome, was detected in 10 cases (4.8%). Compared with non-GNH tumors, GNH DPMs were associated with younger age and less frequent self-reported history of occupational asbestos exposure. Histologically, GNH DPMs were enriched in biphasic subtype (80% vs. 14.5%) and showed abundant tumor-infiltrating lymphocytes (TILs). Genomic analysis revealed a higher frequency of TP53 alterations, whereas SETDB1 mutations were present in nearly all and only in this subset. The clinicopathologic and molecular findings were further validated in a separate cohort. Despite the younger age, patients with GNH DPMs had a shorter overall survival (10.9 vs. 25.4 months, P = 0.004); the poor prognostic impact of GNH remained significant after controlling for biphasic histology. Of three patients with GNH DPMs who received immune checkpoint blockade, two achieved a clinician-assessed partial response. GNH defines an aggressive subtype of mainly biphasic DPMs in younger patients with recurrent alterations in SETDB1 and TP53. The enrichment in biphasic histology and TILs, together with our preliminary immune checkpoint blockade response data and anecdotal clinical trial data, suggests that further evaluation of immunotherapy may be warranted in this subset.

Immune-Mediated Necrotizing Myopathies: Current Landscape.

Immune-mediated necrotizing myopathy (IMNM), characterized by acute or subacute onset, severe weakness, and elevated creatine kinase levels, poses diagnostic and therapeutic challenges. This article provides a succinct overview of IMNM, including clinical features, diagnostic strategies, and treatment approaches. Recent insights highlight the different clinical presentations and therapeutic options of IMNM stratified by autoantibody positivity and type. Additionally, recent findings call into question the reported link between statin use and IMNM. This review synthesizes current knowledge on IMNM, emphasizing its distinct clinical features and challenging management. The evolving understanding of IMNM underscores the need for a comprehensive diagnostic approach that utilizes a growing range of modalities. Early and aggressive immunomodulatory therapy remains pivotal. Ongoing research aims to refine diagnostic tools and therapeutic interventions for this challenging muscle disorder, underscoring the importance of advancing our understanding to enhance patient outcomes.

Cognitive and Behavioral Subtypes of Alzheimer’s and Lewy Body Dementias with Distinct Clinical Characteristics (P3-9.003)

Cognitive and Behavioral Subtypes of Alzheimer’s and Lewy Body Dementias with Distinct Clinical Characteristics (P3-9.003)

Epidemiological Characteristics of Nontuberculous Mycobacterial Pulmonary Disease in South Korea: A Meta-analysis of Individual Participant Data.

Despite the global increase in nontuberculous mycobacterial pulmonary disease (NTM-PD), clinical characteristics show geographical variations. We investigated the clinical characteristics of patients with NTM-PD in South Korea. We systematically reviewed articles concerning patients with NTM-PD in South Korea until February 2022. Individual participant data, regardless of treatment, were collected using a standard case report form. Data of 6,489 patients from 11 hospitals between 2002 and 2019 were analyzed. The mean age was 61.5±11.7 years, of whom 57.7% were women. Mycobacterium avium (41.4%) and Mycobacterium intracellulare (38.4%) comprised most of the causative species, followed by Mycobacterium abscessus subspecies abscessus (8.6%) and M. abscessus subspecies massiliense (7.8%). Bronchiectasis (59.4%) was the most common pulmonary comorbidity. Although reported cases of NTM-PD increased over the years, the proportions of causative species and radiologic forms remained similar. Distinct clinical characteristics were observed according to age and sex. Men were older at the time of diagnosis (median 63.8 years vs. 59.9 years, p<0.001), and had more cavitary lesions than women (38.8% vs. 21.0%, p<0.001). The older group (≥65 years) had higher proportions of patients with body mass index <18.5 kg/m2 (27.4% vs. 18.6%, p<0.001) and cavitary lesions (29.9% vs. 27.6%, p=0.009) than the younger group. We conducted a meta-analysis of the clinical characteristics of patients with NTM-PD in South Korea, and found age- and sex-related differences in disease- specific severity. Further investigation would enhance our comprehension of the nature of the disease, and inherited and acquired host factors.

Molecular and phenotypic characteristics of Bardet-Biedl syndrome in Chinese patients

BackgroundBardet-Biedl syndrome (BBS) is a type of non-motile ciliopathy. To date, 26 genes have been reported to be associated with BBS. However, BBS is genetically heterogeneous, with significant clinical overlap with other ciliopathies, which complicates diagnosis. Disability and mortality rates are high in BBS patients; therefore, it is urgent to improve our understanding of BBS. Thus, our study aimed to describe the genotypic and phenotypic spectra of BBS in China and to elucidate genotype–phenotype correlations.MethodsTwenty Chinese patients diagnosed with BBS were enrolled in this study. We compared the phenotypes of Chinese BBS patients in this study with those from other countries to analyze the phenotypic differences across patients worldwide. In addition, genotype–phenotype correlations were described for our cohort. We also summarized all previously reported cases of BBS in Chinese patients (71 patients) and identified common and specific genetic variants in the Chinese population.ResultsTwenty-eight variants, of which 10 are novel, in 5 different BBS-associated genes were identified in 20 Chinese BBS patients. By comparing the phenotypes of BBSome-coding genes (BBS2,7,9) with those of chaperonin-coding genes (BBS10,12), we found that patients with mutations in BBS10 and 12 had an earlier age of onset (1.10 Vs. 2.20, p < 0.01) and diagnosis (4.64 Vs. 13.17, p < 0.01), whereas patients with mutations in BBS2, 7, and 9 had a higher body mass index (28.35 Vs. 24.21, p < 0.05) and more vision problems (p < 0.05). Furthermore, in 91 Chinese BBS patients, mutations were predominant in BBS2 (28.89%) and BBS7 (15.56%), and the most frequent variants were in BBS2: c.534 + 1G > T (10/182 alleles) and BBS7: c.1002delT (7/182 alleles), marking a difference from the genotypic spectra of BBS reported abroad.ConclusionsWe recruited 20 Chinese patients with BBS for genetic and phenotypic analyses, and identified common clinical manifestations, pathogenic genes, and variants. We also described the phenotypic differences across patients worldwide and among different BBS-associated genes. This study involved the largest cohort of Chinese patients with BBS, and provides new insights into the distinctive clinical features of specific pathogenic variants.

Long-Term Survival in an Adolescent and Young Adult with Metastatic Relapse of an Undifferentiated Embryonal Sarcoma of the Liver.

Undifferentiated embryonal sarcoma of the liver (UESL) is an extremely rare and aggressive malignancy in adults.1 Adults with UESL have a worse prognosis compared to pediatric population.2 Due to the rarity of this disease in adults, there has been a lack of information that assists in treatment decisions within this group. Improved understanding of UESL in adults might assist in understanding biological differences compared to pediatric cohorts as well as tailor treatments to improve their overall outcome. We described the management and outcome of a young adult managed at our center with metastatic relapsed UESL. For comparison, a PubMed search for adolescent and young adult (AYA) and adults with UESL was performed with the aim to review and address any distinct clinical features, different aspects of management and survival outcomes within this population. A 21-year-old male underwent right hepatectomy for a large 16 cm localized UESL with clear surgical margin and did not receive adjuvant chemotherapy. Seven months postsurgery, he relapsed with both local and metastatic disease and underwent chemotherapy with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide achieving a complete metabolic response. This was followed by Stereotactic Ablative Radiation Therapy and surgical resection of residual disease. He remains free of disease 3 years since his diagnosis. We subsequently reviewed 42 AYA and adults (aged >15) with UESL (median age, 33 years) between 1991 and 2022. Most patients presented with localized UESL and for those treated with surgery alone, 67% developed recurrences. Those receiving multimodality treatment, better outcomes, and reduced relapse rate was achieved. Twenty-seven patients developed recurrences, 13 with local recurrences and 14 with metastatic relapse. The median time to relapse was 12 months. We reported a successful outcome in multimodality treatment which resulted in long remission in a young adult with relapsed UESL. Combination of perioperative chemotherapy with locoregional treatment is important to improve long-term survival in adults with metastatic UESL.

Desmoplastic histological subtype of ameloblastoma in 16 dogs.

Ameloblastoma in dogs most often has a highly conserved acanthomatous cell morphology and is recognized as canine acanthomatous ameloblastoma (CAA) while conventional ameloblastoma (CA) makes up a smaller yet morphologically diverse group of epithelial odontogenic tumors. In humans, a rare desmoplastic histological subtype has distinctive clinical, radiological, and microscopic features. Desmoplastic ameloblastoma (DA) has not previously been described in dogs, although it has been rarely referenced in the veterinary literature. This is the first thorough description of a case series of DA in dogs and describes clinical presentation, diagnostic imaging findings, histopathological features for diagnosis, and treatment outcome. Clinically, DA most often presents as a mass or swelling in the rostral mandible or maxilla of middle age to older dogs. On diagnostic imaging, the lesion has a radiolucent or mixed pattern with well-defined borders and variable loculation. As a solid, fibrous tumor with obscured odontogenic epithelium, DA is challenging to diagnose histologically and can mimic several other oral tumors, both benign and malignant. As an ameloblastoma, the biological behavior of DA is locally destructive yet benign and prognosis is favorable following surgical excision.

Can we manage the melanocytic lesions with peripheral globules according to the grade of dysplasia?

Although excision of melanocytic nevi with high-grade dysplasia is recommended by the World Health Organization (WHO), clinical studies investigating the approach based on the grading dysplasia of melanocytic lesions with peripheral globules (PGs) are lacking. We investigated the grades of dysplasia and their distinguishable dermoscopic and clinical features to provide accurate data for managing these lesions. We retrospectively classified histologically confirmed melanocytic lesions with PGs according to the 2018 WHO Classification of Skin Tumours criteria in a university hospital in Turkey. Dermoscopic features, lesions, and patient characteristics were recorded. Sixty-six lesions of 56 patients were included. After classification, 9.1% (n: 6) of lesions were melanomas, 39.4% (n: 26) were high-grade dysplastic nevi, and 50% (n: 33) were low-grade dysplastic nevi (n: 33, 50%). There was one nevus with no dysplasia (n: 1, 1.5%). Univariate analysis revealed that ≥31 years of age, irregular shape of peripheral globules, black colour, total colour count, and maximum diameter of the lesion were associated with high-grade dysplasia and melanoma. In the multivariate analyses, ≥31 years of age (OR = 3.80, 95% CI, 1.17-12.37), irregular shape of peripheral globules (OR = 3.90, 95% CI, 1.15-13.2), and total colour count (OR = 3.21, 95% CI, 1.2-8.5) were significant predictive factors for the lesions with high-grade dysplasia and melanomas. To avoid the underdiagnosis of both melanomas and high-grade dysplastic nevi with PGs, the irregular shape of peripheral globules and multiple colours after the third decade may be useful in making an excision decision. The risk increases every 1-year increase in age. Excision is suggested for all melanocytic lesions with PGs for patients 60 years or older because of the high risk of melanoma and melanocytic nevus with high-grade dysplasia.

Clinical characteristics, HPV involvement, and demographic risk factors in women with cervical intraepithelial neoplasia complicated by vaginal intraepithelial neoplasia

PurposeThis study aimed to explore the clinical characteristics and risk factors associated with cervical intraepithelial neoplasia (CIN) when coexisting with vaginal intraepithelial neoplasia (VAIN).MethodsWe analyzed the clinical data of 212 patients diagnosed with CIN, including 50 patients with concurrent VAIN. The groups were compared to identify distinct clinical features and independent risk factors for the co-occurrence of CIN and VAIN, using logistic regression analysis.ResultsPatients with both CIN and VAIN had a median age of 57, significantly older than the 41-year median age of patients with CIN only (P < 0.05). A higher prevalence of HPV infection (98.0%) was observed in the CIN and VAIN group, with a notable rate of multiple HPV infections (67.3%) compared to the CIN-only group (P < 0.05). Educational levels were significantly lower in the combined CIN and VAIN group (P < 0.05). HPV16, 33, and 52 were identified as significant types for single and multiple infections. Multivariate analysis confirmed age as an independent risk factor for CIN with VAIN (P < 0.05). VAIN3 patients were more likely to exhibit HSIL and ASC-H, whereas VAIN1 cases tended to correspond with ASCUS and LSIL diagnoses.ConclusionThe co-occurrence of CIN and VAIN is significantly influenced by patient age and educational level. The findings advocate for more diligent vaginal examination during colposcopy in older patients, particularly those with multiple HPV infections and cytological abnormalities, to enhance the early detection of vaginal lesions and prevent missed diagnoses and treatments. Additionally, the high prevalence of HPV infection, especially with certain types, underscores the importance of HPV monitoring in this patient population.

Cutaneous metaplastic synovial cyst in the buttock: A comprehensive analysis of etiologic, clinical, ultrasonic, and pathological aspects

Abstract Cutaneous metaplastic synovial cyst (CMSC) is a rare cutaneous cystic lesion, which frequently occurs subsequent to trauma or surgery, forming through the reparative and healing process. It is often misdiagnosed as foreign body granuloma or recurrent epidermoid cyst. Histologically, it is characterized by a cystic structure with multiple villous projections pointing toward the cystic space, lined by cells resembling hyperplastic synovium. To date, only 32 cases have been reported in the English literature. In this article, we present two cases of CMSC with distinctive clinical features and ultrasonic findings. Furthermore, we found only three case reports of CMSC in the gluteal region. All of these cases were elderly patients and developed CMSC at the medial aspect of the buttock. Based on their unique clinical and ultrasonic characteristics, we propose that CMSC in the buttock may be considered a distinct subgroup within CMSC, demonstrating a spectrum of degenerative diseases along with ischiogluteal bursitis.

Artificial Intelligence-Based Distinction of Actinic Keratosis and Seborrheic Keratosis.

Actinic keratosis (AK) and seborrheic keratosis (SK) represent prevalent dermatological conditions with distinct clinical characteristics and potential health implications. This article investigates recent strides in dermatological diagnostics, centered on the development and application of artificial intelligence (AI) technology for discerning between AK and SK. The objective of this study is to develop and evaluate an artificial intelligence (AI) model capable of accurately distinguishing between stage one and stage two gastric carcinoma based on pathology slides. Employing a dataset of high-resolution images obtained from Kaggle.com, consisting of 1000 AK and 1000 SK images, a novel AI model was trained using cutting-edge deep learning methodologies. The dataset underwent meticulous partitioning into training, validation, and testing subsets to ensure robustness and generalizability. The AI model showcased exceptional proficiency in distinguishing AK from SK images, attaining notable levels of accuracy, precision, recall, specificity, F1-score, and area under the curve (AUC). Insights into the etiology and clinical ramifications of AK and SK were presented, emphasizing the critical significance of precise diagnosisand tailored therapeutic approaches. The integration of AI technology into dermatological practice holds considerable potential for enhancing diagnostic precision, refining treatment decisions, and elevating patient outcomes. This article underscores the transformative impact of AI in dermatology and the importance of collaborative efforts between clinicians, researchers, and technologists in advancing the realm of dermatological diagnosis and care.

54 Identifying Geographic Clusters of H. pylori Associated Metastatic Early-Onset Gastric Cancer: A case-control study in Los Angeles

OBJECTIVES/GOALS: More young adults (age &lt;50 years) are diagnosed with metastatic gastric cancer (mGC) every year. We will evaluate the association between environmental risk factors (including historical racial residential segregation) clinical, pathologic, molecular features and H.pylori associated early-onset mGC (mE-GC). METHODS/STUDY POPULATION: This retrospective matched case-control study of patients (1:2 by diagnosis year) with mGC (early-onset [E-GC; &lt;50 years]; vs older-onset [O-GC; &gt;50 years]) from 2000-2022 from the Los Angeles Cancer Surveillance Program (LA-CSP) will be enriched by a chart-abstracted cohort from USC Norris Comprehensive Cancer (NCCC). This annotated database captures sociodemographic, medical, and pathologic features of patients treated for mGC at NCCC. It will link to LA-CSP data exploring neighborhood features (obesity rate, poverty, insurance, access to care, ethnic enclave, historical segregation, etc.) of cases and controls to identify, characterize, and compare geographic “hotspot” neighborhoods of mE-GC. We hypothesize younger Hispanic and Asian patients are at higher risk of H.pylori associated mGC. RESULTS/ANTICIPATED RESULTS: From 2000-2022, 339 patients (mE-GC n = 113; mO-GC n=226) were treated at NCCC. We will have characterized clinical and pathological features of mE-GC vs mO-GC. We determined the proportion of H. pylori associated mE-GC vs mO-GC. We will have established the geographical distribution of patients with mE-GC vs mO-GC to identify high-risk neighborhoods. We will link neighborhood risk factors such as food scarcity, poverty, health care access, ethnic enclaves, to the distinct clinical and pathological features of mE-GC, including H. pylori status. Descriptive statistics, chi-square, t-tests, and multivariable regression will be used to compare mE-GC to mO-GC. After controlling for underlying demographics and tumor features, we anticipate clusters of mE-GC and mO-GC in areas of historical racial segregation. DISCUSSION/SIGNIFICANCE: Linking neighborhood and individual risk factors for mE-GC will inform early detection and prevention efforts for vulnerable individuals in high-risk neighborhoods. Building community partnerships within these neighborhoods is essential for developing interventions targeting H. pylori treatment to reduce health disparities in mE-GC.

Clinicopathologic and Molecular Characterization of High-Risk Human Papillomavirus-Positive Carcinomas of the Urinary Tract.

Human papillomavirus (HPV) is a well-known cause of squamous cell carcinomas of anogenital and oropharyngeal regions, where treatment strategies and prognosis depend on HPV status. The significance of HPV status in tumors arising along the urinary tract is not well established. To provide detailed clinical, morphologic, immunohistochemical, and molecular analysis of HPV+ urinary tract carcinomas (UTCs). We identified and retrospectively examined 12 HPV+ UTCs, confirmed by high-risk HPV in situ hybridization. The HPV+ UTCs originated from the urethra (9) and urinary bladder (3); 5 of 12 (42%) presented with nodal metastasis. On morphology, HPV+ UTCs were predominantly basaloid; well-differentiated squamous areas were focally seen. Available immunohistochemistry (IHC) showed strong staining for p16 (11 of 11), p63 (12 of 12), cytokeratin (CK) 903 (11 of 11), and CK5/6 (11 of 11); variable staining for GATA3 (8 of 12) and CK7 (4 of 11); and rare uroplakin II staining (1 of 12). Molecular analysis revealed the most frequently altered genes: KMT2C (42%), PIK3CA (42%), and KMT2D (25%). In contrast to published conventional urothelial and squamous cell carcinoma molecular data, TERTp mutation was rare (8%), and no TP53 or CDKN2A aberrations were identified. During available follow-up (11 of 12; median, 39 months), 6 patients required treatment for recurrence; ultimately, 1 died of disease, 2 were alive with disease, and 8 had no evidence of disease. Finally, we provide 11 HPV- squamous predominant UTCs for IHC and molecular comparisons; notably, a subset of HPV- UTCs was positive for p16 IHC (27%), making p16 IHC a less-specific surrogate marker for HPV status at this site. HPV+ UTCs show distinct clinical, morphologic, and molecular characteristics, suggesting important roles for HPV in UTC.

Clinical and psychometric characteristics of depression in the elderly

IntroductionDepression in the elderly represents a multifaceted and critical area of study within the realm of geriatric mental health. As the global population continues to age, the prevalence and impact of depression among older adults have garnered increased attention from researchers and clinicians.ObjectivesThis abstract delves into the comprehensive exploration of the clinical and psychometric characteristics of depression in the elderly population. This study aims to contribute to a deeper understanding of depression’s manifestation in the third age, providing invaluable insights that can inform tailored interventions, improve diagnostic accuracy, and enhance the overall quality of life for older adults.MethodsA cross-sectional study was conducted that gathered 80 patients. Their common characteristics were the signing of the consent, their admission to the Psychiatry Clinic in Timișoara and their main diagnosis with one of the ICD-10 codes F32.x, F33.x or F06.8.This selection resulted in three groups: patients younger than 65 years old, patients older than 65 years in whom depression began before this age, and patients older than 65 years in whom depression began after 65 years of age. Anamnestic data, paraclinical, socio-demographic data, psychometric scales that measured the level of depression as well as personality scales were collected. The data that was obtained was compared and examined to find significant correlations between the 3 batches.ResultsThe results show that there are no significant differences between patients with depression from rural or urban areas, showing the universality of the occurrence of this disorder among the population, regardless their environment. Depression in the third age is most often found in the elderly who have only finished secondary school, education levels playing a role in depression prevalence suggest the significance of socio-economic factors, warranting targeted outreach and education efforts in vulnerable populations. Correlations were also found between the level of depression and certain blood parameters. The integration of these findings for an understanding of the etiology of depression can pave the way for new therapeutic approaches. Certain personality traits were correlated more with certain items on the scales that evaluated depression, thus in those with a neurotic personality it is very strongly correlated with the appearance of guilt as a symptom, agreeableness with psychomotor slowness, paranoid with insomnia, and anankastic and dependent personalities were correlated much more with social isolation.ConclusionsBy recognizing the distinct clinical features and implications of depression in older adults, we can pave the way for improved mental health care and better quality of life for this growing population. This study reinforces the importance of continuous research and collaboration in the field of geriatric mental health.Disclosure of InterestNone Declared

Tuberculosis of the thyroid gland: A rare case report

Abstract Tuberculosis (TB) of the thyroid gland is exceedingly rare, even in regions like India, where tuberculosis is prevalent, with an estimated incidence of 0.1–0.4%. While tuberculosis can affect various organs, its involvement in the thyroid, pancreas, striated, and cardiac muscle is uncommon. Diagnosis poses a challenge due to the lack of distinctive clinical features—microscopic examination revealing epithelioid granulomas, sometimes with caseous necrosis and Langhans-type giant cells, aids in diagnosis. Confirmation typically involves detecting acid-fast bacilli through staining techniques like Ziehl Neelsen (ZN), molecular diagnostic methods such as TB Gene Expert or polymerase chain reaction for Mycobacterium tuberculosis (TB PCR), and histopathological examination of excised specimens. Recently, we encountered a case involving a 21-year-old male presenting with a 2-month history of diffuse neck swelling. Clinical examination suggested thyroid swelling, confirmed by ultrasound, showing a cystic lesion with necrotic areas, suggestive of thyroiditis, accompanied by bilateral cervical lymphadenopathy. Fine Needle Aspiration Cytology revealed necrotizing granulomatous thyroiditis, prompting further investigation for tuberculosis. TB Gene Expert and ZN staining performed on fine needle aspiration cytology (FNAC) material confirmed tuberculosis, leading to anti-tuberculous treatment, which resulted in a positive response. In presenting this case, we aim to highlight the rarity of tuberculosis affecting the thyroid gland and emphasize the importance of considering minimally invasive diagnostic methods, such as FNAC and molecular techniques, before resorting to surgical interventions. This case underscores the significance of clinicians’ awareness regarding unusual tuberculosis presentations and the availability of advanced diagnostic tools to ensure timely and appropriate management.

ELAVL2 loss promotes aggressive mesenchymal transition in glioblastoma

Glioblastoma (GBM), the most lethal primary brain cancer, exhibits intratumoral heterogeneity and molecular plasticity, posing challenges for effective treatment. Despite this, the regulatory mechanisms underlying such plasticity, particularly mesenchymal (MES) transition, remain poorly understood. In this study, we elucidate the role of the RNA-binding protein ELAVL2 in regulating aggressive MES transformation in GBM. We found that ELAVL2 is most frequently deleted in GBM compared to other cancers and associated with distinct clinical and molecular features. Transcriptomic analysis revealed that ELAVL2-mediated alterations correspond to specific GBM subtype signatures. Notably, ELAVL2 expression negatively correlated with epithelial-to-mesenchymal transition (EMT)-related genes, and its loss promoted MES process and chemo-resistance in GBM cells, whereas ELAVL2 overexpression exerted the opposite effect. Further investigation via tissue microarray analysis demonstrated that high ELAVL2 protein expression confers a favorable survival outcome in GBM patients. Mechanistically, ELAVL2 was shown to directly bind to the transcripts of EMT-inhibitory molecules, SH3GL3 and DNM3, modulating their mRNA stability, potentially through an m6A-dependent mechanism. In summary, our findings identify ELAVL2 as a critical tumor suppressor and mRNA stabilizer that regulates MES transition in GBM, underscoring its role in transcriptomic plasticity and glioma progression.

New Insights into First-Line Therapy in Diffuse Large B-Cell Lymphoma: Are We Improving Outcomes?

Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of lymphoma, comprising heterogeneous patient subgroups with distinctive biological and clinical characteristics. The R-CHOP combination (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard initial treatment, yielding prolonged remissions in over 60% of patients with advanced-stage disease. Several attempts to enhance the outcomes of this regimen over the last two decades have shown limited success. Various novel therapeutic approaches have recently emerged in lymphoma, demonstrating promising results. These include small molecules, novel monoclonal antibodies, antibody-drug conjugates (ADC), bispecific antibodies (BsAbs), and chimeric antigen receptor (CAR) T-cell therapy. This review explores recent advancements in therapeutic strategies for DLBCL and their potential impact on the initial management of DLBCL patients.

The "Can Do, Do Do" Framework Applied to Assess the Association between Physical Capacity, Physical Activity and Prospective Falls, Subsequent Fractures, and Mortality in Patients Visiting the Fracture Liaison Service.

The "can do, do do" framework combines measures of poor and normal physical capacity (PC, measured by a 6 min walking test, can do/can't do) and physical activity (PA, measured by accelerometer, do do/don't do) into four domains and is able to categorize patient subgroups with distinct clinical characteristics, including fall and fracture risk factors. This study aims to explore the association between domain categorization and prospective fall, fracture, and mortality outcomes. This 6-year prospective study included patients visiting a Fracture Liaison Service with a recent fracture. Outcomes were first fall (at 3 years of follow-up, measured by fall diaries), first subsequent fracture, and mortality (at 6 years). Cumulative incidences of all three outcomes were calculated. The association between domain categorization and time to the three outcomes was assessed by uni- and multivariate Cox proportional hazard analysis with the "can do, do do" group as reference. The physical performance of 400 patients with a recent fracture was assessed (mean age: 64 years; 70.8% female), of whom 61.5%, 20.3%, and 4.9% sustained a first fall, sustained a subsequent fracture, or had died. Domain categorization using the "can do, do do" framework was not associated with time to first fall, subsequent fracture, or mortality in the multivariate Cox regression analysis for all groups. "Can't do, don't do" group: hazard ratio [HR] for first fall: 0.75 (95% confidence interval [CI]: 0.45-1.23), first fracture HR: 0.58 (95% CI: 0.24-1.41), and mortality HR: 1.19 (95% CI: 0.54-6.95). Categorizing patients into a two-dimensional framework seems inadequate to study complex, multifactorial outcomes. A personalized approach based on known fall and fracture risk factors might be preferable.

Abstract 4630: Clinical and epidemiological profile of neuroendocrine differentiation- A hospital-based retrospective study

Abstract Background: Neuroendocrine differentiation (NED) in carcinomas is poorly studied globally, despite its distinct clinical features, disease progression, pathology, treatment outcomes, and poor prognosis. Therefore, it is imperative to conduct further analysis utilizing extensive clinical samples to unveil the clinical and epidemiological profile of NED. Methods: A retrospective study was conducted to analyze the histopathological samples of patients diagnosed with malignant tumor using immunohistochemical techniques for NED markers, such as ChrA, Syno and CD56. The morbidity and prognosis of NED patient would be analyzed subsequently. Eligible patients must have pathologically confirmed gastric cancer, colorectal cancer, lung cancer, esophageal cancer and prostate cancer with no prior neoadjuvant chemotherapy or radiotherapy received before surgery. Patients aged 18-75 years with normal organ functions were enrolled. Results: Between January 2017 and June 2018, over 450 cases were enrolled. Preliminary analysis focused on 36 esophageal cancer (EC) and 44 prostatic cancer (PC) samples. NED markers were expressed in 4 (11.1%) of 36 EC patients, including 4 cases positive for Syno, 1 case positive for ChrA, and 2 cases positive for CD56. Meanwhile, NED markers were expressed in 15 (34.1%) of 44 PC patients, including 10 cases positive for Syno, 15 cases positive for ChrA, and 2 cases positive for CD56. Conclusion: Neuroendocrine differentiation is obviously observed in EC and PC. The encouraging prevalence rate of NED may have clinical implications for individualized treatment. Further research is needed to explore this area in more detail. Citation Format: Yaru Wen, Susheng Shi. Clinical and epidemiological profile of neuroendocrine differentiation- A hospital-based retrospective study [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 4630.

Abstract 5100: Multimodal real world data reveals immunogenomic drivers of acquired and primary resistance to immune checkpoint blockade

Abstract Background: Why some patients fail or have short lived response to immune checkpoint blockade (ICB) immunotherapy remains largely unknown. While baseline molecular assessments have provided clues to prognostic factors, insights into resistance drivers remains elusive. This is partially due to the difficulty in getting access to post progression samples from patients that were either primary resistant or developed acquired resistance after an initial response to ICB. Thus, the tumor-intrinsic and -extrinsic features that are selected for during progression and potentially drive primary and acquired resistance to immunotherapy remain underexplored. Methods: To compare clinical features and immunogenomic drivers of acquired and primary resistance to ICB across major cancers, we analysed and annotated de-identified patient records in the Tempus real-world database. We built an immuno-oncology cohort consisting of &amp;gt;2500 multimodal (DNA, RNA and clinical outcome data) pre-treatment baseline with &amp;gt;1500 post-treatment tumour biopsy samples from mainly NSCLC, TNBC, HNC and Bladder cancer patients. We used bulk RNA-seq data to estimate activation of the hallmark oncogenic pathways and immune cell composition and used panel DNA-seq data (&amp;gt;500 genes) to quantify mutation selection at the gene and pathway levels using dndscv. Results: Compared to acquired, primary resistant patients tended to have a higher observation of liver lesions at progression. Post-ICB, acquired resistant NSCLC and HNC patients showed a significantly inflamed tumour microenvironment (TME) characterised by higher estimation of infiltration of T cells and myeloid cells and higher activation of interferon gamma (IFNg) signalling as compared to primary resistant patients. In addition, in post-ICB acquired resistance in NSCLC we observed selection for mutations in genes involved in known immunomodulatory pathways, including loss-of-function mutations in B2M. Consistently, acquired resistance patients showed stronger selection for mutations in Hedgehog and Notch pathways as compared to primary resistance patients across NSCLC, HNC and TNBC post-ICB. Conclusions: Acquired and primary ICB resistant patients have distinct clinical and molecular features at progression. Their tumours’ TME is fundamentally different with acquired resistance TMEs being infiltrated with immune cells albeit escaped post progression. In addition, ICB selects mutations that potentially activate pathways such as Notch and Hedgehog. This multi-modal Real-World Data with post therapy biopsies has given insights for patient selection strategies and provides rational into combination treatment options for acquired resistant patients. Citation Format: Mohamed Reda Keddar, Sebastian Carrasco Pro, Kathleen Burke, Ana Camelo Stewart, Mark Cobbold, Ross Stewart, Sajan Khosla, Ben Sidders, Scott Hammond, Douglas C. Palmer, Jonathan Dry, Martin L. Miller. Multimodal real world data reveals immunogenomic drivers of acquired and primary resistance to immune checkpoint blockade [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 5100.