Aggressive Disease Course Research Articles

Epigenetic Therapies in Triple-Negative Breast Cancer: Concepts, Visions, and Challenges.

Breast cancer, the most frequent malignancy in women worldwide, is a molecularly and clinically very heterogeneous disease. Triple-negative breast cancer is defined by the absence of hormone receptor and growth factor receptor ERBB2/HER2 expression. It is characterized by a more aggressive course of disease and a shortage of effective therapeutic approaches. Hallmarks of cancer cells are not only genetic alterations, but also epigenetic aberrations. The most studied and best understood alterations are methylation of the DNA base cytosine and the covalent modification of histone proteins. The reversibility of these covalent modifications make them attractive targets for therapeutic intervention, as documented in numerous ongoing clinical trials. Epidrugs, targeting DNA methylation and histone modifications, might offer attractive new options in treating triple-negative breast cancer. Currently, the most promising options are combination therapies in which the epidrug increases the efficiency of immuncheckpoint inhibitors. This review focusses exclusively on DNA methylation and histone modifications. In reviewing the knowledge about epigenetic therapies in breast cancer, and especially triple-negative breast cancer, the focus is on explaining concepts and raising awareness of what is not yet known and what has to be clarified in the future.

A novel role for KIFC1-MYH9 interaction in triple-negative breast cancer aggressiveness and racial disparity

African American (AA) women are twice as likely to develop triple-negative breast cancer (TNBC) as women of European descent. Additionally, AA women with TNBC present a much more aggressive disease course than their European American (EA) counterparts. Thus, there is an unmet clinical need to identify race-specific biomarkers and improve survival outcomes in AA patients with TNBC. The minus-end directed microtubule motor protein kinesin family member C1 (KIFC1) promotes centrosome clustering and chromosomal instability and is often overexpressed in TNBC. Previous findings suggest that KIFC1 plays a role in cell proliferation and migration in TNBC cells from AAs and that the levels of nuclear KIFC1 (nKIFC1) are particularly high in AA patients with TNBC. The nuclear localization of KIFC1 in interphase may underlie its previously unrecognized race-specific association. In this study, we found that in TNBC cells derived from AAs, nKIFC1 interacted with the tumor suppressor myosin heavy chain 9 (MYH9) over EA cells. Treatment of AA TNBC cells with commercial inhibitors of KIFC1 and MYH9 disrupted the interaction between KIFC1 and MYH9. To characterize the racial differences in the KIFC1-MYH9-MYC axis in TNBC, we established homozygous KIFC1 knockout (KO) TNBC cell lines. KIFC1 KO significantly inhibited proliferation, migration, and invasion in AA TNBC cells but not in EA TNBC cells. RNA sequencing analysis showed significant downregulation of genes involved in cell migration, invasion, and metastasis upon KIFC1 KO in TNBC cell lines from AAs compared to those from EAs. These data indicate that mechanistically, the role of nKIFC1 in driving TNBC progression and metastasis is stronger in AA patients than in EA patients, and that KIFC1 may be a critical therapeutic target for AA patients with TNBC.Graphical abstract

A study of a new mechanism: Intracellular retention allo-CART safety and efficacy for extranodal bulky B-NHL.

e19007 Background: Extranodal bulky lesions, a significant adverse prognostic factor in lymphoma, commonly denote a more aggressive disease course, mandating prompt and intensified treatment strategies. In response, we developed ThisCART19A, a non-genetic editing and off-the-shelf anti-CD19 CAR T-cell therapy incorporating intracellular retention of membrane proteins, representing a novel approach that downregulates surface expression of TCRαβ/CD3 complexes. ThisCART19 has exhibited a favorable safety profile and promising efficacy in patients with relapsed/refractory bulky B-cell Non-Hodgkin Lymphoma. Methods: This is an investigator-initiated trial employing an open-label, dose escalation, and expansion design to evaluate the safety and efficacy of ThisCART19A in patients with relapsed or refractory bulky B-cell non-Hodgkin lymphoma (B-NHL). Bulky disease was defined as the longest diameter of the mass >5 cm at baseline. Results: Between June, 2021, and June, 2023, 13 extranodal bulky disease were enrolled in the studies and successfully received ThisCART19A. The median age was 56 (range, 37~67) years. All 13 patients had 3 median prior lines of therapy (range, 2-5). All patients received anti-CD20 and multi- agent chemotherapy. 8 (61.54%) patients had prior auto CART. mSPD was 48 (range, 16~162) cm². mTMTV was 114.9 (range, 14~483) ml. As of February 2024, The most common adverse events were CRS (100%) , infections (30.77%), ICANS (23.08%) and cytopenias(100%); This is no grade 3 or higher CRS occurred;only 1(7.69%)patient experienced grade 4 ICANS and relieved after intravenous dexamethasone treatment. This is no treatment-related deaths occurred. Among the 13 patients, 10 were evaluable, with an ORR and CR of 90% and 80%, respectively, at 28 days post-infusion. mPFS was 62 days (range, 28~227). The patient who achieved a PR received chemotherapy and radiotherapy as consolidation, As of February 5th, 2024, the patient has survived for 263 days and is still under follow-up. Additionally, two patients progressed after CR received sequential chemotherapy and BCL-2 Inhibitor, with an average OS of 326.5 days, still being under follow-up. In 13 evaluable patients, the mean C-max was 1043.13 cells/μL(range, 0.59~10045.4), and the mean AUC0-28d was 1542.23 cells/μL × day(range, 0.91~11724).In this cohort, two patients received low-dose infusions at 1×106 cells/kg and still achieved excellent expansion, the respective C-max were 726.432 cells/μL and 336.67 cells/μL. Conclusions: This CART19A exhibited favorable safety, remarkable expansion potential, and efficacy profiles in the treatment of r/r bulky lymphoma. Notably, it achieved a high ORR of 90%, providing a favorable window of opportunity for subsequent consolidation and intensification treatments. Moreover, this transition from a bulky to a non-bulky disease state reduces the intricacy of follow-up treatments. Clinical trial information: NCT04384393 .

Alemtuzumab, Cladribine, Fingolimod, Natalizumab, and Rituximab as First-Line Treatments in Adults With Highly Active Relapsing-Remitting Multiple Sclerosis

What Is the Problem? Relapsing-remitting multiple sclerosis (RRMS), the most common disease course of multiple sclerosis (MS), is a chronic immune-mediated disease with clearly defined episodes of new or increasing neurologic symptoms followed by periods of relative stability. In contrast, the highly active, aggressive disease course leads to rapid disability, and these patients face an unmet need. The principal goal of MS treatment is to delay and prevent the accumulation of disability by reducing the frequency of relapses. Currently reimbursed first-line drugs fail to prevent the consequences of irreversible damage to the nervous system. There has been a paradigm shift in clinical practice toward the use of a high-efficacy treatment strategy as early as possible during the inflammatory process to provide optimal clinical benefits in preserving neurologic function in patients with highly active RRMS. What Did We Do? A systematic review of the clinical effectiveness and safety of alemtuzumab, natalizumab, cladribine, fingolimod, and rituximab relative to current first-line drugs in adults with highly active RRMS was conducted; it identified post hoc subgroup analyses from 5 randomized controlled trials (RCTs) and 1 prospective comparative cohort study. What Did We Find? Evidence was uncertain and conclusions were limited by risk of bias and small sample sizes; conclusions for some outcome comparisons were also limited by imprecision and incomplete reporting. Compared to placebo, cladribine and natalizumab may result in a clinically important reduction in relapses, disability, and key MRI lesions. Alemtuzumab may result in a clinically important reduction in relapses compared to interferon, while fingolimod may result in a clinically important reduction in relapses compared to placebo. The clinical evidence was insufficient to determine the effect of fingolimod on relapses when compared with interferon. Harms outcomes, when reported, appeared consistent with the known harms profile of the drugs. Assessment of the effectiveness and safety of rituximab could not be performed due to the lack of evidence. Evidence was also lacking for many important outcomes such as health-related quality of life (HRQoL), instrumental activities of daily living, symptoms, and cognitive outcomes. No evidence could be identified to inform on treatment sequencing. Two pragmatic RCTs (the TREAT-MS and DELIVER-MS trials) are currently ongoing, aiming to compare an early, high-efficacy treatment strategy versus a traditional escalation treatment strategy, which may inform treatment sequencing. Further research is needed to compensate for clinical data gaps to inform an appropriate and relevant economic evaluation. What Does This Mean? Jurisdictions may reconsider the current reimbursement criteria for drugs used in the first-line setting specifically for adults demonstrating highly active RRMS; however, caution should be taken given the gaps and uncertainty in evidence. Upon request from public drug plans, this review may inform a future implementation advice panel or expert committee recommendation.

Early- and Late-Onset Alzheimer's Disease: Two Sides of the Same Coin?

Early-onset Alzheimer's disease (EOAD), defined as Alzheimer's disease onset before 65 years of age, has been significantly less studied than the "classic" late-onset form (LOAD), although EOAD often presents with a more aggressive disease course, caused by variants in the APP, PSEN1, and PSEN2 genes. EOAD has significant differences from LOAD, including encompassing diverse phenotypic manifestations, increased genetic predisposition, and variations in neuropathological burden and distribution. Phenotypically, EOAD can be manifested with non-amnestic variants, sparing the hippocampi with increased tau burden. The aim of this article is to review the different genetic bases, risk factors, pathological mechanisms, and diagnostic approaches between EOAD and LOAD and to suggest steps to further our understanding. The comprehension of the monogenic form of the disease can provide valuable insights that may serve as a roadmap for understanding the common form of the disease.

Cholesteatoma in the pediatric aerodigestive population

ObjectivesTo report the prevalence of cholesteatoma and related comorbidities in pediatric aerodigestive patients requiring tracheostomy or airway reconstruction procedures. To use study findings to inform clinical management of these complex patients. MethodsA repository of clinical data drawn from our institution's electronic medical records was queried to identify airway reconstruction (airway) and complex hospital control (control) patient cohorts. Retrospective chart review was then performed to investigate the occurrence of cholesteatoma and related pathologies in these patients, as well as clinical management. ResultsThe prevalence of cholesteatoma in airway and control patients was 6/374 (1.60 %) and 35/30,565 (0.11 %), respectively. The relative risk of cholesteatoma diagnosis in airway patients was 14.01 (95 % CI 6.06–32.14). Airway patients were more likely than control patients to have pressure equalization tube history (relative risk 3.25, 95 % CI 2.73–3.82). Age at cholesteatoma diagnosis and first surgical intervention was younger in airway compared to control patients (5.43 vs. 8.33, p = 0.0182, and 6.07 vs. 8.82, p = 0.0236). However, time from diagnosis to intervention and extent of surgery were similar between the groups. ConclusionThis is the first study to investigate the prevalence of cholesteatoma in the pediatric aerodigestive population. The relative risk of cholesteatoma diagnosis was found to be 14 times higher in patients with tracheostomy or airway reconstruction history. Underlying eustachian tube and palatal dysfunction are likely contributing factors to the elevated risk. Additionally, cholesteatoma in this population was diagnosed and required surgical intervention at a younger age, which may suggest a more aggressive disease course. Providers should maintain a high degree of suspicion for cholesteatoma in this complex population.

Eosinophilic Dermatosis of Hematologic Malignancy: Emerging Evidence for the Role of Insect Bites-A Retrospective Clinico-Pathological Study of 35 Cases.

Background/Objectives: Eosinophilic dermatosis of hematologic malignancy (EDHM) is a rare cutaneous disorder associated with various hematologic malignancies, most commonly chronic lymphocytic leukemia. Detailed clinicopathologic studies of EDHM are lacking and the pathogenesis remains enigmatic. Initially thought to be a hypersensitivity reaction to insect stings, subsequent reports have challenged this understanding. The prognostic implications of EDHM remain unclear. Methods: A retrospective clinicopathologic study was performed on patients diagnosed with EDHM. Hematologic and dermatologic data were reviewed. Histologic specimens were re-evaluated and lesions were classified into acute/subacute, fully developed, and chronic/regressing. Results: The study included 35 patients. In 80% of these patients, EDHM was diagnosed after the hematologic disorder. Approximately 45% of the cohort experienced hematologic disease progression or relapse, while 65% required therapeutic intervention during the course of their hematologic disease. In total, 15/19 CLL patients had non-mutated IgHV, a marker of a more aggressive hematologic disease course. Dermatologic lesion morphology was heterogeneous, with most lesions occurring on exposed areas, and a significant 94% of patients demonstrated lesion seasonality. Histopathologic findings were consistent with features typically associated with insect bites. In addition, examination of lesions at different chronological stages revealed substantial similarities with Wells syndrome. Conclusions: Our findings support the potential role of insect bites in triggering EDHM in the context of adaptive immune dysfunction. EDHM may be associated with a more aggressive disease course or may be a marker of disease progression. The observed co-occurrence of features typical of Wells syndrome in EDHM patients suggests that these conditions are part of a spectrum of disorders that vary in clinical expression.

From biology to the clinic - exploring liver metastasis in prostate cancer.

Liver metastases from prostate cancer are associated with an aggressive disease course and poor prognosis. Results from autopsy studies indicate a liver metastasis prevalence of up to 25% in patients with advanced prostate cancer. Population data estimate that ~3-10% of patients with metastatic castration-resistant prostate cancer harbour liver metastases at the baseline, rising to 20-30% in post-treatment cohorts, suggesting that selective pressure imposed by novel therapies might promote metastatic spread to the liver. Liver metastases are associated with more aggressive tumour biology than lung metastases. Molecular profiling of liver lesions showed an enrichment of low androgen receptor, neuroendocrine phenotypes and high genomic instability. Despite advancements in molecular imaging modalities such as prostate-specific membrane antigen PET-CT, and liquid biopsy markers such as circulating tumour DNA, early detection of liver metastases from prostate cancer remains challenging, as both approaches are hampered by false positive and false negativeresults, impeding the accurate identification of early liver lesions. Current therapeutic strategies showed limited efficacy in this patient population. Emerging targeted radionuclide therapies, metastasis-directed therapy, and novel systemic agents have shown preliminary activity against liver metastases, but require further validation. Treatment with various novel prostate cancer therapies might lead to an increase in the prevalence of liver metastasis, underscoring the urgent need for coordinated efforts across preclinical and clinical researchers to improve characterization, monitoring, and management of liver metastases from prostate cancer. Elucidating molecular drivers of liver tropism and interactions with the liver microenvironment might ultimately help to identify actionable targets to enhance survival in this high-risk patient group.

The need for surgery in pediatric patients with inflammatory bowel disease treated with biologicals

PurposeInflammatory bowel disease (IBD) in childhood often presents with a more extensive and more aggressive disease course than adult-onset disease. We aimed to evaluate if biological treatment started in childhood decreases the need for intestinal surgery over time.MethodsThis was a retrospective, single-center, cohort study. All pediatric patients with IBD initiated to biological therapy at the Children’s Hospital, were included in the study and followed up to the first surgical procedure or re-operation in their adulthood or until 31.12.2021 when ≥ 18 of age. Data were collected from the pediatric registry of IBD patients with biologicals and medical charts.ResultsA total of 207 pediatric IBD patients were identified [150 with Crohn´s disease (CD), 31 with ulcerative colitis (UC), 26 with IBD unclassified (IBDU)] of which 32.9% (n = 68; CD 49, UC 13, IBDU 6) underwent intestinal surgery. At the end of a median follow-up of 9.0 years (range 2.0-25.9), patients reached a median age of 21.4 years (range 18–36). Patients who had intestinal surgery in childhood were more likely to have IBD-related surgery also in early adulthood. The duration of the disease at induction of the first biological treatment emerged as the only risk factor, with a longer duration in the surgical group than in patients with no surgery.ConclusionDespite initiation of biological treatment, the risk of intestinal surgery remains high in pediatric IBD patients and often the need for surgery emerges after the transition to adult IBD clinics.

Atypical Teratoid/Rhabdoid Tumor with Retained SMARCB1 (INI1) Expression and Rare SMARCA4 Gene Mutation: A Case Report of a Pediatric Patient

Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive tumors of the central nervous system (CNS), accounting for 1–3% of all pediatric CNS tumors. In general, AT/RTs are associated with biallelic inactivation of SMARCB1, resulting in the loss of expression of the integrase interactor 1 (INI1) protein. In this report, we describe the clinical course of an infant patient who presented with fatigue, postprandial vomiting, and disability of left side movement. Histological examination revealed classical features indicative of rhabdoid tumors, yet an atypical immunohistochemical profile with preserved INI1 expression was observed. Molecular diagnostics further elucidated the presence of a heterozygous frameshift variant, SMARCA4 c.2693del, p.(Asn898Thrfs*12), underscoring the distinctive genetic foundations of the case. Surgical resection of the tumor was administered with subsequent chemotherapy to the patient, but the condition worsened dynamically, and a decision was made to give the patient palliative therapy. We report on a patient with AT/RT caused by a rare mutation of the SMARCA4 gene and an aggressive course of disease to provide more information and characteristics of these tumors.

Characterization of Adult Patients with Pilocytic Astrocytoma with an Aggressive Clinical Course. Retrospective Cross-Sectional Study. Single Center Experience

Background: Pilocytic astrocytoma (PA) is a common tumor of the central nervous system and is considered a benign condition. However, in some cases PA can have an aggressive clinical behavior. Aim: To analyze and correlate factors leading to an aggressive course of disease in patients with Pilocytic astrocytoma.

Matching proposed clinical and MRI criteria of aggressive multiple sclerosis to serum and cerebrospinal fluid markers of neuroaxonal and glial injury

BackgroundDefinitions of aggressive MS employ clinical and MR imaging criteria to identify highly active, rapidly progressing disease courses. However, the degree of overlap between clinical and radiological parameters and biochemical markers of CNS injury is not fully understood. Aim of this cross-sectional study was to match clinical and MR imaging hallmarks of aggressive MS to serum/CSF markers of neuroaxonal and astroglial injury (neurofilament light chain (sNfL, cNfL), and glial fibrillary acidic protein (sGFAP, cGFAP)).MethodsWe recruited 77 patients with relapsing–remitting MS (RRMS) and 22 patients with clinically isolated syndrome. NfL and GFAP levels in serum and CSF were assessed using a single-molecule-array HD-1-analyzer. A general linear model with each biomarker as a dependent variable was computed. Clinical and imaging criteria of aggressive MS, as recently proposed by the ECTRIMS Consensus Group, were modeled as independent variables. Other demographic, clinical or laboratory parameters, were modeled as covariates. Analyses were repeated in a homogenous subgroup, consisting only of newly diagnosed, treatment-naïve RRMS patients presenting with an acute relapse.ResultsAfter adjusting for covariates and multiplicity of testing, sNfL and cNfL concentrations were strongly associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.00008; pcNfL = 0.004) as well as the presence of infratentorial lesions on MRI (psNfL = 0.0003; pcNfL < 0.004). No other clinical and imaging criteria of aggressive MS correlated significantly with NfL or GFAP in serum and CSF. In the more homogeneous subgroup, sNfL still was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.001), presence of more than 20 T2-lesions (psNfL = 0.049) as well as the presence of infratentorial lesions on MRI (psNfL = 0.034), while cNfL was associated with the presence of ≥2 gadolinium-enhancing lesions (psNfL = 0.011) and presence of more than 20 T2-lesions (psNfL = 0.029).ConclusionsAmong proposed risk factors for an aggressive disease course, MRI findings but not clinical characteristics correlated with sNfL and cNfL as a marker of neuroaxonal injury and should be given appropriate weight considering MS prognosis and therapy. No significant correlation was detected for GFAP alone.

Abstract 649: SOX11 regulates BCR signaling via the PAX5/CD19 axis in MCL

Abstract Background: Mantle cell lymphoma (MCL) is an incurable lymphoid neoplasm, comprising about 6% of all non-Hodgkin lymphoma (NHL). The transcription factor SOX11 is overexpressed in the majority of MCL patients and linked to a more aggressive disease course and poorer clinical outcomes. In MCL, naïve B cells experience continuous proliferation because of the dysregulation of the B-cell receptor (BCR) pathway. Our previously published data (Kuo et. al., Blood 2018) identified that SOX11 aberrantly upregulated BCR signaling in transgenic mouse models. The current study describes the exact mechanism by which SOX11 regulates the BCR pathway using a combination of functional and pharmacological approaches. Methods: To investigate the alterations in signaling pathways regulated by SOX11, we utilized a small molecule SOX11 inhibitor (Jatiani et. al., CCR 2021), performed CRISPR/CAS9 knockout of SOX11, 3X FLAG TAG overexpression, as well as conducted western blot and flow-cytometry experiments. Results: Our prior published results (Kuo et. al., Oncogene 2015), as well as others (Vegliante et. al., Blood 2013), have shown that PAX5 is a direct target of SOX11. We confirmed PAX5 downregulation after SOX11 depletion in three human MCL cell lines (JEKO, MINO, Z138) using CRISPR-CAS9. Decrease of PAX5 expression was associated with reduction in CD19 expression and a concurrent reduction in phospho-BTK (Bruton tyrosine kinase). Conversely, overexpression of SOX11 could rescue PAX5/CD19 expression and restore p-BTK levels. Furthermore, the treatment of SOX11 expressing cells with small molecule SOX11-specific inhibitors resulted in a reduction in PAX5, CD19 and BCR activation (p-BTK). Conclusion: Taken together, these findings delineate PAX5 as the direct target and PAX5/CD19 axis as the downstream pathway by which SOX11 regulates B-cell receptor (BCR) signaling in MCL. Notably, our treatment using a SOX11 inhibitor successfully replicated the effects observed with genetic knockdown. In conclusion, our findings provide valuable insights into the molecular mechanisms by which SOX11 contributes to MCL pathogenesis. The further development of pharmacological inhibitors targeting SOX11 holds promise as a beneficial therapeutic strategy for MCL patients, as these will block signaling upstream of current resistance mechanisms. Citation Format: Rudra Prasad Dutta, Heng-Huan Lee, Violetta V Leshchenko, Ravi Prakash Shukla, Yang Liu, Jian Jin, Michael Wang, Samir Parekh. SOX11 regulates BCR signaling via the PAX5/CD19 axis in MCL [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 649.

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.

Abstract 7361: The prognostic value of TP53 and tumor suppressor gene mutations in temozolomide-treated IDH1 mutant low-grade glioma

Abstract Background: Temozolomide has been extensively utilized in the treatment of gliomas across various grades, offering significant therapeutic benefits. However, the impact of concurrent mutations in TP53 and other tumor suppressor genes (TSG) on treatment outcomes in patients with IDH1 mutant low-grade glioma (LGG) treated with temozolomide remains to be fully understood. This study aims to explore the influence of these genetic factors on the response to temozolomide therapy, focusing on identifying potential genetic markers that can predict therapeutic outcomes. Methods: Our study exclusively analyzed The Cancer Genome Atlas (TCGA) LGG PanCancer dataset from cBioPortal, focusing on IDH1 mutant cases treated with temozolomide. Data analysis was carried out using Python 3.11. The cohort was categorized based on genetic alterations: TP53 mutation with additional TSGs (ATRX, CIC, FUBP1, NOTCH1) mutations (TP53mut/TSGmut), TP53 mutation without additional TSG mutations (TP53mut/TSGwt), and no TP53 mutations (TP53wt). Results: In our study, 178 LGG samples with IDH-1 mutation treated with temozolomide were selected. Of these, 113 samples had a mutation in TP53, and 88 had an additional mutation in a TSG. For TP53mut/TSGmut compared to TP53wt, the analysis revealed significant differences in clinical outcomes (PFS: HR 1.95, CI: 1.17-3.26, p=0.011; OS: HR 1.6, CI: 1.13-2.26, p=0.008). When comparing TP53mut/TSGwt with TP53mut/TSGmut, the findings were (PFS: HR 1.36, CI: 0.63-2.92, p=0.432; OS: HR 0.93, CI: 0.31-2.79, p=0.896). Finally, the comparison between TP53wt and TP53mut/TSGwt showed (PFS: HR 1.45, CI: 0.62-3.39, p=0.397; OS: HR 2.31, CI: 0.64-8.3, p=0.200). Conclusion: The presence of concurrent mutations in TP53 and other TSGs in IDH1 mutant LGG patients (TP53mut/TSGmut) is indicative of a more aggressive disease course and reduced response to temozolomide treatment, as evidenced by significantly worse clinical outcomes. In contrast, the TP53mut/TSGwt group did not exhibit significant differences in treatment outcomes. These findings underscore the importance of detailed genetic profiling in developing personalized treatment strategies for this patient population. Citation Format: Yahia E. Salem, Bayan O. Abu Alragheb. The prognostic value of TP53 and tumor suppressor gene mutations in temozolomide-treated IDH1 mutant low-grade glioma [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 7361.

Patterns of B-cell lymphocyte expression changes in pre- and post-malignant prostate tissue are associated with prostate cancer progression.

Inflammation characterized by the presence of T and B cells is often observed in prostate cancer, but it is unclear how T- and B-cell levels change during carcinogenesis and whether such changes influence disease progression. The study used a retrospective sample of 73 prostate cancer cases (45 whites and 28 African Americans) that underwent surgery as their primary treatment and had a benign prostate biopsy at least 1 year before diagnosis. CD3+, CD4+, and CD20+ lymphocytes were quantified by immunohistochemistry in paired pre- and post-diagnostic benign prostate biopsy and tumor surgical specimens, respectively. Clusters of similar trends of expression across two different timepoints and three distinct prostate regions-benign biopsy glands (BBG), tumor-adjacent benign glands (TAG), and malignant tumor glandular (MTG) regions-were identified using Time-series Anytime Density Peaks Clustering (TADPole). A Cox proportional hazards model was used to estimate the hazard ratio (HR) of time to biochemical recurrence associated with region-specific lymphocyte counts and regional trends. The risk of biochemical recurrence was significantly reduced in men with an elevated CD20+ count in TAG (HR = 0.81, p = 0.01) after adjusting for covariates. Four distinct patterns of expression change across the BBG-TAG-MTG regions were identified for each marker. For CD20+, men with low expression in BBG and higher expression in TAG compared to MTG had an adjusted HR of 3.06 (p = 0.03) compared to the reference group that had nominal differences in CD20+ expression across all three regions. The two CD3+ expression patterns that featured lower CD3+ expression in the BBG compared to the TAG and MTG regions had elevated HRs ranging from 3.03 to 4.82 but did not reach statistical significance. Longitudinal and spatial expression patterns of both CD3+ and CD20+ suggest that increased expression in benign glands during prostate carcinogenesis is associated with an aggressive disease course.

Differentiation of benign and metastatic lymph nodes in soft tissue sarcoma

Lymph node metastasis (LNM) occurs in less than 5% of soft tissue sarcoma (STS) patients and indicates an aggressive course of disease. Suspicious lymph nodes (LN) in staging imaging are a frequent topic of discussion in multidisciplinary tumor boards. Predictive markers are needed to facilitate stratification and improve treatment of STS patients. In this study, 56 STS patients with radiologically suspicious and subsequently histologically examined LN were reviewed. Patients with benign (n = 26) and metastatic (n = 30) LN were analyzed with regard to clinical, laboratory and imaging parameters. Patients with LNM exhibited significantly larger short axis diameter (SAD) and long axis diameter (LAD) vs. patients with benign LN (median 22.5 vs. 14 mm, p < 0.001 and median 29.5 vs. 21 mm, p = 0.003, respectively). Furthermore, the presence of central necrosis and high maximal standardized uptake value (SUVmax) in FDG-PET-CT scans were significantly associated with LNM (60 vs. 11.5% of patients, p < 0.001 and median 8.59 vs. 3.96, p = 0.013, respectively). With systemic therapy, a slight median size regression over time was observed in both metastatic and benign LN. Serum LDH and CRP levels were significantly higher in patients with LNM (median 247 vs. 187.5U/L, p = 0.005 and 1.5 vs. 0.55 mg/dL, p = 0.039, respectively). This study shows significant associations between LNM and imaging features as well as laboratory parameters of STS patients. The largest SAD, SUVmax in FDG-PET-CT scan, the presence of central necrosis, and high serum LDH level are the most important parameters to distinguish benign from metastatic LNs.

Bioinformatics analysis for the identification of Sprouty-related EVH1 domain-containing protein 3 expression and its clinical significance in thyroid carcinoma

The poorly differentiated thyroid carcinoma (THCA) subtype is associated with an aggressive disease course, a less favorable overall prognosis, and an increased risk of distant organ metastasis. In this study, our objective was to explore the potential utility of the Sprouty-related EVH1 domain-containing protein 3 (SPRED3) as a biomarker for early diagnosis and prognosis in THCA patients. The differentially expressed prognostic-related genes associated with THCA were identified by querying The Cancer Genome Atlas (TCGA) database. The difference in the expression of the SPRED3 gene between thyroid carcinoma (THCA) tissues and normal tissues was analyzed using data from The Cancer Genome Atlas (TCGA) and further validated through immunohistochemistry. Univariate and multivariate Cox regression models were used, along with clinical information from THCA patients, to analyze the prognostic value of the SPRED3 gene in THCA patients. Functional enrichment analysis was subsequently performed to elucidate the molecular mechanisms underlying the regulatory effects of the SPRED3 gene on thyroid carcinoma. Additionally, we calculated the percentage of infiltrating immune cells in THCA patients and evaluated their correlation with SPRED3 gene expression. Compared with those in noncancerous thyroid tissue, the gene and protein expression levels of SPRED3 were found to be elevated in thyroid carcinoma tissues. Furthermore, the expression of SPRED3 in thyroid carcinoma exhibited significant correlations with tumor location, histological grade, pathological stage, and tumor node metastasis classification (TNM) stage. Univariate and multivariate Cox proportional hazards (Cox) regression analyses demonstrated that SPRED3 could serve as an independent prognostic factor for predicting the overall survival of THCA patients. The results of functional enrichment analysis suggested the potential involvement of SPRED3 in the regulation of extracellular matrix organization, epidermal development, signaling receptor activator activity, skin development, receptor ligand activity, glycosaminoglycan binding, neuroactive ligand‒receptor interaction, the IL-17 signaling pathway, and the PI3K-Akt signaling pathway. Additionally, there were significant correlations between the expression level of the SPRED3 gene and the infiltration of various immune cells (eosinophils, central memory T cells, neutrophils, macrophages, and NK cells) within the thyroid tumor microenvironment. SPRED3 can be used as a prognostic biomarker in patients with THCA could potentially be therapeutic target for THCA.

Prevalence and Clinical Impact of Immune-Mediated Inflammatory Diseases in Patients with Inflammatory Bowel Disease: Results from a Large Retrospective Observational Study.

(1) Background: Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders involving innate and adaptive immune responses. Despite primarily affecting the gut, recent insights highlight systemic implications, expanding our understanding beyond intestinal boundaries. (2) Methods: This retrospective multicentric study explored the association of IBD and immune-mediated inflammatory diseases (IMIDs) and the impact of concurrent IMIDs on the course of IBD. Clinical data were collected from consecutive medical records of patients with IBD. For assessing the impact of concurrent IMIDs, a control group of IBD patients without associated IMIDs was considered. (3) Results: Of 6589 IBD patients, 6.8% exhibited concomitant IMIDs. Notably, 79.8% of these patients had an aggressive disease course. Psoriasis, atopic dermatitis, and type 1 diabetes mellitus prevalence were lower in the IBD population than in the general population. Conversely, multiple sclerosis, primary sclerosing cholangitis, and pyoderma gangrenosum were more prevalent in IBD patients. Among the patients with a concomitant IMID, 79.8% had an aggressive disease course vs. 8.1% in the control group (p < 0.001). (4) Conclusions: This study underscores the frequency of IMIDs in IBD patients and their association with a more aggressive disease course. The recognition of concurrent IMIDs is crucial for comprehensive patient management, influencing therapeutic decisions and potentially improving outcomes.

Real-world treatment patterns in patients with BRCA 1/2-positive (BRCA+) metastatic castration-resistant prostate cancer (mCRPC) initiating first-line (1L) therapy.

52 Background: Patients with BRCA+ mCRPC have an aggressive disease course. Recently, they have been shown to be responsive to treatment with poly ADP-ribose polymerase inhibitors, such as niraparib, olaparib, and rucaparib, used in combination with abiraterone acetate and prednisone or prednisolone, or as monotherapy. This study aimed to describe real-world treatment patterns and outcomes among patients with BRCA+ mCRPC. Methods: De-identified electronic health records from the Flatiron Health – Foundation Medicine Inc. (FMI) Metastatic PC Clinico-Genomic Database (01/01/2011 – 06/30/2022) were used to select BRCA+ mCRPC patients initiating 1L therapy on or after 01/01/2019 or monotherapy with androgen deprivation therapy (ADT). Patients were classified as recipients of ADT monotherapy if they used ADT at mCRPC diagnosis and did not initiate any subsequent advanced PC therapy. Distribution, line of therapy (LOT) sequences, and reasons for censoring were described in 1L, and among patients who advanced to second-line (2L) therapy. Flatiron Health and FMI did not participate in data analyses. Results: A total of 98 treated patients with BRCA+ mCRPC were included (mean age 72 years, 58% White, 15% Black, 55% Medicare-insured), 19 of whom received ADT monotherapy (mean age 70 years, 53% White, 26% Black, 47% Medicare-insured). The top five treatment regimens for mCRPC were ADT monotherapy (19%), enzalutamide (ENZ; 14%), olaparib (OLA; 13%), abiraterone acetate (AA; 11%), and docetaxel (DOC; 10%), with 14% of patients receiving ≥1 medication. The main reasons for censoring in patients with ADT monotherapy were death (52.6%), loss to follow-up (26.3%), and end of data availability (21.1%). Among the 79 patients treated with other than ADT monotherapy in 1L, 43.0% (n=34) did not advance to 2L, of which 35.3% were lost to follow-up, 29.4% died (median time-to-death: 2.25 months), 29.4% were censored at the end of data availability, and 5.9% initiated a clinical trial drug. The most prescribed 2L therapies were DOC (22.2%), OLA (20.0%), AA (13.3%), and ENZ (11.1%). In those who advanced to 2L (n=45), the most common 1L → 2L treatment sequences were OLA → DOC (11.1%), ENZ → DOC (6.7%), AA → ENZ (6.7%), and AA → OLA (6.7%). In patients receiving 2L, 51.1% (n=23) did not advance to third-line therapy, of which 34.8% died, 34.8% were lost to follow-up, 26.1% were censored at the end of data availability, and 4.3% initiated a clinical trial drug. Conclusions: Among treated patients with BRCA+ mCRPC, ADT monotherapy, ENZ, OLA, AA, and DOC were most commonly used. The majority of ADT monotherapy patients died, while a substantial proportion of patients initiating 1L therapy died or initiated a clinical trial drug and did not advance to 2L, suggesting unmet need for more effective 1L treatment for patients with BRCA+ mCRPC.