High-risk Clinical Features Research Articles

The Risk Factors of High-Risk Human Papillomavirus Susceptibility and Clinical Features in HIV-Positive Patients with Anal Condyloma Acuminatum: A Retrospective Cohort Study

The Risk Factors of High-Risk Human Papillomavirus Susceptibility and Clinical Features in HIV-Positive Patients with Anal Condyloma Acuminatum: A Retrospective Cohort Study

Delineation of features, responses, outcomes, and prognostic factors in pediatric PDGFRB-positive acute lymphoblastic leukemia patients: A retrospective multicenter study.

PDGFRB fusions in acute lymphoblastic leukemia (ALL) is rare. The authors identified 28 pediatric PDGFRB-positive ALL. They analyzed the features, outcomes, and prognostic factors of this disease. This multicenter, retrospective study included 6457 pediatric patients with newly diagnosed PDGFRB fusion ALL according to the CCCG-ALL-2015 and CCCG-ALL-2020 protocols from April 2015 to April 2022 in 20 hospitals in China. Of these patients, 3451 were screened for PDGFRB fusions. Pediatric PDGFRB-positive ALL accounted for only 0.8% of the 3451 cases tested for PDGFRB. These patients included 21 males and seven females and 24 B-ALL and 4 T-ALL; the median age was 10 years; and the median leukocyte count was 29.8 × 109/L at baseline. Only one patient had eosinophilia. Three patients had an IKZF1 deletion, three had chromosome 5q31-33 abnormalities, and one suffered from a complex karyotype. The 3-year event-free survival (EFS), overall survival (OS), and cumulative incidence of relapse (CIR) were 33.1%, 65.5%, and 32.1%, respectively, with a median follow-up of 25.5 months. Twenty patients were treated with chemotherapy plus tyrosine-kinase inhibitors (TKIs) and eight were treated without TKI. Complete remission (CR) rates of them were 90.0% and 63.6%, respectively, but no differences in EFS, OS, or CIR. Univariate analyses showed patients with IKZF1 deletion or measurable residual disease (MRD) ≥0.01% after induction had inferior outcomes (p<.05). Pediatric PDGFRB-positive ALL has a poor outcome associated with high-risk features. Chemotherapy plus TKIs can improve the CR rate, providing an opportunity for lower MRD levels and transplantation. MRD ≥0.01% was a powerful adverse prognostic factor, and stratified treatment based on MRD may improve survival for these patients. Pediatric acute lymphoblastic leukemia patients with PDGFRB fusions are associated with high-risk clinical features such as older age, high white blood cell count at diagnosis, high measurable residual disease after induction therapy, and increased risk of leukemia relapse. Chemotherapy plus tyrosine-kinase inhibitors can improve the complete remission rate and provide an opportunity for lower measurable residual disease (MRD) levels and transplantation for pediatric PDGFRB-positive acute lymphoblastic leukemia (ALL) patients. The MRD level was also a powerful prognostic factor for pediatric PDGFRB-positive ALL patients.

TMIC-04. SPATIAL SEQUENCING OF MEDULLOBLASTOMA REVEALS BIOLOGICAL NICHES CORRELATED WITH HIGH-RISK FEATURES AND RELAPSE

Abstract Medulloblastoma (MB) defines a heterogeneous set of neuroepithelial cancers of the posterior fossa. The MB tumor microenvironment (MB-TME) influences tumor progression and therapy response and has emerged as a growing target for novel therapeutic approaches. Prior single-cell analysis has characterized the MB-TME composition but does not reveal the spatial orientation of components. To address this gap, we performed 10X Visium spatial sequencing on sixteen pediatric MB samples obtained at surgical resection with samples representing the four molecular subtypes (WNT, N=1; SHH, N=6; Group 3, N=2; Group 4, N=5) and two matching samples at diagnosis and relapse. Spatial voxel clustering yielded clusters corresponding to malignant, immune, and stromal components of the TME, including tumor-associated astrocytes (TAAs), macrophages (TAMs), and vascular endothelium. Ten distinct clusters emerged representing malignant cell states, defined primarily by programs of cell cycle progression and neuronal differentiation. Notably, these MB cell clusters were differentially abundant between the MB subgroups, highlighting heterogeneity between disease subtypes. Moreover, examining the patterns of cellular spatial distribution in high-risk (HR) patients revealed dense regions of quiescent MB progenitors, while standard-risk patients showed greater heterogeneity within their TME. Proximity-dependent intercellular signaling further highlighted increased signaling by TAAs and vascular endothelium with decreased heat shock response signaling in HR patients. Comparing samples from relapse to diagnosis, TAMs, TAAs, and vascular endothelium were found to constitute a greater proportion of the TME. Subsequent niche-dependent gene expression and pathway analysis for TAAs localized near tumor vasculature in relapsed samples revealed increased expression of metastasis-associated pathways. Collectively, the results of our study enable new insight into the heterogeneity of the MB-TME, with close spatial association of quiescent MB progenitors correlating with high-risk clinical features. Quiescent MB progenitors have been documented to confer resistance through cellular dormancy, and identifying its molecular drivers may reveal potential targets for anticancer therapy.

The epidemiology, treatments and outcomes of patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node-positive early breast cancer in Taiwan.

Aim: Estimate patient counts, treatment patterns and outcomes of a subset of patients with early breast cancer (EBC) presenting with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive features, who are at high-risk of recurrence, in Taiwan.Materials & methods: Data from Taiwan's National Health Insurance Research Database and Taiwan Cancer Registry from 1 January 2011 to31 December 2020 were analyzed.Results: There were 4500 patients with high-risk EBC (10.4% of all patients with EBC) from 2012 to 2018, with an annual average incidence of 643 that increased over time. Five-year progression was 24.8% in patients with high-risk EBC and 8-year survival was low (69.6%).Conclusion: Patients with hormone receptor positive, human epidermal growth factor receptor 2 negative, node positive high-risk EBC clinical features are an increasing high-risk subset of all patients with EBC.

Mitral annular disjunction as the cause of malignant ventricular arrhythmia in a young adult: a case report

Mitral annular disjunction (MAD) is associated with ventricular arrhythmias and sudden cardiac death (VA/SCD). Risk prediction for VA/SCD in individuals with MAD includes clinical, ECG and imaging markers. Imaging assessment for MAD includes transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMRI) and there are certain features in each modality to aid both diagnosis and risk assessment. A 23-year-old female with no medical history presented to hospital following out of hospital cardiac arrest. Effective bystander CPR and successful cardioversion from ventricular fibrillation to sinus rhythm by paramedics achieved return of spontaneous circulation. Focused transthoracic echocardiography and cardiac magnetic resonance imaging identified MAD. Notably, there were no specific high risk clinical or imaging features. The patient recovered completely and was discharged with implantable defibrillator for secondary prevention. MAD is a rare cause of VA/SCD. Arrhythmias secondary to MAD are more likely with abnormalities on cardiac imaging, including late gadolinium enhancement, fibrosis of the mitral annulus or papillary muscles, mitral valve pathology and ventricular ectopic beats. In this case, none of the traditional risk factors for VA/SCD were present. Thus, MAD remains an important differential in all patients with an otherwise unexplained cardiac arrest, even if high risk features are not present.

Minimally Invasive Surgery: Is It a Risk Factor for Postoperative Peritoneal Metastasis in pT4 Colon Cancer?

Performing laparoscopic surgery for T4 colon cancer remains controversial because of concerns about whether its oncologic outcomes are comparable to those of open surgery, and postoperative peritoneal metastasis (PM) has been reported to occur more frequently in laparoscopic colectomy for T4 colon cancer. We investigated whether minimally invasive surgery (MIS) demonstrated a higher PM rate than open surgery and analyzed the risk factors for PM in pT4 colon cancer. This study included 392 patients with pT4 colon cancer who underwent curative surgery at a referral hospital between January 2000 and December 2018. Patients with previous neoadjuvant therapy, synchronous malignancy, metastasis, or those who underwent hyperthermic intraperitoneal chemotherapy were excluded. The MIS group had fewer high-risk clinical features, such as tumors too large for endoscope admission or complications like perforation and fistula. The group also exhibited shorter operative time, intraoperative blood loss, multivisceral resection, hospital stay, fewer postoperative complications, smaller tumor size, lower pT4b ratio, and higher pN+ rates. Multivariate analysis revealed that high-risk clinical features, MIS, pT4b, pN+, tumor size < 5 cm, high histological grade, lymphovascular invasion, and postoperative complications were significant risk factors for PM. During the median 59-month follow-up, the 5-year cumulative incidence of PM was elevated in the MIS group (17.5% vs. 8.2%; P = 0.057). No significant differences were observed in the 5-year overall and disease-free survival rates. Minimally invasive surgery increases the risk of postoperative PM in patients with pT4 colon cancer. Surgeons may require thorough tumor staging and radical resection to prevent PM.

A Multicentre Prospective Cohort Study to Identify High-Risk Transient Ischemic Attack/Minor Stroke Patients Benefitting from Echocardiography

BackgroundWe aimed to derive a clinical decision rule to identify patients with transient ischemic attack (TIA) or minor stroke most likely to benefit from echocardiography. MethodsThis multicentre prospective cohort study enrolled adults diagnosed with TIA/minor stroke in the emergency department who underwent echocardiograms within 90 days, from 13 Canadian academic emergency departments from October 2006 to May 2017. Our outcome was clinically significant echocardiogram findings. ResultsIn 7149 eligible patients, a clinically significant finding was found in 556 (7.8%). There were a further 2421 (33.9%) with potentially significant findings. History of heart failure (adjusted odds ratio [OR], 3.9) or coronary artery disease (OR, 2.7) were the factors most strongly associated with clinically significant echocardiogram findings, whereas young age, male sex, valvular heart disease, and infarct (any age) on neuroimaging were modestly associated (OR, 1.3-1.9). The model combining these predictors into a score (range: 0-15), had a C-statistic of 0.67 (95% confidence interval [CI], 0.65-0.70). A cut point of 6 points or more classified 6.6% of cases as high likelihood, defined as > 15% for clinically significant echocardiogram findings. ConclusionsEchocardiography is a very useful test in the investigations of patients with TIA/minor stroke. We identified high-risk clinical features—combined to create a clinical decision rule—to identify which patients with TIA/minor stroke are likely to have clinically significant echocardiogram findings requiring an immediate change in management. These patients should have echocardiography prioritized, whereas others may continue to have echocardiography conducted in a less urgent fashion.

A hybrid unsupervised clustering method for predicting the risk of dental implant loss

ObjectivesThe aim of this study was to predict the risk of dental implant loss by clustering features associated with implant survival rates. Materials and methodsMultiple clinical features from 8513 patients who underwent single implant placement were retrospectively analysed. A hybrid method integrating unsupervised learning algorithms with survival analysis was employed for data mining. Two-step cluster, univariate Cox regression, and Kaplan‒Meier survival analyses were performed to identify the clustering features associated with implant survival rates. To predict the risk of dental implant loss, nomograms were constructed on the basis of time-stratified multivariate Cox regression. ResultsSix clusters with distinct features and prognoses were identified using two-step cluster analysis and Kaplan‒Meier survival analysis. Compared with the other clusters, only one cluster presented significantly lower implant survival rates, and six specific clustering features within this cluster were identified as high-risk factors, including age, smoking history, implant diameter, implant length, implant position, and surgical procedure. Nomograms were created to assess the impact of the six high-risk factors on implant loss for three periods: 1) 0–120 days, 2) 120–310 days, and 3) more than 310 days after implant placement. The concordance indices of the models were 0.642, 0.781, and 0.715, respectively. ConclusionsThe hybrid unsupervised clustering method, which clusters and identifies high-risk clinical features associated with implant loss without relying on predefined labels or target variables, represents an effective approach for developing a visual model for predicting implant prognosis. However, further validation with a multimodal, multicentre, prospective cohort is needed. Clinical significanceVisual prognosis prediction utilizing this nomogram that predicts the risk of implant loss on the basis of clustering features can assist dentists in preoperative assessments and clinical decision-making, potentially improving dental implant prognosis.

Cardiac magnetic resonance reveals concealed structural heart disease in patients with frequent premature ventricular contractions and normal echocardiography: A systematic review

Premature ventricular contractions (PVCs) are a common form of arrhythmic events, often representing an idiopathic and benign condition without further therapeutic interventions. However, in certain circumstances PVCs may represent the epiphenomenon of a concealed structural heart disease (SHD). Surface 12‑leads EKG and 24-h dynamic EKG are necessary to assess their main characteristics such as site of origin, frequency and complexity. Echocardiography represents the first-line imaging tool recommended to evaluate cardiac structures and function. Cardiac Magnetic Resonance (CMR) is recognized as a superior modality for detecting structural cardiac alterations, that might evade detection by conventional echocardiography. Moreover, in specific populations such as athletes, CMR may have a crucial role to exclude a concealed SHD and the risk of serious arrhythmic events during sport activity. Some clinical characteristics such as male sex, older age or family history of sudden cardiac death (SCD) or cardiomyopathy, and some electrocardiographic features of PVCs, in particular a right branch bundle block (RBBB) with superior/intermediate axis morphology, the reproducibility of VAs during exercise test (ET) or the evidence of complex ventricular arrhythmias, may warrant a CMR evaluation, due to the high probability of SHD. In this systematic review our objective was to provide an exhaustive overview on the role of CMR in detecting a concealed SHD in patients with high daily burden of PVCs and a normal echocardiographic evaluation, paving the way for a more extensive utilization of CMR in presence of certain high-risk clinical and/or EKG features identified during the diagnostic workup.

Enhanced Survival of Chronic Myelomonocytic Leukemia-Dysplastic over Proliferative Subtype after Allogeneic Hematopoietic Cell Transplant: A Tertiary Center Experience and Literature Review.

CMML is a rare neoplasm with overlapping myelodysplastic and myeloproliferative features whose only potential cure is allogeneic hematopoietic cell transplantation (allo-HCT). This retrospective study examined 27 CMML patients with high-risk clinical features who underwent first allo-HCT at our institution between 2004 and 2022. Nineteen patients were diagnosed with the proliferative subtype (CMML-MPN) and 8 with the dysplastic subtype (CMML-MDS). Median OS was 15 months post-HCT (95% CI: 5-71); OS at 1, 3, and 5 years was 52%, 35%, and 35%, respectively. Compared to those with CMML-MPN, patients with CMML-MDS had longer OS (median, 8.6 vs. 0.9 years; p = 0.025), RFS (4.4 vs. 0.5 years; p = 0.021), and GVHD-free, relapse-free survival (GRFS, 9.4 vs. 3.4 months; p = 0.033) as well as lower 1-year NRM (13 vs. 47%; p = 0.043), with the statistical significance of this CMML subtype effect maintained in multivariable models. High-risk cytogenetics were associated with shorter GRFS in the univariable (median, 3.1 vs. 6.2 months; p = 0.013) and multivariable (HR = 4.88; p = 0.006) settings. Patients who underwent transplant for CMML-MDS experienced substantially better outcomes than those transplanted for CMML-MPN. Future studies are needed for transplantation optimization in CMML, especially CMML-MPN.

Abstract PO3-13-09: Personalized ctDNA testing for detection of molecular residual disease in patients with localized HR+ breast cancer: temporal dynamics and impact on clinical outcomes

Abstract Background: Molecular residual disease (MRD) describes detectable circulating tumor DNA (ctDNA) after definitive surgery and is an expanding field in breast oncology. Multiple studies have demonstrated detectable MRD to be poorly prognostic, and clinical trials are now underway assessing the efficacy of therapeutic interception. However, most retrospective studies did not obtain baseline imaging at the time of MRD detection, such that the proportion of patients with detectable ctDNA and concurrent radiographically evident recurrent disease is not known. Furthermore, the role of serial ctDNA testing in the adjuvant setting remains unclear. Meanwhile, tumor-informed assays such as the SignateraTM platform are now covered by Medicare. To address these outstanding clinical questions, we aimed to determine the temporal dynamics of MRD detection in HR+/HER2- breast cancer, association with radiographic recurrence, and impact on clinical outcomes. Methods: Patients with HR+/HER2- breast cancer who underwent MRD testing either as part of a clinical trial or via an expanded access program were reviewed for MRD positivity and assessed alongside clinically annotated data. All patients completed surgical resection prior to MRD testing. Whole exome sequencing of primary tumor tissue and personalized ctDNA primers were designed for multiplex PCR targeting up to 16 single nucleotide variants for MRD testing via the SignateraTM platform. Clinical data was determined through focused chart review. Results: Among 185 patients with HR+/HER2- breast cancer who underwent MRD testing, 37 patients (20%) did not complete testing due to factors including tumor tissue not meeting pathology parameters, insufficient quantity of primary tissue, or tumor/normal discordance. 14 patients (8%) had detectable ctDNA (1, 5, and 8 patients had stage I, II, and III breast cancer, respectively). Among the 6 patients who did not have stage III disease, 3 had other high-risk features (Oncotype 40; grade 3 disease x2). Overall, 71% (n=10) of the +MRD population tested positive at the first test, while 29% (n=4) tested positive only on serial sampling. Median time from surgery to positive test was 3.5 years (range: 1 month – 10.2 years). Twelve patients (86%) were on adjuvant endocrine therapy at the time of detectable MRD. Among the 14 +MRD patients, 9 underwent staging scans shortly after positive MRD testing, and among these patients, 3 (33%) had radiographic evidence of asymptomatic metastatic recurrence (2 bone-only; 1 visceral); two of these pts had 1 MRD test, while the other had a negative test followed by a positive test 11 months later. The other 3 patients with radiographic recurrences had scans prompted only by clinical symptoms &amp;gt;6 months after +MRD. Among the 4 patients with serial data after first +MRD testing, none experienced subsequent ctDNA clearance. Serial testing occurred over a median of 11.5 months (range 1.1-21.7 months). With median follow up of 8.6 months, 43% (n=6) of patients with +MRD had distant disease recurrence. Conclusions: Personalized tumor-informed ctDNA testing identified patients with high risk of recurrence, including patients without classic high-risk clinical, pathologic, or genomic features, suggesting a complementary role of MRD testing for risk assessment. Serial monitoring was necessary to identify MRD in more than a quarter of patients. Furthermore, one-third of patients with +MRD disease had asymptomatic metastatic recurrence, highlighting the importance of staging scans in studies and clinical trials assessing therapeutic interception in the adjuvant setting. Citation Format: Arielle Medford, Elyssa Denault, Zanta Ephrem, Douglas Micalizzi, Yael Bar, Rachel Abelman, Amy Comander, Justine Knape, Minetta Liu, Angel Rodriguez, Steven Isakoff, Beverly Moy, Laura Spring, Aditya Bardia. Personalized ctDNA testing for detection of molecular residual disease in patients with localized HR+ breast cancer: temporal dynamics and impact on clinical outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-13-09.

Abstract PO1-01-06: Patterns in use and tolerance of adjuvant neratinib in patients with hormone receptor (HR)-positive, HER2-positive early-stage breast cancer

Abstract Background: In the ExteNET study, 1 year of neratinib therapy was shown to derive a significant invasive disease-free survival (iDFS) benefit in HR+, HER2+, node-positive disease after trastuzumab-based adjuvant therapy. Currently, the NCCN guidelines recommend extended adjuvant neratinib following trastuzumab-based therapy for patients (pts) with high-risk HR+ HER2+ disease. Limitations to use of neratinib include significant gastrointestinal side effects which often result in pts discontinuing treatment. In this study, we aimed to identify high-risk clinical features and characteristics of pts who were offered adjuvant neratinib therapy and factors that impacted treatment completion versus discontinuation. Methods: We performed a retrospective review of all pts with early-stage HR+ HER2+ breast cancer who were prescribed neratinib from 2017-2023 at our institution. We used the electronic medical record to extract information on patient characteristics, clinical and high-risk features. High-risk was defined as any of the following: at least 4 lymph nodes positive for disease, 1-3 lymph nodes positive for disease and a grade 3 (poorly differentiated) tumor, tumor &amp;gt; 5 cm, or Ki67 &amp;gt; 20%. Length of time on treatment, treatment holds, dose reductions and up-titrations were documented. Statistical analysis was performed using two-sided T-tests and chi-square tests. Results: We identified 62 eligible pts of whom 34 (55%) completed 1 year of neratinib and 28 (45%) did not. Median age at diagnosis was 51.5 years. 49% of pts were pre-menopausal at diagnosis, 43% were post-menopausal, 5% were peri-menopausal and 3% had undocumented menopausal status at diagnosis. Clinical features of the pts are documented in Table 1. Sixty percent of patients offered neratinib were considered high-risk at diagnosis, based on definitions described above. 73% of pts received neoadjuvant treatment with pertuzumab in addition to trastuzumab. 24 pts (39%) had residual disease and 22 pts (35%) received adjuvant T-DM1. The most common reason for neratinib discontinuation was inability to tolerate side effects (54%) followed by pill burden (18%). The most common side effect experienced by pts was diarrhea despite anti-diarrheal prophylaxis (56%), followed by rash (8%). Pts who received an up-titration of neratinib were more likely to complete the full course of neratinib when compared to those who did not (76% vs. 40.5% p = 0.013). The median starting dose of those who completed neratinib treatment was 140 mg vs. 240 mg in those who did not (p = 0.016). The median length of time on neratinib for those that did not complete the 1-year treatment course was 30 days. Neither group experienced a statistically significant greater likelihood of treatment holds or dose reductions. In terms of outcomes, 10 pts had progression of disease of whom 7 did not complete neratinib treatment (p = 0.169). Interestingly, those 7 pts developed metastatic disease and 57% had central nervous system metastases. Conclusions: Pts are more likely to complete 1 year of adjuvant neratinib with dose up-titration. Dose reductions and interruptions did not affect neratinib adherence in our patient population. Seven pts in our study developed metastatic disease, all of whom did not complete adjuvant neratinib treatment. Future prospective studies are needed to further determine the impact of adjuvant neratinib treatment on iDFS in pts who have received pertuzumab and/or T-DM1. Table 1: Clinical Features of Patients Prescribed Neratinib Citation Format: Julia Blanter, Elena Baldwin, Rima Patel, Tianxiang Sheng, Amy Tiersten. Patterns in use and tolerance of adjuvant neratinib in patients with hormone receptor (HR)-positive, HER2-positive early-stage breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-06.

Qualitative and Quantitative Magnetic Resonance Imaging in Bacterial Orbital Cellulitis

ABSTRACT Purpose To summarise the qualitative and quantitative parameters of bacterial orbital cellulitis (OC) on magnetic resonance imaging (MRI) and explore their clinical correlations. Methods Multi-centre retrospective study with inclusion of patients of all ages with OC who underwent MRI. Patients with isolated pre-septal cellulitis, bilateral disease and poor-quality scans were excluded. An enlargement ratio for extraocular muscles (EOMs) was calculated by dividing maximal EOM measurements from the affected side by the contralateral side. Results Twenty MRI scans from twenty patients (Mean age: 40.8 ± 24.3 years old, M: F = 15:5) between 2011 and 2022 were analysed. Three (15.0%) cases were paediatric patients (<18 years old). All cases had both pre-septal and orbital fat involvement. The EOM were affected in nineteen cases, with the superior muscle complex (18/19, 94.7%) most commonly affected. Mean enlargement ratio (1.30, Range: 1.04–1.82) was greatest for the medial rectus on axial views on T1 and fat-suppressed contrast-enhanced T1 (FS CE T1). Optic peri-neuritis was present in eleven (55.0%) patients, whilst two (9.5%) cases had optic neuritis. A greater degree of proptosis was observed in patients with optic neuropathy and those who underwent surgical intervention compared to those without (p = .002 and p = .002, respectively). Conclusion MRI remains an important imaging modality for evaluating complicated OC. However, qualitative features may lack accuracy and is not a reproducible means of analysis. Simple quantitative parameters, such as proptosis and EOM measurements, correlate with high-risk clinical features and may have utility in predicting clinical course.

Correlation Analysis of Peripheral Blood B Cell Count with Clinical Features and Prognosis in Patients Newly Diagnosed with Diffuse Large B-Cell Lymphoma

To explore the correlation between peripheral blood B cell count and clinical features and prognosis of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). The relationship of peripheral blood B cell count with clinical features, laboratory indexes and prognosis in 67 patients with newly diagnosed DLBCL was retrospectively analyzed. Patients were divided into low B-cell count group (B cell＜0.1×109/L, n=34) and high B-cell count group (B cell≥0.1×109/L, n=33) according to the median B cell count values. Compared with the high B cell count group, the low B cell count group had a higher proportion of patients with Lugano stage III-IV, elevated LDH, elevated β2-MG and IPI score 3-5 and increased CRP (P =0.033, 0.000, 0.023, 0.001, 0.033). The peripheral CD3+ and CD4+ cell counts of patients in the low B cell count group were significantly lower than those in the high B cell count group (P =0.010, 0.017). After initial treatment, overall response rate (ORR) and complete remission (CR) rate in high B cell count group were significantly higher than those in low B cell count group (P =0.032, 0.013). The median follow-up time of patients was 23(2-77) months, progression-free survival (PFS) and overall survival (OS) of patients in the high B cell count group were significantly better than those in the low B cell count group (P =0.001, 0.002). Univariate analysis showed that pretreatment low B cell count in the peripheral blood was associated with shortened PFS and OS (HR=4.108, P =0.002; HR=8.218, P =0.006). Multivariate analysis showed that low B cell count was an independent prognostic factor for shortened PFS (HR=3.116, P =0.037). Decreased peripheral blood B cell count in newly diagnosed DLBCL patients is associated with high-risk clinical features and may affect the efficacy of immunochemotherapy, which is associated with poor clinical prognosis.

Abstract 5117: CK2 inhibiton exhibits synergistic effect in acute lymphoblastic leukemia

Abstract Survival for pre-B cell Acute lymphoblastic leukemia (B ALL) has improved greatly, however. High risk (HR) subgroups continue to result in significant mortality and morbidity of pediatric oncology patients. Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a lethal disease, often associated with high-risk clinical features. T-ALL therapy has made less improvement than B ALL and continues to represent a significant number of high-risk outcomes. Novel treatment strategies are required to overcome chemotherapy resistance and improve morbidity for HR B ALL. The development of treatments that can overcome chemotherapy resistance is essential for improving survival in T-ALL. Deletions of IKZF1, resulting in decreased IKAROS function, are present in High-risk ALL patients. Casein kinase 2 (CK2), a protein kinase upregulated in ALL, phosphorylates IKAROS preventing DNA binding reducing transcriptional regulation in ALL patients. Past studies have shown that pharmacologic inhibition of CK2 with CX-4945 rescues IKAROS function as a transcriptional regulator. Receptor tyrosine kinase c-KIT is transcriptionally regulated by IKAROS and is often upregulated in cancer. The purpose of this study was to determine whether restoration of IKAROS via CX-4945 would act in a synergistic manner with c-KIT inhibitor imatinib in ALL.Methods/results B-ALL Nalm6 cells were treated with imatinib over 72-hours to establish the half-maximal inhibitory concentration (IC50). The IC50 was used to determine the concentration range of imatinib to be used in combination with CX-4945 in a 72-hour synergy analysis of cytotoxicity.. Cell viability was measured using WST-1 cell proliferation assay. The data were analyzed using Calcusyn and synergy was defined as a combination index below 0.85. The study was repeated to determine a more precise range of synergy. The cytotoxicity of single drug c-KIT inhibitor, Imatinib, in Nalm6 B-ALL yielded an IC50 of 25uM while CK2 inhibitor CX-4945 resulted in 4uM. When a combination was administered with a constant dose of CX-4945 at 4uM and varying concentrations of imatinib, synergy was observed at multiple dose combinations. Conclusion: The data shows that CK2 inhibitor, CX-4945, and c-KIT inhibitor, imatinib, exhibit a synergistic therapeutic effect. Imatinib is indicated for use in Philadelphia positive (Ph+) acute lymphoblastic leukemia so future studies will include testing CX-4945/imatinib synergy in Ph+ BALL where we expect to see more potent synergistic effect. Citation Format: Daniel Gary Bogush, Joseph Schramm, Katarina Dovat, Yali Ding, Chingakham Singh, Sinisa Dovat. CK2 inhibiton exhibits synergistic effect in acute lymphoblastic leukemia [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 5117.

Clinical features combined with ultrasound characteristics to predict TERT promoter mutations in papillary thyroid carcinoma: a single-center study over the past 5 years.

Telomerase reverse transcriptase (TERT) has been reported in papillary thyroid carcinoma (PTC). This study aimed to investigate the correlation of TERT promoter mutations with clinical and ultrasound (US) features in PTC and to develop a model to predict TERT promoter mutations. Preoperative US images, postoperative pathological features, and TERT promoter mutation information were evaluated in 365 PTC patients confirmed by surgery. Univariate and multivariate factor analyses were performed to identify risk factors for TERT promoter mutations. A predictive model was established to assess the clinical predictive value. Of the 365 patients with PTC (498 nodules), the number of those with TERT promoter mutations was 67 cases (75 nodules), and the number of those without mutations was 298 cases (423 nodules). The median age was 40 years in the wild-type group and 60 years in the mutant group. Male patients made up 35.82% of the mutant group and 22.82% of the wild-type group. Multivariate analysis revealed that the independent risk factors associated with the occurrence of TERT promoter mutation in PTC were as follows: older age (odds ratio (OR) = 1.07; p = 0.002), maximum diameter of ≥ 10 mm (OR = 3.94; p < 0.0001), unilateral (OR = 4.15; p < 0.0001), multifocal (OR = 7.69; p < 0.0001), adjacent to the thyroid capsule (OR = 1.94; p = 0.044), and accompanied by other benign nodules (OR = 1.94, p = 0.039). A predictive model was established, and the area under the curve (AUC) of the receiver operating characteristic was 0.839. TERT promoter mutations were associated with high-risk US and clinical features compared with the wild-type group. TERT promoter mutations were associated with older ages. They were also found to be multifocal, with a maximum diameter of ≥ 10 mm, unilateral, adjacent to the thyroid capsule, and accompanied by other benign nodules. The predictive model was of high diagnostic value.

Abstract TP215: Endovascular and Medical Management Strategies for Caroticocavernous Fistulae: A Single Center Retrospective Safety and Efficacy Analysis

Background: Caroticocavernous fistulae (CCF) are a rare subtype of intracranial arteriovenous fistulae with variable clinical and angiographic presentations. This study aimed to describe the clinical outcomes in a cohort of CCF patients and identify clinical and angiographic features differentiating patients more likely to benefit from endovascular intervention. Methods: A single-center, retrospective analysis was performed to identify all patients with angiographically-confirmed CCF between 2000 and 2022. Pertinent data, including clinical symptoms, angiographic findings, treatment strategies, recurrence rates, and complications, was collected. Results: A total of 84 patients were included, of whom 67 (80%) underwent endovascular intervention and 17 (20%) were conservatively managed. Primary endovascular techniques were transvenous coil embolization (78%), feeder artery embolization (16%), and ICA flow diversion (8%). High-risk clinical symptoms, such as reduced visual acuity, and angiographic features, such as cortical and ophthalmic venous reflux, were more common in the intervention group (p&lt;0.05). All direct (Barrow Type A) CCFs underwent endovascular intervention (32% vs 0%, p=0.005), while indirect (Barrow types B-D) CCFs were common in the conservatively managed group (100% vs 68%, p=0.005). 31% of treated CCFs required retreatment, which primarily occurred with Barrow type D CCFs and following transvenous coil embolization. Procedure-related complications occurred in 10% of cases and consisted of cranial nerve palsies (n=5), asymptomatic intracranial dissection (n=1), and asymptomatic distal thromboembolic occlusion (n=1). Conclusion: High-risk symptoms and angiographic features favor endovascular intervention. Various embolization techniques, including transvenous coil embolization, proved safe and effective. In select CCF patients without high-risk clinical or angiographic features, conservative observation is a safe and effective alternative to endovascular embolization. Complications were rare, and most were transient, emphasizing the safety of endovascular management. Longitudinal angiographic surveillance is essential for monitoring fistula persistence or recurrence.

Outcomes after stenting of renal artery stenosis in patients with high-risk clinical features

BackgroundIn patients with renal artery stenosis, revascularization was seen as a mean to improve outcomes, but large studies failed to show significant benefit in general population. However, data on benefits of renal artery stenting in patients with high-risk features, such as rapidly declining renal function and cardiac destabilization syndromes, are limited, as they were excluded from trials. In this descriptive study, we aimed to evaluate short- and long-term outcomes in high-risk patients with renal artery stenosis, treated by angioplasty and stenting. We have retrospectively interrogated our local databases for renal artery percutaneous interventions; patients at high-risk (rapidly declining renal function; stable chronic renal failure and bilateral renal artery disease; severe hypertensive crisis) were selected for the current analysis.ResultsOf 30 patients undergoing renal artery stenting, 18 patients were deemed "high-risk." On short term, good in-hospital control of hypertension and cardiac stabilization were obtained in all patients. Renal function improved significantly only in patients admitted with rapidly declining renal function, with significant creatinine level fall from median 3.98 mg/dL to 2.02 mg/dL, p = 0.023. However, for the whole group, creatinine change was non-significant (− 0.12 mg/dL, p = NS). On the long term, five patients (27.8%) ended-up on chronic hemodialysis and six patients died (33.3%) after a median of 20 months. No death occurred during the first year after the procedure.ConclusionsPercutaneous procedures are feasible and safe in patients with high-risk renal artery stenosis, especially in those with rapidly declining renal function, probably saving some of them from the immediate need for renal replacement therapy, but long-term results are negatively influenced by the precarious general and cardio-vascular status of these patients and by the pre-existing significant renal parenchymal disease, non-related to the renal artery stenosis.

Inguinal lymph node metastases from prostate cancer: clinical, pathology, and multimodality imaging considerations.

To investigate clinical, pathology, and imaging findings associated with inguinal lymph node (LN) metastases in patients with prostate cancer (PCa). This was a retrospective single-center study of patients with PCa who underwent imaging and inguinal LN biopsy between 2000 and 2023. We assessed the following aspects on multimodality imaging: inguinal LN morphology; extrainguinal lymphadenopathy; the extent of primary and recurrent tumors; and non-nodal metastases. Imaging, clinical, and pathology features were compared between patients with and without metastatic inguinal LNs. We evaluated 79 patients, of whom 38 (48.1%) had pathology-proven inguinal LN metastasis. Certain imaging aspects- short-axis diameter, prostate-specific membrane antigen uptake on positron-emission tomography, membranous urethra involvement by the tumor, extra-inguinal lymphadenopathy, and distant metastases-were associated with pathology-proven inguinal LN metastases (p < 0.01 for all). Associations with long-axis diameter, fatty hilum, laterality, and uptake of other tracers on positronemission tomography were not significant (p = 0.09-1.00). The patients with metastatic inguinal LNs had higher prostate-specific antigen levels and more commonly had castration-resistant PCa (p < 0.01), whereas age, histological grade, and treatment type were not significant factors (p = 0.07-0.37). None of the patients had inguinal LN metastasis in the absence of locally advanced disease with membranous urethra involvement or distant metastasis. Several imaging, clinical, and pathology features are associated with inguinal LN metastases in patients with PCa. Isolated metastasis to inguinal LNs is extremely rare and unlikely to occur in the absence of high-risk imaging, clinical, or pathology features.

Dysregulation of Cellular Immunity in High-Risk Multiple Myeloma

Introduction: Multiple myeloma (MM) is the second most prevalent hematological malignancy, characterized by the abnormal proliferation of plasma cells in the bone marrow. Approximately 20% of MM patients present with high-risk (HR) clinical and genetic features that are associated with aggressive disease course and poor prognosis. Novel immune therapies are changing the paradigm of MM treatment. A comprehensive understanding of immune dysregulation within the tumor microenvironment (TME) of HR vs standard risk (SR) MM patients could inform the development of targeted immunotherapeutic strategies for HR MM. Methods: 55 HR and 25 SR patients were selected from the Mt. Sinai Hematologic Malignancies Tissue Bank (IRB# STUDY-11-01978). HR included one or more cytogenic abnormalities (HRCA) such as translocations t(4;14), deletion of chromosome 17 (del17p), and gain/amplification of 1q (1q+/++) based on the Second Revised International Staging System (R2-ISS). We also included nine patients with t(14;16) translocation alone or combined with one or two of the other HRCA. We performed comprehensive immune phenotyping of the bone marrow micro-environment on specimens from HR and SR patients using mass cytometry (CyTOF) and single cell RNA sequencing (scRNASeq) of bone marrow mononuclear cells (BMMC) depleted of CD138 positive MM cells. Results: ScRNAseq of BMMC from HR MM patients revealed a robust cytotoxic and cytolytic signature on CD4+ T cells relative to SR, characterized by the upregulation of genes such as GNLY, NKG7, PRF1, and IFNG, and a higher frequency of Granzyme K-positive (GZMK+) CD8+ T cells, previously described as progenitors of exhausted cells. Both CD4 and CD8 T cells, along with monocytes, exhibited high expression of a group of Interferon-stimulated genes (ISGs) including IFI27, IFIT3, IFI44L, IFITM1/3, and OASL. Notably, high expression of this group of ISGs was associated with T cell exhaustion and poor prognosis in the setting of immune checkpoint inhibitor therapy for solid tumors. Mass cytometry analysis confirmed the activated state of T cells in HR MM patients, with increased expression of immune activation markers HLA-DR, CD38, and the senescence marker CD57. Furthermore, HR patients exhibited higher frequencies of mast cells, CD14+ Monocytes and plasmacytoid dendritic cells compared to SR, suggesting an inflammatory and immunosuppressive environment that may dampen effective antitumor immune responses. Conclusions: These results indicate distinct bone marrow microenvironments of HR and SR MM. CD4 and CD8 T cells appear to be more activated in HR patients compared to SR. However, the higher frequencies of mast cells and plasmacytoid dendritic cells, and the prominent expression of ISGs associated with inhibition of anti-tumor immunity suggest dysregulation and exhaustion of T cell activity in HR patients. Collectively, these findings highlight the complex immune dynamics in HR MM and provide insights into the underlying immune dysfunction which may contribute to disease progression and therapy resistance in HR MM. Such insights have the potential to inform the design of targeted therapeutic interventions aimed at modulating the immune response and improving treatment outcomes for HR MM patients.