Prospective Clinical Trials Research Articles

Exploring Denosumab's potential in aneurysmal bone cyst treatment: A scoping review.

Background: Denosumab effectively treats RANKL-mediated bone disorders by inhibiting osteoclast activity. While approved for giant cell tumours, its role in aneurysmal bone cysts (ABC) remains unclear. This review explores denosumab's application in ABCs, focusing on its role, outcomes, and adverse effects. Methods: A scoping review adhering to PRISMA Extension for Scoping Reviews guidelines was conducted. The search involved five databases from inception until 31 December 2023. Results: From an initial 390 studies, 29 were selected post-screening involving 67 patients. The most common ABC sites were the spine (n = 42) and pelvis (n = 7). Denosumab served as primary treatment in 25 patients (37.3%), neoadjuvant in 11 (16.4%), second-line therapies after inadequate initial therapies in 24 (35.8%), and adjunct therapy in seven cases. All patients demonstrated favourable clinical and radiological responses post-denosumab. 10 patients (15%) experienced tumour recurrences: six after denosumab discontinuation (3-17months post-cessation), three post-surgery following neoadjuvant denosumab, and one during ongoing treatment. Adverse effects reported were hypocalcaemia (n = 10), hypercalcemia (n = 14), and sclerotic metaphyseal bands (n = 2), all in the paediatric age group. While hypocalcaemia surfaced early in denosumab therapy, hypercalcaemia manifested 2.5-6months post-discontinuation, mainly managed with bisphosphonates. Fewer than half of the studies had follow-ups that exceeded 2years. Conclusion: Denosumab may be an effective therapy for ABC, especially for high-risk cases like spinal and pelvic tumours. It can also be utilized as a second-line for recurrence/failed initial intervention or as neoadjuvant therapy. Concerns exist about tumour recurrence and rebound hypercalcemia, necessitating careful monitoring, longer follow-up, and prophylactic measures. Prospective clinical trials are warranted for deeper insights.

Trends in local therapy utilization and survival of patients with de-novo metastatic prostate cancer treated by hormone therapy with or without systemic therapy intensification with chemotherapy.

90 Background: Guideline-recommended treatment for de novo metastatic prostate cancer (mPCa) includes hormone therapy (HT) and androgen receptor axis-targeted (ARAT) therapy with or without chemotherapy. While retrospective data have implicated the potential survival benefit of treating the primary tumor with radical prostatectomy, prospective clinical trials have demonstrated a benefit of definitive local radiotherapy in the context of low-volume mPCa. Given this emerging data, we sought to assess population-based treatment trends in the utilization of local therapy (LT) for mPCa and the association between the receipt of contemporary LT and overall survival in patients with mPCa. Methods: Using the National Cancer Database from 2004 to 2020, we identified men aged 18-90+ who were diagnosed with de-novo mPCa. To mitigate potential confounding, propensity score matching (PSM) was employed to balance patient characteristics between the two groups, including metastatic volume. High-volume mPCa was defined as the presence of any visceral metastases or bone metastases with at least 1 distant invasion. Cox proportional hazard models with clustering were utilized to estimate hazard ratios (HRs) for the risk of all-cause mortality to account for the inherent correlation created by PSM. Results: Among 30,713 patients, 2,569 (8.36%) received both LT and systemic therapy, while 26,038 (84.78%) received systemic therapy alone. Of these, 5,453 (19.06%) had high-volume PCa, and 23,154 (80.94%) had low-volume PCa. No upward trend in LT utilization was observed from 2004 to 2020, with fluctuations in rates observed over time. After PSM, LT was associated with lower all-cause mortality risk (HR=0.87, 95% CI: 0.81-0.93, p<0.001). In patients without chemotherapy intensification, LT was correlated with an 18% lower all-cause mortality risk (HR=0.82, 95% CI: 0.26-0.70, p<0.001), specifically, radical prostatectomy with a 72% lower risk (HR=0.28, 95% CI: 0.20-0.38, p<0.001). For patients receiving chemotherapy intensification, definitive radiotherapy was related to an 18% increased all-cause mortality risk (HR=1.18, 95% CI: 1.01-1.39, p=0.04), while radical prostatectomy showed a 54% decreased risk (HR=0.46, 95% CI: 0.29-0.74, p=0.001). Conclusions: We did not observe an increasing population-based utilization of LT. This contemporary analysis showed that LT was associated with a 13% reduction in the risk of all-cause mortality. Importantly, this observation was also seen in patients receiving systemic therapy intensification with chemotherapy. The retrospective nature of this data, as well as residual confounding despite PSM (including metastatic volume), remain important limitations in this study. Ongoing Phase 3 trials (S1802) will be critical for informing future widespread uptake of LT in mPCa.

Comparison of adverse event rate of prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT) with antibody or small molecule ligand targeting vector.

161 Background: PSMA-targeted radionuclide therapy (PSMA-TRT) has been established with use of either monoclonal antibodies (mAb) or small molecule ligands (SML) as the targeting vectors for delivery of 177Lu to PSMA-expressing prostate cancer. mAb and SML differ in their molecular weight, pharmacokinetics, and biodistribution which is predicted to result in different adverse effect profiles. Methods: In this study with written informed consent, we compare the adverse effects from individual patients receiving PSMA-TRT for mCRPC using mAb (J591) vs SML (PSMA-617 or PSMA I&T) for delivering 177Lu in prospective clinical trials or registry. All-grade treatment-emergent adverse events (TEAEs) were extracted from trial databases. Adverse effects were graded 0-5. Pearson’s Chi-squared test was used to assess TEAEs and association with treatment type. Multivariable logistic regression was used to compare TEAEs after adjusting for administered radioactivity dose and CALGB (Halabi) prognostic score. Results: 248 patients with mCRPC were treated from March 2001 to February 2023. 166 (67.7%) received mAb (177Lu-J591), 81 received SML [76 (30.6%) 177Lu-PSMA-617, 5 (2%) 177Lu-PSMA-I&T)]. The median age was 70.9 years (44.5 yrs to 93.8 yrs). At the time of trial enrollment, 137 (55.2% [68% SML and 49% mAb]) patients had exposure to chemotherapy, 112 (45.1%) had exposure to androgen-receptor pathway therapy, 193 (77.8%) had bone metastases, 120 (48.3%) LN mets, 42 (16.9%) lung mets, and 20 (8.0%) liver mets. 142 (57.2%) had Halabi score high disease. All-grade hematologic TEAEs were more common with mAb: neutropenia in 122 (74%) patients vs 16 (20%) (p<0.001), anemia in 122 (73%) vs 26 (33%) (P<0.001), and thrombocytopenia in 145 (87%) vs 25 (32%) (p<0.001). Gr >3 neutropenia occurred in 79 (47%) and Gr >3 thrombocytopenia in 98 (59%) receiving mAb. All-grade non-hematologic TEAEs were generally more common with SML: fatigue in 31 (53%) vs 79 (48%) (p=0.5), pain in 32 (54%) vs 73 (44%) (p=0.2), nausea in 21 (36%) vs 34 (20%) (p=0.02) and xerostomia in 36 (61%) vs 1 (0.6%) (p<0.001). After adjusting for administered dose and Halabi score, treatment with 177Lu via SML vector was associated with less neutropenia (OR 0.04, 95% CI 0.02-0.09, p<0.001), anemia (OR 0.11, 95% CI 0.06-0.22, p<0.001), and thrombocytopenia (OR 0.04, 95% CI 0.02-0.09, p<0.001) but more nausea (OR 3.2, 95% CI 1.54-6.72, p=0.002) and xerostomia (NA due to low event rate in mAb). Conclusions: As predicted, PSMA-TRT with mAb vs SML is associated with different toxicity profiles. PSMA-TRT with the mAb 177Lu-J591 is more commonly associated with hematologic toxicities compared to the SML 177Lu-PSMA-617 and 177Lu-PSMA-I&T, which are more commonly associated with non-hematologic toxicities.

Comprehensive analysis of targetable alterations in urachal cancer by NGS.

663 Background: Urachal cancer (UrC) is a rare genitourinary cancer with molecular drivers commonly found in colorectal cancer and harbors fewer actionable alterations. Although prior studies have identified genomic alterations associated with UrC, these lack comprehensive genomic profiling, often using targeted panels, and lack RNA interrogation. This study presents detailed characterization of molecular profiles and the tumor microenvironment of real-world UrC patient samples. Methods: UrC samples (n = 42) were profiled using next-generation sequencing (NGS) of DNA and RNA. Prevalence was calculated for pathogenic SNVs/Indels and copy number amplifications, dMMR/MSI status assessed by IHC and NGS, PD-L1 expression measured by IHC, and TMB-H defined as ≥ 10 mut/Mb. Immune cell fractions of TME were estimated using RNA deconvolution. Mann-Whitney U, chi-square, and Fisher exact tests were applied where appropriate, with p-values adjusted for multiple comparisons. Histological features were reviewed by a genitourinary pathologist. Results: UrC samples were collected from 19 males and 23 females with a median age at sample collection was 58.5 years (range: 24-86 years). Pathology review revealed the majority were adenocarcinomas (n=41/42, 97.6%), including mucinous (n=17/41, 41.5%) and enteric adenocarcinomas (n=10/41, 24.4%). Pathogenic variants were most commonly observed in TP53 (n = 35, 83.3%), KRAS (n=15, 36%), GNAS (n=5, 12%), SMAD4 (n=4, 10%), PIK3CA (n=4, 10%), STK11 (n=3, 7%), BRCA2 (n=3, 7%), ARID1A (n=2, 5%), PTEN (n=2, 5%), ERBB2 (n=2, 5%), BRAF (n=2, 5%), and APC (n=2, 5%). MAPK pathway alterations were present in 52.3% (n=22) overall, with increased MAPK pathway activation in MAPK-altered UrC (median MPAS: 0.77 vs -0.61, p = 0.066). Loss of heterozygosity was prevalent (n = 9, 29%). While no UrC tumors had dMMR/MSI, 5% (n=2) were TMB-H and 9% (n=3) were PD-L1+. The mean fraction of T cells – CD8 (0.4%) and monocytes (0.0%) represented a smaller fraction UrC TME composition compared to macrophages M1 (5.19%) and neutrophil (6.4%). The median NK cell fraction was significantly higher in MAPK-altered UrC patients (3.5 vs 2.7%, p = 0.022), yet a transcriptional signature of response to immunotherapy (IFN-g) was similar between MAPK-altered and MAPK-WT UrC patients (median IFN: -0.366 vs -0.384, p = 0.052). Conclusions: This study provides a comprehensive molecular characterization of UrC and the associated immune landscape. While MAPK and DNA repair gene alterations were common, UrC tumors rarely harbored predictive markers of response to immunotherapy, suggesting limited efficacy in this patient population. However, the recurrence of MAPK alterations and associated pathway activation in UrC warrants further investigation of MAPK-targeted therapies in prospective clinical trials.

Feasibility and Tolerability of Anlotinib Plus PD-1 Blockades for Patients with Treatment-Refractory Metastatic Colorectal Cancer: A Retrospective Exploratory Study.

Therapeutic regimens are relatively scarce among patients with treatment-refractory metastatic colorectal cancer (CRC). This study aimed to determine the feasibility and tolerability of anlotinib plus PD-1 blockades in patients with treatment-refractory metastatic CRC retrospectively. A total of 68 patients with previously treated metastatic CRC who received anlotinib plus PD-1 blockades in clinical practice were included in this study retrospectively. Demographic and clinical characteristics of the patients, therapeutic outcomes and safety profile during administration were collected and briefly analyzed. All subjects were followed up regularly. Therapeutic outcomes, including drug response and prognosis, were presented, and a safety profile was depicted to illustrate the adverse reactions. A total of 68 patients with treatment-refractory metastatic CRC who received anlotinib plus PD-1 blockades in clinical practice were included in the final analysis. Best therapeutic response during treatment indicated that partial response was observed in 11 patients, stable disease was noted in 41 patients, and progressive disease was found in 16 patients, producing an objective response rate of 16.2% (95% CI: 8.4%-27.1%) and a disease control rate of 76.5% (95% CI: 64.6%-85.9%). Prognostic analysis suggested that the median progression-free survival (PFS) of the 68 patients was 5.3 months (95% CI: 3.01-7.59), and the median overall survival (OS) was 12.5 months (95% CI: 9.40-15.60). Of the 11 patients who responded, the median duration of response was 6.7 months (95% CI: 2.89-10.53). Safety profile during treatment showed that patients experienced adverse reactions regardless of grade, and grade ≥3 adverse reactions were found in 61 patients (89.7%) and 41 patients (60.3%), respectively. Common adverse reactions were hypertension, myelosuppression (including leukopenia, neutropenia, thrombocytopenia, and anemia), fatigue, and hand-foot syndrome. Anlotinib plus PD-1 blockades demonstrated encouraging efficacy and acceptable safety profile in patients with treatment-refractory metastatic CRC preliminarily in clinical practice. This conclusion should be confirmed in prospective clinical trials.

Paradigm Shifting Research: Key Studies in Urologic Oncology.

Genitourinary malignancies have a substantial impact on men and women in the USA as they include three of the ten most common cancers (prostate, renal, and bladder). Other urinary tract cancers are less common (testis and penile) but still have profound treatment implications related to potential deficits in sexual, urinary, and reproductive function. Evidenced-based practice remains the cornerstone of treatment for urologic malignancies. The authors reviewed the literature in consideration of the four top articles influencing clinical practice in the prior calendar year, 2022. The PROTECT trial demonstrates favorable 15-years outcomes for active monitoring of localized prostate cancer. The SEMS trial establishes retroperitoneal lymph node dissection as a viable option for patients with seminoma of the testis with limited retroperitoneal lymph node metastases. CheckMate 274 supports adjuvant immunotherapy following radical cystectomy for muscle-invasive bladder cancer with a high risk of recurrence. Data reported from the IROCK consortium reinforce stereotactic ablative radiotherapy as an option for localized renal cell carcinoma. The care for patients with urologic cancers has been greatly improved through advances in surgical, medical, and radiation oncologic treatments realized through prospective randomized clinical trials and large multicenter collaborative groups.

Abstract 25: Intravenous Thrombolysis for Acute Ischemic Stroke in Patients With Recent Direct Oral Anticoagulant Use: A Systematic Review and Meta-Analysis

Introduction: Intravenous thrombolysis (IVT) is efficacious treatment of acute ischemic stroke (AIS). However, certain circumstances associated with increased bleeding risk, such as recent direct oral anticoagulation (DOAC) intake limits its use. Nonetheless, emerging evidence has shown promising results in this patient group. We investigated the safety and efficacy of IVT in patients with AIS and recent DOAC use. Methods: We conducted systematic review and meta-analysis of proportions evaluating IVT with recent DOAC use. Outcomes of interest were symptomatic intracranial hemorrhage (sICH), any ICH, serious systemic bleeding (SSB), and 90-day functional independence (mRS 0-2). Moreover, we calculated pooled odds ratios (OR) for each outcome using a random effect meta-analysis to compare the rates between the patients with DOAC and non-DOAC upon IVT. Ultimately, we completed a sensitivity analysis for idarucizumab, NIHSS, and the timing of DOAC administration. Results: Our meta-analysis included 14 studies with 247079 patients (3610 in DOAC and 243469 in non-DOAC). In the DOAC group, the rate of sICH was 3% (95%CI 3 - 4%), any ICH was 12% (95%CI 7 - 19%), SSB 0.7% (95%CI 0 - 1%), and 90-day mRS 0-2 was 57% (95%CI 43 - 70%). No difference in the rates of sICH (3.4vs.3.5%; OR=0.95; 95%CI 0.67 - 1.36), any ICH (17.7vs.17.3%; OR=1.23; 95%CI 0.61 - 2.48), SSB (0.7vs.0.6%; OR=1.27; 95%CI 0.79 - 2.02), and 90-day mRS 0-2 (46.4vs.56.8%; OR=1.21; 95%CI 0.400 - 3.67) was found between DOAC and non-DOAC groups. Subgroup analysis revealed no significant difference in the sICH rate between idaricuzumab and no idaricizumab administration prior to IVT [Figure 1]. Conclusions: Our analysis demonstrated no significant difference in functional independence and hemorrhagic complication rates in AIS patients treated with IVT with recent DOAC compared to the no-DOAC group. Further prospective randomized clinical trials are needed to shed more light on this topic.

Thromboembolic events associated with neoadjuvant chemotherapy for muscle invasive cancer of the bladder.

586 Background: Patients with muscle invasive bladder cancer who undergo platinum-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy or radiotherapy are at high risk of venous and arterial thromboembolic events (TEE). TEE is associated with delay to radical cancer treatment, significant morbidity and even mortality. This study aimed to document the incidence and characteristics of TEE during NAC and prior to radical treatment. Methods: Retrospective data was collected on all patients in our centre who underwent NAC prior to radical treatment. TEE events were identified based on routine imaging to assess for response to NAC; or imaging based on clinical symptoms developed during (or within 28 days) of NAC but prior to radical treatment. Results: Data was collected on 148 patients between January 2015 and September 2023. Age range: 44 - 82 years, the majority (73.6%) of whom were male. All patients received platinum-based chemotherapy (median 4 cycles). A total of 31 patients (20.9%) developed 35 TEE, including 27 venous events (24 pulmonary emboli and 3 deep venous thromboses), and 8 arterial events (3 aortic thrombus, 4 limb ischaemia, 1 ischemic stroke). Four patients had a venous and arterial TEE. The majority of pulmonary venous TEE were subclinical. Conclusions: Our single-centre study demonstrates that the incidence of TEE during NAC prior to radical treatment for bladder cancer is high. Improved imaging techniques and routine scans post-NAC led to identification of subclinical TEE that require treatment as they are likely to become clinically significant. The high rate of TEE in this patient population is likely to benefit from prophylactic anticoagulation during NAC and should be investigated in future prospective clinical trials.

Practical guidance for direct oral anticoagulant use in the treatment of venous thromboembolism in primary and metastatic brain tumor patients.

Management of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors (BT) is challenging because of the risk of intracranial hemorrhage (ICH). There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants (DOACs), specifically in patients with BT, but they are widely used for VTE in this population. A group of neuro-oncology experts convened to provide practical clinical guidance for the off-label use of DOACs in treating VTE in patients with BT. We searched PubMed for the following terms: BTs, glioma, glioblastoma (GBM), brain metastasis, VTE, heparin, low-molecular-weight heparin (LWMH), DOACs, and ICH. Although prospective clinical trials are needed, the recommendations presented aim to assist clinicians in making informed decisions regarding DOACs for VTE in patients with BT.

Fluid biomarkers in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid β, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.

Minimally invasive sacroiliac joint fusion using triangular titanium implants versus nonsurgical management for sacroiliac joint dysfunction: a systematic review and meta-analysis.

Minimally invasive sacroiliac joint (MISIJ) fusion is a surgical option to relieve SIJ pain. The aim of this systematic review and meta-analysis was to compare MISIJ fusion with triangular titanium implants (TTI) to nonoperative management of SIJ dysfunction. We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. We included prospective clinical trials that compared MISIJ fusion to nonoperative management in individuals with chronic low back pain attributed to SIJ dysfunction. We evaluated pain on visual analogue scale, Oswestry Disability Index (ODI) score, health-related quality of life (HRQoL) using the 36-Item Short Form Health Survey (SF-36) physical component (PCS) and mental component summary (MCS) scores, patient satisfaction, and adverse events. A total of 8 articles representing 3 trials that enrolled 423 participants were deemed eligible. There was a significant reduction in pain score with MISIJ fusion compared with nonoperative management (standardized mean difference [SMD] -1.71, 95% confidence interval [CI] -2.03 to -1.39). Similarly, ODI scores (SMD -1.03, 95% CI -1.24 to -0.81), SF-36 PCS scores (SMD 1.01, 95% CI 0.83 to 1.19), SF-36 MCS scores (SMD 0.72, 95% CI 0.54 to 0.9), and patient satisfaction (odds ratio 6.87, 95% CI 3.73 to 12.64) were significantly improved with MISIJ fusion. No significant difference was found between the 2 groups with respect to adverse events (SMD -0.03, 95% CI -0.28 to 0.23). Our analysis showed that MISIJ fusion with TTI shows a clinically important and statistically significant improvement in pain, disability score, HRQoL, and patient satisfaction with a similar adverse event profile to nonoperative management in patients with chronic low back pain attributed to SIJ dysfunction.

Daratumumab-based immunotherapy vs. lenalidomide, bortezomib and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: a systemic review

BackgroundSince no randomized controlled trials have directly compared the efficacy and safety of immunotherapy with daratumumab versus lenalidomide/bortezomib/dexamethasone (RVD) in the frontline treatment of transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM), this study systematically reviewed the clinical studies regarding immunotherapy with daratumumab and RVD regimen in the treatment of TIE-NDMM to explore the optimization direction of the best first-line therapy.MethodsThe Cochrane Library, PubMed, Embase, and Web of Science databases were searched to collect studies on regimens containing daratumumab or RVD/RVD-lite for TIE-NDMM. Pooled and meta-analysis was then performed to compare the overall response rate (ORR), stringent complete remission (sCR) and CR rate, progression-free survival (PFS), overall survival (OS) and treatment-related discontinuation rate between daratumumab-containing immunotherapy regimen and RVD/RVD-lite regimen by using R 4.3.1 software.ResultsNine prospective clinical trials were included, including 1795 TIE-NDMM or NDMM without intent for immediate ASCT. Among them, 938 patients were treated with daratumumab-based immunotherapy and 857 with RVD/RVD-lite regimens. Meta-analysis results showed that The daratumumab-based regimen showed a significantly higher CR/sCR rate than RVD/RVD-lite for TIE-NDMM (47% vs. 24%, P<0.01). The median PFS of the daratumumab-based and RVD/RVD-lite groups were 52.6 months and 35.1 months respectively (HR 0.77, 95%CI, 0.66-0.90). The median OS of both groups was not reached, and there were no significant differences in OS between the two groups (HR 1.03, 95%CI, 0.86-1.23). The therapy discontinuation rate led by adverse events was significantly higher in the RVD/RVD-lite group than in the daratumumab-based regimen group for the TIE-NDMM (16% vs. 7%, P=0.03).ConclusionThis meta-analysis suggests that daratumumab-containing immunotherapy is superior to RVD in the depth of treatment efficacy, progression-free survival, and lower treatment-related discontinuation rates. Limited by the lack of head-to-head clinical trials, this conclusion needs to be verified by concurrent cohort studies.

Extent of Surgery for Medullary Thyroid Cancer and Prevalence of Occult Contralateral Foci

Standard treatment for patients with medullary thyroid cancer (MTC) consists of total thyroidectomy with central neck dissection, but the rationale for bilateral surgery in patients with unilateral disease on ultrasonography remains unclear. To determine the presence of occult contralateral disease (lesions not seen on preoperative ultrasonography) in patients with MTC as a rationale for total thyroidectomy. This multi-institutional, retrospective cohort study was conducted from September 1998 to April 2022 in academic medical centers and included patients with MTC who underwent thyroidectomy with preoperative imaging. The primary end point was the prevalence of sonographically occult foci of MTC in the contralateral lobe among patients with sporadic MTC. The cohort comprised 176 patients with a median age at diagnosis of 55 years (range, 2-87 years), 69 (57.6%) of whom were female. Genetic testing was performed in 109 patients (61.9%), 48 (27.5%) of whom carried germline RET variants. Initial surgical management consisted of total thyroidectomy (161 [91.0%]), lobectomy followed by completion thyroidectomy (7 [4.0%]), and lobectomy alone (8 [4.5%]). Central and lateral neck dissections were performed as part of initial therapy for 146 patients (83.1%). In the entire cohort of 176 patients, 46 (26.0%) had contralateral foci disease and 9 (5.1%) had occult contralateral foci that were not identified on preoperative ultrasonography. Among 109 patients who underwent genetic testing, 38 (34.9%) had contralateral disease, 8 (7.3%) of whom had occult contralateral disease not seen on preoperative ultrasonography. Patients with sporadic MTC experienced a 95.7% reduction in the odds of having a focus of MTC in the contralateral lobe compared with patients with a germline RET variant (odds ratio, 0.043; 95% CI, 0.013-0.123). When adjusting for age, sex, tumor size, and lymph node involvement, the odds ratio of having contralateral MTC in patients with sporadic disease was 0.034 (95% CI, 0.007-0.116). Among patients who underwent lobectomy alone with postoperative calcitonin levels, 5 of 12 (41.7%) achieved undetectable calcitonin levels (<2.0 pg/mL; to convert to pmol/L, multiply by 0.292). The results of this cohort study suggest that a staged approach involving initial thyroid lobectomy could be considered in patients with sporadic MTC and no contralateral ultrasonography findings, with no further surgery if calcitonin levels became undetectable. Further work using prospective randomized clinical trials to evaluate lobectomy as a biochemical cure in patients presenting with unilateral disease is warranted.

Transcriptomic-Based Microenvironment Classification Reveals Precision Medicine Strategies for Pancreatic Ductal Adenocarcinoma

Background & AimsThe complex tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) has hindered the development of reliable predictive biomarkers for targeted therapy and immunomodulatory strategies. A comprehensive characterization of the TME is necessary to advance precision therapeutics in PDAC. MethodsA transcriptomic profiling platform for TME classification based on functional gene signatures was applied to 14 publicly available PDAC datasets (n = 1657) and validated in a clinically annotated independent cohort of patients with PDAC (n = 79). Four distinct subtypes were identified using unsupervised clustering and assessed to evaluate predictive and prognostic utility. ResultsTME classification using transcriptomic profiling identified 4 biologically distinct subtypes based on their TME immune composition: immune enriched (IE); immune enriched, fibrotic (IE/F); fibrotic (F); and immune depleted (D). The IE and IE/F subtypes demonstrated a more favorable prognosis and potential for response to immunotherapy compared with the F and D subtypes. Most lung metastases and liver metastases were subtypes IE and D, respectively, indicating the role of clonal phenotype and immune milieu in developing personalized therapeutic strategies. In addition, distinct TMEs with potential therapeutic implications were identified in treatment-naive primary tumors compared with tumors that underwent neoadjuvant therapy. ConclusionsThis novel approach defines a distinct subgroup of PADC patients that may benefit from immunotherapeutic strategies based on their TME subtype and provides a framework to select patients for prospective clinical trials investigating precision immunotherapy in PDAC. Further, the predictive utility and real-world clinical applicability espoused by this transcriptomic-based TME classification approach will accelerate the advancement of precision medicine in PDAC.

P213 ArgesMES: A high-performance, generalizable AI model for scoring Ulcerative Colitis severity from endoscopy videos

Abstract Background The Mayo endoscopic subscore (MES) is widely used to assess endoscopic disease severity assigned by human readers in Ulcerative Colitis (UC) clinical trials. AI-based automation of the MES could reduce inter-rater variability and allow for the development of more sensitive endoscopic measures. This report assesses whether a previously trained (locked) algorithm is suitable for automating full colon or segment-level MES scoring on a prospective UC clinical trial. Methods Endoscopy videos from two UC clinical trials (UNIFI: NCT02407236, Phase 3, 965 subjects, 3128 videos; and JAK-UC: NCT01959282, Phase 2, 211 subjects, 448 videos) were used to train an AI-based MES classifier, where 20% of the total data was retained as a holdout set. This AI model training had two steps: 1) training a feature extraction module using self-supervised learning (SSL), and 2) supervised training of a small transformer network with an attention-based classifier using SSL features to estimate full colon MES. Videos from an independent, prospective UC trial (QUASAR: NCT04033445, Phase 2b induction study, 313 subjects, 615 videos) were used to validate the locked AI model. MES scoring in QUASAR included full colon MES values and additional MES values for three left colon segments: descending colon, sigmoid colon, and rectum. Comparisons between AI-model and human reader scores were performed using AUC, Accuracy, F1 score, and Fleiss kappa. A non-inferiority test was also conducted to determine interchangeability between AI- and human-derived full colon MES values. Results Full colon MES on the QUASAR data showed AUC, Accuracy, and F1 scores of 0.810, 0.687, and 0.693, respectively, comparable to results obtained on the UNIFI holdout data (0.803, 0.645, and 0.647). The Fleiss kappa score was 0.682, comparable to the inter-rater agreement between two human readers-local and central readers (Fleiss kappa = 0.712). The non-inferiority test (p-value &amp;lt; 0.05) indicated that the AI-computed full colon MES readout was interchangeable to that of human readers. Similar performance was observed for the AI-computed segment-level MES: descending colon, sigmoid colon, and rectum as shown in Table 1. This result demonstrates the model's effectiveness at scoring the segment-level MES despite not being trained with segment level ground truth. Conclusion ArgesMES, an AI-based model, underwent successful prospective validation, demonstrating proficiency in automating full colon and segment-level MES scores. ArgesMES has the potential to facilitate rapid, reliable, and reproducible MES scoring at full colon and segment levels in prospective clinical trials.

Radiosensitizing Favors Response to Peptide Receptor Radionuclide Therapy in Patients With Highly Proliferative Neuroendocrine Malignancies: Preliminary Evidence From a Clinical Pilot Study.

Peptide receptor radionuclide therapy (PRRT) represents a cornerstone of treatment regimens for patients with low proliferative neuroendocrine tumors (NETs). However, in patients experiencing somatostatin receptor-positive NET with higher proliferation rates, a value and potential therapeutic benefit of PRRT as part of multimodal treatment approaches and potentially with addition of radiosensitizing agents has not yet been established. In this study, 20 patients with histologically confirmed gastroenteropancreatic (GEP) NET with proliferation rates (Ki67) between 15% and 55% were treated either with PRRT only (n = 10) or with a combination therapy (n = 10) comprising PRRT and capecitabine/temozolomide (CAP/TEM) for at least 2 consecutive cycles. Disease control rate in patients treated with PRRT alone was 60% (40% stable disease and 20% partial response). Strikingly, in patients treated with PRRT in combination with radiosensitization (CAP/TEM), the disease control rate was 90% (20% stable disease and 70% partial response). The median progression-free survival in the PRRT only group was 12 months, whereas the median progression-free survival in the PRRT + CAP/TEM group was 26 months and has not been yet reached for all patients in the group during the observation period. The median disease-specific survival for patients with PRRT alone was 51 months, whereas this end point was not yet reached in the PRRT + CAP/TEM group. Moreover, the PRRT + CAP/TEM group showed a significantly higher reduction of SSTR-PET-based metabolic tumor volume and chromogranin A levels compared with the PRRT only group. Importantly, adverse events of all grades did not differ between both groups. PRRT + CAP/TEM represents a highly promising and well-tolerated therapeutic regimen for patients experiencing somatostatin receptor-positive NET with higher (Ki67 ≥ 15%) proliferation rate. Prospective randomized clinical trials are warranted.

First-line therapies in a Latino-rich cohort of US patients (pts) with hepatocellular carcinoma (HCC) and Child Pugh B (CPB) cirrhosis.

453 Background: There are limited prospective clinical trials in patients with both HCC and CPB cirrhosis. As the prevalence of HCC and cirrhosis has been rising among Latinos in South Texas, it is crucial to examine the liver dysfunction within this demographic to understand the contributing factors to treatment patterns. Therefore, we conducted a retrospective analysis of 36 patients with both HCC and Child Pugh B (CPB) cirrhosis. Methods: A dataset of 65 patients with HCC and cirrhosis from 2009 – 2019 was used to identify 36 patients with CPB treated at a Latino-Rich NCI-designated Cancer Center. We further segmented patients of Child Pugh Class B by ALBI grades (1-3) to explore variations in demographics, liver dysfunction, and first-line therapies. Results: Median age overall of the cohort is 59 (50-71). Ethnicity: Latino White (83%), Non-Latino White (14%), Black (3%). Etiology: HCV (78 %) EtOH (50%), NASH (19%), and HBV (3%). ALBI Grade: I (6%), II (50%), III (44%). First line treatment in CPB: Sorafenib (86%), Nivolumab (8%), Lenvatinib (6%). Sorafenib was used across all ALBI grades, while Lenvatinib and Nivolumab were given only in ALBI II (Table). Conclusions: Sorafenib was more often given to patients with CPB cirrhosis, in the first line setting; however, more patients were treated with nivolumab or lenvatinib with ALBI II. Further investigation of survival based on ALBI levels and the trajectory of liver function over time in response to different treatment approaches is underway in a larger cohort who has received newer immunotherapy-based regimens. With more agents approved for HCC, prospective clinical trials are needed in CPB and HCC. [Table: see text]

Efficacy of immune checkpoint inhibitors in patients with HIV-associated unresectable HCC (uHCC): Propensity-score matched analyses from two international consortia.

442 Background: HIV-associated HCC is an incompletely characterized disease with poor prognosis. People living with HIV (PWH) are commonly excluded from clinical trials, leading to a paucity of high-level evidence for optimal management. Whether ICIs are tolerated and effective in HIV-associated uHCC remains unclear. Methods: Using data from the CATCH-IT consortium and from a global dataset recruiting patients with HCC from 14 centers in 3 continents, we selected patients with HIV-associated uHCC treated with ICIs and compared their outcomes with a matched cohort of HIV negative (HIV-) patients. Primary endpoints were overall (OS) and progression-free survival (PFS). Propensity score matching (PSM) between the two groups was performed for the following variables: age, sex, HCC aetiology, Child-Pugh class (CP-C), ECOG-PS, BCLC stage, alpha-fetoprotein (AFP) levels, treatment line, portal vein tumor thrombosis (PVTT), and extrahepatic spread (EHS). Restricted mean survival time (RMST) difference analyses stratified by HIV status were performed for OS and PFS at 3, 6 and 9 months. Results: We accrued 46 PWH and 400 HIV-, treated mostly in the first-line setting (58.7% vs. 43.7%) with either atezolizumab plus bevacizumab (28.3% vs 17.5%) or anti-PD-1 monotherapy. Median age at ICI start was 62 (38-76) and 64 (18-87); viral hepatitis (HCV: 58.7%; HBV: 34.8%) were the prevalent aetiologies in PWH, non-viral (46%) was the most common in HIV-; most patients had BCLC-C HCC (84.8% and 82.3%). In PWH, median CD4 count was 345 cells/mm3 (IQR: 200-465); viral load was undetectable in 45 patients, all were established on combined anti-retroviral therapy. Following PSM, 44 PWH and 117 HIV- were included. Median OS was 7.5 months (95%CI: 5.2-NR) in PWH and 10.8 months (95%CI: 7.3-19.5) in HIV- (HR: 0.89; 95%CI: 0.56-1.42; p=0.58). Presence of PVTT, AFP&gt;400 ng/mL, and ECOG-PS=1 but not HIV status were associated with worse OS in uni- and multivariable models. Median PFS was 2.8 months (95%CI: 2.6-4.8) for PWH vs 3.0 months (95%CI: 2.4-5.3) for HIV- (HR: 0.83-95%CI:0.56-1.24 ;p=0.38); HIV status was not associated with worse PFS. RMST confirmed no OS or PFS differences based on HIV status. In matched cohorts, neither ORR (21% vs. 19.1%, p=0.97) nor DCR (44.7% vs. 55.4%, p=0.19) were associated with HIV status. All grade immune-related adverse events (irAEs) were more frequent in HIV (44.0% vs 21.7%, p=0.003), with similar incidence of grade ≥3 irAEs (22.2% vs 13.0%). PWH had lower incidence of dermatological toxicities (4.3% vs 22%, p=0.003) and a trend towards lower incidence of hepatotoxicity (6.5% vs 18%, p=0.059). Conclusions: This study provides practice-informing evidence to support the use of ICIs in PWH and uHCC. Our findings encourage the inclusion of patients with well-controlled HIV in prospective clinical trials.

The impact of CARE Frailty Index on overall survival in older adults with hepatocellular carcinoma.

462 Background: Pre-treatment frailty is associated with unfavorable short and long-term outcomes among patients with hepatocellular cancer (HCC) post liver resection.However, there is a knowledge gap in identifying the subset of older adults with HCC at high risk for inferior survival outcomes. Methods: We evaluated the association between patient-reported geriatric assessment (GA)-based frailty index and overall survival (OS) among older adults (≥60y) diagnosed with HCC enrolled in a single institutional prospective registry (Cancer and Aging Resilience Assessment (CARE) registry). All patients underwent a patient-reported GA at enrollment that encompassed multiple health domains related to aging. To determine frailty, we utilized a 44-item CARE Frailty Index (CARE-FI) based on the principles of deficit accumulation (Giri S et al JAGS 2021). We categorized frailty into robust, pre-frail and frail. The primary outcome was OS from the time of GA. Comparison of survival between groups was made using log-rank statistic. A multivariable Cox regression model measured the independent association between frailty and OS adjusted for age, etiology, Child-Pugh score and cancer stage. Results: A total of 116 older adults with HCC were identified with a median follow-up 2.1 year, median age was 67y (63-72) with 82% males, 27% blacks, 64% with Child-Pugh-A and 78% with stage III/IV disease. Overall, 50.1% (n=58) were frail, 33.6% (n=39) pre-frail and 16.3% (n=19) robust. No significant clinico-demographic differences across the 3 frailty groups were observed. In univariable analysis, there was a marginally significant difference between the three frailty groups (p value 0.06). However, in multivariable analysis, being frail vs robust was associated with an increased risk of mortality (HR 2.6 [95% CI 1.03 – 6.56]; p=0.04) after adjustment for aforementioned confounders. Conclusions: Frailty status assessed by patient-reported GA using CARE-FI is associated with an increased risk of mortality in older adults with HCC. Frailty assessment should be encouraged and considered in prospective clinical trials to estimate the impact of treatment on the most vulnerable adults. [Table: see text]

Risk of relapse after surgical resection of localized appendiceal adenocarcinoma.

58 Background: Appendiceal adenocarcinoma (AA) encompasses a heterogenous mix of histologic subtypes and frequently presents with peritoneal metastases. Data regarding the risk of relapse after surgical resection in patients with localized AA (stages I–III) is limited. More accurate evaluation of features predictive of relapse is critical to counsel patients, determine follow-up, and guide decisions regarding adjuvant therapy. Methods: The Foundry software platform was used to query the MD Anderson Cancer Center (MDA) Electronic Health Record database to identify and extract clinical information from AA patients presented to MDA from 2004 to 2023. Results: We identified 296 patients with localized AA, split into two cohorts: patients who underwent surgery at MDA (n=133) and patients with surgery at an outside institution later referred to MDA (n=163). The most common histologic subtypes were mucinous (n=124, 41.9%) and goblet (n=121, 40.9%) with less frequent colonic-type (n=42, 14.2%) and signet ring cell (SRC, n=9, 3%). With a median follow-up of 47 months, the relapse rate (RR) for the MDA surgical cohort was only 6% (n=8), with a median time to relapse of 24 months (range=8-74). Evaluating all 296 localized AA patients, histologic subtype was significantly associated with risk of relapse, with goblet AAs having lowest risk (6%, n=7), followed by colonic-type (12%, n=5), mucinous (27%, n=33), and SRC (44%, n=4; overall P&lt; 0.001), with a median time of relapse of 26 months (range=3-96). Patients with a positive LN, higher grade, and/or higher T stage showed a higher RR (Table). Use of adjuvant chemotherapy (AC) was not associated with RR in our cohort, with odds ratio trending towards increased risk of relapse (14.4% vs 19.2%, OR=1.4, 95% CI=0.76-2.6; P=0.27). Restricting to only high-risk patients (poorly differentiated, LN-positive, and/or T4, n=205), similar results were observed with 18.4% (n=17) relapsed without AC vs 19.4% (n=22) relapsed with AC (OR=1.06, 95%CI=0.52-2.15; P=0.85). AC was also not associated with improved RFS (HR=1.2, 95%CI=0.63-2.2, P=0.59). Conclusions: Patients with localized AA who undergo surgical resection have a low risk of relapse, especially those with goblet AA. This retrospective analysis did not identify a benefit from adjuvant chemotherapy. Considering the clear histologic and molecular differences between AA and CRC, these data call into question the current practice of applying CRC data to guide AC decisions in AA. Prospective clinical trials of AC in AA, stratified by histologic subtype, are urgently needed. [Table: see text]