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OBJECTIVE Recent studies have suggested that biologically effective dose (BED) is an important correlate of pain relief and sensory dysfunction after Gamma Knife radiosurgery (GKRS) for trigeminal neuralgia (TN). The goal of this study was to determine if BED is superior to prescription dose in predicting outcomes in TN patients undergoing GKRS as a first procedure. METHODS This was a retrospective study of 871 patients with type 1 TN from 13 GKRS centers. Patient demographics, pain characteristics, treatment parameters, and outcomes were reviewed. BED was compared with prescription dose and other dosimetric factors for their predictive value. RESULTS The median age of the patients was 68 years, and 60% were female. Nearly 70% of patients experienced pain in the V2 and/or V3 dermatomes, predominantly on the right side (60%). Most patients had modified BNI Pain Intensity Scale grade IV or V pain (89.2%) and were taking 1 or 2 pain medications (74.1%). The median prescription dose was 80 Gy (range 62.5–95 Gy). The proximal trigeminal nerve was targeted in 77.9% of cases, and the median follow-up was 21 months (range 6–156 months). Initial pain relief (modified BNI Pain Intensity Scale grades I–IIIa) was noted in 81.8% of evaluable patients at a median of 30 days. Of 709 patients who achieved initial pain relief, 42.3% experienced at least one pain recurrence after GKRS at a median of 44 months, with 49.0% of these patients undergoing a second procedure. New-onset facial numbness occurred in 25.3% of patients after a median of 8 months. Age ≥ 63 years was associated with a higher probability of both initial pain relief and maintaining pain relief. A distal target location was associated with a higher probability of initial and long-term pain relief, but also a higher incidence of sensory dysfunction. BED ≥ 2100 Gy2.47 was predictive of pain relief at 30 days and 1 year for the distal target, whereas physical dose ≥ 85 Gy was significant for the proximal target, but the restricted range of BED values in this subgroup could be a confounding factor. A maximum brainstem point dose ≥ 29.5 Gy was associated with a higher probability of bothersome facial numbness. CONCLUSIONS BED and physical dose were both predictive of pain relief and could be used as treatment planning goals for distal and proximal targets, respectively, while considering maximum brainstem point dose < 29.5 Gy as a potential constraint for bothersome numbness.

Abstract Sorafenib blocks nonstructural protein 5A (NS5A)-recruited c-Raf–mediated hepatitis C virus (HCV) replication and gene expression. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via sorafenib putatively differ in the presence or absence of doxorubicin. Cancer and Leukemia Group B (CALGB) 80802 (Alliance) randomized phase III trial of doxorubicin plus sorafenib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC), showed no improvement in median overall survival (OS). Whether HCV viral load impacts therapy and whether any correlation between HCV titers and outcome based on HCV was studied. In patients with HCV, HCV titer levels were evaluated at baseline and at multiple postbaseline timepoints until disease progression or treatment discontinuation. HCV titer levels were evaluated in relation to OS and progression-free survival (PFS). Among 53 patients with baseline HCV data, 12 patients had undetectable HCV (HCV-UN). Postbaseline HCV titer levels did not significantly differ between treatment arms. One patient in each arm went from detectable to HCV-UN with greater than 2 log-fold titer levels reduction. Aside from these 2 HCV-UN patients, HCV titers remained stable on treatment. Patients who had HCV-UN at baseline were 3.5 times more likely to progress and/or die from HCC compared with HCV detectable (HR = 3.51; 95% confidence interval: 1.58–7.78; P = 0.002). HCV titer levels remained unchanged, negating any sorafenib impact onto HCV titer levels. Although an overall negative phase III study, patients treated with doxorubicin plus sorafenib and sorafenib only, on CALGB 80802 had worse PFS if HCV-UN. Higher levels of HCV titers at baseline were associated with significantly improved PFS. Significance: Sorafenib therapy for HCC may impact HCV replication and viral gene expression. In HCV-positive patients accrued to CLAGB 80802 phase III study evaluating the addition of doxorubicin to sorafenib, HCV titer levels were evaluated at baseline and different timepoints. Sorafenib did not impact HCV titer levels. Despite an improved PFS in patients with detectable higher level HCV titers at baseline, no difference in OS was noted.

Abstract High-count monoclonal B-cell lymphocytosis (HCMBL) is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL, the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 individuals with HCMBL using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results with that of our treatment-naïve CLL cohort (N = 855) and used Cox regression to estimate hazard ratios and 95% confidence intervals (CIs) for associations with TTFT. The frequencies of any mutated genes were lower in HCMBL (52%) than CLL (70%). At 10 years, 37% of individuals with HCMBL with any mutated gene had progressed requiring treatment compared with 10% among individuals with HCMBL with no mutations; this led to 5.4-fold shorter TTFT (95% CI, 2.6-11.0) among HCMBL with any mutated gene vs none, independent of CLL-IPI. When considering individuals with low risk of progression according to CLL-IPI, those with HCMBL with any mutations had 4.3-fold shorter TTFT (95% CI, 1.6-11.8) vs those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed individuals with HCMBL who were high risk for both prognostic factors had worse prognosis than patients with low-risk CLL (ie, 5-year progression rate of 32% vs 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify individuals with HCMBL with more aggressive clinical course.

Abstract Background Efficient and accurate delineation of organs at risk (OARs) is a critical procedure for treatment planning and dose evaluation. Deep learning‐based auto‐segmentation of OARs has shown promising results and is increasingly being used in radiation therapy. However, existing deep learning‐based auto‐segmentation approaches face two challenges in clinical practice: generalizability and human‐AI interaction. A generalizable and promptable auto‐segmentation model, which segments OARs of multiple disease sites simultaneously and supports on‐the‐fly human‐AI interaction, can significantly enhance the efficiency of radiation therapy treatment planning. Purpose Meta's segment anything model (SAM) was proposed as a generalizable and promptable model for next‐generation natural image segmentation. We further evaluated the performance of SAM in radiotherapy segmentation. Methods Computed tomography (CT) images of clinical cases from four disease sites at our institute were collected: prostate, lung, gastrointestinal, and head & neck. For each case, we selected the OARs important in radiotherapy treatment planning. We then compared both the Dice coefficients and Jaccard indices derived from three distinct methods: manual delineation (ground truth), automatic segmentation using SAM's ’segment anything’ mode, and automatic segmentation using SAM's ‘box prompt’ mode that implements manual interaction via live prompts during segmentation. Results Our results indicate that SAM's segment anything mode can achieve clinically acceptable segmentation results in most OARs with Dice scores higher than 0.7. SAM's box prompt mode further improves Dice scores by 0.1∼0.5. Similar results were observed for Jaccard indices. The results show that SAM performs better for prostate and lung, but worse for gastrointestinal and head & neck. When considering the size of organs and the distinctiveness of their boundaries, SAM shows better performance for large organs with distinct boundaries, such as lung and liver, and worse for smaller organs with less distinct boundaries, like parotid and cochlea. Conclusions Our results demonstrate SAM's robust generalizability with consistent accuracy in automatic segmentation for radiotherapy. Furthermore, the advanced box‐prompt method enables the users to augment auto‐segmentation interactively and dynamically, leading to patient‐specific auto‐segmentation in radiation therapy. SAM's generalizability across different disease sites and different modalities makes it feasible to develop a generic auto‐segmentation model in radiotherapy.

686 Background: Immune checkpoint inhibitors (ICI) have been used to treat advanced muscle invasive and/or metastatic bladder cancer. However, ICIs are only effective in 30-40% of cases. In light of potentially significant IRAE’s, tools to predict individual patient level benefits are desirable. AI technology offers the opportunity to apply computational methods to predict outcomes from readily available digitized pathology slides. We investigated the utility of an AI platform integrating computational biomarkers based on morphological characterization of digitized H&E slide whole images (WSI) to predict response to ICI. Methods: We analyzed H&E-stained whole slide images (WSI) of bladder tumor tissue collected from transurethral resection of bladder tumor (TURBT) from 116 patients with advanced or metastatic bladder cancer at a single institution between 2015-2020. Adjacent multiplex IHC stained specimens were analyzed myeloid and lymphoid marker panels. 20 patients from the overall cohort treated with ICI were designated ‘responders’ (complete response, partial response, stable disease) and 20 patients were identified as non-responders (progressive disease) based on ICI best clinical/radiographic response. WSIs were divided into small non-overlapping image patches. These image tiles were processed into multiple AI encoder models to extract morphological features. The tile morphological features, represented by high dimensional vectors, were combined by an aggregation model to represent the whole slide morphology and then used to classify the patients into responders vs non-responders to immunotherapy. Area-under-the-receiver operating characteristic (AUC) was used to measure the performance of response prediction. Results: Our method shows AUC of 0.708 at classification of the patients (n=40) into responder and non-responder groups. With a cutoff that identifies the top 50% patients (n=20) of high probability of responding to immunotherapy predicted by our models, 75% of them are responders. In the bottom 50% patients (n=20) of the low scores, 75% of them are non-responders. . Multiplex IHC (myeloid and lymphoid panel) was performed using adjacent sections and were characterized yielding deeper mechanistic insight into the inflammatory populations driving predictive morphologic patterns. Conclusions: By applying innovative AI morphological analysis on patient WSIs, we generated a computational biomarker that shows promising ability to predict patient response to immunotherapy in bladder cancer. This approach merits future prospective validation and additional patient level analysis in broader cohorts. [Table: see text]

Abstract During the 20th century, inflammatory bowel disease (IBD) was considered a disease of early-industrialized regions in North America, Europe, and Oceania. At the turn of the 21st century, incidence of IBD increased in newly-industrialized and emerging regions in Africa, Asia, and Latin America, while prevalence in early-industrialized regions started to grow steadily. Changes in incidence and prevalence denote evolution of IBD across four epidemiologic stages: Stage 1 (Emergence), characterized by low incidence and prevalence; stage 2 (Acceleration in Incidence), characterized by rapidly rising incidence and low prevalence; and stage 3 (Compounding Prevalence), characterized by decelerating, plateauing, or declining incidence and steadily rising prevalence. A fourth stage (Prevalence Equilibrium) has been proposed where the slope of prevalence plateaus due to shifting demographics of an aging IBD population, but it has not yet been evidenced. To date, these stages have been theoretical without specific incidence/prevalence indicators defining transition points. Using real-world data from 490 population-based studies comprising 80 global regions and spanning over a century (1920–2023), we show spatiotemporal transitions across stages 1–3 and model transition towards stage 4. Understanding the evolution of IBD across epidemiologic stages allows healthcare systems to better prepare for the future worldwide burden of IBD.

163 Background: Testing for BRAF and KRAS/NRAS mutations, HER2 amplifications, and MSI/MMR status is a standard of care for all patients with mCRC. There are limited real-world (RW) data regarding biomarker testing patterns among robust patients who are candidates for multiple LOT. We evaluated biomarker testing patterns among patients treated in community oncology practices who initiated regorafenib (REGO) and/or trifluridine/tipiracil (FTD/TPI), predominantly in 3rd or later lines of therapy. Methods: A retrospective analysis utilizing electronic medical record data from The US Oncology Network examined adult patients with mCRC who initiated REGO and/or FTD/TPI between 09/01/2015 and 11/30/2022 with follow-up until 05/31/2023. The proportion of patients tested for various biomarkers was assessed. Results: A total of 2684 mCRC patients initiated REGO and/or FTD/TPI (including 895 pts receiving both) in any LOT during the study period. The mean age of patients at baseline was 62.9 years, of whom 54.9% were male, 1599 (59.6%) patients were White and 436 (16.2%) were underrepresented minorities (Black or Hispanic/Latino). Patients were most commonly tested for KRAS mutations (75.2%) and least commonly for HER2 amplifications (22.6%). Age, gender, and race/ethnicity characteristics were similar between treatment subgroups, with 29.6% of minority and 23.1% of white patients not undergoing KRAS testing. Types of biomarkers tested and proportion of patients tested are reported in the table below. Conclusions: About one quarter of patients who were sufficiently robust to receive aggressive therapy did not undergo testing for KRAS, the oldest standard of care biomarker in CRC. We observed disparities by race/ethnicity. We also observed a correlation between rates of testing and treatment intensity, with patients who received both REGO and FTD/TPI having a higher rate of testing than those who received only one of the treatments. Understanding the pitfalls in biomarker testing will help pave the way for appropriate and equitable access to cancer care. [Table: see text]

Abstract Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors’ association with colorectal cancer risk and survival differs by SBS88. Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer–specific survival using Cox proportional hazards regression (N = 3,465 cases). Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66–0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer–specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47–7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78–1.21, Pheterogeneity = 0.066). Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer–specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available. Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.

Abstract A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.