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Influence of time to first therapy (TTFT) variable on survival outcomes of neoadjuvant chemotherapy versus upfront surgery approach in resectable pancreatic ductal adenocarcinoma.

720 Background: Evidence demonstrating overall survival (OS) benefit of neoadjuvant chemotherapy (NAC) followed by surgical resection over upfront surgical resection for resectable pancreatic ductal adenocarcinoma (PDAC) has been mixed. The time to first therapy (TTFT) variable has not been studied as a contributing factor. Methods: A nationwide retrospective analysis using the National Cancer Database to evaluate patients with clinical stage T1 and T2 PDACs from 2010 to 2020. Cox proportional hazards model was used to evaluate the impact of NAC followed by definitive surgery compared to upfront surgery on OS with and without TTFT. Results: Total of 43,196 patients were included – 9,880 patients with clinical stage T1 and 33,316 patients with T2 PDACs. There were increasing trends in the NAC approach from 2.9% in 2010 to over 25% by 2020 and decreasing trends in the upfront surgery approach from 69.35% in 2010 to 31.84% by 2020. There were significant differences in TTFT according to the treatment choice with upfront surgery group having a significantly shorter TTFT – proportion of those receiving first treatment within the 1 st week was 24.32% in the upfront surgery compared to 4.22% in the NAC group. In the adjusted cox regression without the TTFT variable, there was a 25% higher rate of death in the upfront surgery compared to the NAC group (HR 1.25, 95% CI 1.19 – 1.30). When the adjusted regression was performed with addition of a TTFT interaction term, there was survival disadvantage of upfront surgery approach in patients whose TTFT occurred after 1 week, but not in those with TTFT occurring in less than 1 week (HR 1.01, 95% CI 0.86 - 1.17). Conclusions: Our study emphasizes the importance of incorporating TTFT variable when comparing NAC versus upfront surgery approach in PDAC. Future studies comparing NAC to upfront surgery in resectable PDAC should consider incorporating the TTFT variable.

Patient-reported outcomes in physical, cognitive, and sexual health in early-onset gastrointestinal cancers (EOGIC).

72 Background: Incidence of early-onset (ages 18-49) gastrointestinal cancers is alarmingly increasing. To assess unmet needs in health-related quality of life (HRQoL), we conducted this pilot study using PRO measures in patients with EOGIC. Methods: Patients ages 18-49 with any GI cancer seen at our center during a clinic visit were invited to participate in this cross-sectional study. Validated PRO tools PROMIS 29+2, GP5 from FACT-G, AYA Sexual Health PRO Battery and Adult Neuro-QOL Cognitive Function short form were administered. Participants’ PROMIS 29+2 responses were scored to generate a T score, and two-tailed t-tests were used to compare T scores with the average score from a large general US population. The electronic medical record was reviewed to collect demographic, diagnosis and treatment information. Results: 39 (85% response rate) patients were enrolled from 03-08/24. Table 1 describes demographics, diagnoses, and treatment. In the PROMIS 29+2, EOGIC patients reported significantly lower physical function and higher anxiety, depression, fatigue and pain interference compared to the general US population: t-score (T-test p-value) 40.4 (p 0.0003), 57.7 (p 0.005), 55.7 (p 0.017), 55.1 (p 0.033) and 58.5 (p 0.0001), respectively. 56% reported being at least somewhat “bothered by side effects of treatment,” and this measure has a known correlation with clinician reported adverse events. Regarding sexual health (SH) in prior 30 days, 79% of participants felt less whole or “damaged” due to their disease, 64% were sexually active, 56% had some distress due to change in SH, and 50% were worried about their romantic relationship(s). Patients identified discussing safe sex with low counts, body image, contraception and addressing sexual problems as areas of unmet need during their care. They reported not receiving counseling from their care teams: only 15% discussed safe sex with low counts, 28% contraception, 13% STI prevention, and 18% discussed effect of cancer on body image. No significant change in cognitive functioning over the preceding 7 days was reported in this study. Conclusions: PROs are an important tool in clinical and survivorship care of young patients with GI cancers. We discovered that decreased physical function, increased anxiety, depression, fatigue and pain significantly effect HRQoL patients with EOGIC. We also found high unmet need to address sexual health in patients with EOGIC. Our ongoing work aims to better understand and address these needs for our patients. Demographic, diagnostic, and therapeutic characteristics of participants. Age At study participation 24-49 median 43 Gender Female 26 66.7% Primary cancer Colorectal 19 48.7% Pancreatic 5 12.8% Biliary tract cancers 5 12.8% Esophageal/Gastric 3 7.7% Other (including anal, NET, GIST, appendiceal) 7 17.9% Stage Metastatic 22 56.4% Treatment On any active treatment 24 61.5% On chemotherapy 20 51.2%

On QSPR analysis of pulmonary cancer drugs using python-driven topological modeling

Comparison of screening outcomes associated with advanced precancerous lesion versus colorectal cancer sensitivity for a blood-based test: A simulation study.

89 Background: With estimates of over 150,000 incident and 50,000 fatal colorectal cancer (CRC) cases in 2024, efforts are ongoing to improve the national screening performance and engagement in the US. The Centers for Medicare & Medicaid Services (CMS) have established criteria for covering new blood-based CRC screening tests if minimum CRC sensitivity and specificity thresholds are met. However, the current blood-based tests are challenged by their relative inability to detect advanced precancerous lesions (APLs). At present, the importance of APL versus CRC sensitivity on screening outcomes remains undetermined. To address this knowledge gap, we conducted a simulation study to compare the screening effectiveness and outcomes of a hypothetical blood-based test across a range of sensitivities for CRC and APL detection. Methods: Outcomes were simulated using the CRC-AIM microsimulation model, which has been previously calibrated and validated. Predicted outcomes were calculated for average-risk individuals screened triennially with a blood-based test between ages 45-75 years, assuming perfect adherence. Base-case screening sensitivity and specificity inputs were based on CMS minimum thresholds (74% CRC sensitivity, 90% specificity) with assumed 10% APL sensitivity. Additional scenarios considered an increase in either APL or CRC sensitivity. Outcomes of interest included life years-gained (LYG), CRC incidence, and mortality reductions. Results: Compared to the CMS minimum performance (Table), increasing APL sensitivity by 1% (from 10% to 11%) resulted in a similar increase in LYG as compared to increasing CRC sensitivity by 11% (from 74% to 85%). Additionally, increasing APL sensitivity by 1% resulted in greater reductions in CRC cases and deaths (3% decrease) as compared to increasing CRC sensitivity by 11% (0% and 1% reductions, respectively). Conclusions: Data from this study show that increased APL sensitivity is a key determinant of screening-related outcomes, such as LYG, derived from a blood-based strategy, and that similar results would require much larger increases in CRC sensitivity. With the current CMS minimum performance threshold, blood-based tests that are designed to have high APL sensitivity can outperform tests with higher CRC sensitivity and little to no APL sensitivity. Comparison of CRC screening health outcomes with CMS proposed minimum threshold blood-test versus hypothetical tests with either increased APL and CRC sensitivity. APL Sensitivity CRC Sensitivity CRC Specificity Follow-up Colonoscopies CRC Cases (% reduction) CRC Deaths (% reduction) Life-Years Gained (LYG) (% increase) 10% 74% 90% 809 50 (ref) 18 (ref) 220 (ref) 11% 74% 90% 813 48 (-3%) 17 (-3%) 226 (3%) 10% 85% 90% 809 50 (0%) 18 (-1%) 227 (3%) APL: Advanced precancerous lesions; CRC: Colorectal cancer.

Development and validation of a prognostic model for advanced gastric and oesophageal carcinoma (AGOC) using individual patient data from two clinical trials.

499 Background: Estimating survival in advanced gastric and oesophageal carcinoma (AGOC) remains a significant challenge. We developed a prognostic model incorporating readily accessible patient and clinical data and specific patient-reported outcomes (PROs), utilizing individual participant data from two randomized trials. Methods: We used data from 2 trials comparing regorafenib to placebo; AGITG INTEGRATE IIa (n=251) for model development and AGITG INTEGRATE (n=152) for validation. Both trials enrolled metastatic or AGOC following failure of 1 or more prior lines of systemic therapy. Candidate variables were chosen from systematic literature review and expert consultation. Significant prognostic factors for inclusion in the multivariable model were identified using univariable Cox proportional hazards models with p-value threshold of 0.1. Multivariable models were developed via Lasso regression. An initial model was created using clinical variables alone, followed by the integration of PROs. C statistics were used to discriminate the model’s efficiency. Results: Univariable analysis identified 9 clinical variables and 4 PRO domains as significant, including body mass index (BMI)(p=0.08), ECOG PS (0.02), extent of cancer (p<0.001), liver involvement (p=0.04), treatment with regorafenib (p=0.005), neutrophil-lymphocyte ratio (NLR) (p<0.001), LDH (p<0.001), albumin (p<0.001), and CA 19-9 (p=0.007). Significant baseline PROs included appetite loss (p<0.001), constipation (p<0.001), fatigue (p<0.001), and pain (p<0.001). Gastrectomy violated the Cox model proportional hazards assumption necessitating that the analysis be stratification by gastrectomy. The primary model (M1) incorporated region (Asia vs non-Asia, p=0.25, was included because it was significant in previous analysis (INTEGRATE), ECOG PS status, cancer extent, treatment with regorafenib, NLR, BMI, LDH, CA 19-9, and albumin. The final model (M2), which included PROs, demonstrated superior discriminative ability with the highest c-statistic values in both the gastrectomy and non-gastrectomy strata. The c-statistic increased from 0.695 for M1 to 0.723 for M2, indicating the added prognostic value of including PROs. Conclusions: The prognostic model that integrated both clinical data and PROs, proved robust for predicting survival in AGOC. The addition of PROs significantly enhanced prognostic accuracy, highlighting their importance in survival models. Further validation and refinement of the model is ongoing.

Updated results from the phase Ib/II study of fruquintinib combined with SOX and toripalimab in patients with advanced metastatic gastric/gastroesophageal junction adenocarcinoma (GC/GEJC).

423 Background: The efficacy of first-line treatment in advanced GC/GEJC patients (pts) with negative or low PD-L1 expression still needs to be improved. This phase Ib/II, open-label study (NCT05024812) evaluating fruquintinib (a highly selective VEGFR-1, -2, -3 inhibitor) plus toripalimab (anti-PD-1), and SOX has shown preliminary antitumor activity as first-line therapy in GC/GEJC. Here we update the results with longer follow-up duration and a specific focus on PD-L1 CPS features. Methods: The study of phase Ib employed a 3+3 dose escalation design, pts were treated with fruquintinib 3mg/d (dose level; DL1), 4mg/d (DL2), or 5mg/d (DL3) po, d1-14, in combination with fixed dose of toripalimab (240mg, iv, d1), oxaliplatin (130 mg/m 2 , iv, d1) and S-1 (40-60mg based on BSA, po, d1-14) every 3 weeks. It had been reported in phase Ib that fruquintinib 5mg/d was defined as the RP2D. In phase II, a further 64 pts would be treated with the same regimen. Primary endpoint of phase II was PFS per RECIST 1.1. Secondary endpoints included ORR, DCR, OS, DOR and safety. Results: As of August 15, 2024, 32 pts (9 in phase Ib; 23 in phase II) had been enrolled. Pts characteristics included: median age 62 (range 38–73); 66% male; 88% with ECOG PS 1, and 31% with liver metastasis. 31 pts had PD-L1 CPS available. 40.6% were CPS < 1 and 68.8% were CPS < 5. Of the 30 pts evaluable for tumor response, the ORR was 63.5% (95% CI 43.9–80.1) with 4 pts achieving complete responses and DCR was 96.7% (95% CI 82.8–99.9). After a median follow-up of 10.94 months, the median PFS was 9.33 (95% CI: 5.68–NA) months and OS result was not reached. Pts with CPS < 5 were more likely to achieve higher response rate (65.0 vs 55.6%) and longer PFS than CPS ≥5 (12.68 vs 8.11 months). Similar trends were observed in pts with CPS < 1 and CPS ≥1 (ORR: 75.0 vs 52.9%; PFS: 12.68 vs 8.11 months). Treatment-related adverse events (TRAEs) were mainly grade 1-2 and the most common ones were hypoalbuminemia (50%), neutrophil count decreased (34%), anemia (41%), platelet count decreased (34%) and white blood cell decreased (34%). Grade 4 TRAEs occurred in 2 pts (impaired liver function, hypertriglyceridemia). There were no treatment related deaths in the trial. Conclusions: Fruquintinib combined with SOX and toripalimab provided favorable efficacy and manageable toxicity profile as first-line therapy for pts with advanced metastatic GC/GEJC, especially in pts with negative or low PD-L1 expression. More data including the potential predictive response biomarkers would be further analyzed and reported. Clinical trial information: NCT05024812 .

Habitat conservation enhances the resilience of the lizard Liolaemus cuyumhue to high summer temperatures

A phase 2 study of amplitude-modulated radiofrequency electromagnetic fields (AM RF EMF) in metastatic pancreatic cancer.

TPS790 Background: Patients with advanced pancreatic adenocarcinoma (PDC) that progresses after first-line therapy face limited treatment options. Despite advances in systemic therapy, the prognosis for PDC is dismal, with a five-year overall survival (OS) of about 5% . Due to the high morbidity of this disease, there is a critical need for innovative treatments to improve patient outcomes. TheraBionic P1, a hand-held device, delivers tumor specific radio frequencies via a spoon-shaped antenna placed on the patient's tongue. The FDA and EMA have confirmed the safety of the device for amplitude-modulated electromagnetic field (AM-EMF) therapy. Improved efficacy outcomes were reported with AM RF EMF in other solid organ tumors including pancreatic cancer in preliminary studies. Preclinical and clinical evidence suggests that AM-EMF can inhibit tumor growth and was recently approved for use in hepatocellular cancer. The safety and clinical activity observed with AM RF EMF, paired with the unmet medical need for additional effective therapies in pancreatic cancer, provided a strong rationale for further clinical investigation. This protocol evaluates the efficacy and tolerability of AM RF EMF in combination with standard of care frontline therapy, gemcitabine and nab-paclitaxel for metastatic PDC. Methods: This is an ongoing, single-center, Phase II, non-randomized study using a Simon two-stage minimax design to assess the efficacy of AM-EMF in combination with gemcitabine/nab-paclitaxel as a first-line treatment in metastatic pancreatic cancer. Gemcitabine and nab-paclitaxel are administered per standard care. AM RF EMF are delivered to patients with a spoon-shaped applicator placed on the tongue three daily 60-minute treatments. Patients will be assessed for response every 8 weeks. Treatment is continued until progression or toxicity. The primary objective of this study is to evaluate the efficacy of the combination of nab-paclitaxel, gemcitabine, and AM RF EMF in improving 6-month overall survival rates in patients with metastatic PDC. Secondary objectives evaluate the safety, tolerability, profession free survival, objective response rate and disease control rate. Exploratory objectives evaluate change in CA19-9 and quality of life using FACT-General (FACT-G) and determine any possible correlation with clinical outcomes. Key eligibility includes treatment-naïve, histologically confirmed metastatic PC, age eighteen years old or greater, ECOG 0-1, and optimal organ function. Clinical trial information: NCT05776524 .

Costs of generic vs. branded nab-paclitaxel (nP) during first-line (1L) treatment of metastatic pancreatic adenocarcinoma (mPDAC) with gemcitabine + nab-paclitaxel (GnP) in a real-world commercial database.

694 Background: In 2013, the FDA approved GnP for 1L treatment of mPDAC. The total cost of care (TCoC) to payers during treatment is driven by the cost of nP, which first faced competition from generics in April 2022. We examined cost per generic vs. branded nP claim and cost per patient (pt) before and after generic entry. Methods: This retrospective observational study utilized Optum Market Clarity claims + EHR data. Inclusion criteria were: adult pts diagnosed with mPDAC between January 1, 2015 and May 31, 2023; initiated 1L GnP (index date) -14 to +90 days from diagnosis; 6 months pre-index enrollment. Claims were grouped into branded vs. generic based on NDC. For per-pt-per-month (PPPM) analyses, pts were required to have ≥30 days post-index enrollment and no nP claims missing NDCs. Pts were grouped into 1) branded pts with all nP claims for the branded NDC, and 2) generic pts with all claims for generic NDCs. TCoC, inpatient, outpatient, and chemotherapy drug cost to payers were calculated. The full study period and the period of generic entry beginning April 1, 2022 were examined. Results: Costs for branded vs. generic nP claims and GnP pts for 1L treatment initiated April 1, 2022 and after are shown (Table). The mean cost of generic claims was affected by outliers and was more than twice that of branded. The median nP claim cost, less affected by outliers, was still $2,408 greater for generic vs. branded. Costs for branded nP claims were similar before and after generic entry (not shown). 20 1L GnP pts had only branded nP claims, 24 had only generic, and 156 had mixed or were missing ≥1 NDC. PPPM mean TCoC was approximately twice as high for generic vs. branded. Medians were more similar, with generic median $2,037 higher vs. branded. Differences were driven by drug cost; other inpatient and outpatient costs were similar between the two groups (not shown). Costs of branded GnP pts before and after generic entry were similar (not shown). Conclusions: Publicly available prices for branded nP are $1,673 vs. $1,460 for generic per 100mg. In real-world data, we found generic nP costs per claim and PPPM tended to be higher than branded. While GnP is accepted by payers and clinicians as a standard 1L regimen for mPDAC, its real-world drug cost is at the level of branded therapy, despite generic availability. Future research should evaluate this finding as more post-generic-entry data becomes available. Branded vs generic costs. Statistic Branded Generic Claims N 343 308 Cost per claim Mean (SD) 4,721 (2,197) 11,761 (40,559) Median (IQR) 3,482 (2,945–6,583) 5,890 (3,482–6,964) Patients N 20 24 TCoC, PPPM Mean (SD) 25,410 (9,531) 52,129 (121,166) Median (IQR) 22,276 (17,911–32,180) 24,313 (17,231–36,774) GnP drug cost PPPM Mean (SD) 11,056 (4,334) 35,910 (118,205) Median (IQR) 10,162 (7,658–13,508) 10,554 (7,162–16,797)

Ethnic and socioeconomic disparities in cancer-free and all-cause survival in cholangiocarcinoma patients under 60: A population-based study.

527 Background: Cholangiocarcinoma in individuals under 60 years of age is rare, and survival outcomes can vary based on ethnic and socioeconomic factors. While previous studies have examined these disparities in other cancers, little is known about their impact on cancer-free and all-cause survival in younger cholangiocarcinoma patients. This study investigates the role of race and income in survival outcomes for this population. Methods: Data for individuals under 60 diagnosed with cholangiocarcinoma were extracted from the Surveillance, Epidemiology, and End Results (SEER) 22 registry. Kaplan-Meier curves were constructed to assess overall and cancer-free survival. Median survival times were calculated for each racial and income group, and log-rank tests were used to compare survival differences across the groups. Results: A total of 11,214 individuals under 60 years of age diagnosed with cholangiocarcinoma were included. Median all-cause survival was 12.0 months for Asian patients, 11.0 months for White patients, and 9.0 months for both Black and Hispanic patients. Significant differences were observed between Asian vs White (p < 0.005), Asian vs Black (p < 0.005), Asian vs Hispanic (p < 0.005), White vs Black (p < 0.005), and White vs Hispanic (p < 0.005), with no significant difference between Black and Hispanic patients (p = 0.859). For cancer-free survival, the median was 13.0 months for Asians, 12.0 months for Whites, 11.0 months for Blacks, and 10.0 months for Hispanics, with significant differences between Asian vs Black (p < 0.005), Asian vs Hispanic (p < 0.005), and White vs Black (p = 0.017). The difference between Asian vs White was not statistically significant (p = 0.052), and no significant difference was observed between White vs Hispanic (p = 0.418) or Black vs Hispanic (p = 0.418). By income, patients with an income >$75,000 had significantly longer all-cause survival (12.0 months vs 9.0 months, p < 0.005) and cancer-free survival (13.0 months vs 11.0 months, p < 0.005) compared to those with an income of $0-$75,000. Conclusions: Significant disparities in cancer-free and all-cause survival were found based on ethnicity and income. Asian and White patients had longer survival compared to Black and Hispanic patients, and higher-income patients experienced better outcomes. These findings highlight the need for targeted efforts to address healthcare inequalities in cholangiocarcinoma care.

Analysis of anxiety and pain in patients undergoing immediate sequential bilateral cataract surgery or unilateral cataract surgery

Genomic landscape study of esophago-gastric adenocarcinoma (EGAC) in young patients under the age of 30 years.

480 Background: Despite recent advances in treatment of EGAC, prognosis continues to be poor with reported 5-year survival of less than 30%. EGAC is more frequently diagnosed at an old age with the median age at diagnosis around 65 years. However, approximately 10% of EGAC are diagnosed at a younger age of less than 50 years and those patients present with more advanced stages resulting in worse prognosis. Our study investigated the genomic landscape of EGAC diagnosed under the age of 30 years to better understand the characteristics of EGAC occurring in very young population. Methods: 8,001 cases of clinically advanced EGAC who underwent comprehensive genomic profiling (CGP) from 2012 to 2024 were included in the study. Patients aged less than 30 years were classified as ‘EGAC-young’ and patients aged 50 and older were classified as ‘EGAC-old’. All classes of genomic alterations (GA), microsatellite instability high (MSI-high) status, tumor mutation burden (TMB), genomic ancestry, genomic signature, and homologous recombination defect signature (HRDSig) were determined from the sequencing data. PD-L1 was measured by IHC using the Dako 22C3 tumor proportional score (TPS) system. Comparisons utilized the Fisher Exact method with the Benjamini-Hochberg adjustment to reduce the false discovery rate. Results: Out of 8,001 cases, 7389 (92.4%) were classified as ‘EGAC-old’ and 26 (0.3%) as ‘EGAC-young’. Both groups had a higher frequency of male patients but there was no significant difference between the two groups (86.4% vs 76.9%; NS). Median GA per tumor was 6 in both groups. The ‘EGAC-old’ featured a significantly higher frequency of EUR ancestry (92.0% vs 73.1%; P=0.026). There were no significant differences in clinically important GA between both groups, including similar ERBB2 GA (21.2% vs 30.8%; NS) and FGFR3 GA (1.2% vs 7.7%; NS). There was a trend of more frequent GA of AKT2, CCNE1, and KEAP1 noted in ‘EGAC-young’ (0.9% vs 11.5%, 8.5% vs 26.9%, 1.3% vs 11.5%, respectively; P=0.071). MSI-high status was 3.1% in the ‘EGAC-old’ but not detected in the ‘EGAC-young’ (NS). The median TMB was higher in the ‘EGAC-old’ vs ‘EGAC young’ (3.8 mutations/Mb vs 1.9 mutations/Mb; P=.003). The frequencies of a positive HRDSig were similar in both groups (5.6% vs 8.0%; NS). There were no significant differences in COSMIC trinucleotide signatures. PD-L1 expression was identified in greater than 20% of the ‘EGAC-old’ but was not measured in the ‘EGAC-young’. Conclusions: Clinically advanced EGAC in young patients under the age of 30 years features a genomic landscape that differs from EGAC identified in older patients, including lower TMB and a trend of increased GA frequency of genes related to poor prognosis in other types of cancer. Further studies are warranted to utilize CGP findings in identifying potential implications for treatment and prognostication in these rare cases of EGAC occurring in very young patients.

The safety and short-term efficacy of induction DCF plus nivolumab therapy in patients with unresectable locally advanced esophageal squamous cell carcinoma.

425 Background: Definitive chemoradiotherapy (dCRT) is the standard treatment for unresectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) based on the results of the JCOG 0303 study. However, the prognosis in this population remains poor with a median overall survival (OS) of 13.1 months, and fistula formation was reported in about 20% of patients who received dCRT. In such a circumstance, a more effective and safer treatment strategy, such as induction chemotherapy followed by conversion surgery or dCRT, was developed. A phase II study of induction chemotherapy consisting of docetaxel (DTX), cisplatin (CDDP), and 5-fluorouracil (5-FU) (DCF) therapy (IC-DCF) showed a conversion rate of 37.5%, promising efficacy with a median OS of 33.8 months and a fistula formation rate of 4.2%. Therefore, we evaluated whether adding nivolumab to IC-DCF (IC-DCF+Nivo) could improve clinical outcomes. Methods: We retrospectively reviewed the medical records of patients with unresectable LA-ESCC who received IC-DCF+Nivo between Nov 2023 and Aug 2024. IC-DCF+Nivo (DTX 70mg/m2 day1, CDDP 70mg/m2 day1, 5-FU 750mg/m2 day1-5, Nivo 360 mg/body day1, every 3 weeks) was administered for 3 courses. We administered prophylactic levofloxacin from day 5 to day 15 during each cycle, and used granulocyte colony-stimulating factor (G-CSF) as a treatment. We evaluated adverse events according to the CTCAE ver5.0 during induction chemotherapy as safety, and objective response rate (ORR) of IC-DCF+Nivo according to the RECIST version 1.1., conversion surgery rate, complete resection (R0) rate, pathological complete response (pCR) rate and clinical CR (cCR) rate after dCRT as efficacy. Results: The median follow-up period was 5.5 months. We identified 23 eligible LA-ESCC patients, median age (range): 65 (44-76), 83% male, PS 0/1: 57%/44%, T status T3/T4b 44%/57%, clinical stage III/IVA/IVB 22%/57%/22%. Seven patients (30%) had supraclavicular lymph node metastases, and the most common unresectable factors were tracheal invasion (52%), bronchial invasion (22%) and aortic invasion (13%) of primary tumor or metastatic lymph nodes. Eighteen patients (78%) completed the 3 courses of IC-DCF+Nivo. The frequent grade 3-4 hematological adverse events were neutropenia (13/23, 57%) and anemia (3/23, 13%), and 1 patient (4.3%) had grade 3 diarrhea as non-hematological toxicity. Febrile neutropenia occurred in 3 patients (13%), and G-CSF was used in 7 patients (30%). One patient (4.3%) experienced primary tumor perforation. The ORR after 3 cycles of induction chemotherapy was 53%. Fourteen patients (61%) achieved resectability, and 10 patients (44%) underwent surgery. R0 resection rate was 90% (9/10), and the pCR rate was 20% (1/10). No one achieved cCR in dCRT. Conclusions: Induction DCF plus nivolumab therapy showed well-tolerated and well conversion rate.

Quantitative amplification ratio for established and emerging biomarkers in gastroesophageal (GE) cancer.

470 Background: Gene copy number (CN) amplifications (amps) and/or protein overexpression in ERBB2 , EGFR , FGFR2 , and MET represent established and emerging clinical targets in GE. Various methodologies are used to report gene amp or overexpression with some data suggesting FISH ratio may predict therapy response. Quantitative methods for NGS CN and relationship to ISH/IHC remains largely unresolved. We studied the landscape of targetable CN amps in GE to understand correlations of quantitative CN amp ratio and outcomes. Methods: GE tissue (N = 20,468) and liquid (N = 1,760) samples underwent NGS-based comprehensive genomic profiling (CGP). A genome-wide CN model for each sample was generated, segmented, and combined with variant allele frequencies of heterozygous SNPs to estimate the sample purity, ploidy, and CN for each segment. Genes were considered amplified at CN ≥ ploidy + 3 for ERBB2 and + 4 for other genes. Sub-analysis using amp ratio (ratio of the gene CN to the sample ploidy) ≥ 3 was performed. ctDNA tumor fraction (TF) was quantified using a composite algorithm (PMID: 38990098). The Flatiron Health-Foundation Medicine clinico genomic database, a nationwide (US-based) de-identified EHR-derived database linked to CGP data, was queried to assess external HER2 FISH or IHC and describe real-world (rw) progression-free survival (rwPFS) and overall survival (rwOS) of GE patients (pts) with ERBB2 amp on trastuzumab-based regimens. Results: ≥1 gene amps were detected in 15,341 (75%) GE tissue cases, and in 67% of cases using an amp ratio ≥3 threshold. The rates of amps in current clinical targets using each threshold were ERBB2 : 17%/12%, KRAS : 13%/12%, EGFR: 8.7%/7.2%, MET: 5.2%/4.0% , FGFR2: 3.1%/2.7% of tissue samples. The median amp ratio and percent of amps with ratio ≥ 3 were ERBB2 : 7.1/73%, KRAS : 14/92%, EGFR : 13/82%, MET : 6.3/76%, and FGFR2 : 29/88%. Amp ratio ≥ 3 was associated with focal amplicons vs amp ratio < 3 (median amplicon size 0.95 vs. 3.8 Mbp, p < 0.001). Of 1,382 pts with HER2 NGS and IHC results, concordance with IHC3+ was 68% and increasing ERBB2 amp ratio was associated with IHC 3+ status. Of 604 pts with HER2 NGS and FISH, concordance was 80% (118 positive, 366 negative). Higher ERBB2 amp ratio was also associated with longer rwOS and rwPFS as a continuous variable on first-line trastuzumab-based regimens. ≥1 gene amps were detected in 597 (34%) liquid samples (median TF 18%) and 32% with the amp ratio ≥3 threshold, increasing to 79% and 73% with TF ≥ 20% (n=355). Conclusions: Gene amps are common established or emerging GE targets and ERBB2 amp ratio is associated with outcomes for pts on trastuzumab-based regimens. Amp detection in liquid correlates with higher TF and amp ratio. As the number of therapies targeting gene amps and overexpression grows, quantification of the degree of amplification and harmonization across methodologies may be an important tool to select pts for optimal outcomes.

Exploring the feasibility and clinical impact of ultrasound microvascular flow imaging in detecting brain injury in hyperbilirubinemia neonates

Development and validation of a deep learning–based pathomics signature for prognosis and chemotherapy benefits in colorectal cancer: A retrospective multicenter cohort study.

298 Background: The current TNM staging system fails to provide adequate information for prognosis and adjuvant chemotherapy benefits in colorectal cancer (CRC). Pathomics, an emerging field, shows promise in improving prognosis estimation and decision-making. In this study, we developed and validated a pathomics signature (PS CRC ) that directly analyzes hematoxylin and eosin–stained slides using deep learning to predict outcomes. Methods: A total of 883 whole slide images from two cohorts, Harbin Medical University Cancer Hospital and The Cancer Genome Atlas (TCGA), were retrospectively analyzed. An interpretable, multi-instance deep learning model was proposed to establish the PS CRC . Shapley additive explanations were employed to interpret the model's decisions, and gradient-weighted class activation mapping was applied to visualise the pathological phenotypes of the PS CRC . The transcriptomics data from TCGA cohort was used to explore the potential pathogenesis underlying the PS CRC . Results: The PS CRC was identified as an independent prognostic factor associated with both overall survival and disease-free survival. Incorporating the PS CRC into the TNM stage model resulted in a significant improvement in prognosis estimation, as evidenced by a notable increase in net reclassification improvement and integrated discrimination improvement. Moreover, among stage II and III CRC patients with low levels of PS CRC , satisfactory benefits from chemotherapy were observed. Notably, the main underlying features of PS CRC include tumor cell infiltration, adipocyte accumulation, fibrous tissue deposition, and stromal infiltration. Transcriptome analysis further support the relevance of PS CRC to tumor progression and immune suppression. Conclusions: Our finds highlight the significant potential of histopathology images-based deep learning in predicting prognosis and assess therapeutic response of CRC. The PS CRC could serve as an effective tool in clinical decision for CRC management, providing insights into the underlying pathogenic mechanisms. However, prospective studies are still necessary for further validation.

Assessment of clinical value and barriers to use of new investigational targeted agents in the community setting: A study of claudin 18.2 and zolbetuximab.

500 Background: Rapid integration of novel agents in clinical practice can be lifesaving. However, community-based practices may experience extended adoption times, due to practical barriers. REFLECT was developed to assess new drug implementation in the community setting. Methods: REFLECT consists of a 20-minute prerecorded presentation, followed by a data-collection event for community oncologists. It was developed to evaluate and assess challenges of implementing novel targeted agents in the community practice setting. In this pilot study, awareness of zolbetuximab (zolbe), a potential first-in-class claudin 18.2 (CLDN18.2) monoclonal antibody and companion diagnostic, was assessed. Between April and August 2024, 53 data-collection events were held representing 26 states across the US. Data from 492 oncologists were recorded and analyzed. Results: Nearly half the community oncologists (47%) were not familiar with CLDN18.2 as a therapeutic target in gastric/gastroesophageal junction (G/GEJ) cancer. Awareness of zolbe data was low among community oncologists; 79% indicated they had not seen the results from the phase 3 studies. However, 96% of oncologists reported the data will at least moderately impact their treatment of CLDN18.2+ patients with metastatic (m)G/GEJ cancer. Only 40% of oncologists reported having access to CLDN18.2 testing. Uncertainty regarding availability of CLDN18.2 testing was high among oncologists in the Central US (52%), representing a significant awareness gap for CLDN18.2 testing. Opinions were divided regarding the treatment approach for CLDN18.2+, immunosensitive patients (Table). In a HER2–, CLDN18.2+ patient with mG/GEJ cancer and a combined positive score (CPS) of 10; 58.1% would recommend first-line chemotherapy (chemo) plus immunotherapy (IO) and 40.4% would recommend chemo plus zolbe. Conclusions: First-in-class targeted agents often encounter additional challenges and knowledge gaps regarding adoption in the community practice setting, particularly associated with molecular testing. Timely education on patient identification and correct utilization may accelerate adoption of new regimens, and potentially save lives. Data-sharing and -collection platforms including REFLECT can be instrumental in the identification of challenges associated with widespread and rapid implementation of novel agents in the community oncology setting. What treatment approach would you recommend in a patient with the following characteristics, if all treatments were available? mGEJ adenocarcinoma, HER2– disease, CLDN18.2+ staining in >75% of tumor cells, CPS 10. Treatment Total: N = 492% (n) Chemo mFOLFOX6 1.0 (5) CAPOX 0 (0) Chemo + IO mFOLFOX6 + IO 52.8 (260) CAPOX + IO 5.3 (26) Chemo + zolbe mFOLFOX6 + zolbe 33.9 (167) CAPOX + zolbe 6.5 (32) Other 0.4 (2)

Efficacy and safety of cabozantinib for advanced gastrointestinal (GI) neuroendocrine tumors (NET) after progression on prior therapy: Subgroup analysis of the phase 3 CABINET trial (Alliance A021602).

666 Background: In the phase 3 CABINET trial (NCT03375320), cabozantinib (CABO) significantly prolonged median progression-free survival (PFS) compared to placebo (PB) in patients with advanced, previously treated, progressive extrapancreatic NET (epNET) [HR 0.38 (95% CI, 0.25-0.59, P<0.0001)] and pancreatic NET (pNET) [HR 0.23 (95% CI, 0.12-0.42, P<0.0001)] (Chan et al., NEJM, 2024). In this analysis, we focus on outcomes of patients with epNET arising in the GI tract. Methods: Patients with locally advanced or metastatic epNET or pNET were randomized 2:1 in separate cohorts to receive CABO 60 mg daily vs PB. The epNET cohort included patients with tumors arising in the GI tract (not including pancreas), lung, unknown primary, and other rare primary sites. In this subgroup analysis of the epNET cohort, patients with GI NET were included. Eligibility included progression by RECIST within 12 months (mo) prior to registration, ≥ 1 prior systemic therapy. Primary endpoint: PFS by blinded independent central review (BICR). Secondary endpoints: objective response rate, overall survival, safety. Results: 116 of the 203 patients in the epNET cohort had GI NET (CABO, n=70; PB, n=46). Median age was 66 yrs; females: 46%; G1/G2/G3/unknown grade: 35%/57%/6%/2%. ECOG performance status: 0/1-2: 43%/57%. White race: 86%. The most common primary tumor locations were ileum/cecum (54%), small intestine with location not specified (20%); non-cecum colon or rectum (11%), stomach (4%); duodenum (3%); jejunum and nonspecified midgut site (3% each). Prior systemic therapies included somatostatin analogs (SSA) (100%), everolimus (59%); Lu-177 dotatate (77%); temozolomide +/- capecitabine (16%). In patients with GI NET, CABO was associated with improved PFS by BICR compared to PB (stratified HR, 0.50; 95% CI: 0.28-0.88, 1-sided stratified log-rank P=0.007). Median PFS with cabozantinib was 8.5 mo (95% CI, 6.0-16.7) compared to 5.6 mo (95% CI, 3.9-11.0) with PB. CABO demonstrated potential benefit in patients with midgut GI NET and across clinical factors including grade, functional status related to hormone secretion, concurrent SSA use, and prior therapy with Lu-177 dotatate or everolimus. The most frequent grade 3/4 adverse events attributed to therapy with CABO included hypertension (19%), diarrhea (13%), fatigue (10%). Conclusions: CABO is associated with improvement in PFS compared to PB in patients with advanced GI NET. Potential benefit was observed across clinical factors including grade, functional status, concurrent SSA, and prior treatment. The safety profile for CABO in patients with GI NET is consistent with that previously reported. Support: U10CA180821, U10CA180882; U10CA180820 (ECOG-ACRIN), U10CA180868 (NRG Oncology), U10CA180888 (SWOG); Exelixis; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03375320 .

AI-based prediction of androgen receptor expression and its prognostic significance in prostate cancer

Size‐Dependent Cascade Enhancement of T ₁ ‐T ₂ Dual‐Modal MRI in Tumors

Abstract Currently, there is no conclusive evidence indicating that in situ self‐assembled Gd nanostructures of varying sizes demonstrate distinct T 1 and T 2 signal enhancement capabilities. Furthermore, it remains uncertain whether size adjustment can effectively achieve enhanced T 1 ‐T 2 dual‐modal MRI. To address these uncertainties, a two‐step in situ self‐assembly strategy is developed. This approach began with a small‐sized nanoprobe, Gd‐TCO‐P, with a hydrodynamic diameter (dH) of 16 ± 3 nm. This nanoprobe underwent alkaline phosphatase (ALP) cleavage and self‐assembled intracellularly into short nanofibers termed Gd‐NFs (dH: 200 ± 51 nm). The subsequent introduction of tetrazine‐tetrazine crosslinked these Gd‐NFs, leading to the formation of larger two‐stage dendritic nanofibers known as Gd‐TS‐NFs (dH: 4371 ± 236 nm). This process achieves size‐dependent enhancement of both T 1 and T 2 signals, which is validated through both in vitro and in vivo experiments, enabling precise long‐term imaging of ALP‐overexpressing tumors. This study not only provides valuable insights into the relationship between the size of in situ formed Gd nanostructures and T 1 /T 2 MRI contrast enhancement, but also suggests a promising strategy for clinical applications of T 1 ‐T 2 dual‐modal MRI.