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Risk of second primary cancer among patients with a first primary appendiceal adenocarcinoma.
819 Background: Incidence rates of rare appendiceal cancers are increasing across the United States. Although this is suggestive of a growing population of appendiceal cancer survivors over time, the risk of second primary cancers specific to patients with a first primary appendiceal adenocarcinoma remains unknown. Methods: We conducted a population-based study of adults (age ≥18 years) diagnosed with a first primary appendiceal adenocarcinoma from 1992 to 2021, using data from the Surveillance, Epidemiology, and End Results (SEER) Program. We estimated cumulative incidence of second primary cancer, defined as any primary cancer diagnosed at least 3 months after appendiceal adenocarcinoma, with Fine and Gray methods to account for the competing risk of death. For comparison to the general population, we also estimated standardized incidence ratios [SIRs], or the observed number of second cancers relative to the expected number based on age-, sex-, and race-specific incidence rates. Results: A total of 5,827 adults diagnosed with a first primary appendiceal adenocarcinoma (mean age 58.0 years; 51.8% female; 68.5% non-Hispanic White) were identified during the study period, of whom 418 developed a second primary cancer. The most common types of second primary cancer were prostate (17.7%), colorectal (14.4%), female breast (10.5%), lung (8.4%), and melanoma (6.0%). At 10 and 20 years after appendiceal adenocarcinoma diagnosis, the cumulative incidence of second primary cancer was 7.5% (95%CI 6.8%-8.4%) and 11.7% (95%CI 10.5%-12.9%), respectively. Cumulative incidence significantly differed by sex (p<0.01) and age at appendiceal adenocarcinoma diagnosis (early-onset [age<50] vs late-onset; p<0.01). For example, at 10 years post-diagnosis, the cumulative incidence of second primary cancer was 6.4% (95%CI 5.4%-7.4%) for females and 8.8% (95%CI 7.6%-10.1%) for males. The overall SIR for any second primary cancer was 1.12 (95%CI, 1.02-1.23)—corresponding to 14.8 excess cancers per 10,000 person-years. SIRs for common types of second primary cancers were: 1.07 (95%CI 0.84-1.35) for prostate, 2.12 (95%CI 1.63-2.70) for colorectal, 0.91 (95%CI 0.68-1.19) for female breast, 0.81 (95%CI 0.58-1.09) for lung, and 1.20 (95%CI 0.79-1.73) for melanoma. Conclusions: Approximately one in every 13 adults diagnosed with a first primary appendiceal adenocarcinoma in the United States will be diagnosed with a second primary cancer within 10 years. After diagnosis of an appendiceal adenocarcinoma, patients have a 12% excess incidence in second primary cancers and double the excess incidence in second primary colorectal cancers compared to the general population. Implementation of cancer prevention and early detection strategies (e.g., colonoscopy screening, genetic testing) for patients with an appendiceal adenocarcinoma is a clinical priority.
Effect of SHR-1701 on chemotherapy (chemo)-induced myelosuppression: Data from a phase 3 study in HER2-negative gastric/gastroesophageal junction adenocarcinoma (G/GEJA).
335 Background: Blocking TGF-β signaling has the potential to facilitate the recovery from chemo-induced myelosuppression. SHR-1701 is a bifunctional agent targeting PD-L1 and TGF-β. Methods: In the multicenter, randomized, double-blind phase 3 study (NCT04950322), SHR-1701 plus CAPOX demonstrated a statistically significant and clinically meaningful benefit in OS compared with placebo plus CAPOX in patients (pts) with previously untreated, unresectable locally advanced or metastatic HER2-negative G/GEJA (ESMO 2024, LBA60). Here, we reported the effect of SHR-1701 on chemo-associated myelosuppression. Results: In total, 364 and 366 pts in the SHR-1701 and placebo arm received assigned treatment. As of May 20, 2024, with a KM estimated median follow-up of 13.6 mo, all study medications showed similar exposure duration between the two arms (Table). Occurrence of treatment-related adverse events was generally comparable (any grade, 97.8% in SHR-1701 arm vs 98.4% in placebo arm; grade ≥3, 62.6% vs 59.0%). SHR-1701 reduced the incidence of any grade decreased platelet count, decreased neutrophil count, and decreased white blood cell count by 8.7%, 10.1%, and 11.2%, and for grade ≥3, by 9.1%, 4.3%, and 1.6%, respectively (Table). Compared with the placebo arm, less pts in the SHR-1701 arm used platelet growth factors (30.2% vs 42.9%) and white blood cell growth factors (32.7% vs 39.6%). Conclusions: SHR-1701 showed the capacity to suppress chemo-associated myelosuppression. Clinical trial information: NCT04950322 . Safety. SHR-1701 plus CAPOX(N=364) Placebo plus CAPOX(N=366) Treatment difference (SHR-1701 vs placebo) Treatment exposure (day), median (IQR) SHR-1701/placebo 137.0 (65.5-251.5) 127.5 (62.0-190.0) NA Capecitabine 122.0 (83.0-138.0) 122.0 (73.5-135.0) NA Oxaliplatin 107.0 (66.0-123.0) 108.5 (64.0-121.0) NA Treatment-related hematological toxicities, n (%) or % Any grade Grade ≥ 3 Any grade Grade ≥ 3 Any grade Grade ≥ 3 Platelet count decreased 217 (59.6%) 69 (19.0%) 250 (68.3%) 103 (28.1%) -8.7% -9.1% Neutrophil count decreased 163 (44.8%) 44 (12.1%) 201 (54.9%) 60 (16.4%) -10.1% -4.3% White blood cell count decreased 147 (40.4%) 13 (3.6%) 189 (51.6%) 19 (5.2%) -11.2% -1.6%
Effects of disease aetiology on outcomes for unresectable HCC treated with lenvatanib or atezobev: A real world retrospective study.
554 Background: Hepatocellular Carcinoma (HCC) is the most common primary liver cancer and a leading cause of cancer-death worldwide. 1 Standard of care first line treatment for unresectable HCC is Atezolizumab plus Bevacizumab (AtezoBev) 1 while the multi-kinase inhibitor Lenvatinib 2 is also available in the first line setting. No randomised studies have compared these treatments directly. Real world data suggests similar overall survival (OS) with AtezoBev possibly superior in patients with a viral hepatitis aetiology and Lenvatinib superior in NAFLD. 3,4,5,6,7 Methods: We evaluated patients treated with Lenvatinib or AtezoBev in a retrospective cohort of patients who commenced first-line treatment in the West of Scotland from 04/12/2015 to 28/11/2023. 102 received Lenvatinib and 52 AtezoBev. We collected data on progression free survival (PFS), OS, demographics and disease aetiology- classified primarily as viral hepatitis, acholic liver disease (ALD) or NAFLD. Results: AtezoBev patients had improved mOS compared with Lenvatinib (13.8 vs 9. 1 months, p = 0.04). No statistically significant differences were observed in mPFS (5.5 vs 3.5 months, p = 0.31). Of the three aetiologies considered, the only statistically significant (p<0.05) difference between the treatments was OS in the NAFLD group (24.1 vs 9.1 months, p = 0.04). When considering patient demographic and disease factors, Child-Pugh score was most significant. Patients with Childs=5 liver disease had much longer OS and PFS compared with Childs≥6 disease. Similarly, patients with ECOG PS=0 had improved survival than PS≥1. There were no statistically significant (p<0.05) differences between AtezoBev and Lenvatinib. Age, sex and social deprivation (SIMD) score had minimal effects on survival although high levels of social deprivation and male sex were over-represented in our population. Conclusions: In contrast to other real world analyses, our patients demonstrated improved mOS with Atezo/Bev vs Lenvatinib. 3 However, mPFS was similar for the two regimes. The difference in OS may be explained by differences in patient selection, with the Lenvatinib group disproportionately representing patients with a poorer performance status (PS>0) and higher Childs-Pugh scores (CP>5). Furthermore, patients in the AtezoBev group who progressed were often offered Lenvatinib second-line, possibly improving mOS, whereas Lenvatinib patients who progressed were offered either Sorafenib, a clinical trial or best supportive care. However, we cannot rule out a direct survival benefit from the use of AtezoBev vs Lenvatinib in the first line setting. The choice of first line therapy for HCC remains complex and must account for patient preferences such as convenience and side effect profile in addition to observed trial outcomes and the increasing body of real world evidence. 1. Finn RS et. al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N. Engl. J. Med. 2020 May 14;382(20):1894-1905. 2. Kudo, Masatoshi et. al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018. Volume 391, Issue 10126, 1163 – 1173. 3. Wang, BC. et. al. Lenvatinib Versus Atezolizumab Plus Bevacizumab in the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Meta-Analysis of Real-World Studies. Targ. Oncol. 2024. 19, 203–212. 4. Casadei-Gardini A et. al. Atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a large real-life worldwide population. Eur. J. Cancer. 2023; 180:9-20. 5. Rimini M et. al. Atezolizumab plus bevacizumab versus lenvatinib or sorafenib in non-viral unresectable hepatocellular carcinoma: an international propensity score matching analysis. ESMO Open. 2022 Dec;7(6):100591. 6. Su CW et. al. Similar efficacy and safety between lenvatinib versus atezolizumab plus bevacizumab as the first-line treatment for unresectable hepatocellular carcinoma. Cancer Med. 2023. 12(6):7077-7089. 7. Rimini, M., et al. Survival outcomes from atezolizumab plus bevacizumab versus Lenvatinib in Child Pugh B unresectable hepatocellular carcinoma patients. J. Cancer. Res. Clin. Oncol. 2023. 149, 7565–7577.
The TAB-EOAO study: Trends in use and benefit of adjuvant chemotherapy between early onset and average onset locally advanced colon cancer.
105 Background: Despite the declining incidence rates (IR) in average onset colon cancer (AO-CC), IR for early onset colon cancer (EO-CC), defined as patients (pts) younger than 50-years-old at diagnosis, has been increasing. Treatment for high risk locally advanced colon cancer (CC) is surgical resection followed by adjuvant chemotherapy (AC). Data indicates a more permissive chemotherapy use in EO-CC. There is limited data about treatment and survival trends in EO-CC. Thus, we aimed to assess the use and benefit of AC between in EO vs AO CC in locally advanced disease. Methods: CC diagnosed between 2000-2020 were identified in the Surveillance, Epidemiology, and End Results Program (SEER) Database. Eligible pts were adults (≥18), Stage II or III at diagnosis. Stage II disease was further stratified as low risk (pT1-3) and high risk (pT4). Logistic regression methods were used to assess Odds Ratio (OR) of AC between EO-CC and AO-CC; Cox models were used to compare overall survival (OS) and Cancer-specific survival (CSS) between both groups during 2000-2010 and 2011-2020. Results: Our study included 136,676 pts (AO-CC= 121,606; EO-CC =15,070). The median age for EO-CC was 44 years versus 71 years for AO-CC population. The use of AC increased over time for both the EO-CC (63% vs 66%) and AO-CC (33% vs 40%). Moreover, pts with AO-CC received less AC than EO-CC in the entire study time (see table). In pts with AO-CC, AC improved CSS (HR=0.69 for 2000-2010, HR=0.50 2011-2020). However, among those with EO-CC, AC improved CSS in 2011-2020 (HR=0.76) but did not improve CSS in 2000-2010 (HR=1.02). Conclusions: Over the past 20 years EO-CC has been managed aggressively, especially for stage II low risk patients where current guidelines do not support the use of AC. In this real world data set we show that for EO-CC AC did not improve CSS in the decade 2000- 2010 but did improve CSS in the 2011- 2020 period. Further analysis may clarify stage specific benefits of AC. There clearly remains a need for better risk stratification, including the use of ctDNA, to identify the subpopulations of EO-CC patients that will best benefit from AC. Multivariable logistic regression model of chemotherapy by timeframe with interaction term: Age* stage. 2000-2010 2011-2020 AO-CC vs EO-CC OR 95% CI OR 95% CI Stage II low risk 0.23 (0.21, 0.26) 0.28 (0.24, 0.32) Stage II high risk 0.28 (0.22, 0.36) 0.28 (0.21, 0.36) Stage III 0.36 (0.32, 0.4) 0.30 (0.26, 0.34)
Prussian Blue Analogues “Dressed” in MXene Nanosheets Tightly for High Performance Lithium‐Ion Batteries
AbstractMXenes, have been considered as a new generation anode material in lithium‐ion batteries for lower lithium‐ion diffusion barriers and superior conductivity. Unfortunately, their structures are prone to aggregation and stacking, hindering further shuttle of lithium ions and electrons, resulting in lower discharge capacity. Therefore, the introduction of interlayer spacers for the preparation of MXene‐based hybrids has attracted much attention. Introducing Prubssian blue analogues (PBAs) as a new interlayer spacer to combine with MXene nanosheets can not only preserve the high conductivity of MXene and inhibit the volume expansion and structural degradation of the PBA component, but also inherit the characteristics of large specific surface area and high porosity of PBAs. By intelligent regulating the size of MXene sheets, Co‐PBA@MXene hybrids with common sandwich‐like structures and superior core‐shell‐like structures have been successfully obtained. Furthermore, Co@M(x:y) hybrids are prepared by intelligently adjusting the shell thickness of MXene through intelligently controlling of the mass ratio between Co‐PBA and MXene. Among them, the Co@M(5:2) anode exhibits an excellent capacity (603 mA h g−1 at 0.2 A g−1 after 100 cycles) and superior long‐term cycling stability due to the protective and conductive properties provided by the MXene shell and multi‐redox pairs and rich porosity from Co‐PBA core.
Real-world survival differences in advanced biliary tract cancer patients with ctDNA detected IDH1 mutations and FGFR2 fusions receiving first-line gemcitabine-cisplatin with and without immunotherapy.
548 Background: Comprehensive genomic profiling (CGP) is recommended for patients (pts) with metastatic BTC (mBTC) given its aggressive, heterogeneous disease profile. Liquid biopsy is a rapid, non-invasive option with high concordance to tissue-based CGP. First-line (1L) therapy in mBTC is gemcitabine-cisplatin (GemCis) +/- durvalumab or pembrolizumab (IO) regardless of CGP results. However, data suggests pts with targetable alterations may have worse outcomes with addition of IO compared to all comers. We examined outcomes for mBTC pts receiving 1L GemCis vs. GemCis+IO following ctDNA-detected IDH1 mutation ( IDH1 +) or FGFR2 fusion ( FGFR2 +). Methods: Real-world data was sourced from GuardantINFORM, which comprises aggregated commercial payer health claims and de-identified records from pts with clinical ctDNA testing via Guardant360 (G360). Pts with mBTC and >1 treatment claim after G360 results, and IDH+ or FGFR2+ between April 2019 and June 2024 were analyzed. Only pts treated with 1L GemCis +/- IO were included. Outcomes were assessed via real-world time to treatment discontinuation (rwTTD), real-world time to next treatment (rwTTNT), and real-world overall survival (rwOS), all in months with 95% confidence intervals. Log-rank test was used to compare Kaplan-Meier survival curves. Results: 412 pts were IDH1+ and 154 were FGFR2+ . In the IDH1 + cohort, 184 pts were treated with GemCis and 106 pts with GemCis+IO. Pts receiving GemCis demonstrated improved rwOS vs. GemCis+IO [27.2 (23.6-37.8) vs. 16 (13.6-19.9) mo.; HR=0.4 (95CI 0.27-0.59), p<0.001]; there was no difference in rwTTNT [13 (10.8-14.3) vs. 10 (8.4-12.3); HR=0.85(95CI 0.6-1.22), p=0.4] or rwTTD [4.8 (4.1-5.5) vs. 6.6 (4.7-8.1); HR=1.17 (95CI 0.9-1.5), p=0.25]. Similarly, in the FGFR2 + cohort, pts receiving GemCis + IO (n=44) had worse rwOS than pts on GemCis (n=70) [NR (15.6-NR) vs. 43 (34.2-2.1); HR=0.37(95CI 0.18-0.74), p=0.005], with no difference in rwTTNT [8.9 (4.89-NR) vs. 13.78 (7.42-NR); HR=0.63 (95CI 0.36-1.1), p=0.1] or rwTTD [5.0 (3.1-7.8) vs. 4.2 (3.5-5.5); HR=1.08 (95CI 0.72-1.6), p=0.7]. Among all mBTC pts receiving GemCis+IO (n=1113), non- IDH1 + pts (n=1007) had numerically better rwOS compared to IDH1 + pts (n=106) [18.6 (17.2-21.3) vs. 16.0 (13.6-19.);HR=0.76 (95CI 0.6-1.03), p=0.075]. No survival difference was observed between IDH1+ (n=184) and non- IDH1 + (n=2333) pts receiving GemCis [27.2 (23.6-37.8) vs. 26.2 (24.5-28.2); HR=1.08 (95CI 0.88-1.32), p=0.4]. Conclusions: Addition of IO to GemCis in IDH1 + and FGFR2 + mBTC pts resulted in decreased rwOS. This data supports ctDNA CGP to inform clinical decision-making prior to 1L as well as at progression. Further studies in clinical cohorts are needed to confirm these findings.
A comprehensive study of clinical and molecular features in patients with metastatic colorectal cancer with and without liver mets.
242 Background: Colorectal cancer (CRC) most frequently metastasizes to the liver, and patients (pts) with liver metastasis (mets) at the time of metastatic diagnosis tend to have poorer outcomes compared to pts with non-liver mets. However, the reason for this discrepancy is not well-defined. We thus aimed to identify any distinct molecular or clinical characteristics that could contribute to the poor outcomes associated with liver mets of CRC. Methods: Pts diagnosed with metastatic CRC from 2014-2022 were identified using the institutional molecular database of CRC. Demographic, clinical, and molecular data were collected by reviewing electronic medical records. Time to next treatment was defined as the time between 1st and 2nd line treatment. We utilized Fisher’s exact tests for categorical variables and both Kaplan-Meier analysis and multivariate Cox proportional hazards models to analyze survival data, with a p-value threshold of <0.05 for statistical significance. Results: We identified a total of 217 pts, including pts with liver mets (N=146) and non-liver mets (N=71) at time of diagnosis. Pts with non-liver mets were more likely to have rectal primary than those pts with liver mets (40% vs. 15%, p=0.0001), indicating a distinct pattern of recurrence. Common driver mutations such as KRAS, BRAF, and TP53 were observed at equal frequencies in the liver and non-liver cohorts. In pts without liver mets, age had a significant effect on OS (p < 0.05, HR 1.1). Pts without liver mets with colon primary had worse OS compared to rectum primary (HR= 0.48, 95% CI: 0.24–0.96, p = 0.038). For pts without liver mets, KRAS was not a predictor of outcomes, while BRAF was associated with poorer OS (p<0.001, HR 7.09, 95%CI: 2.31-21.8). Contrarily, for pts with liver mets, KRAS mutation was significantly associated with worse survival (mOS 40.4 vs 61.7 mos, HR 2.04, 95% CI: 1.26-3.30, p=0.004). BRAF mutations were also associated with worse OS for this cohort (p=0.039 and HR 2.86, 95%CI: 1.06-7.77). Median time to the next treatment was significantly shorter in pts with liver mets (13.6 mos) than in pts with non-liver mets (22.6 mos) (HR 1.82, 95% CI 1.28-2.59; p<0.001). OS was longer for pts with non-liver mets compared to those with liver mets (mOS 52.9 mos vs 46.7 mos) though it did not reach statistical significance, likely due to the small sample size. Conclusions: Liver metastasis of CRC is associated with systemic therapy resistance with a shorter time on treatment, indicating treatment resistance associated with liver mets is not limited to immunotherapy. Given similar molecular characteristics in pts with and without liver mets, treatment resistance may be related to the inherent tumor microenvironment of the liver. In this study, pts with distinct molecular features had poorer outcomes, highlighting the importance of developing targeted therapeutics in this population.
Characteristics and outcomes of patients with early-onset versus average-onset small bowel neuroendocrine tumors.
670 Background: The global incidence of early-onset gastrointestinal cancers (GI) is increasing. Although patients with more common early-onset GI cancers, e.g. colorectal cancer, often present with more advanced disease and experience relatively worse outcomes; the characteristics and treatment outcomes for less common early-onset small bowel neuroendocrine tumors (SBNETs) have yet to be explored. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify patients with SBNETs (2004-2021), using ICD-0-3 SEER histology codes (8240/3, 8241/3, 8243/3, 8244/3, 8249/3, 8246/3). Patients with poorly differentiated histology were excluded. We used the chi-square test to compare categorical variables between early-onset SBNETs (EO-SBNETs, aged 30-49 years) and average-onset SBNETs (AO-SBNETs, aged ≥ 50 years) patients. Overall survival was estimated using the Kaplan-Meier method followed by application of the log-rank test to assess for differences in survival. A multivariable Cox regression analysis included early onset of disease, sex, race/ethnicity, marital status, urban/rural residence, prior treatments, and disease extent as covariates. All tests were conducted with a significance threshold of p < 0.05 using RStudio. Results: A total of 3,713 patients were included, of which, 925 (25%) were EO-SBNETs. Compared to AO-SBNETs, EO-SBNETs patients were more likely to be females (51.1% vs 46.7%, p=0.02), non-Hispanic Black (20.8% vs 17.6%, p=0.04), Hispanic (13.6% vs 8.8%, p<0.0001) and less likely to be non-Hispanic White 60.8% vs 69.9%, p<0.0001). There were no differences in stage at diagnosis between the EO-SBNETs and AO-SBNETs, i.e,, localized disease (33.5% vs 31.0%, p=0.15), regional spread (41.9% vs 42.8%, p=0.64) and distant metastatic disease (20.9% vs 21.9%, p=0.50). There were no differences in receipt of surgical resection (90.5% vs 89.1%, p=0.25) or chemotherapy (5% vs 6.3%, p=0.15) comparing EO-SBNETs and AO-SBNETs respectively. In a multivariate cox regression analysis, early onset was associated with a significantly better overall survival (HR=0.49, 95% CI 0.41-0.59, p<0.0001). Conclusions: With this first of its kind analysis, significantly superior overall outcomes among EO-SBNETs despite no differences in stage and receipt of surgery establishes age at diagnosis as a significant prognostic factor for SBNETs. Further studies investigating the role of factors such as differences in tumor biology and patient preferences in receipt of other therapies besides surgery are needed.
Longitudinal and Noninvasive Intracellular Recordings of Spontaneous Electrophysiological Activity in Rat Primary Neurons on Planar MEA Electrodes
Abstract Presently, the in vitro recording of intracellular neuronal signals on microelectrode arrays (MEAs) requires complex 3D nanostructures or invasive and approaches such as electroporation. Here, it is shown that laser poration enables intracellular coupling on planar electrodes without damaging neurons or altering their spontaneous electrophysiological activity, allowing the process to be repeated multiple times on the same cells. This capability distinguishes laser‐based neuron poration from more invasive methods like electroporation, which typically serve as endpoint measurement for cells. It is demonstrated that planar MEA electrodes, when combined with laser cell optoporation and live cell staining, can record spontaneous intracellular signaling from primary neurons in vitro. This approach allows for the detection of attenuated signals resembling positive monophasic intracellular action potentials. Recordings after laser optoporation also reveal subthreshold signals such as post‐synaptic potentials that are essential for assessing neuronal network plasticity and connectivity. Moreover, the noninvasiveness of the process enables repeated intracellular recordings over multiple days from the same cells.
Development and validation of machine learning model for mortality after curative gastrectomy for gastric cancer.
386 Background: The risk for postoperative complications can significantly impact perioperative planning. The aim of this study is to develop and validate a model based on various machine learning techniques to predict postoperative mortality (PM) after curative radical gastrectomy for gastric cancer. Methods: Data from a nationwide survey led by the Korean Gastric Cancer Association was used for the development set, which included 12,722 patients who underwent gastrectomy in 2019 across 68 institutions in South Korea. The validation set comprised 4,887 patients from 8 institutions between 2009 and 2017. PM was defined as all-cause death within 30 days after surgery or in-hospital death beyond 30 days. Five machine learning models (CatBoost, Gradient Boosting, Light GBM, Random Forest, XGBoost) were evaluated using perioperative clinical characteristics. Model performance was assessed using the area under the receiver operation characteristic curve (AUROC) with 5-fold cross-validation. Results: The PM rates were 0.83% and 1.04% in the development and validation set, respectively. In the development set, the Random Forest model demonstrated the highest discrimination capacity with an AUROC of 0.772, followed by Gradient Boosting at 0.767, CatBoost at 0.742, XGBoost at 0.732, and LightGBM at 0.717. However, in the validation set, CaBoost showed the highest AUROC at 0.747, while the AUROC for Random Forest decreased to 0.688. Conclusions: The CatBoost model demonstrated robust and consistent performance in predicting PM risk across both development and validation datasets. To further enhance the performance of the model and ensure stable clinical application, future research should focus on developing methods for quantitative measurement of perioperative factors such as surgical techniques.
Leveraging large-scale PDO-based assays to optimize antibody-drug conjugate efficacy in CRC.
261 Background: Clinical trials are one of the major barriers in contemporary drug development. Functional assays based on patient-derived organoids (PDO) are a promising new tool for derisking clinical development of new therapies, but their use has been limited due to small cohort sizes and the absence of systematic validation studies. Using the largest cohort of matched PDOs, longitudinal clinical data, transcriptomic and WES data in CRC, we explore the use of large PDOs collections to characterize ADC efficacy and affinity through systematic mapping of the relationship between target antigen affinity and payload efficacy. Methods: We have assembled a collection of 85 PDOs from colorectal cancer (CRC), generated from primary tumour samples and metastatic biopsies. Patients ranged from 32 to 89 years old and had experienced an average of 1.54 lines of treatment prior to the PDO-generating tissue sampling. Using gene expression levels of well known target antigens such as CEACAM5, ERBB2, MSLN and TROP2 as a proxy for protein concentration, we explore the relationship between the target antigen affinity and the efficacy of a subset of common payloads including topoisomerase and microtubule inhibitors. This allows us to identify the relationship between two of the three main vectors of ADC efficacy in CRC. Results: We show that topoismerase inhibitor and microtubule inhibitor efficacy relates to the RNA expression level of multiple target antigens commonly used in active clinical trials in CRC. These data match the target antigen and payload couples currently under development or approved in the clinic. We are developing a tool to optimize clinical trial design. This approach will allow us to match patients more accurately with the appropriate payload, ensuring a higher likelihood of response. Conclusions: We report that large-scale PDO-based assays can be a useful tool to anticipate clinical readouts. This work suggests that well-characterized PDO collections could also help redefine patient populations, increasing the likelihood of identifying those more likely to respond to a given ADC, and thus improving the success rates of clinical studies for new treatments in CRC.
Exploring predictive factors for detecting KRAS mutations in pancreatic cancer using liquid biopsy.
782 Background: Liquid biopsy offers an alternative to tissue specimens for comprehensive genetic profiling. However, circulating tumor DNA is sometimes insufficient to detect genomic alterations in pancreatic cancer (PC). The detection rate of KRAS mutations was reportedly increased in PC with liver metastasis. In contrast, the predictive value of CA19-9 levels, the timing of liquid biopsy, or the type of liquid biopsy for detecting KRAS mutations remains unclear. We investigated whether these factors could be predictive of detecting KRAS mutations in PC. Methods: From September 2021 to August 2024, we retrospectively reviewed patients with PC who underwent liquid biopsy. Results: A total of 106 patients were enrolled (median age: 64 years, male: 66). Patient characteristics were as follows: tumor status: locally advanced: 10, metastatic: 90, recurrence: 6; metastatic site: liver: 51, lung: 26, lymph nodes: 20, peritoneum: 38, others: 7; number of metastatic sites: 1: 63, 2: 25, ≥3: 8; treatment line at liquid biopsy: 1: 21, 2: 77, 3:8; median CA19-9 level: 1053.4 U/mL; type of liquid biopsy: FoundationOne Liquid CDx (FL): 75 or Guardant360 (G): 31. The overall rate of KRAS mutations was 47%, with a median variant allele frequency of 0.83 [range:0.1-71.0]. The patterns of KRAS mutations were as follows: G12D: 23, G12V: 18, G12R: 4, and others: 14. The detection rate of KRAS mutations varied by the follows factors: metastatic site: liver: 65%, other organs: 44%; number of metastatic sites: ≥2: 47%, <2: 48%; CA19-9 level: ≥2,000 U/mL: 68%, <2,000: 38%; timing of liquid biopsy: 1st line: 42%, ≥2nd line: 67%; types of liquid biopsy: FL: 49%, G: 42%. In multivariate analysis, liver metastasis and CA19-9 level ≥2,000 U/mL were identified as independent factors associated with improved detection of KRAS mutations. In PC with these two factors, the detection rate of KRAS mutation increased to 76%. Conclusions: Our findings indicate that liver metastasis and CA19-9 levels above 2,000 U/mL are predictive factors for detecting KRAS mutations in PC through liquid biopsy.
Optical Activity of Chiral Excitons
AbstractRecent activity in the area of chiroptical phenomena has been focused on the connection between structural asymmetry, electron spin configuration and light/matter interactions in chiral semiconductors. In these systems, spin‐splitting phenomena emerge due to inversion symmetry breaking and the presence of extended electronic states, yet the connection to chiroptical phenomena is lacking. Here, we develop an analytical effective mass model of chiral excitons, parameterized by density functional theory. The model accounts for parity mixing of the band edge Bloch functions resulting from polar distortions, resulting in allowed magnetic dipole transitions. Through the study of a prototypical chiral 2D hybrid perovskite semiconductor, we show that circular dichroism of the chiral exciton and its interband continuum emerges from spin‐splitting via cross‐coupling of Rashba‐like and chiral/helical spin‐texture components. To demonstrate the generality of our approach, and as a counterpoint, we apply our model to describe chiroptical properties of three‐dimensionally confined excitons in perovskite nanocrystals that occur without chiral lattice distortions.
QL1203 vs placebo plus mFOLFOX6 as first-line therapy in RAS wild-type, metastatic colorectal cancer (mCRC): Interim analysis (IA) of a multicenter, randomized, double-blinded, parallel, phase 3 trial.
190 Background: Panitumumab plus FOLFOX or FOLFIRI has been approved as the first-line therapy for RAS wild-type mCRC. QL1203 is a panitumumab biosimilar showing similarity to the originator panitumumab (Vectibix, Amgen) in preclinical studies and phase 1 clinical pharmacokinetic study. Here we present results from interim analysis of a phase 3 trial (NCT04233151) investigating QL1203 vs placebo plus mFOLFOX6 as first-line therapy in Chinese patients (pts) with RAS wild-type mCRC. Methods: Pts with treatment-naïve, RAS and BRAF wild-type, mCRC unsuitable for radical resection and local therapy were enrolled and randomly assigned (2:1) to receive QL1203 (6 mg/kg) plus mFOLFOX6 once every 2 weeks (Q2W) or placebo plus mFOLFOX6 Q2W, stratified by primary tumor site, liver metastases, and previous neoadjuvant/adjuvant therapy. The primary endpoint was PFS assessed by a Blinded Independ Review Committee (BICR) per RECIST v1.1. Key secondary endpoints include PFS by investigator (INV), OS, ORR, DoR, and safety. This planned IA was conducted at 338 (81.25%) of 416 PFS events occurred. Results: From Jan 8, 2020 to Jun 12, 2023, 641 pts were randomized (QL1203/placebo, n=426/215). 551 (86.0%) pts had left-sided tumors (QL1203/placebo, 85.9%/86.0%). 433 (67.6%) pts had liver metastases (QL1203/placebo, 68.1%/66.5%). As of data cutoff of this IA (Mar 22, 2024), median follow-up was 23.8 months. Median PFS by BIRC was 11.20 months for QL1203 and 8.34 months for placebo (hazard ratio [HR], 0.61 [97.42% confidence interval [CI], 0.47-0.79]; stratified one-sided log-rank p<0.0001). Other efficacy results are presented (Table). Incidence of grade≥ 3 adverse events (AEs) related to study drug was 59.9% for QL1203 and 32.9% for placebo. The most common grade≥3 AE related to QL1203 was neutrophil count decreased (20.3%). Conclusions: QL1203 demonstrated significantly improved PFS versus placebo and higher ORR. Clinical trial information: NCT04233151 . QL1203 (n=426) Placebo (n=215) PFS by BIRC mPFS, months (95% CI) 11.20 (9.89-13.11) 8.34 (7.26-8.54) HR (97.42% CI) 0.61 (0.47-0.79) PFS by INV mPFS, months (95% CI) 10.91 (9.69-11.30) 8.41 (7.39-9.07) HR (95% CI) 0.74 (0.60-0.91) mOS, months (95% CI) 27.66 (24.74-32.79) 24.54 (20.17-27.79) HR (95% CI) 0.82 (0.64-1.06) ORR by BIRC, n (%) 68.31% 47.91% 95% CI 63.66-72.70 41.07-54.81 ORR by INV, n (%) 64.08% 49.30% 95% CI 59.33-68.65 42.44-56.19
A multicenter prospective study to evaluate the efficacy of resection for initially unresectable hepatocellular carcinoma after atezolizumab combined with bevacizumab (the RACB study): Short-term outcomes.
521 Background: The IMbrave150 study showed that atezolizumab plus bevacizumab (atezo+bev) is superior to sorafenib in progression-free survival and overall survival, making it the recommended first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). The RACB study was scheduled to evaluate the efficacy of atezo+bev in achieving conversion surgery for initially unresectable HCC. This time, we report the short-term outcomes of the RACB study. Methods: This prospective, single-arm, multicenter Phase II trial evaluates atezo+bev to achieve conversion surgery in patients with technically or oncologically unresectable HCC. Eligible patients had unresectable HCC without prior systemic chemotherapy and at least one target lesion based on RECIST ver1.1. Patients received atezolizumab (1200 mg) plus bevacizumab (15 mg/kg) every three weeks. If resectable on radiological assessment at 12 weeks, atezolizumab monotherapy was given followed by surgery. The primary endpoint was the progression-free survival. The secondary endpoints included the overall response rate, overall survival, resection rate, curative resection rate, on-protocol resection rate, and ICG retention rate at 15 min after atezo+bev therapy. The study is registered with the Japan Registry of Clinical Trials (jRCTs051210148). Results: Between March 2022 and March 2024, 55 patients from 17 centers were enrolled. Four patients were excluded due to ineligible lesions or other reasons. A total of 50 patients were included in the efficacy evaluation set. Macrovascular invasion and extrahepatic metastases were observed in 38 (76.0%) and 6 patients (12.0%), respectively. Two patients (4.0%) had metachronous extrahepatic metastases without intrahepatic tumors. The complete and partial response rates were 0% and 13% based on RECIST, and 2.2% and 26.1% based on mRECIST. The overall resection rate was 48%, corresponding to 24 cases. R0, R1, and R2 resections were performed in 21 (87.5%), 1 (4.2%), and 2 (8.3%) patients, respectively. Complications ≥Grade III according to the Clavien-Dindo classification included 3 bile leakages, 2 infections, 1 anastomotic leakage, and 1 hemoptysis. There were no surgery-related deaths. Of the 51 patients included in the safety analysis set, adverse events occurred in 34 cases (66.7%), with 16 Grade 3 or higher instances with one Grade 4 upper gastrointestinal bleeding, 1 Grade 4 encephalopathy, and 1 unexpected death after 1 cycle of atezo+bev. Conclusions: The RACB study's short-term outcomes demonstrated the feasibility of conversion surgery after atezo+bev in patients with initially unresectable HCC. The response rate of atezo+bev, as measured by mRECIST, was similar to IMbrave150, with a 48% resection rate, though careful monitoring of severe adverse events is essential. Clinical trial information: 051210148.
Clinical-pathologic characteristics in young patients with metastatic colorectal cancer: Experience from a specialized cancer institute in Peru.
279 Background: Colorectal cancer (CRC) represents the third cause of malignant neoplasm in the world and the second in terms of mortality. CRC is a major cause of cancer-related morbidity and mortality in Peru. Diagnosis at younger ages represents a challenge. In this study, we evaluated prognostic factors in patients who were metastatic at diagnosis or progressed to metastatic disease during follow-up. Methods: A descriptive cross-sectional study, between 2013 and 2022, 66 patients under 40 years old and stage IV at diagnosis were analyzed. Parameters evaluated were age, gender, comorbidity, performance status and stage of the disease at the diagnosis, localization, surgery undergone, systemic treatment regimen, response to first-line treatment, incidence of K-RAS, sites and number of metastases, expression of tumor predictors (CEA levels), and survival times. A multivariate analysis was conducted with factors that were considered statistically significant in the univariate analysis. Results: Median age was 35 years [29.25-37] and the female/male ratio was 34/32. From 66 patients at stage IV disease, 30 patients (45.5%) were right-side, 36 (54.5%) were left-side colon cancer. At the end of follow-up, 51 patients had died, and 15 survived. Overall survival (OS) was significantly better in patients older than 35 years old (p<0,05), those who underwent primary tumor surgery (p<0,001), negative perineural invasion (p<0.0045). The treatment most common was CAPOX with a median OS of 17 months (p<0.013). The multivariate analysis shows that patients who did not undergo primary surgery had worse disease-specific OS (hazard ratio, CI 2.21.95% [1.15-4.25], p< 0.018) and there was no statistical difference between chemotherapy regimens and treatment line. Conclusions: In young patients with metastatic CRC, Primary tumor surgery and negative perineural invasion are significant factors influencing overall survival. Patients older than 35 years and those who underwent surgery showed better survival. These findings reflect the importance of early colorectal cancer screening and improve the risk assessment.
A Multiresonant Thermally Activated Delayed Fluorescent Dendrimer with Intramolecular Energy Transfer: Application for Efficient Host‐Free Green Solution‐Processed Organic Light‐emitting Diodes
Abstract The development of narrowband emissive, bright, and stable solution‐processed organic light‐emitting diodes (SP‐OLEDs) remains a challenge. Here, a strategy is presented that merges within a single emitter a TADF sensitizer responsible for exciton harvesting and an MR‐TADF motif that provides bright and narrowband emission. This emitter design also shows strong resistance to aggregate formation and aggregation‐cause quenching. It is based on a known MR‐TADF emitter DtBuCzB with a donor‐acceptor TADF moiety consisting of either tert ‐butylcarbazole donors ( tBuCzCO 2 HDCzB ) or second‐generation carbazole‐based donor dendrons ( 2GtBuCzCO 2 HDCzB ) and a benzoate acceptor. The TADF moiety acts as an exciton harvesting antenna and transfers these excitons via Förster resonance energy transfer to the MR‐TADF emissive core. The SP‐OLEDs with 2GtBuCzCO 2 HDCzB and tBuCzCO 2 HDCzB thus show very high maximum external quantum efficiencies (EQE max of 27.9 and 22.0%) and minimal efficiency roll‐off out to 5000 cd m −2 .
Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial
PURPOSE The CLL12 trial reassesses the watch-and-wait consensus for early-stage chronic lymphocytic leukemia (CLL) in the context of targeted therapies. METHODS The German CLL Study Group conducted a randomized, double-blind, placebo-controlled phase III trial with 363 patients with asymptomatic, treatment-naïve Binet stage A CLL at increased risk of progression to receive ibrutinib (n = 182) at a daily dose of 420 mg or placebo (n = 181). Additionally, 152 low-risk patients were allocated to the watch-and-wait group. The final analysis included event-free survival, progression-free survival, time to next treatment, overall survival, and safety assessments. RESULTS Ibrutinib significantly delayed progression to symptomatic disease ( P < .001; hazard ratio, 0.276 [95% CI, 0.188 to 0.407]), but no survival benefit was observed with 26 death cases ( P = .562) at a median observation time of 69.3 months. Five-year survival rates were excellent: 93.3% (95% CI, 89.3 to 97.3) in the ibrutinib group, 93.6% (95% CI, 89.5 to 97.7) in the placebo group, and 97.9% (95% CI, 95.6 to 100) in the watch-and-wait cohort. Estimated 10-year survival rates from diagnosis were 86.5% (95% CI, 78.7 to 94.3, placebo), 89.8% (95% CI, 83.3 to 96.3, ibrutinib), and 95.3% (95% CI, 91.1 to 99.4, watch and wait). In the ibrutinib group, one of 12 deaths was CLL-associated, compared with four of 14 fatal cases of CLL progression or Richter transformation in the placebo group. Adverse and serious adverse events occurred in 99.4% and 60% of both treatment groups, respectively. The safety profile indicated increased cardiovascular toxicity in the ibrutinib group. CONCLUSION Ibrutinib treatment in early-stage CLL delayed disease progression compared with placebo. However, with the given observation time and few deaths, no survival benefit was demonstrated. In the era of targeted therapies, watch and wait remains the standard of care irrespective of risk factors.
EVEREST-2: A seamless phase 1/2 study of A2B694, a logic-gated Tmod chimeric antigen receptor T-cell (CAR T) therapy, in patients with pancreatic cancer (PANC) or other mesothelin (MSLN)-expressing solid tumors and human leukocyte antigen (HLA)–A*02 loss of heterozygosity (LOH).
TPS788 Background: MSLN is a desirable candidate for targeted therapy given its limited expression in normal tissues and its overexpression in several malignancies, including PANC, mesothelioma, non-small cell lung, and ovarian cancers (TCGA 2022). MSLN-targeted CAR T and T-cell receptor therapies have shown promising clinical activity; however, on-target, off-tumor toxicity, including fatal events, have occurred (1-3). Autologous logic-gated Tmod CAR T therapies address the challenges of on-target, off-tumor toxicity by combining 2 CARs: activating and blocking receptors. The activator recognizes a tumor-associated antigen present on the surface of both tumor and normal cells; the blocker prevents CAR T activity when it binds HLA-A*02, which is present in normal cells and often lost in tumor cells. Thus, in patients with tumor-associated HLA-A*02 LOH, the blocker prevents on-target, off-tumor toxicity on normal cells due to retained HLA-A*02 expression (4). HLA-A*02 LOH is observed in various solid tumors, including ~20% of PANC (5). Two autologous CAR T therapies are currently under investigation: A2B530, targeting carcinoembryonic antigen, in the EVEREST-1 trial, and A2B694, targeting MSLN, in the EVEREST-2 trial, described herein. A2B694 may provide a therapeutic window to treat patients with PANC and other MSLN-expressing solid tumors exhibiting HLA-A*02 LOH due to its unique discriminatory mechanism. Methods: EVEREST-2 (NCT06051695) is a first-in-human, phase 1/2, open-label, nonrandomized study to evaluate the safety and efficacy of A2B694 for recurrent unresectable, locally advanced, or metastatic cancers with MSLN expression, including PANC. Eligible patients must have exhausted options of potentially curative therapy and have recurrent disease. Enrollment to EVEREST-2 occurs through the prescreening study BASECAMP-1 (NCT04981119), in which patients with tumor-associated HLA-A*02 LOH are identified via next-generation sequencing (Tempus AI, Inc) and leukapheresis product is collected. A2B694 is manufactured from cryopreserved T cells when clinically appropriate for patients. The primary objective of phase 1 is to evaluate the safety and tolerability of A2B694 and identify the recommended phase 2 dose (RP2D). The dose-expansion phase will confirm RP2D and collect biomarker data to further characterize A2B694. Phase 2 will assess the primary endpoint overall response rate per RECIST v1.1 and secondary endpoints progression-free survival and overall survival. The first patient was dosed on April 24, 2024 and dose escalation is ongoing. 1. Beatty, et al. Gastroenterology . 2018. 2. Haas, et al. Mol Ther . 2023. 3. Hong, et al. ESMO 2021. Abstr 9590. 4. Hamburger, et al. Mol Immunol . 2020. 5. Hecht, et al. J Clin Oncol . 2022. Clinical trial information: NCT06051695 .
Impact of inpatient palliative care consultation on end-of-life care among patients with esophageal cancer.
502 Background: Esophageal cancer is an aggressive malignancy with a high global prevalence. Patients often suffer from various debilitating symptoms like dysphagia and cachexia, particularly with more advanced stage disease. Most patients continue to receive aggressive interventions until terminal stages of disease without timely initiation of formal palliative care (PC). We sought to investigate the impact of formal inpatient palliative care consultation on end-of-life (EOL) care among patients with esophageal cancer. Methods: The National Inpatient Sample (NIS) was queried to identify all hospitalizations with esophageal cancer utilizing ICD-10 codes C15.x from 2016 to 2020. Hospitalizations with documented inpatient mortality events were extracted and stratified based on reception of PC consultation (ICD-10 code Z51.5). Demographic and clinical data were analyzed using chi-squared tests and independent sample t-tests. A threshold of p-value less than 0.05 was set to determine statistical significance. Results: A total of 17,745 patients with esophageal cancer were included, of which 10,370 (58.4%) received PC consultation. Patients that received PC consultation at EOL were more likely to have higher comorbidities per CCI. No significant difference between age and sex was observed between the two cohorts. Patients who received PC consultations at EOL had higher rates of Do Not Resuscitate (DNR) code status (78.1% vs 43.2%, p <0.001) and lower rates of aggressive interventions such as chemotherapy (0.9% vs 1.6%, p<.001), blood transfusions (12.3% vs 18%, p<.001), and mechanical ventilation (28.5% vs 41%, p<0.001). No significant difference was observed in the rates of vasopressor use between the two groups (p=0.83). Hospitalizations with PC consultations were associated with significantly lower total hospitalization cost ($97,879 vs $146,128, p<.001). Conclusions: Inpatient PC consultations among patients with esophageal cancer were associated with lower rates of aggressive interventions and higher rates of DNR code status in addition to significantly lower total hospitalization costs. These findings underscore the importance of inpatient PC consultation at the EOL in helping minimize aggressive interpretation and facilitate a greater focus on comfort and quality of life. No PalliativeN=7375 PalliativeN=10370 p-value Age (in years) 67.58 ± 10.9 67.58 ± 10.9 .98 CCI 9.1 ± 3.5 9.4 ± 3.3 <.001 Mean length of stay (days) 8.9 ± 14.9 7.5 ± 11.3 <.001 Total Charges 146128 ± 321830 97879 ± 195868 <.001 DNR 3170 (43.2%) 8100 (78.1%) <.001 Blood transfusion 1320 (18.0%) 1280 (12.3%) <.001 Mechanical ventilation 3015 (41.0%) 2960 (28.5%) <.001 Vasopressor 585 (8.0%) 835 (8.1%) 0.83 Chemotherapy 115 (1.6%) 95 (0.9%) <.001