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Real-world dose intensity (DI) and time to adverse events (AEs) in a commercial database during first-line (1L) treatment of metastatic pancreatic adenocarcinoma (mPDAC) with FOLFIRINOX (FFX), FFX without 5FU bolus, and gemcitabine + nab-paclitaxel (GnP).
692 Background: Onset of severe AEs during 1L FFX and GnP treatment for mPDAC negatively impacts clinical outcomes, requiring supportive care and/or treatment adjustment. Occasionally they lead to discontinuation. The 5FU bolus may be omitted from FFX (FFXnb) to increase tolerability. We examined DI and time to key AEs (anemia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea/vomiting, and neuropathy) during 1L FFX, FFXnb, and GnP. Methods: This retrospective study utilized Optum Market Clarity claims + EHR linked data. Inclusion criteria were: adults diagnosed with mPDAC between 1/1/2015 and 5/31/2023; initiated 1L FFX, FFXnb, or GnP (index date) within -14 to +90 days; ≥6 pre- and ≥1 month post-index enrollment; ≥1 AE of interest in 1L. Follow-up was index to earliest of death, disenrollment, start of 2L, or last administration + 14 days. DI was defined as cumulative dose divided by follow-up in months. Grade 3/4 hematologic AEs (hAEs) were measured from lab values. Ungraded AEs were sourced from EHR notes and claims diagnoses. FFX was defined as including 5FU bolus + infusion in the 1st cycle; FFXnb as 5FU infusion only. Kaplan-Meier (KM) methods estimated time AE. Results: Median follow-up in months for patients (pts) with hAEs was: FFX 4.2; mFFX 3.6; GnP 3.1. Median DI (mg/m2/month) for FFX vs FFXnb pts with hAEs was: 5FU 4567 vs 4581; leucovorin 632 vs 398; oxaliplatin 119 vs 142; irinotecan 253 vs 251. For GnP, DI was: gemcitabine 2230; nab-paclitaxel 269. The table below presents sample size (N) and median (95% CI) time to AE. Median time to anemia was numerically 2–4 weeks shorter for GnP and FFXnb vs FFX. Time to neutropenia was 8–12 days less for FFXnb vs GnP and FFX. Time to thrombocytopenia was 7 weeks less for GnP vs FFX and FFXnb. Time to neuropathy was nearly 4 weeks shorter for FFXnb vs FFX and GnP. Conclusions: While neutropenia is higher risk for FFX vs GnP, prophylactic growth factor is standard during FFX, which may result in the similar onset time vs GnP. Early onset of severe thrombocytopenia differentiates the GnP sample. Oxaliplatin DI was higher for FFXnb vs FFX pts, and may be associated with earlier onset of anemia, neutropenia, diarrhea, and neuropathy. Research is merited on interactions between dosing, AE timing, and treatment discontinuation. Time to AE. Grade 3/4 hAEs FFX N FFXnb N GnP N FFX median days (95% CI) FFXnb median days(95% CI) GnP median days (95% CI) Anemia 47 25 97 64 (38–96) 36 (19–70) 47 (39–56) Neutropenia 75 53 112 35 (25–47) 23 (14–43) 31.5 (18–42) Thrombocytopenia 33 22 54 63 (35–79) 65.5 (32–94) 14 (13–34) Ungraded AEs Diarrhea 216 264 297 27.5 (22–36) 17.5 (14–27) 27 (21–36) Fatigue 211 267 418 34 (23–43) 27 (17–34) 27 (21–30) Nausea/vomiting 337 403 561 6 (3–8) 9 (7–14) 9 (7–12) Neuropathy 151 155 190 92 (70–112) 67 (48–79) 92 (80–111)
Exclusive liver invasion as prognostic indicator in T3 gallbladder cancer.
631 Background: T3 gallbladder cancer (GBC) contains a diverse range of invasive tumors. However, distinct prognostic outcomes may be observed among T3GBC confined to localized range despite sharing the same T3GBC. There is uncertainty regarding whether there are noticeable prognostic variances between tumors that invade the liver, or serosa only and those that extend to adjacent organs. This study aims to investigate prognostic differences according to the extent of invasion in patient with T3GBC. Methods: The patients with T3GBC who underwent curative intent surgery from February 2002 to December 2021 were analyzed. The patients were divided into those who had tumor invaded liver only, serosa only, or extended beyond. Their clinicopathologic characteristics, perioperative details and prognostic data were compared. Survival analyses were carried out using the log-rand test including subgroups considering nodal metastasis, and other T stages. Cox-proportional hazard model including other factors were used to identify the independent risk factors for survival. Results: We identified 194 patients with T3GBC. The patients with tumor invaded liver only, serosa only, and adjacent organs were 86, 33, and 35, respectively. The median survival was 23 months. The patients with invasion limited to the liver showed better survival than those who involve adjacent structures (26 months vs 9 months, p < 0.001). In multivariate analysis, it was demonstrated that the concomitant presence of invasion in structures other than the liver serves as independent prognostic factors for survival. (hazard ratio [HR], 6.8, 95% confidence interval [CI] 1.746 – 26.803, p = 0.006) as well as lymphovascular invasion (HR 2.5, 95% CI 1.093 – 4.193, p= 0.026 ). Conclusions: In the T3 gallbladder cancer, exclusive liver invasion is a better prognostic indicator compared to concurrent invasion around adjacent structure. It is crucial to recognize that the extent of invasion in T3GBC patients before surgery. Multicenter studies are needed for the definite results.
First line atezolizumab + bevacizumab (atezo/bev) or durvalumab ± tremelimumab (durva±treme) in unresectable hepatocellular carcinoma (HCC): A real world, multi-institutional retrospective cohort study.
532 Background: HCC accounts for 80% of primary liver cancers, and worldwide, is the third common cause of cancer-related death. Two FDA approved 1st line systemic treatment options include atezo/bev and durva ± treme. Herein we report outcomes of these regimens in the 1st line setting via a real-world, multi-institutional retrospective cohort study. Methods: We reviewed clinical outcomes of patients (pts) who initiated 1st line atezo/bev or durva ± treme for unresectable HCC between March 2017 and February 2024, across 5 institutions (Mayo Clinic, University of Alabama, Cedars-Sinai Medical Center, University Hospitals Seidman Cancer Center and University of Michigan). Time to treatment failure (TTF) and overall survival (OS) were analyzed using the Kaplan-Meier method. Best (objective) response was tabulated. Multivariable analyses were performed using Cox models and logistic regression for time-to-event and binary outcomes, respectively, while adjusting for age, sex, race, HCC etiology, Child-Pugh class, and ALBI grade. Results: A total of 433 HCC pts were included; atezo/bev (336), durva ± treme (97). Median age at the start of therapy was 68 years; 77% were male, 82% were Caucasian. Etiologies of HCC were viral hepatitis (38%), MASLD (20%), alcohol (10%), non-viral multifactorial (10%), or unknown (22%). Pts receiving durva ± treme were less likely to have cirrhosis (11% vs. 28%, p<0.01) but similar in terms of macrovascular invasion (63% vs. 58%, p=0.35) compared to pts receiving atezo/bev. Reasons for treatment discontinuation were similar between the two groups, with the most common being disease progression - atezo/bev (56%) and durva ± treme (47%). The differences in clinical outcomes were not statistically significantly and remained consistent after multivariable adjustment. (Table, atezo/bev as the reference group). Outcomes were significantly different between Child-Pugh classes (CP: A,B,C) respectively, OS: 19.0 m, 6.4 m, 1.9 m (p<0.001); TTF: 6.1 m, 2.7 m, 1.3 m (p<0.001). Conclusions: In this real-world retrospective cohort study of unresectable HCC, the differences in overall survival, objective response, and time to treatment failure were not statistically significant between atezo/bev and durva ± treme in the 1st line setting. Outcome Atezo/bev Durva±treme Univariate p-value Multivariable adjusted hazard ratio (95% CI) Multivariable adjusted odds ratio (95% CI) Overall Survival, Median (month) 14.0 14.6 0.77 0.78 (0.54-1.14) --- Time to Treatment Failure, Median (month) 4.9 4.1 0.71 0.95 (0.72-1.26) --- Objective response, % 26.3% 21.1% 0.31 --- 0.78 (0.43-1.39)
Intrinsic Anti‐Freezing, Tough, and Transparent Hydrogels for Smart Optical and Multi‐Modal Sensing Applications
AbstractHydrogels have received great attention due to their molecular designability and wide application range. However, they are prone to freeze at low temperatures due to the existence of mass water molecules, which can damage their flexibility and transparency, greatly limiting their use in cold environments. Although adding cryoprotectants can reduce the freezing point of hydrogels, it may also deteriorate the mechanical properties and face the risk of cryoprotectant leakage. Herein, the microphase‐separated structures of hydrogels are regulated to confine water molecules in sub‐6 nm nanochannels and increase the proportion of bound water, endowing the hydrogels with intrinsic anti‐freezing properties, high mechanical strength, good stretchability, remarkable fracture energy, and puncture resistance. Even after being kept in liquid nitrogen for 1000 h, the hydrogel still maintains good transparency. The hydrogel can exhibit excellent low‐temperature shape memory and intelligent optical waveguide properties. Additionally, the hydrogel can be assembled into strain and pressure sensors for flexible sensing at both room and low temperatures. The intrinsically anti‐freezing microphase‐separated hydrogel offers broad prospects in low‐temperature electronic and optical applications.
KRAS status in lung oligometastases treated with SBRT.
264 Background: Stereotactic Body Radiotherapy (SBRT) to lung metastases (LM) from colorectal cancer (CRC) has been applied to improve disease control in in the oligometastatic (OM) and oligoprogressive (OP) setting. The aim of this study is to assess the impact of KRAS mutational (KRASmut) status in the response to SBRT in LM. Methods: Data from a consecutive cohort of OM/OP CRC patients treated at our Institution with SBRT for LM from May 2019 to March 2024 were retrospectively reviewed. Patients (age, KRASmut in primary tumor, OM/OP disease, chemotherapy lines prior to SBRT) and treatment-related variables (dose regimen and Biologically Effective Dose: BED, toxicity) were collected. Local Control (LC) was defined as time from SBRT to local failure or last radiologic follow-up. Results: Sixty-two patients (median age: 74 years, range 49-85), accounting for 103 LM were included. LM were treated in the OM and OP setting in 65(63%) and 38(37%) cases, respectively. SBRT was delivered before chemotherapy (n=49,48%) or following first (n=31,30%) or further chemotherapy lines (n=23,22%). KRASmut was present ab initio in 49% of cases (n=50). Dose regimens included 48-60 Gy in 3-8 fractions, resulting in a median BED of 115.5 (range 76.8-151.2) Gy 10 : a BED>100Gy 10 was delivered in 92% (n=95) of treatment courses. Median follow-up was 16 (range 2-45) months. Median LC was not reached; 1- and 3 years LC rates were 85% and 67% respectively. At multivariate analysis (MVA), only a BED≤100Gy 10 (p=0.029, HR 2.99, IC95% 1.1- 9.5) and prior second or further chemotherapy line (p=0.031, HR 3.2, IC95% 1.1- 8.1) were independently correlated with impaired LC. No grade >2 toxicity was observed. Focusing on patients receiving no chemotherapy or first-line treatment before SBRT, 1- and 3 years LC rates were 92% and 77% respectively (median: NR). At MVA, while BED≤100Gy 10 (p=0.036, HR 6.96, IC95% 1.9-25.7) was associated with poorer LC, lack of KRASmut (p=0.037, HR 0.26, IC95% 0.07- 0.9) was independently correlated with improved LC. Conclusions: SBRT in LM from OM/OP CRC results in high LC rates, particularly with intensive regimens in non-heavily pretreated patients. No impact of KRASmut was observed. Due to possible occurrence of secondary mutations in the pretreated population, a subset analysis in the chemotherapy-naive/first-line subset suggests an impact of KRASmut in radioresistance that should be further explored in a dose-escalation perspective. Re-biopsy or liquid biopsy may be useful to identify de-novo mutations.
Survival analysis using neoadjuvant rectal score in patients with locally advanced rectal cancer who underwent surgery after neoadjuvant chemoradiotherapy: An ambispective study.
172 Background: Colorectal cancer, the third most common malignancy and a major cause of cancer deaths, is treated using a standard protocol of neoadjuvant chemoradiotherapy (NACTRT) or short-course radiotherapy (SCRT) followed by total mesorectal excision (TME) for locally advanced rectal cancers (LARC). Long-term follow-up is essential to determine study endpoints, necessitating surrogate markers for short-term outcomes. This study aims to stratify patients into risk groups based on their Neoadjuvant Rectal Cancer (NAR) score and evaluate its predictive value for oncological outcomes, including overall survival, disease-free survival (DFS), locoregional relapse-free interval (LRFI), and distant metastasis-free interval (DMFI), while also correlating clinicopathological characteristics with these outcomes. Methods: This ambispective observational study at the Regional Cancer Centre, Thiruvananthapuram, involved 459 patients with biopsy-proven, locally advanced rectal adenocarcinoma (T3/T4 and/or node positive) who underwent long-course neoadjuvant chemoradiotherapy (NACTRT) followed by curative surgery (Anterior Resection or Abdomino-Perineal Resection) between 2010 and 2015, with a minimum follow-up of three years. Exclusion criteria included previous malignancies, synchronous colorectal cancers, oligometastatic disease, and loss to follow-up. The study aimed to determine the predictive value of the Neoadjuvant Rectal Cancer (NAR) score for oncological outcomes. Clinicopathological details were collected from case records, imaging, and operative notes, and postoperative histopathological records were used to calculate the NAR score. Patients were categorized into three groups based on their NAR scores and followed prospectively for recurrence or death. Data were analyzed using frequency, percentages, mean, standard deviation, Chi-square test, Kaplan-Meier method, log-rank test, and Cox regression analysis, with a significance level set at p < 0.05. Results: 459 patients were included in the study, with 41.4% females, and 44% being less than 60 years. Most of the patients had lesion 5-10 cm from anal verge (46%). 77% of patients had T3 disease prior to the start of NATCTRT. 51.9% had underwent APR, and 80.4% had open surgery. 11.1% had PCR attained. 27% had disease recurrence of which most were distant metastasis. NAR was a significant predictor of overall survival, disease free survival, distant metastasis free interval and locoregional failure free interval. Other significant predictors of overall survival were pre-NACTRT T stage, pN stage, PLNR, CRM status and PCR, but only NAR was found to be significant on multivariate analysis. Conclusions: NAR score is a significant predictor of OS, DFS,LRFI and DMFI and can be used as a short term surrogate for survival data in anticipated trials.
Obesity and biliary tract cancers: Changing epidemiology.
643 Background: The incidence of biliary tract cancers (BTC) continues to rise (Sung et al. 2024). The reasons remain ill-defined. Over 70% of patients are diagnosed without identifiable predisposing factors. Obesity and overweight have emerged as putative contributors. We examined the epidemiologic and molecular characteristics of patients with BTC, with a focus on body mass index (BMI) at presentation and overall survival (OS). Methods: A retrospective cohort study of patients diagnosed with BTC at Memorial Sloan Kettering was conducted from January 2022 to December 2023. Patients were divided based on BMI into: obese (BMI≥30 kg/m 2 ) and non-obese (BMI<30 kg/m 2 ). We collected patients' baseline demographics, and results of somatic next generation sequencing using the MSK-IMPACT platform and compared between obese and non -obese groups using Fisher’s exact test for categorical and Wilcoxon rank sum test for continuous variables. OS was calculated from date of diagnosis, estimated using Kaplan-Meier methods and compared between groups using log rank test. Results: A total of 142 patients were identified. The table summarizes the baseline characteristics including age, BMI, sex, stage at diagnosis, family history, history of malignancy, and race. Obesity was significantly associated with family history of malignancy and white race. Among surviving patients (n=93), with a median follow-up of 13.8 months, 6-month, 1-year, and 2-year overall survival (OS) rates were 85% [95%CI: 80%-92%], 71% [95%CI: 64%-79%], and 54% [95%CI: 43%-68%] respectively. OS was not statistically different among obese and non-obese patients. However, when stratifying OS by BMI and gender, obese males were noted to have inferior OS compared to obese females (6-mo OS 75% and 90% respectively), though not statistically significant. Genetic sequencing did not reveal a specific molecular pattern in either group. Conclusions: Obesity appears not to be associated with young age, stage, or particular somatic alterations in this limited study. OS was not statistically different among obese and non-obese patients. Males with obesity appeared to have a worse prognosis. This observed gender-based difference needs to be further studied, and if confirmed further research is needed to explore potential factors that may explain the clinical observation. Baseline characteristics. Characteristics Overall n=142 Obese (BMI≥30 kg/m 2 ) n=54 Non-Obese (BMI<30 kg/m 2 )n=88 p-value Age 68 (35-91) 69 (35-87) 67 (36-91) >0.9 BMI (kg/m 2 ) 28.1 (16.6-48.5) 33.5 (30-48.5) 24.7 (16.6-29.6) Sex female/male 79 (56%)/63 (44%) 32 (59%)/22 (41%) 47 (53%)/41 (47%) 0.6 Stage Localized/advanced 21 (15%)/121 (85%) 11 (20%)/ 43 (80%) 10 (11%)/ 78 (89%) 0.3 Family history of cancer 91 (65%) 41 (76%) 50 (57%) 0.030 History of second malignancy 26 (18%) 12 (22%) 14 (16%) 0.4 Race White African Asian Other 99 (70%)12 (8.5%)20 (14%)11 (7.7%) 44 (81%)4 (7.4%)1 (1.9%)5 (9.3%) 55 (63%)8 (9.1%)19 (22%)6 (6.8%) 0.004
A Chain Entanglement Gelled SnO₂ Electron Transport Layer for Enhanced Perovskite Solar Cell Performance and Effective Lead Capture
AbstractSnO₂ is a widely used electron transport layer (ETL) material in perovskite solar cells (PSCs), and its design and optimization are essential for achieving efficient and stable PSCs. In this study, the in situ formation of a chain entanglement gel polymer electrolyte is reported in an aqueous phase, integrated with SnO₂ as the ETL. Based on the self‐polymerization of 3‐[[2‐(methacryloyloxy)ethyl]dimethylammonium]propane‐1‐sulfonic acid (DAES) in an aqueous environment, combining the catalytic effect of LiCl (as a Lewis acid) with the salting‐out effect, and the introduction of polyvinylpyrrolidone (PVP) as the other polymer chain, a chain entanglement gelled SnO2 (G‐SnO2) structure is successfully constructed with a wide range of functions. The PDEAS‐PVP chain entanglement gel achieves passivation and Pb2⁺ capture through chemical chelation mechanisms is explored. The results demonstrated that the all‐in‐air prepared PSC based on G‐SnO2 exhibited an excellent power conversion efficiency (PCE) of 24.77% and retained 83.3% of their initial efficiency after 2100 h of air exposure. Additionally, the PDEAS‐PVP exposes more C═O and S═O active sites, significantly enhanced the lead absorption capability of the PSCs.
Annual incidence of colorectal cancer among patients with average risk in the United States between 2017 and 2023.
83 Background: Colorectal cancer (CRC) is the second most common cause of cancer-related mortality and third most common cancer in the United States. In 2021, 141,902 new cases of CRC were reported. With recent increases in early onset of CRC incidence, a shift in patterns amongst various demographics has been observed. Together with an estimated 60% increase in burden of CRC globally, it is important to continuously assess the nationwide incidence rates and monitor the changing patterns. In this study, we examined the annual incidence rates of CRC in average risk adults using a large national claims database and report patterns of incidence based on various demographic characteristics. Methods: CRC diagnoses were retrospectively identified from a large national claims database, which covers over 165 million lives and is representative of the U.S. population, for each calendar year during the study period from 2017 to 2023. Individuals aged 45 to 75 years, with an average risk of CRC before each index calendar year were included in the study. Individuals were required to be continuously enrolled in the same health plan for at least 1 year prior to and 1 year following the index year. Annual CRC incidence rates per 100,000 people were calculated for each year from 2017 to 2023 within various subgroups based on baseline demographics. Results: Overall, annual CRC incidences remained consistent during the study period with 186.86 (95% CI, 184.87-188.86) cases in 2017 and 183.40 (95% CI, 181.32-185.5) cases in 2023 per 100,000. Among younger adults aged 45-49 years, the annual CRC incidence increased by 66% from 2017 (92.04 cases/100,000) to 2023 (153.12 cases/100,000). Conversely, annual CRC incidence decreased by 25% between 2017 (328.52 cases/100,000) and 2023 (244.93/100,000) in older adults aged 65-75 years. Over the study period, CRC incidence in men was higher than women with an overall rate ratio (RR) of 1.206 (95% CI, 1.122-1.297). African American adults had higher CRC incidence than White Americans with an overall rate ratio (RR) of 1.216 (95% CI, 1.152-1.283). Conclusions: Based on this large study of national claims data, CRC incidence rates remained relatively stable in the total population among average-risk patients from 2017 to 2023. The continuing increase in recommended CRC screening utilization showed a decreased incidence rate in the older population, while observing increased incidences among younger patients.
Disparities in outcomes of pancreatic cancer hospitalizations: A ten-year trend study.
683 Background: Pancreatic cancer is the third leading cause of cancer mortality in the United States with 51,750 estimated deaths from Pancreatic cancer in 2024. Demographic variations have been reported with Pancreatic cancer. Our aim was to identify trends in demographic-specific disparities in inpatient pancreatic cancer outcomes. Methods: This is a retrospective longitudinal trends study using the Nationwide Inpatient Sample (NIS) database (2010-2019). We identified hospitalizations with pancreatic cancer using ICD-9 and ICD-10 codes. We highlight disparities in mortality outcomes stratified by age, gender and race. Results: There were 992,550 hospitalizations of pancreatic cancer patients between 2010 and 2019. Over the period, the mean age at hospitalization was similar at 68 years (P = 0.006). A majority of the admissions were elderly patients (≥65 years) identifying as males and Caucasians (P < 0.01). Most patients had Medicare and were in large and urban teaching hospitals (P < 0.001). Over the decade, there was an overall decline in inpatient mortality, from 8.2% in 2010 to 7.1% in 2019 (P trend = 0.004). Amidst the age subgroups, only the elderly patient group experienced a significant decline in mortality rate (8.8% to 7.3%; P trend = 0.004). The young adult population (<45 years) had a trend towards increasing mortality rate, but it was not significant (P trend= 0.139). On gender subgroup analysis, only males had a significant decline in mortality rate (P trend= 0.003). On racial subgroup analysis, only Caucasians had a significant decline in mortality trend (P trend= 0.004) during the study period. Conclusions: There was an overall improvement in the mortality outcome of pancreatic cancer hospitalizations. On sub-group analysis, significant decline in mortality over the decade were seen only in elderly, male and Caucasian patient groups. Targeted research is needed in understanding the root causes of these disparities in pancreatic cancer outcomes and develop effective intervention to bridge this gap. Trends in mortality outcomes of pancreatic cancer hospitalizations by demographic subgroups. Mortality rate, % 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 P- Trend value Overall 8.21 7.94 7.85 7.70 7.73 7.68 7.46 7.87 7.47 7.14 0.004 Young (<45 years) 4.45 5.55 5.23 6.08 6.27 5.32 3.63 6.84 6.95 6.35 0.14 Middle-aged (45- 64 years) 7.55 7.24 7.74 7.32 7.03 6.99 7.62 6.80 6.74 6.91 0.06 Elderly (>65 years) 8.81 8.44 8.04 8.00 8.22 8.19 7.54 8.48 7.87 7.29 0.004 Females 7.72 7.32 7.23 7.15 6.99 7.31 6.72 7.38 7.01 6.87 0.08 Males 8.67 8.57 8.44 8.22 8.44 8.04 8.13 8.32 7.90 7.38 0.003 Whites 7.94 7.49 7.48 7.39 7.81 7.29 6.81 7.39 7.19 6.80 0.004 Blacks 9.87 9.40 9.38 9.15 8.35 8.13 9.40 9.01 8.55 8.41 0.07 Hispanics 7.10 8.99 8.02 6.85 6.66 8.80 7.54 7.43 7.10 6.14 0.05
Risk of proteinuria with atezolizumab plus bevacizumab versus lenvatinib in first-line systemic treatment for hepatocellular carcinoma.
558 Background: Proteinuria presents a challenging complication during systemic therapy for hepatocellular carcinoma (HCC). This study aims to identify risk factors for proteinuria in patients with HCC treated with atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic treatment. Methods: A retrospective analysis was conducted on 622 consecutive patients with unresectable HCC who received Atezo/Bev or LEN as first-line systemic treatment between October 2013 and October 2022. Cumulative incidence of proteinuria was estimated using Kaplan–Meier curves and compared using log-rank tests. Risk factors for proteinuria were identified using Cox proportional-hazard models, along with propensity score-matched and subgroup analyses. Results: Among 367 patients treated with Atezo/Bev and 255 with LEN, the cumulative incidence of proteinuria at 12 months was 27.5%. In the multivariable analysis, Atezo/Bev treatment (HR, 1.57; 95% CI, 1.03–2.42), diabetes (HR, 1.64; 95% CI, 1.03–2.61), Child–Pugh class B (HR, 3.43; 95% CI, 1.34–8.78), macrovascular invasion (MVI; HR, 1.58; 95% CI, 1.04–2.38), and an estimated glomerular filtration rate ≤60 mL/min/1.73 m 2 (HR, 3.21; 95% CI, 1.84–5.62) were identified as risk factors for proteinuria. A higher risk of proteinuria in Atezo/Bev patients compared with LEN was consistently observed in the PS-matched cohort, particularly pronounced in subgroups with MVI (HR, 2.84; 95% CI, 1.23–6.54) compared with those without MVI (HR, 1.31; 95% CI, 0.69–2.47). Conclusions: Patients treated with Atezo/Bev as first-line systemic treatmentfor HCC exhibited a higher risk of proteinuria compared with those with LEN, particularly when accompanied by MVI.
Ferroelectric Optical Memristors Enabled by Non‐Volatile Electro‐Optic Effect
Abstract Memristors enable non‐volatile memory and neuromorphic computing. Optical memristors are the fundamental element for programmable photonic integrated circuits due to their high‐bandwidth computing, low crosstalk, and minimal power consumption. Here, an optical memristor enabled by a non‐volatile electro‐optic (EO) effect, where refractive index modulation under zero field is realized by deliberate control of domain alignment in the ferroelectric material Pb(Mg 1/3 Nb 2/3 )O 3 ‐PbTiO 3 (PMN‐PT) is proposed. The non‐volatile EO memristor is designed exclusively for the modulation of the optical phase without degrading the optical transparency, and it allows the support for deterministic and repeated non‐volatile multilevel EO states. A non‐volatile tunable waveplate composed of the optical memrisor for free‐space optics, which allows for deterministic multilevel, and non‐volatile phase shifts from 0 to π /2 is presented. The state switching rate of the memristor is less than 100 ms, with a switching energy consumption of 234 nJ, and the states can be retained for up to 12 h without requiring static power consumption. These results demonstrate a novel approach to fully realizing non‐volatile optical memristors, where only optical phase modulation is involved, providing unprecedented opportunities for the development of new ferroelectric memristors.
Spatial transcriptomics and lethality-associated stromal remodeling of colorectal cancer.
227 Background: Colorectal cancer (CRC) is surgically resectable and eminently screenable yet remains a lethal entity with high affinity to metastasise synchronously and metachronously. It has been proposed that cellular and extracellular components of the microenvironment contribute to metastatic potential. Dissociative profiling techniques such as bulk transcriptomic and single-cell RNA sequencing have contributed insight but limited therapeutic progress. Spatial transcriptomic (ST) assessment allows molecular profiling of tissue while preserving tissue architecture. Here we employ ST approaches to interrogate tumor compartments of primary resectable and matched synchronous CRC demonstrating stromal signatures with distinct collagen expression associated with outcome. Methods: 25 patients with primary resectable CRC and 4 patients with matched primary CRC and liver metastasis (CRLM) underwent single-cell spatial transcriptomics using the Nanostring CosMx Spatial Molecular Imager (SMI, 1000plex gene panel) (Discovery cohort). 71681 epithelial and 88806 stromal cells with intact spatial resolution were analysed. The spatial single-cell signatures were reconstituted in 89 patients using the Nanostring GeoMx Digital Spatial Profiler (Validation cohort). 3 GeoMx compartments were analysed: Epithelial (PanCK+); Stroma (aSMA+); Immune (PanCK-aSMA-). Results: CosMx demonstrated 2 distinct collagen signatures: COL1A1,COL1A2,COL3A1 associated with normal fibroblasts; COL9A2 associated with cancer-related stroma and lethal subtypes of epithelial cell. In the GeoMx validation cohort, 42 patients expressed the COL1A1 signature in the aSMA compartment and 47 did not (5 year recurrence free survival: 0.88 vs 0.49, p < 0.005) with different morphological patterns of each distinct aSMA group. In patients with favourable prognosis, chemokine high epithelial subtypes expressed CXCL5 and recruited COL9A2-, IL6+ neutrophils to the surrounding microenvironment. In contrast, epithelial cells in patients with poor prognosis expressed CXCL8 and recruited COL9A2+ neutrophils which were frequently in contact with SPP1+ macrophages. Conclusions: We have used ST approaches to interrogate cellular compartments of CRC demonstrating stromal subtypes that impact outcome. These insights could be used in the clinical setting to quantify COL9A2 expression in aSMA+ cells to prognosticate patients. Targeting of tumor collagen has been proposed to augment existing anti-cancer therapies and this work has demonstrated COL9A2 as a potential target in need of further investigation.
Systematic literature review (SLR) of prognostic factors (PFs) in locally advanced rectal cancer (LARC) and mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer (RC).
303 Background: Innovative immunotherapies arebeing developed to improve clinical outcomes in patients (pts) withdMMR/MSI-H LARC who respond poorly to the current standard of care. A comprehensive overview of PFs in dMMR/MSI-H LARC may provide insight into the natural history of this disease to inform clinical study design and pt risk stratification. Methods: Systematic searches of bibliographic databases (EMBASE, MEDLINE, Cochrane; 2013–2023) and congress websites (2021–2023) were conducted to identify PFs for tumor response and survival outcomes in adult pts with LARC (SLR1) and dMMR/MSI-H RC (SLR2). Given the expected high volume of evidence, SLR1 was limited to large observational studies (≥1000 pts) and clinical trials (≥100 pts); SLR2 had no such limits. Results: 95 of 2307 publications met the inclusion criteria for SLR1. Of the PFs reported in ≥20 studies, older age, more lymph node involvement or fewer nodes assessed, higher T-stage or larger tumor size, higher histologic grade, and more comorbidities were most frequently significantly associated with poorer patient prognosis (Table). 3 of 289 publications met the inclusion criteria for SLR2. Neoadjuvant chemoradiation therapy (CRT) compared to chemotherapy (CT) was associated with statistically significant worse disease-free survival (DFS) and distant metastasis-free survival (DMFS), while T- or N-stage, age, and sex did not significantly impact these outcomes. Low vs middle tumor localization was also associated with worse DMFS. Stage III and IV disease were associated with worse RC-specific survival, while surgical procedure (segmental vs extended) showed no difference in overall survival (OS). The addition of neoadjuvant CRT or adjuvant CRT/CT to surgery alone had no impact on OS but was associated with worse DFS. Conclusions: Evidence regarding PFs in dMMR/MSI-H RC is scarce and may limit its interpretability, highlighting the need for further research that may be informed by the PFs identified from SLR1. The results from these SLRs may be helpful for optimizing patient management and treatment decision making, and to further contextualize RC clinical trials. PFs reported in ≥20 studies with ≥75% of studies reporting significant results in pts with LARC. PF Studies reporting PF (n) Studies reporting significant* impact of PF on prognosis (%) Poorer prognosis group Top 2 most frequently reported outcomes Age 59 81.4 Older OS, DFS Lymph node involvement/assessment 55 78.2 Yes or higher N stage OS, DFS T-stage or tumor size 53 79.2 Higher or larger OS, DFS Histologic grade 37 75.7 Higher OS, pathological complete response (pCR) Comorbidities 23 87.0 More OS, pCR *p-value <0.05 was considered significant as reported in the identified studies.
Combining low-dose regorafenib with pembrolizumab for patients with MSI-H colorectal cancer: REGPEM-CRC-01.
TPS313 Background: Currently, pembrolizumab is one of the front-line therapies for patients with MSI-H CRC. However, approximately 40% of patients who received pembrolizumab experienced disease progression early in the course of disease (KEYNOTE 177). Therefore, there is still an unmet need to enhance the efficacy of checkpoint inhibitors in MSI-H CRC. MSI-H CRC has a higher level of expression of VEGF in blood compared to patients compared to its MSS counterpart (Hansen et al. Colorectal Dis. 2011). Consistently, exploratory analysis of CALBG-80405 and PARADIGM trial showed that patients with MSI-H CRC were more likely to benefit from anti-VEGF therapy than anti-EGFR therapy regardless of the side of the tumor. NSABP C-08 also suggested that anti-VEGF therapy may have biological activity even in as adjuvant therapy for patients with MSI-H colon cancer. Regorafenib is a potent VEGF inhibitor, with preclinical evidence showing its immune modulatory effect in the tumor microenvironment. In this trial, we hypothesize that adding low-dose regorafenib to pembrolizumab may induce synergistic activity beyond their independent clinical efficacy and create deep and durable responses for patients with MSI-H CRC. Methods: In the lead arm of this prospective randomized study, 22 patients will be enrolled through Hoosier Cancer Research Network (HCRN-GI23-643). Patients with treatment naïve MSI-H CRC will be enrolled in this front-line trial. One cycle of pembrolizumab and up to 3 cycles of chemotherapy prior to determination of MMR-D/MSI-H is allowed. Patients will receive regorafenib 60 mg daily in combination with pembrolizumab 200mg IV in cycle 1, followed by regorafenib 90mg in subsequent cycles to improve treatment tolerance. The primary outcome that will be measured is ORR, defined as the percentage of partial or complete response to the treatment within 12 months. ORR will be measured using RECIST 1.1. criteria. A formal one-sided hypothesis test will be conducted for futility, assuming that we will reject the null hypothesis of a target ORR only if we have strong evidence. In this study, we assume a null hypothesis that ORR is 0.60, which would reflect significant clinical improvement over the current standard of ORR = 0.43 from KEYNOTE 177. The alternative hypothesis is that ORR is less than 0.60. For the lead-in phase of the study, the emphasis is on controlling Type I error to be small, approximately 0.05. The test statistic will be the number of ORRs in the 22 patients, which we assume to follow a binomial distribution. Clinical trial information: NCT06006923 .
Prediction of relapse-free survival in stage III gastric cancer patients treated with postoperative adjuvant chemotherapy: Random survival forest analysis from the START-2 trial.
446 Background: The START-2 trial demonstrated that docetaxel plus S-1 (DS) was superior to S-1 alone (S-1) in terms of recurrence-free survival (RFS) and overall survival (OS) as the adjuvant chemotherapy for stage III gastric cancer (GC) patients (pts) (J Clin Oncol 2019, Gastric Cancer 2022). We conducted the START-2 AR study as a retrospective analysis using data from the START-2 trial to develop a prognostic model for stage III GC pts treated with postoperative chemotherapy. Methods: Among 912 pts in the START-2 trial, 599 pts signed the consent form to participate in the START-2 AR study. There were 542 pts (265 pts in DS group and 277 pts in S-1 group) without missing values of prognostic candidates. Pts were randomly divided into a training set and a validation set with a ratio of 7:3. Prognostic model for RFS was developed using random survival forest (RSF) with the training set. The RSF model was applied to the validation set to assess its performance, evaluated using Harrell's C-index. We calculated tertiles of risk scores from the RSF model to divide the training set into low-, middle-, and high-risk subgroups. These cut-off values were used to classify the validation set. A Cox proportional hazard model was applied to compare the prognosis among the risk groups. Results: There were no statistically significant differences in patient characteristicsbetween the 599 pts in the START-2 AR study and the 912 pts in the STRAT-2 trial. RFS was comparable between the two groups. The RSF model for the training set (n = 380) yielded a C-index of 0.873, identifying the number of metastatic lymph nodes, serum albumin, CEA, tumor diameter, the primary tumor location, platelet count, age as prognostic factors in order of importance. In the validation set (n = 162), the C-index was 0.648. Both the low-risk group (n = 35) (hazard ratio [HR]: 0.34, 95% confidence interval [CI]: 0.17 – 0.68, p < 0.01) and the middle-risk group (n = 74) (HR: 0.55, 95% CI: 0.33 – 0.89, p = 0.02) in the validation set had significantly better RFS compared to the high-risk group (n = 53). Among the 76 pts in the low-risk group treated with DS, 44 were categorized into the low-risk group when assuming they had been treated with S-1 alone. The analysis of 599 pts after multiple imputation yielded results consistent with those from the complete data. Conclusions: We developed the RSF-based predictive model for stage III GC pts, which demonstrated good performance. The number of metastatic lymph modes was identified as the most important prognostic factor. Risk stratification based on this model effectively differentiated prognostic outcomes. Future external validation of the model is required. Clinical trial information: UMIN000011438.
Investigating the clinical and molecular characteristics of class II and III BRAF mutations and their response to anti-EGFR therapy in MSS CRC: A comprehensive analysis.
274 Background: BRAF mutations (mts) are a heterogeneous group of molecular alterations seen in colorectal cancer (CRC). Class I BRAF mts (V600) are known to be associated with aggressive biology to CRC, but the knowledge of clinical characteristics of class II and III BRAF mts is limited. In this large cohort analysis, we evaluated the clinical and molecular features of class II and III BRAF mts and performed comparative analyses for their impact on survival outcomes. Methods: A total of 24402 MSS CRC samples were profiled by NGS (592-gene, NextSeq; WES, WTS NovaSeq) (Caris Life Sciences, Phoenix, AZ). BRAF mts were detected by NGS and classified using published literature (1). MAPK pathway activity score (MPAS) was calculated using RNA expression data. Real-world overall survival (OS) was obtained from insurance claims and calculated from tissue collection to last contact, while post-treatment survival from first treatment to last contact. KM estimates were calculated for defined patient cohorts. Significance was determined as P<0.05. Results: A total of 1270, 134, and 327 patients with class I, II, and III BRAF mts were identified. BRAF mts overall and class I BRAF mts were significantly less common among younger pts (age<50) compared to patients ≥ 50 (4.7% vs. 7.4 %; P< 0.001 and 3.2% vs. 5.7%, respectively, P<0.001). Class I BRAF mts were enriched with consensus molecular subtype 1 (CMS1) (class I, II, and III: 46% vs. 14% vs. 18% respectively) while class II and III mts had more CMS2 subtype compared to class I (2%, 30% and 29%, p<0.05). Higher MPAS scores were noted among patients with class I BRAF mts than those with class II and III mts (1.73 versus 0.38 vs 0.79). Class I BRAF mts and KRAS mts were nearly mutually exclusive (0.5%), while KRAS mts were relatively common among class II and III mts (12.8% and 27.4%, respectively). Median OS for patients with wild-type BRAF , class I, II, and III BRAF mts were significantly different (29.8, 17.3, 21.8, and 24.6 months, respectively, p<0.01). Similar OS was seen among patients who did not receive anti-EGFR therapy (28.3, 15.2, 20.7- and 21.9 months P<0.001). Patients with class III mts had significantly better OS compared to patients with class I mts (HR=1.28 CI: 1.09-1.48 p=0.002), and while no significant difference was noted for patients with class II vs class I mts, numerically more favorable outcomes were noted (mOS 21.8 vs 17.3 months P=0.133). Among treated with anti-EGFR, patients with class II and III BRAF mts had numerically better post-anti-EGFR survival compared to class I mts; however, this was not statistically significant (21.2 vs 14.2 vs. 10.4 respectively P=0.3). Conclusions: Class II and III BRAF mts represent a distinct biological subgroup of MSS CRC with distinct prognoses. Class II and III BRAF mts are associated with improved survival outcomes compared to patients with class I mts. 1. Sahin et al. JCO OP 2021.
Predictive methylation signature for gemcitabine sensitivity in pancreatic ductal adenocarcinoma: A pathway to personalized treatment.
768 Background: Gemcitabine (Gem) is a key drug used in chemotherapy regimens for treating pancreatic ductal adenocarcinoma (PDA). Identifying a biomarker to predict patient response to Gem could be crucial in personalizing treatment selection between Gemcitabine and fluorouracil (5-FU)-based therapies, thereby improving patient outcomes. We hypothesize that DNA methylation changes in genes linked to Gem resistance may serve as surrogates for the expression of corresponding proteins, thereby predicting treatment outcomes in patients with PDA receiving this therapy. Methods: We curated a 93-gene panel through a literature review spanning from January 1970 to April 2024. The proteins encoded by these genes have demonstrated either preclinical evidence (from cell line or mouse models) or clinical evidence (from tissue-based studies) of affecting the response to Gem in PDA. We evaluated the prognostic significance of methylation at specific CpG (cytosine-phosphate-guanine) sites within these genes using data from The Cancer Genome Atlas (TCGA) database, focusing on patients who had received Gem (106 /184 patients). We utilized elastic net multivariate analysis to analyze survival and created Kaplan-Meier plots based on our gene panel to estimate overall survival (OS). We compared RNA and gene expression levels for the clinically significant gene signatures between normal (NT) and PDA tissues using TNMplot.com, a web-based tool developed from data in the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO), TCGA, Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories. This tool employs Mann-Whitney or Kruskal-Wallis tests to determine statistical significance. Results: We identified an 8-CpG site methylation signature across eight genes, distinguishing a high-risk subgroup within the Gem-treated cohort in the TCGA database. Patients exhibiting methylation at specific CpG sites in this signature experienced significantly worse OS, with median survival times of 20.35 months compared to 49.38 months (p=0.0068). Additionally, the RNA expression (fold change: 2.11, p=2.12e-55) and gene expression (fold change: 1.42, p=3.14e-18) of these genes were markedly higher in PDA tissues compared to normal tissues. Notably, the candidate genes in our signature do not overlap with those used to classify PDA into classical versus basal subtypes. In an ongoing study, we are also investigating methylation changes of these candidate genes in the blood (cell-free DNA) of PDA patients. Conclusions: We present a signature that can predict Gem sensitivity or resistance in patients with PDA. This signature serves as a critical first step toward personalizing treatment strategies.
Programmable Electromagnetic Wave Absorption via Tailored Metal Single Atom‐Support Interactions
Abstract Metal single atoms (SA)‐support interactions inherently exhibit significant electrochemical activity, demonstrating potential in energy catalysis. However, leveraging these interactions to modulate electronic properties and extend application fields is a formidable challenge, demanding in‐depth understanding and quantitative control of atomic‐scale interactions. Herein, in situ, off‐axis electron holography technique is utilized to directly visualize the interactions between SAs and the graphene surface. These interactions facilitate the formation of dispersed nanoscale regions with high charge density and are highly sensitive to external electromagnetic (EM) fields, resulting in controllable dynamic relaxation processes for charge accumulation and restoration. This leads to customized dielectric relaxation, which is difficult to achieve with current band engineering methods. Moreover, these electronic behaviors are insensitive to elevated temperatures, having characteristics distinct from those of typical metallic or semiconducting materials. Based on these results, programmable EM wave absorption properties are achieved by developing a library of SA‐graphene materials and precisely controlling SA‐support interactions to tailor their responses to EM waves in terms of frequency and intensity. This advancement addresses the customized anti‐EM interference requirements of electronic components, greatly enhancing the development of integrated circuits and micro‐nano chips. Future efforts will concentrate on manipulating atomic interactions in SA‐support, potentially revolutionizing nanoelectronics and optoelectronics.
Efficacy and safety of trifluridine/tipiracil and bevacizumab (FTD/TPI+BEV) in patients with metastatic colorectal cancer (mCRC) in real-world practice.
204 Background: In Sunlight trial, the combination of FTD/TPI + BEV showed a significant improvement in Overall Survival (OS) and Progression-Free Survival (PFS), along with better Objective Response Rate (ORR) and Disease Control Rate (DCR), compared to FTD/TPI alone, in patients with mCRC progressing after two chemotherapy regimens. The BeTAS trial aimed to evaluate the effectiveness and safety of the FTD/TPI + BEV combination in real-world practice. Methods: This was a retrospective, observational, multicenter study of mCRC patients treated with FTD/TPI+BEV in routine clinical practice across 11 Spanish university hospitals. It included patients with mCRC who were refractory or intolerant to standard therapies. Results: A total of 208 patients treated with FTD/TPI+BEV between July 2019 and December 2023 were included. The median age was 69 years (range 33 to 88 years), with 59.8% being male. 15.3% had an ECOG performance status of 2, 55.9% had RAS mutations, 30.3% had three or more metastatic sites, and 81.2% had liver metastases. Additionally, 19.8% had a time from diagnosis of first metastasis of less than 18 months, and 55.3% were categorized in Tabernero's Unfavorable Prognostic Subgroup. Most patients (81.3%) received FTD/TPI+BEV as third-line therapy, with 90.5% having previously received anti-VEGF therapy. The median number of treatment cycles was 4 (range 1 to 31 cycles). The ORR was 4.6%, and the DCR was 50%. The median PFS was 4.9 months (95% CI, 4.0-5.7 months), and the median OS was 11.1 months (95% CI, 9.5-12.8 months). The most common grade 3-4 toxicities included neutropenia (41.8%), asthenia (7.2%), and hepatic toxicity (5.5%). No treatment-related deaths were reported. Conclusions: Our series confirms the efficacy and safety of FTD/TPI + BEV in routine clinical practice, even in a population with poor prognosis and an extensive history of previous treatments.