Citations

3614 Background: Conventional neoadjuvant chemoradiotherapy (nCRT) yields a pathologic complete response (pCR) rate of about 15%–- 30% for locally advanced rectal cancer (LARC). This PRECAM study aimed to investigate the efficacy and safety of neoadjuvant short-course radiotherapy combined with CAPEOX plus Envafolimab in Patients with Microsatellite Stable (MSS) LARC, redefining the standard of care (SOC) for LARC. Methods: The study is an open-label, prospective, single-arm, phase II clinical study . Eligible patients with MSS LARC were consecutively enrolled. Participants received short-course radiotherapy (25Gy/5f) with subsequent two cycles of CAPEOX (capecitabine and oxaliplatin) and 6 cycles of Envafolimab (subcutaneous injection, 150 mg, QW ) followed by total mesorectal excision surgery. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was major pathologic (MPR) rate and safety. Results: From April to December 2022, 34 patients were enrolled, of whom 32 completed the study. Remarkably, The pCR rate was62.5% (20/32), and the (MPR) rate was 75% (24/32). Furthermore, 65.6% (21/32) patients achieved a neoadjuvant rectal (NAR) score below 8, suggesting an effective treatment response. Common adverse events included tenesmus (78.1%), diarrhea (62.5%), and leukocyte decrease (40.6%), with two cases of Grade 3 adverse events. Surgical procedures were performed in all 32 cases, with minor complications observed. During the follow-up period of up to 20 months, no recurrence or death were reported. Conclusions: Short-course radiotherapy combined with CAPEOX plus Envafolimab showed favorable pCR rate with manageable adverse effects and surgical complications in LARC, underscoring the potential of the combination therapy for MSS LARC. A Randomized controlled trial is warranted for further exploration and validation. Clinical trial information: NCT05216653 .

AbstractBiliary tract cancer (BTC) is a rare and aggressive malignancy with increasing incidence. Most BTC cases are diagnosed with metastatic disease which carries a 5‐year survival rate of <5%. Physical activity, diet, and obesity might be associated with BTC risk, but studies have been limited particularly in African descendants. We addressed this knowledge gap by evaluating associations of BTC risk with obesity, physical activity, and dietary intakes in 723,326 adult participants in four cohort studies conducted in China, the United Kingdom, and the United States. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) in each cohort; results were combined using meta‐analysis. All cohorts had ≥11 median follow‐up years with 839 incident BTC cases combined. BTC risk was positively associated with body mass index (BMI) and waist‐to‐hip ratio (WHR) whereas physical activity, fruit intake, and fish intake were inversely associated. HR and (95% CI) comparing BMI >35.0 to 18.5–24.9: 1.71 (1.26, 2.31), p‐trend <.0001; comparing BMI‐adjusted WHR top to bottom quartile: 1.20 (0.94, 1.53), p‐trend = .05; comparing ≥15–0 metabolic equivalent task‐hours/week 0.76 (0.61, 0.94), p‐trend = .009; comparing highest to lowest intake tertile for fruit and fish 0.79 (0.66, 0.95), p‐trend = .01; 0.82 (0.68, 0.98), p‐trend = .04, respectively. Associations were, in general, similar across ancestry groups. Our study provides strong evidence for important roles of obesity, diet, and physical activity in BTC etiology and stresses the need for lifestyle modification to combat the rising incidence of this fatal malignancy.

e15543 Background: In the last two decades, colorectal cancer (CRC) mortality has been decreasing in the United States (US). However, the mortality trends for the different subtypes of CRC, including different sides of colon, rectosigmoid, and rectal cancer remain unclear. Methods: We analyzed death certificate data from CDC WONDER from 1999 to 2020. We calculated age-adjusted mortality rates (AAMR) per 100,000 individuals of CRC and its different subtypes and examined the trends over time by estimating the average annual percent change (AAPC) using the Joinpoint Regression Program. Results: From 1999 to 2020, 1,166,099 deaths were attributed to CRC, of which 957,182 deaths (82.08%) were due to colon cancer, 148,862 deaths (12.77%) from rectal cancer, and 60,055 deaths (5.15%) from rectosigmoid cancer. The overall CRC rates decreased significantly from 26.42 (95% CI, 26.20-26.64) to 15.98 (95% CI, 15.84-16.12) per 100,000 individuals, with AAPC of -2.41 (95% CI, -2.55, -2.27). However, the AAMR of rectosigmoid cancer increased significantly from 0.82 (95% CI, 0.78 -0.86) to 1.08 (95% CI, 1.04-1.11) per 100,000 individuals and the AAMR of right-sided colon cancer increased from 0.57 (95% CI, 0.54-0.60) to 0.70 (95% CI, 0.67-0.73) per 100,000 individuals, with AAPC of +1.10 (95%, 0.21-2.00) and +2.06 (95% CI, 0.85 - 3.27) respectively. Men had higher AAMR of CRC than women (23.90 [95% CI, 23.84-23.96] vs. 17.03 [95% CI, 16.99-17.08] per 100,000 individuals). African Americans had the highest AAMR of CRC (26.93 [95% CI, 26.79-27.07]), followed by Whites (19.60 [95%, 19.56-19.64] per 100,000 individuals), American Indians (14.53 [95%, 14.15-14.92] per 100,000 individuals), and Asians (13.04 [95%, 12.89-13.19] per 100,000 individuals). The overall AAMR of CRC decreased for those aged ≥ 50 years but increased significantly from 1.02 to 1.58 per 100,000 individuals for those aged 15-49 years, with an AAPC of +0.75. The AAMR from CRC was the highest in the Midwest (21.04 [95% CI, 20.96-21.12] per 100,000 individuals), followed by the South (20.51 [95% CI, 20.44-20.57]), the Northeast (20.30 [95% CI, 20.22-20.38] per 100,000 individuals), and the West (18.03 [95% CI, 17.95-18.10] per 100,000 individuals). Rural populations had higher AAMR than urban populations (22.40 [95% CI, 22.30-22.49] vs. 19.60 [95%, 19.56-19.64] per 100,000 individuals). Conclusions: Although overall CRC mortality declined, there were rising trends in young-onset CRC, rectosigmoid cancer, and right-sided colon cancer. Disparities persist in terms of sex, race, geographic region, and urbanization level, emphasizing the need for targeted public health measures.

e23252 Background: The UPMC-Kline Health Center (KHC) in Harrisburg, PA, shows a lower cervical cancer screening rate compared to the general population in the USA (57.08% vs 78%, respectively, based on the Medical Group Fiscal Year 2023 Internal Quality Measures). To understand this gap, we distributed a comprehensive questionnaire to patients, aiming to pinpoint factors contributing to the lower screening rate and plan targeted interventions for improvement. Methods: We randomly distributed questionnaires to female patients aged 21 to 61 during appointment check-in at the KHC, considering our linguistically diverse patient population with surveys available in Spanish, English, and Nepali. Given the diverse linguistic landscape of our patient population, we prepared questionnaires in Spanish, English, and Nepali. The survey aims to identify and address specific clinic-related problems, with a follow-up assessment after a few months to gauge improvements following interventions targeting the underlying causes of screening gaps. Results: Over a three-month span, 65 questionnaires were completed. Among the participants, 38% (25 patients - 7 white/Caucasian, 11 black/African American, 1 Asian, 7 others; 12 Hispanic, 13 non-Hispanic) revealed that they had not undergone screening within the past three years. The analysis of this subgroup unveiled significant issues: 84% (21/25) did not receive paperwork to schedule the test, 88% (22/25) were not contacted to schedule the test, 76% (19/25) did not receive reminder notifications before appointments, and 72%(18/25) expressed concerns about the lack of insurance coverage for costs. Furthermore, 76% (19/25) indicated the requirement to pay a co-pay, and an equal percentage reported difficulties in obtaining the screening test. Additionally, 72%(18/25) mentioned that their healthcare providers did not discuss the screening's importance, while 76%(19/25) noted their providers did not explain the purpose of the test. Conclusions: These findings underscore critical gaps in communication, accessibility, and cost-related barriers to cervical cancer screening at KHC. This ongoing quality improvement project, scheduled for data recollection in a few months, encompasses proposed interventions such as automated reminders, technology integration for communication, and distributing flyers in clinic and waiting areas to foster open communication and address inadequate discussions about the importance of screening. The aim is to improve patient awareness, engagement, and ultimately prevent delayed cancer diagnoses. KHC is committed to enhancing the cervical cancer screening rate to minimize the likelihood of delayed cancer diagnoses.

Abstract Background: In breast cancer, the spatial relationship between immune and tumor cells is increasingly recognized as critical in determining the efficacy of neoadjuvant therapy (NAT). This study investigated how the distribution of immune cells, particularly CD8+ T cells, relative to tumor cells affects treatment outcomes. Methods: Biopsies from 104 breast cancer patients were examined, both pre- and post-NAT, using multiplex immunohistochemistry (mIHC). This study focused on the density and distribution of CD8+ T cells, CD68+ macrophages, FoxP3+ regulatory T cells, and other immune markers. Results: The spatial proximity of CD8+ T cells within 20 µm of cancer cells (N20-CD8+T) was strongly correlated with improved clinical outcomes across diverse tumor subtypes and NAT regimens. A significant post-NAT decrease in CD4+, CD68+, and FoxP3+ cells highlights notable shifts in the tumor immune landscape. A noteworthy finding was the positive correlation between CXCL9 expression and N20-CD8+T cells, suggesting a mechanism for immune cell recruitment and interaction within the tumor microenvironment. These results highlight the complex interplay among NAT, immune cell modifications, and patient outcomes. Conclusions: This study revealed that the proximity of N20-CD8+ T cells to tumor cells is consistently associated with favorable NAT outcomes, transcending tumor subtypes, and treatment differences. This highlights the potential of immune cell dynamics, especially CD8+ T cells, as predictive biomarkers for therapeutic responses in breast cancer, underscoring their vital role in tumor immunity.

AbstractIschemia‒reperfusion (I/R) is a common complication in the clinical treatment of acute myocardial infarction (MI), in which cardiomyocytes play a pivotal role in the recovery of cardiac function after reperfusion injury. The expression of numerous circular ribonucleic acids (circRNAs) is disrupted in I/R‐induced cardiac damage, but the potential role of circRNAs in I/R damage has not been fully elucidated. The purpose of the present study was to clarify the biological action and molecular mechanism of circRNA 002166 (also termed circCL2L13) in postmyocardial I/R. Oxygen–glucose deprivation/reoxygenation (OGD/R) in an in vivo model was performed to simulate I/R damage. real‐time polymerase chain reaction analysis was also conducted to evaluate the relationships of the SOD1, SOD2, NRF2, HO1 and GPX4 indicators with oxidative stress injury. TUNEL immunofluorescence was used to evaluate the degree of cardiomyocyte apoptosis in the different treatment groups. The circBCL2L13 level was markedly upregulated in myocardial tissues from a mouse I/R model. Overexpression of circBCL2L13 markedly attenuated the expression of oxidative stress‐related genes and apoptosis in OGD/R‐induced cardiomyocytes. A mechanistic study revealed that circBCL2L13 functions as a ceRNA for miR‐1246 and modulates paternally expressed gene 3 (PEG3). Eventually, circBCL2L13 was proven to regulate PEG3 by targeting miR‐1246, thereby protecting against OGD/R‐induced cardiomyocyte oxidative damage and apoptosis. In conclusion, our study confirmed that the circBCL2L13/miR‐1246/PEG3 axis suppressed the progression of OGD/R injury in cardiomyocytes, which might lead to new therapeutic strategies for cardiac I/R injury.

PURPOSE KRAS is the most commonly mutated driver oncogene in non–small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRAS G12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRAS G12C -mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRAS G12C -mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRAS G12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

Abstract In the last two decades, colorectal cancer (CRC) mortality has been decreasing in the United States. However, the mortality trends for the different subtypes of CRC, including different sides of colon, rectosigmoid, and rectal cancer remain unclear. We analyzed the mortality trends of different subtypes of CRC based on Centers for Disease Control and Prevention's Wide‐Ranging Online Data for Epidemiologic Research data from 1999 to 2020. We calculated age‐adjusted mortality rates (AAMR) per 100,000 individuals and examined the trends over time by estimating the average annual percent change (AAPC) using the Joinpoint Regression Program. Our study shows that the overall CRC rates decreased significantly from 26.42 to 15.98 per 100,000 individuals, with an AAPC of −2.41. However, the AAMR of rectosigmoid cancer increased significantly from 0.82 to 1.08 per 100,000 individuals, with the AAPC of +1.10. Men and Black individuals had the highest AAMRs respectively (23.90 vs. 26.93 per 100,000 individuals). The overall AAMR of CRC decreased for those aged ≥50 years but increased significantly from 1.02 to 1.58 per 100,000 individuals for those aged 15–49 years, with an AAPC of +0.75. Rural populations had a higher AAMR than the urban populations (22.40 vs. 19.60 per 100,000 individuals). Although overall CRC mortality declined, rising trends in young‐onset CRC and rectosigmoid cancer warrant attention. Disparities persist in terms of sex, race, and geographic region, and urbanization level, emphasizing the need for targeted public health measures.