Citations

Background Despite significant cardiac involvement in sarcoidosis, real‐world data on death due to cardiovascular disease among patients with sarcoidosis is not well established. Methods and Results We queried the Centers for Disease Control and Prevention's Wide‐Ranging Online Data for Epidemiologic Research database for data on patients with sarcoidosis aged ≥25 years from 1999 to 2020. Diseases of the circulatory system except ischemic heart disease were listed as the underlying cause of death, and sarcoidosis was stated as a contributing cause of death. We calculated age‐adjusted mortality rate (AAMR) per 1 million individuals and determined the trends over time by estimating the annual percentage change using the Joinpoint Regression Program. Subgroup analyses were performed on the basis of demographic and geographic factors. In the 22‐year study period, 3301 cardiovascular deaths with comorbid sarcoidosis were identified. The AAMR from cardiovascular deaths with comorbid sarcoidosis increased from 0.53 (95% CI, 0.43–0.65) per 1 million individuals in 1999 to 0.87 (95% CI, 0.75–0.98) per 1 million individuals in 2020. Overall, women recorded a higher AAMR compared with men (0.77 [95% CI, 0.74–0.81] versus 0.58 [95% CI, 0.55–0.62]). People with Black ancestry had higher AAMR than people with White ancestry (3.23 [95% CI, 3.07–3.39] versus 0.39 [95% CI, 0.37–0.41]). A higher percentage of death was seen in the age groups of 55 to 64 years in men (23.11%) and women (21.81%), respectively. In terms of US census regions, the South region has the highest AAMR from cardiovascular deaths with comorbid sarcoidosis compared with other regions (0.78 [95% CI, 0.74–0.82]). Conclusions The increase of AAMR from cardiovascular deaths with comorbid sarcoidosis and higher cardiovascular mortality rates among adults aged 55 to 64 years highlight the importance of early screening for cardiovascular diseases among patients with sarcoidosis.

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.

Abstract The selectivity of the blood-brain-barrier (BBB) can prevent therapeutics from reaching the brain, and this may contribute to the high failure rate of new drugs for tumors like glioblastoma (GBM) and brain metastasis. The capacity to detect BBB penetrance in real-time in a noninvasive manner would arguably aid the rate of therapeutic development. Extracellular vesicles, which are membrane bound particles secreted by all cell types in the body, have potential as a neuro pharmacodynamic reporter given that their protein and RNA cargo reflect the originating cell population. We hypothesized that the exposure of GBM cells to therapy results in altered EV cargo, and that the detection of this shift can be leveraged as a liquid biopsy from patients during early clinical trials to determine BBB penetrance and tumor engagement. To identify cargo shifts indicative of treatment, we exposed four short-term patient derived glioma cell lines to arsenic trioxide (an idiopathic toxin), MLN4924 (a neddylation inhibitor), and the alkylating agent temozolomide, then harvested EVs for unbiased mass spectrometry and RNA sequencing. Interestingly, we identified conserved upregulated and downregulated protein and RNA species across cell lines and across drug treatments, despite the diverse mechanisms of action. Candidate proteins were further validated by mesoscale immunoassays and exoview evaluation of tetraspanin-captured EVs. RNA species were validated by qRT-PCR. Overall, we demonstrate that GBM-derived EV cargo changes in response to therapy, supporting the development of EVs as a reporter of drug delivery in GBM. Ongoing and future work is focused on identifying enrichment handles in order to selectively evaluate GBM-derived EV cargo from patient biofluids. Thus far, B7H3, PTPRZ1, EGFRvII and IL13Ra2 have been screened as putative handles. Success in this pursuit could substantially enhance findings and accelerate drug testing in early-stage clinical trials in brain tumor patients by reporting drug accessibility to the tumor and engagement with drug targets. Citation Format: Valerie DeLuca, Nanyun Tang, Nathaniel Hansen, Anjali Raju, Charles Shaffer, Yue Hao, Terry C. Burns, Jann N. Sarkaria, Ian Parney, Patrick Pirrotte, Kendall Van Keuren-Jensen, Michael E. Berens. Glioblastoma-derived extracellular vesicle cargo as a reporter of drug delivery and effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2130.

Abstract Background: It is a common practice to monitor trastuzumab-related cardiac toxicity (TRCT) using left ventricular ejection fraction (LVEF) in patients who receive trastuzumab-containing therapy for human epidermal growth factor receptor 2 (HER2)-positive cancers. However, this monitoring approach does not appear cost effective in patients with HER2-positive gastrointestinal (GI) cancers given poor overall survival (OS). Here, we aim to examine the incidence of clinically significant TRCT in this target population. Methods: This is a retrospective cohort study of patients with advanced HER2-positive GI cancers who received trastuzumab-containing therapies (trastuzumab +/- pertuzumab, chemotherapy +/- immunotherapy + trastuzumab, trastuzumab deruxtecan) between 2011 and 2023. HER2 status was determined by immunohistochemistry, fluorescent in situ hybridization, and/or next generation sequencing. LVEF was estimated by serial transthoracic echocardiograms (TTE). Continuous variables were summarized as median and interquartile range (IQR). Paired Wilcoxon signed rank test was used to compare serial LVEF. OS was estimated using Kaplan-Meier method. Results: A total of 243 patients were included in this study with a median age of 64 (IQR: 55-70) years. 139 (57%) patients had esophageal or GEJ adenocarcinoma; 45 (19%) patients had gastric cancer; 37 (15%) patients had colorectal cancer; and the rest had other GI cancers. Median follow-up time was 18.6 (IQR: 9.2-36) months. Median OS from cancer diagnosis and the first dose of trastuzumab-containing therapy were 24.1 (95%CI: 20.2-30.2) and 11.7 (95%CI: 10.4-15.6) months, respectively. Patients received a median of 13 cycles of trastuzumab-containing therapy for a median duration of 4.1 (IQR: 1.4-10.1) months. The median number of TTE each patient had throughout therapy was 2 (IQR: 1-4). Median baseline LVEF was 61% (IQR: 56-65%) which was significantly higher (p<0.001) than the median lowest LVEF of 58% (IQR: 53-62%) during therapy, but not different (p=0.14) from the most recent median LVEF of 60% (IQR: 56-64%) after discontinuation of trastuzumab. Among 176 patients with serial LVEF data, 16 (9%) had > 10% LVEF drop; 7 (44%) of these 16 patients had LVEF recovery. None of the cardiovascular risk factors prior to trastuzumab treatment including hypertension, diabetes, hyperlipidemia, peripheral arterial disease, coronary artery disease, and stroke were significantly associated with the development of TRCT. Conclusion: The incidence of clinically significant LVEF drop appears low in patients with advanced GI cancers as post-treatment LVEF recovery to baseline was observed at the population level. The value of using TTE to monitor TRCT in these patients with short OS should be further assessed in the perspective of cost effectiveness. Citation Format: Samual R. Kosydar, Matteo Castrichini, Mojun Zhu, Hao Xie. The value of routine trastuzumab-related cardiac toxicity monitoring in gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6298.

Abstract Background: Benefit from single-agent immune checkpoint inhibitor has been observed in 5-10% of the patients with microsatellite stable (MSS) gastrointestinal (GI) cancers. However, a reliable predictive marker to immune checkpoint inhibitor has not been discovered in this patient population. We sought to assess the incidence of mismatch repair (MMR) gene alterations and their association with tumor mutational burden (TMB) in MSS GI cancers. Methods: This is a retrospective cohort study of patients with advanced GI cancer who had molecular profiling of the tumor using either Guardant360 blood-based or Tempus tissue next generation sequencing (NGS) platforms between 2020 and 2023. We assessed four MMR genes including MLH1, MSH2, MSH6 and PMS2 for alterations. Continuous variables were summarized as median and interquartile range (IQR) and compared using Mann-Whitney test. Categorical variables were summarized as counts and proportions and compared using Fisher’s exact test. Results: A total of 2920 patients with Guardant360 were included with a median age of 65 (IQR: 56-73) years. 870 (30%) patients had pancreas cancer; 846 (29%) patients had colorectal cancer; 688 (24%) patients had biliary tract cancers; and the rest had other GI cancers. Among patients evaluable for microsatellite instability (MSI) status, 58 patients (2%) had MSI-high GI cancers, 31 (53%) of whom had MMR gene alterations. 2445 (98%) patients had MSS GI cancers, 130 (5.3%) of whom had MMR gene alterations. Patients with MSS GI cancers bearing MMR gene alterations had a median age of 70 (IQR: 62-75) years, significantly older than those without MMR gene alterations (p<0.001). In addition, patients with MMR gene alterations had significantly higher median blood TMB of 11 (IQR: 7.4-16) mut/Mb compared to 7.7 (IQR: 4.8-11) mut/Mb in patients without MMR gene alterations. In MSS GI cancers, MMR gene alterations are more commonly associated with the presence of alterations in APC (p=0.03), TP53 (p=0.01), CTNNB1 (p<0.001) and SMAD4 (p=0.01). 1453 patients with GI cancer and Tempus tissue NGS data were included as a validation cohort. They had comparable demographics with the Guardant360 cohort. 14 (1.6%) of 896 patients with MSS GI cancers had MMR gene alterations, significantly fewer (p<0.001) than those found in the Guardant360 cohort. Patients with MMR gene alterations and wild type POLE had significantly higher (p=0.001) median TMB of 9.8 (IQR: 4.8-14) mut/Mb compared to 4.7 (IQR: 3.2-6.3) mut/Mb in patients without MMR gene alterations. Conclusions: MMR gene alterations can be identified by clinical NGS platforms in a small proportion of patients with MSS GI cancers. They are associated with elevated TMB, which may suggest a hypermutated profile serving as a basis for potential role of immune checkpoint inhibitor in MSS GI cancers. Citation Format: Conor D. O'Donnell, Mojun Zhu, Hao Xie. The association of mismatch repair gene alterations with elevated tumor mutational burden in microsatellite stable gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6469.

Abstract Background: HER2-positive (HER2+) breast cancer accounts for 20–30% of all breast cancers. Although trastuzumab has significantly improved the survival of patients with HER2+ breast cancer, more than 70% of patients develop drug resistance within one year of treatment. Understanding the molecular mechanisms of trastuzumab resistance and identifying biomarkers that predict early trastuzumab resistance would greatly benefit patients receiving trastuzumab therapy. Methods: Differential-gene-expression analysis of trastuzumab-sensitive and resistant HER2+ breast cancer cell lines from GSE15043 was performed to identify the biomarkers associated with trastuzumab resistance. Differential biomarker expression was confirmed in FFPE tissues collected from clinical HER2+ breast cancer tumor samples that were sensitive or resistant to trastuzumab treatment. The function of the biomarkers associated with trastuzumab resistance was studied using western blotting, immunofluorescence, electron microscopy, and siRNA knockdown and overexpression to elucidate the role and mechanisms of the biomarker in affecting the trastuzumab response. Results: UGT1A7, a member of the uronic acid transferase family, was associated with trastuzumab resistance. UGT1A7 expression was downregulated in trastuzumab-resistant tumor tissues and in a cell line that developed trastuzumab resistance (BT474TR). Overexpressing UGT1A7 in BT474TR restored their sensitivity to trastuzumab treatment, whereas downregulating UGT1A7 expression in parental cells led to trastuzumab resistance. Importantly, UGT1A7 localized to the endoplasmic reticulum and altered stress responses. Furthermore, downregulating UGT1A7 expression promoted epithelial-to-mesenchymal transition (EMT) by affecting TWIST, SNAIL, and GRP78 expression and the AMP-activated protein kinase signaling pathway, thus contributing to trastuzumab resistance. Conclusions: This study demonstrated the important role and novel mechanisms of UGT1A7 in tumor responses to trastuzumab. Low UGT1A7 expression plays an important role in EMT and contributes to trastuzumab resistance. UGT1A7 has the potential to be developed as a biomarker for identifying patients who are resistant to trastuzumab treatment.

Abstract Purpose: There is a need to improve current risk stratification of stage II colorectal cancer to better inform risk of recurrence and guide adjuvant chemotherapy. We sought to examine whether integration of QuantCRC, a digital pathology biomarker utilizing hematoxylin and eosin–stained slides, provides improved risk stratification over current American Society of Clinical Oncology (ASCO) guidelines. Experimental Design: ASCO and QuantCRC-integrated schemes were applied to a cohort of 398 mismatch-repair proficient (MMRP) stage II colorectal cancers from three large academic medical centers. The ASCO stage II scheme was taken from recent guidelines. The QuantCRC-integrated scheme utilized pT3 versus pT4 and a QuantCRC-derived risk classification. Evaluation of recurrence-free survival (RFS) according to these risk schemes was compared using the log-rank test and HR. Results: Integration of QuantCRC provides improved risk stratification compared with the ASCO scheme for stage II MMRP colorectal cancers. The QuantCRC-integrated scheme placed more stage II tumors in the low-risk group compared with the ASCO scheme (62.5% vs. 42.2%) without compromising excellent 3-year RFS. The QuantCRC-integrated scheme provided larger HR for both intermediate-risk (2.27; 95% CI, 1.32–3.91; P = 0.003) and high-risk (3.27; 95% CI, 1.42–7.55; P = 0.006) groups compared with ASCO intermediate-risk (1.58; 95% CI, 0.87–2.87; P = 0.1) and high-risk (2.24; 95% CI, 1.09–4.62; P = 0.03) groups. The QuantCRC-integrated risk groups remained prognostic in the subgroup of patients that did not receive any adjuvant chemotherapy. Conclusions: Incorporation of QuantCRC into risk stratification provides a powerful predictor of RFS that has potential to guide subsequent treatment and surveillance for stage II MMRP colorectal cancers.

Abstract Accumulating evidence suggests that changes in the tumor microenvironment caused by radiotherapy are closely related to the recurrence of glioma. However, the mechanisms by which such radiation‐induced changes are involved in tumor regrowth have not yet been fully investigated. In the present study, how cranial irradiation‐induced senescence in non‐neoplastic brain cells contributes to glioma progression is explored. It is observed that senescent brain cells facilitated tumor regrowth by enhancing the peripheral recruitment of myeloid inflammatory cells in glioblastoma. Further, it is identified that astrocytes are one of the most susceptible senescent populations and that they promoted chemokine secretion in glioma cells via the senescence‐associated secretory phenotype. By using senolytic agents after radiotherapy to eliminate these senescent cells substantially prolonged survival time in preclinical models. The findings suggest the tumor‐promoting role of senescent astrocytes in the irradiated glioma microenvironment and emphasize the translational relevance of senolytic agents for enhancing the efficacy of radiotherapy in gliomas.

Purpose To evaluate return to play (RTP) and return to same level of play (RTSP) rates as well as preoperative and postoperative in‐game performance metrics in baseball pitchers who underwent ulnar collateral ligament reconstruction (UCLR). Secondarily, this review sought to assess outcomes based on primary versus revision UCLR as well as level of competition. Methods This review was performed using Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. PubMed/MEDLINE, Embase, Web of Science, and Cochrane Database of Systematic Reviews were queried to identify articles evaluating UCLR in baseball players between January 2002 and October 2022. Data included RTP, RTSP, and performance metrics including earned run average, innings pitched, walks and hits per inning pitched, batting average against, strikeouts per 9 innings, walks per 9 innings, percentage of fastballs thrown, and average fastball velocity. The Methodological Index for Non‐randomized Studies criteria were used for quality assessment. Results Analysis included 25 articles reporting on 2,100 elbows. After primary UCLR, RTP ranged from 336 to 615 days (57% to 100% achieved) and RTSP ranged from 330 to 513 days (61% to 95%). After revision UCLR, RTP ranged from 381 to 631 days (67% to 98%) and RTSP ranged from 518 to 575 days (42% to 78%). When stratifying primary UCLR outcomes by competitive level, RTP and RTSP ranged respectively from 417 to 615 days (75% to 100%) and 513 days (73% to 87%) for Major League Baseball only, 409 to 615 days (57% to 100%) and 470 to 513 days (61% to 95%) for Major League Baseball plus Minor League Baseball, and 336 to 516 days (73% to 85%) and 330 days (55% to 74%) for college plus high school. Heterogeneity was seen in postoperative sports performance metrics. Conclusions Although more than half of baseball players appear able to RTP after primary and revision UCLR, RTSP rates after revision UCLR were as low as 42% in the literature. Preoperative and postoperative performance metrics varied. Level of Evidence Level IV, systematic review of Level II‐IV studies.

AbstractBackgroundThe real‐world data on the safety profile of transvenous lead extraction (TLE) for infected cardiac implantable electronic devices (CIED) among elderly patients is not well‐established. This study aimed to evaluate the hospital outcomes between patients of different age groups who underwent TLE for infected CIED.MethodUsing the Nationwide Readmissions Database, our study included patients aged ≥18 years who underwent TLE for infected CIED between 2017 and 2020. We divided the patients into four groups: Group A. Young (<50 years), Group B. Young intermediate (50–69 years old), Group C. Older intermediate (70–79 years old), and Group D. Octogenarian (≥80 years old). We then analyzed the in‐hospital outcome and 30‐day readmission between these age groups.ResultsA total of 10,928 patients who were admitted for TLE of infected CIED were included in this study: 982 (9.0%) patients in group A, 4,234 (38.7%) patients in group B, 3,204 (29.3%) patients in group C and 2,508 (23.0%) of patients in group D. Our study demonstrated that the risk of early mortality increased with older age (Group B vs. Group A: OR: 1.92, 95% CI: 1.19‐3.09, p < .01; Group C vs. Group A: OR: 2.47, 95% CI: 1.51‐4.04, p < .01; Group D vs. Group A: OR: 2.82, 95% CI: 1.69‐4.72, p < .01). The risk of non‐home discharge also increased in elderly groups (Group B vs. Group A: OR: 1.89; 95% CI: 1.52‐2.36; p < .01; Group C vs. Group A: OR: 2.82; 95% CI 2.24‐3.56; p < .01; Group D vs. Group A: OR: 4.16; 95% CI: 3.28‐5.28; p < .01). There was no significant difference in hospitalization length and 30‐day readmission between different age groups. Apart from a higher rate of open heart surgery in group A, the procedural complications were comparable between these age groups.ConclusionElderly patients had worse in‐hospital outcomes in early mortality and non‐home discharge following the TLE for infected CIED. There was no significant difference between elderly and non‐elderly groups in prolonged hospital stay and 30‐day readmission. Elderly patients did not have a higher risk of procedural complications.