Citations

Importance Tumor deposits have prognostic value in colon cancer, but the current American Joint Committee on Cancer (AJCC) staging only considers them if there are no concurrent positive lymph nodes. Objective To devise a staging system for colon cancer by integrating counts of tumor deposits with positive lymph nodes while retaining the current AJCC staging framework. Design, Setting, and Participants This retrospective cohort study examines data from a large-volume, tertiary care center database (January 2010 through March 2023 with follow-up until December 2023) and the population-based National Cancer Database (January 2010 through December 2020 with follow-up until December 2021). Participants were adults (age 18-75 years) with stage III colon adenocarcinoma who underwent chemotherapy, and had a specified positive lymph node count and tumor deposit count were selected. Exposure A real positive lymph nodes count was developed and used to derive Sassun-Mayo N/tumor, lymph node, and metastasis (TNM) stages that were compared with the AJCC N/TNM stages. Main Outcomes and Measures Receiver operating characteristic (ROC) curves and Kaplan-Meier analyses for 3-year overall survival were performed to assess the efficiency of the 2 staging systems. The concordance index was used for validation using the National Cancer Database. Results From a total patient number of 11 162 (institutional) and 848 704 (national), the final patient numbers were 788 and 77 790, respectively. The institutional database patients had a mean (SD) age of 58.5 (11.5) years; there were 433 male patients (54.9%) and 355 female (45.1%). The national database patients had a mean (SD) age of 59.3 (10.6) years; there were 40 315 male patients (51.8%) and 37 475 female (48.2%). ROC curve areas were improved using the Sassun-Mayo stages (3-year death for AJCC TMN, 0.63 [95% CI, 0.57-0.69] vs 0.66 [95% CI, for 0.60-0.72] for Sassun-Mayo TNM). Kaplan-Meier curves revealed visible overlaps among AJCC N stages, which were absent in the Sassun-Mayo N stages. The concordance index in the Sassun-Mayo N/TNM stages was 0.611 and 0.616, respectively, while in the AJCC N/TNM stages, it was 0.598 and 0.606, respectively. Patients upstaged from N1 to N2 (n = 10 307; 13.2%) had a 3-year overall survival rate nearly identical to that of AJCC N2a patients. Additionally, 3001 patients (3.9%) were upstaged from N2a to N2b, indicating that 13 308 patients (17.1%) with stage III colon cancer across cohorts were understaged. Conclusions and Relevance This study found that Sassun-Mayo N/TNM staging provided superior overall survival stratification compared with the current AJCC staging, suggesting that their implementation could improve prognostication in colon cancer.

Abstract Metastasis accounts for the overwhelming majority of cancer deaths. In prostate cancer and many other solid tumors, progression to metastasis is associated with drastically reduced survival outcomes, yet the mechanisms behind this progression remain largely unknown. ATPase family AAA domain containing 2 (ATAD2) is an epigenetic reader of acetylated histones that is overexpressed in multiple cancer types and usually associated with poor patient outcomes. However, the functional role of ATAD2 in cancer progression and metastasis has been relatively understudied. Here, we employ genetically engineered mouse models of prostate cancer bone metastasis, as well as multiple independent human cohorts, to show that ATAD2 is highly enriched in bone metastasis compared with primary tumors and significantly associated with the development of metastasis. We show that ATAD2 expression is associated with MYC pathway activation in patient datasets and that, at least in a subset of tumors, MYC and ATAD2 can regulate each other’s expression. Using functional studies on mouse bone metastatic cell lines and innovative organ-on-a-chip bone invasion assays, we establish a functional role for ATAD2 inhibition in reducing prostate cancer metastasis and growth in bone. Implications: Our study highlights ATAD2 as a driver of prostate cancer progression and metastasis and suggests it may constitute a promising novel therapeutic target.

Background: Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to characterize the genetic alterations in chordoma using a large national patient-level genomic repository, the AACR Project GENIE, to identify potential therapeutic targets and improve disease modeling. Methods: A retrospective analysis of chordoma samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were observed in genes associated with SWI/SNF complex affecting chromatin remodeling (SETD2, PBRM1, ARID1A). Mutations were also common among the TERT promoter regions, and cell cycle regulation (CDKN2A). Significant co-occurrences were identified among PBRM1, BRCA2, and KMT2D mutations. CDKN2A/B deletions were enriched in metastatic tumors, and pediatric cases demonstrated distinct mutation profiles compared to adults. Conclusions: This study provides a genomic profile of chordoma, identifying key mutations and potential therapeutic targets. These findings highlight the roles of chromatin remodeling and cell cycle pathways in chordoma biology, offering insights for future precision medicine approaches and therapeutic interventions.

BACKGROUND AND OBJECTIVES: Aggressive resection for primary tumors of the spine are associated with a high rate of adverse events (AEs), but the impact of AEs on patient-reported outcomes (PROs) remains unknown and is critical to the shared decision-making. Our primary objective was to assess the impact of surgical AEs on PROs using an international registry. Assessing the impact on clinical outcomes and identifying risk factors for AEs were our secondary objectives. METHODS: Patients who underwent surgery for a primary spinal tumor were selected through the Primary Tumor Research and Outcomes Network. Our primary outcome was the impact of AEs on PROs at 3 and 12 months after surgery (measured with Spinal Oncology Study Group Outcomes Questionnaire, Short-Form 36, and EuroQol 5 Dimension). We also assessed the impact on clinical outcomes (local control, surgical margins, readmission, reoperation, and mortality). We stratified our results according to severity of AEs, histology, and type of resection. RESULTS: 374 patients met inclusion criteria (219 males/155 females). The mean age of the cohort was 48.7 years. The most frequent histology was chordoma (37.3%) followed by chondrosarcoma (8.8%). Sixty-seven patients (17.9%) experienced at least 1 intraoperative AE and 117 patients (31.3%) had at least 1 postoperative AE within 3 months. Overall, 159 patients (42.5%) experienced AEs. The readmission rate was significantly higher in patients who experienced AEs (Any AE: 10.1% vs no AE: 1.9% within 3 months; P = <0.001). PROs were not significantly affected by AEs in most questionnaires. Local control, risk of reoperation, mortality, and achieving preplanned margins were similar between AE groups. CONCLUSION: The rate of surgical AEs is considerable in this population. Surgical AEs seem to be associated with a higher number of readmissions, but do not seem to result in significant differences in PROs or in a higher risk of reoperation, mortality, and failure to achieve preplanned margins.

INTRODUCTION: Opioids are used to treat pain in chronic pancreatitis (CP), but little is known about current use patterns. The aim of this study was to characterize the utilization of opioids and associations with clinical characteristics in adult patients with CP. METHODS: This cross-sectional analysis used baseline data from participants with definite CP enrolled in a cohort study in the United States (PROspective Evaluation of CP for EpidEmiologic and Translational StuDies). Data on demographics, pain medication use, healthcare utilization, disability, and pain patterns were systematically collected in case report forms while quality of life was assessed with patient-reported outcome instruments. Opioid use was classified according to strength (weak or strong) and frequency (scheduled or as-needed). RESULTS: A total of 681 participants (n = 364, 53% male) were included: 299 (44%) were current opioid users (22% only weak opioids and 22% at least 1 strong opioid). Increasing frequency and severity of pain was associated with increase of weak, strong, as-needed, or scheduled opioids. Neuromodulators were used by ∼40% of participants; increasing use was associated with increasing frequency and severity of pain. On multivariate analysis, independent predictors associated with strength and frequency of current opioid use were pain patterns (odds ratios [ORs] 1.84–8.32 and ORs 1.92–8.52, respectively, P < 0.001) and prior celiac plexus block (OR 3.54, 95% confidence intervals 1.82–6.87 and OR 3.42, 95% confidence intervals 1.76–6.64, respectively). Participants using opioids had higher prevalence of disability, healthcare utilization, and poorer quality of life. DISCUSSION: Opioid use in CP is common and associated with increased pain severity and constancy. These data provide foundational estimates for future trials that can elucidate the complex interactions between patient factors, pain, and interventions.

Salivary glands are common organs at risk in both head and neck external beam radiotherapy (EBRT) and radiopharmaceutical therapy (RPT), but incidences of xerostomia in RPT are inconsistent with the EBRT Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) limits. In EBRT, salivary glands are usually assumed to be parallel organs, with QUANTEC guidelines based on Dmean, but this is known to be a gross over-simplification of the full complexity of the underlying functional organization. The goal of this work is to combine machine learning of EBRT dose–outcome data with stylized small-scale RPT dosimetry to discover more reliable normal tissue complication probability (NTCP) models of xerostomia across both modalities. A retrospective cohort of 211 EBRT patients was analyzed using a custom-designed in-house machine learning workflow. From this, a hierarchy of three models of increasing complexity was trained, evaluated for performance and generalization, and coupled with stylized small-scale salivary gland dosimetry to assess the influence of model complexity on the predicted NTCP for plausible patterns of RPT dose nonuniformity. The three models in the hierarchy (A, B, C), in increasing order of complexity, associate xerostomia with the following: the mean dose to the whole contralateral parotid (model A), the mean dose to a ductally localized region (model B) and a serial interaction dose term between two ductal sub-compartments (model C). While the difference between the three models for EBRT p-values and AUCs is rather marginal, for physiologically driven ductal dose distributions in RPT, the predicted reduction in TD50 can be as large as a factor of 10. These results provide hints towards a plausible reconciliation of the observed inconsistency of xerostomia in RPT with EBRT dose limits.

Abstract Internal herniation through the foramen of Winslow is one of the rarest types of hernia. As signs and symptoms can be quite generalized, prompt identification can prove difficult, leading to increased morbidity and mortality. The majority of reported cases of foramen of Winslow herniation result in obstruction of either the small or large bowel requiring operative intervention. As they are so rare, there is no established treatment algorithm for foramen of Winslow hernias. We present here a unique case of cecal herniation through the foramen of Winslow resulting in biliary compression and acute cholecystitis without bowel obstruction that was managed with laparoscopic cholecystectomy and right hemicolectomy.