Background:With negligible risk of distant metastasis, the primary treatment focus in patients with primary retroperitoneal well-differentiated liposarcoma (pRP-WDLPS) is local control. The recently completed phase 3 STRASS trial suggested a potential benefit to neoadjuvant radiotherapy (RT) in optimizing local control in these patients. This study investigates outcomes associated with neoadjuvant RT in a larger cohort of patients undergoing surgery for pRP-WDLPS. Methods:In this study from 24 participating sites, we retrospectively identified all patients with pRP-WDLPS who underwent curative-intent resection between January 1, 2002 and December 31, 2017. The primary endpoint was the cumulative incidence function (CIF) of local recurrence (LR), and the secondary endpoint was overall survival (OS). The impact of neoadjuvant RT on the CIF of LR was analyzed using a 1:2 propensity score matching (PSM). Findings:Of 582 patients included in the entire cohort, 72 patients (12%) received neoadjuvant RT. The 1:2 PSM group included 208 patients of which 138 patients (66%) underwent surgery alone and 70 patients (34%) underwent neoadjuvant RT and surgery. With a median follow up of 73 months, the 5- and 8-year CIF of LR for neoadjuvant RT and surgery group was 6% and 10%, respectively, and 26% and 33%, respectively, for the surgery alone group (odds ratio (OR) 0·85, 95% confidence interval (CI) 0·76-0·97, P < 0·001). The 5- and 10-year OS for the neoadjuvant RT and surgery group was 92% and 80%, respectively, and 84% and 71%, respectively, for the surgery alone group (HR 0·50, 95% CI 0·27-1·21, P = 0·07). Interpretation:To the best of our knowledge, this is the largest study to report outcomes of neoadjuvant RT for pRP-WDLPS. Neoadjuvant RT was associated with a significant decrease in LR compared to surgery alone. These data further validate the use of neoadjuvant RT for pRP-WDLPS. Funding:Funding was received from the Susan and Habib Gorgi Family Fund for Sarcoma Research.

BACKGROUND & AIMS:Gastric cancer surveillance in CDH1 pathogenic variant carriers is challenging, as predictors of localized (stage T1a) and advanced (stage >T1a) signet ring cell carcinoma (SRCC) are not well-defined. We established the Group of Investigators Striving Toward Research in CDH1 (GASTRIC) consortium to identify clinicopathologic factors associated with localized and advanced SRCC. METHODS:A retrospective observational study (1998-2025) of CDH1 carriers across 12 academic centers was performed. Clinical, endoscopic, and pathologic data were compared between carriers with and without SRCC on endoscopy, and between those with advanced vs localized or no cancer on gastrectomy specimens. RESULTS:Overall, 390 CDH1 carriers from 235 families were included. The presence of biopsy-detected SRCCs on endoscopy was significantly associated with thickened folds, nodularity, masses, and intestinal metaplasia, whereas gastritis was negatively associated. Of 196 carriers (52.4%) undergoing gastrectomy, 11 (5.6%) had advanced cancers, 10 (90.9%) of which showed endoscopic abnormalities. Identification of biopsy-detected SRCC on baseline endoscopy was the most sensitive feature for advanced disease (0.81) but had moderate specificity (0.74) and low positive predictive value (0.21), whereas masses and thickened folds were highly specific (0.99 and 0.96, respectively) but less sensitive. The negative predictive values were high (0.94-1.0), whereas the positive predictive values were modest (0.13-0.66). On multivariable analysis, masses and SRCC foci on baseline endoscopy were independent predictors of advanced disease. CONCLUSIONS:Among CDH1 carriers, the absence of endoscopic findings was reassuring, whereas the significance of detected endoscopic and pathologic abnormalities was less certain. Advanced cancer occurred in a small number of carriers, with endoscopic abnormalities in nearly all cases. Endoscopic surveillance might be an alternative to surgery in carriers without worrisome mucosal findings.

Peritoneal dissemination portends a dismal prognosis in patients with gastric adenocarcinoma in the context of limited effective treatments. The underlying cellular processes that drive gastric peritoneal carcinomatosis remain unclear, limiting the application of novel targeted therapies. In this comprehensive review, we aimed to identify and summarize all existing context-dependent molecular mechanisms that have been implicated in peritoneal dissemination and peritoneal carcinomatosis establishment from primary gastric adenocarcinoma. We applied a multilevel examination including data from in vivo murine models using human gastric cancer cell lines, in vitro technique-based studies, ex vivo models, and genomic/proteomic and molecular profiling analyses to report on various aspects of gastric cancer peritoneal metastasis biology. Mechanisms promoting peritoneal dissemination were grouped into three main functional categories: (1) intrinsic cancer cell biology, (2) cancer cell-peritoneal surface adhesion, and (3) peritoneal tumor microenvironment. We identified significant overlap among the three categories, indicating a complex interplay between multiple molecular mechanisms. By interrupting these pathways, peritoneal-directed therapies have the potential to improve quality and length of life in patients with high-risk primary gastric cancer.

e23549 Background: We aimed to determine the impact of early recurrence on the prognosis of patients who have undergone resection of primary retroperitoneal sarcoma (RPS) and to discover which preoperative patient/tumor features predict early recurrence. Methods: Consecutive patients with primary non-metastatic RPS who were managed at two high volume RPS referral centers between 03/2012 and 10/2019 were identified from prospectively maintained institutional databases. The primary study endpoint was Overall Survival (OS), defined as the time from diagnosis to death from any cause, estimated by the KM method. Patients were grouped by Disease-Free Interval following resection (DFI = 0-6, 7-12, 13-18, 19-24, > 24 mos). Univariate and multivariable analyses (UVA, MVA) were performed. The Sarculator risk calculator and the Inflammatory Biomarkers Prognostic Index (IBPI) were assessed as potential predictors of early recurrence, defined as DFI 0-6 mos. Results: 651 patients (median age = 62.7yrs, IQR = 51.9-71.3; F:M = 301:350) met inclusion criteria and form the study cohort. Median follow-up time was 75.9 mos (IQR 58.6-99.5). 566 of the 651 (87%) patients underwent resection of their primary RPS, while 85 (13%) did not, most commonly due to suboptimal PS. Of the 566 patients who underwent resection, 259 (46%) had developed a recurrence by the time of last follow-up, while 307 patients (54%) had not recurred. In the 259 patients whose tumor recurred, 49 (19%) recurred within 6 mos of primary RPS resection, 42 (16%) between 7 and 12 mos, 35 (14%) between 13 and 18 mos, 31 (12%) between 19 and 24 mos, and 102 (39%) after 24 mos. Patients who developed recurrence within 6 mos of resection had similar OS from the time of diagnosis to the 85 patients who did not have a resection (1-year estimates: 77.3% [95% CI: 66.4-90.1] vs 65.7% [56.1-76.8], respectively; 2-year estimates: 51.6% [39.1-68.0] vs 42.7% [33.1-55.1], p = 0.32), while patients who relapsed more than 6 mos after resection had longer OS than either of these groups (p < 0.001). Upon MVA, the HR for death in patients who recurred within 6 mos vs. that of patients who were not resected was 0.96 (95% CI: 0.60-1.53). No standard clinico-pathologic variable available preoperatively could be identified that predicted recurrence within 6 mos of primary resection. Neither composite score (Sarculator, IBPI) was able to reliably predict recurrence within 6 mos. Conclusions: DFI from primary RPS resection to first recurrence was less than 6 mos in ≈20% of patients. DFI directly correlated with OS from time of diagnosis. Patients who recurred within 6 mos of resection had an equivalent OS to patients who didn’t undergo resection, raising the question of whether resection was of any benefit. Current efforts focus on discovery of genomic characteristics that reflect adverse biology/host response and are discoverable preoperatively, in order to improve patient selection for surgery and for neoadjuvant therapy.

PURPOSE:The development of improved therapies is complicated by the limited availability of well-characterized human models, especially in rare tumors such as soft-tissue sarcoma (STS). We report the optimization of conditions and clinical factors that correlate with the successful establishment of primary STS cell lines. We focus on leiomyosarcoma, myxofibrosarcoma, and undifferentiated pleomorphic sarcoma, which are adult STS with complex genomics and poor survival rates. EXPERIMENTAL DESIGN:We initiated cell lines from 165 fresh STS specimens. Cultures were classified as (i) no/little in vitro growth or (ii) persistent growth. Tumor and clinical characteristics were analyzed to determine their correlation with cell line growth. To determine whether cell lines shared tumor-specific variations (TSV) and mutational signatures with bulk specimens, comparative and Catalogue of Somatic Mutations in Cancer mutational signature analyses were performed on a subset of cases with cell line, tumor, and blood DNAs available. RESULTS:Cell lines were established from 46 specimens (28%). Myxofibrosarcoma specimens yielded more successful cell lines (P < 0.05) than leiomyosarcoma specimens. Primary specimens from treatment-naïve patients and those who presented with metastases demonstrated higher success rates (P < 0.05) compared with treated specimens and those who had only local disease, respectively. Cell line growth was not associated with patient outcomes or specimen grade. Six of the eight cases retained TSVs, including in ATRX or TP53, whereas two did not retain TSVs. Paired samples shared clock-like mutational signatures. Xenograft mouse models were created with a subset of the cell lines. CONCLUSIONS:The development and characterization of preclinical STS models will advance our understanding of STS biology.

According to the National Comprehensive Cancer Network (NCCN), submucosally invasive (pT1) colorectal carcinomas (CRCs) should be evaluated for tumor grade, lymphatic invasion, and tumor budding to determine the risk of lymph node metastasis. The presence of any one of these high-risk features is an indication for surgery in endoscopically removed pT1 CRCs. In this study, we determined if quantitative pathologic analysis with the QuantCRC algorithm can augment NCCN risk stratification in a multi-institutional cohort of 512 surgically resected pT1 CRC. LASSO regression identified

OBJECTIVE:To examine variations in patterns of care for retroperitoneal sarcoma (RPS) among sarcoma centres globally, including diagnostic work-up, surgical strategies and (neo)adjuvant therapies. METHODS:Retrospective analysis for primary RPS, from 19 RPS referral centres worldwide, prospectively collected within the RESAR repository (NCT03838718) between Feb 2017 - July 2022. Centres were categorised high volume (HVC) or low volume (LVC). Comprehensive resection (CR) was defined as en-bloc resection of ipsilateral kidney and colon. RESULTS:1718 primary RPS were included. Preoperative biopsy was utilised frequently (median rate 98%) for solid (non-liposarcoma) RPS. In liposarcoma, the median rate of CR was 64%, with wide variation (IQR 37% [43%-80%], range 0-100%). There was greater variation in CR in liposarcoma in LVC (IQR 39.5% [40.5%-80%]) versus HVC (IQR 9.5% [58.3%-67.8%]). Perioperative chemotherapy was seldom used for liposarcoma (median 0%), with higher rates for leiomyosarcoma (median 10%) with high variation (IQR 26% [2%-28%]). Radiotherapy was used consistently infrequently in leiomyosarcoma (IQR 13% [0%-13%]. There was higher use of radiotherapy in HVC than LVC (median HVC 18.5% vs. LVC 5%). There was a significant decrease in radiotherapy use after the STRASS trial (pre 19% vs. post 14%, P=0.045). CONCLUSIONS:Low variation was found in pre-operative biopsy of non-liposarcomas, use of chemotherapy in liposarcoma and radiotherapy in leiomyosarcoma, suggesting agreement between centres. There was high variation, suggesting equipoise, in the role of chemotherapy in leiomyosarcoma and the value of CR in liposarcoma. The STRASS study results seem to have been accepted, with a reduction in radiotherapy after its publication.

ABSTRACT Background The majority of esophageal and gastric cancers are diagnosed at an advanced stage with poor overall survival (OS). Whether the pre‐diagnostic interval from symptom onset has any impact on OS is unclear. We investigated this question in the peri‐COVID19 pandemic era. Methods We retrospectively analyzed a cohort of 308 patients with esophageal, gastroesophageal junction, or gastric carcinoma treated with curative intent at the Princess Margaret Cancer Centre from January 2017 to December 2021. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. Cox proportional hazards regression models were used to assess the association between pre‐diagnostic intervals and OS, adjusting for baseline patient characteristics. Results The median interval from symptom onset to diagnosis was 98 days (IQR 47–169 days). Using a cox proportional hazard model, prolonged pre‐diagnostic interval was not associated with worse OS (HR 1.00, p = 0.62). Comparing patients diagnosed before and during the COVID19 pandemic, there was a notable increase in diagnostic delay with median pre‐diagnostic interval increasing from 92 to 126 days (p = 0.007). Median age at time of diagnosis was 69.6 during the pandemic vs. 64.7 before the pandemic. Linear regression showed squamous cell histology was significantly associated with increasing time to initial diagnosis (p = 0.04), but this did not hold true in a multivariable model. Looking at other delay metrics, there were no changes in time interval from diagnosis to treatment during versus before the pandemic (median = 1.7 weeks for both), and there was no change in time from diagnosis to resection in those patients who underwent surgery. Conclusion The COVID19 pandemic caused significant diagnostic delay for patients presenting with curative gastroesophageal and gastric cancer. The lack of correlation of pre‐diagnostic interval with OS may reflect underlying tumor biology as the driving force that determines prognosis.

AIMS:This study aimed to determine the impact of venous invasion (VI) characteristics on oncological outcomes in colorectal cancer (CRC). METHODS AND RESULTS:Resection specimens from 368 patients with TNM stages I-III CRC were assessed for VI including its presence/absence, location [intramural (IMVI) or extramural (EMVI)], number and size of the largest VI focus. VI and EMVI were identified in 55% and 32% of cases, respectively. EMVI, but not IMVI, was significantly associated with decreased 5-year recurrence-free survival (RFS) and disease-specific survival (DSS) (hazard ratio [HR] 4.2, 95% confidence interval CI [2.6-6.9] and 3.7 [95% CI 1.9-6.9], p < 0.0001, respectively). Multifocal EMVI (mEMVI), defined as 2 or more EMVI foci, was identified in 67% of EMVI-positive cases. In multivariable analysis, EMVI (HR 2.4 [95% CI 1.3-4.3], P = 0.003) and mEMVI (HR 2.4 [95% CI: 1.3-4.4], P = 0.02) were independently associated with RFS and demonstrated stronger associations than all other examined features, including T and N stage. These associations were maintained when the cohort was expanded to include 113 patients who received neoadjuvant therapy in addition to the original 368 patients who had not ('expanded cohort', n = 481). An increasing number of EMVI foci was significantly associated with decreased RFS and DSS (P < 0.0001). Patients with >5 EMVI foci (n = 31) had a particularly poor prognosis with 5-year RFS and DSS of 29% and 56%, respectively. EMVI dimensions were not associated with oncological outcomes. CONCLUSIONS:Extramural location and multifocality are features of VI strongly associated with adverse oncological outcomes. If externally validated, incorporation of EMVI multifocality into future reporting protocols merits consideration.

Supplementary Figure S1. Flow diagram outlining the steps undertaken in this study.

162 Background: There is a need to improve current risk stratification of stage II and III colorectal cancer (CRC) to better inform risk of recurrence and guide adjuvant chemotherapy. The purpose of this study is to examine whether integration of QuantCRC, an AI-based digital pathology biomarker utilizing hematoxylin and eosin-stained slides, provides improved risk stratification over current American Society of Clinical Oncology (ASCO) guidelines. Methods: ASCO and QuantCRC-integrated risk schemes were applied to an observational cohort of 1,068 stage II and III CRCs. The stage II integrated scheme utilizes pT3 vs. pT4 and QuantCRC-derived risk groups. The stage III integrated scheme utilizes pT1-3 vs. pT4, pN1 vs. pN2, and QuantCRC-derived risk groups. Performance metrics included log-rank test, hazard ratios and Somers’ Dxy rank correlation. Results: Integration of QuantCRC provides improved risk stratification compared to the ASCO scheme for stage II and III CRC. The QuantCRC-integrated scheme placed more stage II tumors in the low-risk group compared to the ASCO scheme (69.3% vs. 60.4%) without decreased 3-year RFS. The QuantCRC-integrated scheme provided larger hazard ratios (HR) for both intermediate-risk (3.04, 95%CI 1.81-5.10, P=2.8x10-5) and high-risk (4.62, 95%CI 2.02-10.61, P=0.0003) groups compared to ASCO intermediate-risk (2.09, 95%CI 1.21-3.63, P=0.008) and high-risk (3.08, 95%CI 1.57-6.01, P=0.001) groups. The QuantCRC-integrated scheme for stage III tumors identified a small group of 80/518 (15.4%) CRCs at very high risk of recurrence with HR of 4.08 (95%CI 2.68-6.23, P=6.5x10-11) compared to a HR of 2.42 (95%CI 1.72-3.38, P=3.1x10-7) for 228/518 (44.0%) high-risk CRCs in the ASCO scheme. QuantCRC-integrated risk groups remained prognostic in stage III CRCs when stratified by presence or absence of any adjuvant chemotherapy. No difference in RFS were seen in QuantCRC-integrated low-risk and intermediate-risk stage III CRCs stratified by 3 vs. 6-months of oxaliplatin-based adjuvant chemotherapy suggesting that these two groups can be treated with 3-months of adjuvant therapy. Conclusions: Incorporation of QuantCRC into risk stratification provides a powerful predictor of RFS that has potential to guide subsequent treatment and surveillance.

Background: We hypothesized that abdominal venous leiomyosarcoma (AV-LMS) disproportionately originates in veins of the sex- hormone drainage pathway (SHDP). Our purpose was to classify the anatomical origin of AV-LMS in a large cohort using imaging and explore prognostic implications. Methods: A retrospective review of imaging of all patients presenting with abdominal non-uterine LMS at a single tertiary oncology center was performed. Inclusion criteria were a biopsy-proven LMS of non- uterine abdominal/pelvic origin with pretreatment enhanced computed tomography (CT)/magnetic resonance imaging (MRI). Patients with uterine LMS or prior radiation were excluded. LMS site of origin was assigned by one expert radiologist and indeterminate sites were reviewed with a second external expert radiologist. Locations of inferior vena cava (IVC) tumors were subclassified based on a modification of prior literature. SHDP was defined as originating from ovarian/testicular vein, distal left renal vein, adrenal vein or mid-IVC (IIA). Results: One hundred fifty-five (155) patients were included (92/152 (61%) female) with distant metastases found at presentation in 23/155 (14.8%). Most common organs of origins were veins (84/152, 55.3%), gastrointestinal (24, 15.8%), genital (11, 7.2%) and paratesticular/spermatic cord (11, 7.2%). For venous LMS, the adrenal (both sexes), midIVC (IVC IIA, females) and ovarian veins had the highest relative predilection for abdominal non-uterine LMS. Eighty-four (84/152, 55.3%) of tumors were SHDP. On multivariable analysis, both size and SHDP were significant predictors of distant metastases at presentation (P = Conclusions: For both sexes, tumors arising from SHDP constitute the majority of AV-LMS and may impart a significantly lower risk of metastatic disease at presentation. Among veins, the adrenal veins had the highest predilection for LMS.

Multivariable models for the prediction of TTR by morphologic features and clinicopathological variables in initial cohort [p-MMR (n = 189) or d-MMR (n = 191) stage III colon cancers]

Supplementary Table S2. Concordance between ASCO and QuantCRC-Integrated risk groups

On a global scale, gastric adenocarcinoma (GCa) accounts for a large burden of death from cancer. Despite advances in systemic therapy and surgical technique, the fatality rate for GCa remains unacceptably high in Europe and North America, where diagnosis is typically made at an advanced stage. Biomarkers that can accurately predict response to new therapies and provide novel therapeutic strategies are urgently sought. FAM46C, a putative noncanonical nucleotidyltransferase, has garnered interest for its tumor suppressor function in multiple myeloma. A frequent and profound depletion of FAM46C has been described in GCa patients from China, Japan and now Canada. Furthermore, the degree of FAM46C depletion meaningfully portends cancer recurrence following resection, and death from GCa. In this review, we provide an updated summary of the literature regarding FAM46C as a biomarker in GCa and explore the potential mechanism(s) through which FAM46C depletion promotes GCa progression, including disinhibition of oncogenic Plk4 kinase activity. We highlight the potential for restoration of FAM46C levels as a therapeutic strategy. Norcantharidin, a synthetic analogue of the traditional Chinese medicine cantharidin derived from the blister beetle, is the only bio-available compound presently known to upregulate FAM46C expression and is under investigation in phase one trials in cancer patients.

Supplementary Table S5. Adjuvant chemotherapy according to ASCO and QuantCRC-Integrated risk groups.

Supplementary Figure S2. Scatter plots of QuantCRC features stratified by QuantCRC-integrated and ASCO risk schemes.