PURPOSE Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between patients with young-onset pancreatic cancer (YOPC; younger than 50 years) and patients with average-onset pancreatic cancer (AOPC; 70 years and older). METHODS We analyzed matched whole-transcriptome and DNA sequencing data from 2,430 patient samples (YOPC, n = 292; AOPC, n = 2,138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data were obtained from insurance claims (n = 4,928); Kaplan-Meier estimates were calculated for age- and molecularly defined cohorts. Significance was determined as FDR-corrected P values (Q) < .05. RESULTS Patients with YOPC had higher proportions of mismatch repair–deficient/microsatellite instability-high, BRCA2-mutant, and PALB2-mutant tumors compared with patients with AOPC, but fewer SMAD4-, RNF43-, CDKN2A-, and SF3B1-mutant tumors. Notably, patients with YOPC demonstrated significantly lower incidence of KRAS mutations compared with patients with AOPC (81.3% v 90.9%; Q = .004). In the KRAS wild-type subset (n = 227), YOPC tumors demonstrated fewer TP53 mutations and were more likely driven by NRG1 and MET fusions, whereas BRAF fusions were exclusively observed in patients with AOPC. Immune deconvolution revealed significant enrichment of natural killer cells, CD8+ T cells, monocytes, and M2 macrophages in patients with YOPC relative to patients with AOPC, which corresponded with lower rates of HLA-DPA1 homozygosity. There was an association with improved OS in patients with YOPC compared with patients with AOPC with KRAS wild-type tumors (median, 16.2 [YOPC-KRASWT] v 10.6 [AOPC-KRASWT] months; P = .008) but not KRAS-mutant tumors (P = .084). CONCLUSION In this large, real-world multiomic characterization of age-stratified molecular differences in pancreatic ductal adenocarcinoma, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

Purpose: Numerous experimental and targeted therapies are under investigation for patients with cholangiocarcinoma (CCA). Objective health-related quality of life (HRQoL) data for patients receiving these therapies are limited. Methods: Patients engaged in the Cholangiocarcinoma Foundation completed two validated HRQoL surveys: Functional Assessment of Cancer Therapy (FACT)-Hepatobiliary and COmprehensive Score for financial Toxicity (COST). Results: Two hundred eight patients were included. Seventy-five percent had intrahepatic CCA and 57% underwent resection, of which 48% had disease recurrence. Twenty-two percent enrolled in a clinical trial and 80% underwent molecular profiling, of which 29% received targeted therapy. While patients enrolled in a clinical trial or received targeted therapy reported similar HRQoL compared to those who did not, they reported higher financial toxicity (p = 0.05 and p = 0.01, respectively). Conclusion: Enrollment in a clinical trial or receipt of targeted therapy do not affect a patient’s physical, emotional, social, or functional well-being. However, patients report higher financial burden. These therapies are mainly offered in the advanced setting after significant financial strain has been endured and are often only available at large academic centers, creating a physical barrier to access. These findings underscore the need to increase availability and eliminate physical and financial barriers that threaten access and utilization of personalized and progressive therapies.

Objective: This study aimed to enhance hepatocellular carcinoma (HCC) screening to achieve earlier diagnosis of patients with hepatitis C (HCV) cirrhosis in our Safety-Net population. Background: Adherence to HCC screening guidelines at Safety-Net hospitals is poor. Only 23% of patients with HCC at our health system had a screening exam within 1-year of diagnosis and 46% presented with stage IV disease. HCV-induced cirrhosis remains the most common etiology of HCC (75%) in our patients. Methods: In the setting of an established HCV treatment clinic, an HCC screening quality improvement initiative was initiated for patients with stage 3 fibrosis or cirrhosis by transient elastography. The program consisted of semiannual imaging. Navigators scheduled imaging appointments and tracked compliance. Results: From April 2018 to April 2021, 318 patients were enrolled (mean age 61 years, 81% Black race, 38% uninsured). Adherence to screening was higher than previously reported: 94%, 75%, and 74% of patients completed their first, second, and third imaging tests. Twenty-two patients (7%) were diagnosed with HCC; 55% stage I and 14% stage IV. All patients were referred and 13 (59%) received treatment. Median time to receipt of treatment was 77 days (range, 32–282). Median overall survival for treated patients was 32 months. Conclusions: Implementation of an HCC screening program at a safety-net hospital is feasible and facilitated earlier diagnosis in this study. Patient navigation and tracking completion of imaging tests were key components of the program’s success. Next steps include expanding the program to additional at-risk populations.

Background Use of adjuvant chemotherapy (CTx) and chemoradiation therapy (cXRT) for the treatment of gall-bladder cancer (GBC) remains varied. We sought to define the utilization and effect of adjuvant therapy for patients with GBC. Methods Using a multi-institutional national database, 291 patients with GBC who underwent curative-intent resection between 2000 and 2015 were included. Patients with metastasis or an R2 margin were excluded. Results Median patient age was 66.6 years. Most patients had a T2 (46.2 %) or T3 (38.6 %) lesion, and 37.8 % of patients had lymph node (LN) metastasis. A total of 186 (63.9 %) patients underwent surgery alone, 61 (21.0 %) received CTx, and 44 (15.1 %) patients received cXRT. On multivariable analysis, factors associated with worse overall survival (OS) included T3/T4 stage [hazard ratio (HR) 1.82], LN-metastasis (HR 1.84), lymphovascular invasion (HR 2.02), perineural invasion (HR 1.42), and R1 surgical margin status (HR 2.06); all P <0.05). In contrast, receipt of CTx/cXRT was associated with improved OS (CTx, HR 0.38; cXRT, HR 0.26; P < 0.001) compared with surgery alone. Similar results were observed for disease-free survival (DFS) (CTx, HR 0.61; cXRT, HR 0.43; P < 0.05). Of note, only patients with high-risk features, such as AJCC T3/T4 stage (HR 0.41), LN metastasis (HR 0.45), and R1 disease (HR 0.21) (all P <0.05) derived an OS benefit from CTx/cXRT. Conclusions Adjuvant CTx/cXRT was utilized in 36 % of patients undergoing curative-intent resection for GBC. After adjusted analyses, CTx/cXRT were independently associated with improved long-term outcomes, but the benefit was isolated to only patients with high-risk characteristics.

Objective: To characterize clinical and radiological features associated with biliary cystic tumors (BCTs) of the liver, and to define recurrence-free and overall survival. Background: Biliary cystadenoma (BCA) and biliary cystadenocarcinoma (BCAC) are rare tumors that arise in the liver. Methods: Between 1984 and 2013, 248 patients who underwent surgical resection of BCA or BCAC were identified. Clinical and outcome data were analyzed. Results: Median total bilirubin, CA19-9, and carcinoembryonic antigen (CEA) levels were 0.6 mg/dL, 15.0 U/mL, and 2.7 ng/mL, respectively. Preoperative imaging included computed tomography only (62.5%), magnetic resonance imaging only (6.9%), or CT + MRI (18.5%). Features on cross-sectional imaging included multiloculation (56.9%), mural nodularity (16.5%), and biliary ductal dilatation (17.7%). The presence of these factors did not reliably predict BCAC versus BCA (sensitivity, 81%; specificity, 21%). Median biliary cyst size was 10.0 cm(interquartile range, 7-13 cm). Operative interventions included unroofing/partial excision of the lesion (14.1%), less than hemihepatectomy (48.8%), or hemi-/extended hepatectomy (36.3%). On pathology most lesions were BCA (89.1%), whereas 27 (10.9%) were BCAC. At last follow-up, there were 46 (18.3%) recurrences; 2 patients who initially had BCA recurred with BCAC. Median overall survival was 18.1 years; 1-year, 3-year, and 5-year survival was 95.0%, 86.8%, and 84.2%, respectively. Long-term outcomes were associated with BCAC versus BCA, as well as the presence of spindle cell/ovarian stroma (both P<0.05). Conclusions: Among patients undergoing surgery for BCT, associated malignancy was uncommon (10%) and no preoperative findings reliably predicted underlying BCAC. After excision of BCA, long-term outcomes were good; however, patients with BCAC had a worse long-term prognosis.

Background: The role of surgical resection for patients with large or multifocal intrahepatic cholangiocarcinoma (ICC) remains unclear. This study evaluated the long-term outcome of patients who underwent hepatic resection for large (≥7 cm) or multifocal (≥2) ICC. Methods: Between 1990 and 2013, 557 patients who underwent liver resection for ICC were identified from a multi-institutional database. Clinicopathologic characteristics, operative details, and long-term survival data were evaluated. Results: Of the 557 patients, 215 (38.6 %) had a small, solitary ICC (group A) and 342 (61.4 %) had a large or multifocal ICC (group B). The patients in group B underwent an extended hepatectomy more frequently (16.9 vs. 30.4 %; P < 0.001). At the final pathology exam, the patients in group B were more likely to show evidence of vascular invasion (22.5 vs. 38.5 %), direct invasion of contiguous organs (6.5 vs. 12.9 %), and nodal metastasis (13.3 vs. 21.0 %) (all P < 0.05). Interestingly, the incidences of postoperative complications (39.3 vs. 46.8 %) and hospital mortality (1.1 vs. 3.7 %) were similar between the two groups (both P > 0.05). The group A patients had better rates for 5-year overall survival (OS) (30.5 vs. 18.7 %; P < 0.05) and disease-free survival (DFS) (22.6 vs. 8.2 %; P < 0.05) than the group B patients. For the patients in group B, the factors associated with a worse OS included more than three tumor nodules [hazard ratio (HR), 1.56], nodal metastasis (HR, 1.47), and poor differentiation (HR, 1.48). Conclusions: Liver resection can be performed safely for patients with large or multifocal ICC. The long-term outcome for these patients can be stratified on the basis of a prognostic score that includes tumor number, nodal metastasis, and poor differentiation.

Background Current nodal staging (N-staging) of am-pullary carcinoma in the TNM staging system distinguishes between node-negative (N0) and node-positive (N1) disease but does not consider the metastatic lymph node (LN) number. Methods Overall, 313 patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma were categorized as N0, N1 (1–2 metastatic LNs), or N2 (≥3 metastatic LNs), as proposed by Kang et al. Clinico-pathological features and overall survival (OS) of the three groups were compared. Results The median number of LNs examined was 11, and LN metastasis was present in 142 cases (45 %). When LN-positive cases were re-classified according to the proposed staging system, 82 were N1 (26 %) and 60 were N2 (19 %). There was a significant correlation between proposed N-stage and lymphovascular invasion, perineural invasion, increased tumor size (each p < 0.001), and surgical margin positivity (p = 0.001). The median OS in LN-negative cases was significantly longer than that in LN-positive cases (107.5 vs. 32 months; p < 0.001). Patients with N1 and N2 disease had median survivals of 40 and 24.5 months, respectively (p < 0.0001). In addition, 1-, 3-, and 5-year survivals were 88, 76, 62 %, respectively, for N0; 90, 55, 31.5 %, respectively, for N1; and 68, 34, 30 %, respectively for N2 (p < 0.001). Even with multivariate modeling, the association between higher proposed N stage and shorter survival persisted (hazard ratio 1.6 for N1 and 1.9 for N2; p = 0.018). Conclusions Classification of nodal status in ampullary carcinomas based on the number of metastatic LNs has a significant prognostic value. A revised N-staging classification system should be incorporated into the TNM staging of ampullary cancers.

Background and Objectives: Although minority race has been associated with worse cancer outcomes, the interaction of race with pathologic variables and outcomes of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is not known. Methods: Patients from the US Neuroendocrine Study Group (2000–2016) undergoing curative-intent resection of GEP-NETs were included. Given few patients of other races, only Black and White patients were analyzed. Results: A total of 1143 patients were included. Median age was 58 years, 49% were male, 14% Black, and 86% White. Black patients were more likely to be uninsured (7% vs 2%, P = .011), and to have symptomatic bleeding (13% vs 7%, P = .009), emergency surgery (7% vs 3%, P = .006), and positive lymph nodes (LN) (47% vs 36%, P = .021). However, Black patients had improved 5-year recurrence-free survival (RFS) (90% vs 80%, P = .008). Quality of care was comparable between races, seen by similar LN yield, R0 resections, postoperative complications, and need for reoperation/readmission (all P > .05). While both races were more likely to have pancreas-NETs, Black patients had more small bowel-NETs (22% vs 13%, P < .001). LN positivity was prognostic for pancreas-NETs (5-year RFS 67% vs 83%, P = .001) but not for small-bowel NETs. Conclusions: Black patients with GEP-NETs had more adverse characteristics and higher LN positivity. Despite this, Black patients have improved RFS. This may be attributed to the epidemiologic differences in the primary site of GEP-NETs and variable prognostic value of LN-positive disease.

Background: Given the propensity for lung metastases, National Comprehensive Cancer Network guidelines recommend lung surveillance with either chest x-ray (CXR) or CT in high-grade soft tissue sarcoma. Considering survival, diagnostic sensitivity, and cost, the optimal modality is unknown. Methods: The US Sarcoma Collaborative database (2000 to 2016) was reviewed for patients who underwent resection of a primary high-grade soft tissue sarcoma. Primary end point was overall survival (OS). Cost analysis was performed. Results: Among 909 patients, 83% had truncal/extremity and 17% had retroperitoneal tumors. Recurrence occurred in 48%, of which 54% were lung metastases. Lung surveillance was performed with CT in 80% and CXR in 20%. Both groups were clinically similar, although CT patients had more retroperitoneal tumors and recurrences. Regardless of modality, 85% to 90% of lung metastases were detected within the first 2 years with a similar re-intervention rate. When considering age, tumor size, location, margin status, and receipt of radiation, lung metastasis was independently associated with worse OS (hazard ratio 4.26; p < 0.01) and imaging modality was not (hazard ratio 1.01; p = 0.97). Chest x-ray patients did not have an inferior 5-year OS rate compared with CT (71% vs 60%; p < 0.01). When analyzing patients in whom no lung metastases were detected, both cohorts had a similar 5-year OS rate (73% vs 74%; p = 0.42), suggesting CXR was not missing clinically relevant lung nodules. When adhering to a guideline-specified protocol for 2018 projected 4,406 cases, surveillance with CXR for 5 years results in savings of $5 million to $8 million/year to the US healthcare system. Conclusions: In this large multicenter study, lung surveillance with CXR did not result in worse overall survival compared with CT. With considerable savings, a CXR-based protocol can optimize resource use for lung surveillance in high-grade soft tissue sarcoma; prospective trials are needed.

Background/Objective: Staging and type of resection for rectal neuroendocrine tumors (R-NETS) relies on preoperative identification of lymph node (LN) involvement. Study objective was to develop a Preoperative Rectal Stratification Score (PReSS) for LN-positivity and to assess the association of PReSS with overall survival (OS). Methods: All patients in the National Cancer Database (2004-2014) with non-metastatic/nonfunctional R-NETS were included. Tumor size was divided into three categories (<1, 1-2, and ≥2 cm). Results: Among 383 patients, median age was 57 years, 52% were male (n = 200), median tumor size was 1.4 cm, 43% had positive LNs (n = 163). On univariate analysis, age > 60, poorly differentiated grade, depth of invasion past submucosa, and size >1 cm were associated with LN positivity. On multivariable analysis, depth of invasion past submucosa, and increasing tumor size >1 cm remained associated with LN positivity. As these can be determined preoperatively, incidence of LN positivity was determined for each combination of tumor size and depth of invasion. Each variable was assigned a score to create a PReSS of four groups (0-3) associated with an increasing rate of LN-positivity (PReSS group 0: 11%, 1: 38%, 2: 50%, 3: 78%, P <.01). PReSS correlated with 10-year OS (PReSS 0: 90%; 1: 81%; 2: 59%; 3: 41%). Conclusion: For R-NETS, depth of invasion and tumor size predict LN positivity and both can be obtained preoperatively. PReSS incorporates both variables and stratifies tumors into four risk groups of progressively increasing LN positivity and should be used to guide surgical approach.