Integrative genomic analyses of European intrahepatic cholangiocarcinoma: Novel ROS1 fusion gene and PBX1 as prognostic marker.

BACKGROUND: Cholangiocarcinoma (CCA) is a fatal cancer of the bile duct with a poor prognosis owing to limited therapeutic options. The incidence of intrahepatic CCA (iCCA) is increasing worldwide, and its molecular basis is emerging. Environmental factors may contribute to regional differences in the mutation spectrum of European patients with iCCA, which are underrepresented in systematic genomic and transcriptomic studies of the disease. METHODS: We describe an integrated whole-exome sequencing and transcriptomic study of 37 iCCAs patients in Germany. RESULTS: We observed as most frequently mutated genes ARID1A (14%), IDH1, BAP1, TP53, KRAS, and ATM in 8% of patients. We identified FGFR2::BICC1 fusions in two tumours, and FGFR2::KCTD1 and TMEM106B::ROS1 as novel fusions with potential therapeutic implications in iCCA and confirmed oncogenic properties of TMEM106B::ROS1 in vitro. Using a data integration framework, we identified PBX1 as a novel central regulatory gene in iCCA. We performed extended screening by targeted sequencing of an additional 40 CCAs. In the joint analysis, IDH1 (13%), BAP1 (10%), TP53 (9%), KRAS (7%), ARID1A (7%), NF1 (5%), and ATM (5%) were the most frequently mutated genes, and we found PBX1 to show copy gain in 20% of the tumours. According to other studies, amplifications of PBX1 tend to occur in European iCCAs in contrast to liver fluke-associated Asian iCCAs. CONCLUSIONS: By analyzing an additional European cohort of iCCA patients, we found that PBX1 protein expression was a marker of poor prognosis. Overall, our findings provide insight into key molecular alterations in iCCA, reveal new targetable fusion genes, and suggest that PBX1 is a novel modulator of this disease.

Premature mortality for patients after completely resected early adenocarcinoma of the esophagus or stomach.

OBJECTIVE: To establish the life expectancy burden of esophago-gastric cancer by analyzing years of life lost (YLL) for a Western patient population after treatment of early esophageal (EAC) or early gastric (GAC) adenocarcinoma. BACKGROUND: For patients with early EAC or GAC, the short-term prognosis after surgical resection is very good. Little data is available regarding long-term prognosis when compared to the general population. METHODS: Two hundred and fourteen patients with pT1 EAC (n = 112) or GAC (n = 102) were included in the study. Patients with EAC underwent transthoracic en-bloc esophagectomy; those with GAC had total or subtotal gastrectomy with D2-lymphadenectomy. Surviving patients had a median follow-up of approximately 14 years. YLL was calculated using average life expectancy data from Germany. RESULTS: Patients with EAC were younger (median age 61 years) than those with GAC (66 years) (p = 0.031). The male:female ratio was 10:1 for EAC and 3:2 for GAC (p < 0.001). Multivariate survival analysis showed the age of the patients ≥60 years and the existence of lymph node metastasis was associated with poor prognosis. The median YLL for all patients who died over follow-up was 8.0 years. For patients under 60 years, it was approximately 20 years, and for older patients, approximately 5 years (p < 0.001) without difference in tumor stage between these age cohorts. YLL did not differ for GAC vs. EAC. CONCLUSION: After surgical resection, the prognostic burden as measured by YLL is relevant for all patients with early esophageal and gastric adenocarcinomas and especially for younger patients. Reasons for YLL need further studies.

Pan-cancer analysis and in vitro validation of the oncogenic and prognostic roles of AURKA in human cancers.

Background: Aurora kinase A (AURKA) plays a pivotal role in regulating cell mitosis and tumor progression. However, its prognostic significance across diverse cancer types remains relatively unexplored. Methods: We conducted a comprehensive analysis of AURKA expression in various cancers using data from The Cancer Genome Atlas, Genotype-Tissue Expression, and The Human Protein Atlas databases. Our investigation encompassed an exploration of the associations between AURKA expression and clinical characteristics, shedding light on potential functional roles of AURKA. Additionally, we delved into the relationship between AURKA and the tumor microenvironment. To substantiate the role of AURKA, we carried out in vitro experiments in esophageal adenocarcinoma (EAC), prostate cancer (PRAD), and pancreatic cancer (PAAD) cells. Results: Our analysis revealed that AURKA is prominently overexpressed in a majority of the cancer types under investigation. Elevated AURKA expression correlated closely with poorer prognosis and advanced tumor stages. AURKA was found to be associated with key pathways involved in the cell cycle and arachidonic acid metabolism. Moreover, AURKA expression exhibited significant correlations with immunoregulatory genes and immune cell profiles. Notably, in vitro experiments demonstrated that silencing AURKA expression resulted in reduced cell viability in EAC, PRAD, and PAAD cells, as well as a decrease in clone formation, cell cycle elongation, diminished cell invasion and reduced spheroid size in EAC cells (OE33 and OE19). Conclusion: Our study elucidates the oncogenic role of AURKA and underscores its prognostic value across a spectrum of cancers, including EAC. These findings suggest that AURKA holds promise as a predictive biomarker for EAC and various other tumor types.

Extension of resection after positive intraoperative pathology during surgery for gastric and gastroesophageal junction adenocarcinoma: a retrospective cohort study.

BACKGROUND: Residual tumor at the resection margins after surgery for gastric and gastroesophageal junction (GEJ) adenocarcinoma is a known prognostic factor. In this single-center, retrospective cohort study in a tertiary referral center, the authors aimed to evaluate the relevance of intraoperative pathology consultation (IOC) and consecutive extension of surgery on patient survival. STUDY DESIGN: Of 737 consecutive patients undergoing (sub)total gastrectomy for gastric or GEJ adenocarcinoma, 679 cases with curative intent surgery between 05/1996 and 03/2019 were included. Patients were categorized into: R0 without further resection (direct R0), R0 after positive IOC and extension of resection (converted R0), and R1. RESULTS: IOC was performed in 242 (35.6%) patients, in 216 (89.3%) at the proximal resection margin. Direct R0-status was achieved in 598 (88.1%), converted R0 in 26 (3.8%) of 38 (5.6%) patients with positive IOC and R1 in 55 (8.1%) patients. The median follow-up was 29 months for surviving patients. 3-year survival rate (3-YSR) was significantly higher for direct R0 compared to converted R0 with 62.3% compared to 21.8% (hazard ratio=0.298; 95% CI=0.186-0.477, P <0.001). 3-YSR was similar between converted R0 and R1 (21.8 vs. 13.3%; hazard ratio =0.928; 95% CI=0.526-1.636, P =0.792). In multivariate analysis, advanced T ( P <0.001), N ( P <0.001), R ( P =0.003), and M1 status ( P <0.001) were associated with worse overall survival. CONCLUSION: IOC and consecutive extended resection for positive resection margins in gastrectomy for the proximal gastric and GEJ adenocarcinoma does not achieve long-term survival benefits in advanced tumor stages.

Long-Term Postsurgical Outcomes of Neoadjuvant Chemoradiation (CROSS) Versus Chemotherapy (FLOT) for Multimodal Treatment of Adenocarcinoma of the Esophagus and the Esophagogastric Junction.

BACKGROUND: The question of the ideal neoadjuvant therapy for locally advanced esophagogastric adenocarcinoma has not been answered to date. Multimodal treatment has become a standard treatment for these adenocarcinomas. Currently, perioperative chemotherapy (FLOT) or neoadjuvant chemoradiation (CROSS) is recommended. METHODS: A monocentric retrospective analysis compared long-term survival after CROSS versus FLOT. The study enrolled patients with adenocarcinoma of the esophagus (EAC) or the esophagogastric junction type I or II undergoing oncologic Ivor-Lewis esophagectomy between January 2012 and December 2019. The primary objective was to determine the long-term outcome in terms of overall survival. The secondary objectives were to determine differences regarding the histopathologic categories after neoadjuvant treatment and the histomorphologic regression. RESULTS: The findings showed no survival advantage for one or the other treatment in this highly standardized cohort. All the patients underwent open (CROSS: 9.4% vs. FLOT: 22%), hybrid (CROSS: 82% vs. FLOT: 72%), or minimally invasive (CROSS: 8.9% vs. FLOT: 5.6%) thoracoabdominal esophagectomy. The median post-surgical follow-up period was 57.6 months (95% confidence interval [CI] 23.2-109.7 months), and the median survival was longer for the CROSS patients (54 months) than for the FLOT patients (37.2 months) (p = 0.053). The overall 5-years survival was 47% for the entire cohort (48% for the CROSS and 43% for the FLOT patients). The CROSS patients showed a better pathologic response and fewer advanced tumor stages. CONCLUSION: The improved pathologic response after CROSS cannot be translated into longer overall survival. To date, the choice of which neoadjuvant treatment to use can be made only on the basis of clinical parameters and the patient's performance status.

Two decades of gastric and gastroesophageal junction cancer surgery.

PURPOSE: Diagnosis and treatment of gastric and gastroesophageal junction cancer have undergone many critical changes during the last two decades. We addressed the question of how clinical reality outside of clinical trials has changed for gastric and gastroesophageal junction cancer patients in a European center for upper gastrointestinal surgery. METHODS: In this retrospective cohort study, patients undergoing (sub)total gastrectomy for gastric or gastroesophageal junction adenocarcinoma between 1996 and 2017 in a tertiary upper gastrointestinal center were included. The time was divided into a) before (1996-2006) (pre-CTx) and b) after (2006-2017) (CTx) the MAGIC trial. Data were comprehensively analyzed for demographics, tumor stage, perioperative treatment, surgery, histopathology, and survival rates (SR). RESULTS: 737 patients (32% female) underwent gastrectomy, 255 patients in the pre-CTx era and 482 patients in the CTx era. The median age was 65 years and the median follow-up was 27.5 months for surviving patients. Around 16.9% of patients received neoadjuvant treatment in the pre-CTx era versus 46.3% in the CTx era. The 3-year survival rate (3-YSR) was 46.4% in the pre-CTx and 60.9% in the CTx era (p < 0.001). For pretreated patients, 3-YSR was 39.0% (pre-CTx) versus 55.3% (CTx) (p = 0.168). Survival rate (SR) for locally advanced tumor stages (cT3/cT4) was higher when neoadjuvant therapy was administered (3-YSR: 56.7% vs 40.6%; p = 0.022). There were no significant differences according to sex (p = 0.357), age (p = 0.379), pT category (p = 0.817), pN stage (p = 0.074), cM stage (p = 0.112), Laurén classification (p = 0.158), and SRs (3-YSR: 60.3% vs 59.4%; p = 0.898) between the MAGIC and FLOT regimens. CONCLUSIONS: Survival rates have dramatically improved for gastric cancer patients during the last two decades. MAGIC and FLOT regimens showed similar results in the postsurgical follow-up.