ß-catenin plus PROX1 immunostaining stratifies disease progression and patient survival in neoadjuvant-treated pancreatic cancer.

BACKGROUND: Wnt/ß-catenin signaling is a highly conserved signaling pathway that regulates the transcription factor PROX1. The role of ß-catenin and PROX1 in pancreatic cancer is ambiguous, as some studies have associated their expression with tumor regression and some with tumor progression. OBJECTIVE: We have investigated their expression in surgically treated pancreatic cancer patients receiving neoadjuvant therapy (NAT), and patients treated upfront with surgery (US). We furthermore compared the expression of ß-catenin and PROX1 between patients who had a good or poor response to NAT. METHODS: We evaluated ß-catenin and PROX1 expression through immunohistochemistry in 88 neoadjuvant and 144 upfront surgery patients by scoring the intensity of the immunopositivity as 0-3, corresponding to negative, weak, moderate, or strong. We developed a six-tier grading scheme for the neoadjuvant responses by analyzing the remaining tumor cells in surgical specimen histological sections. RESULTS: Strong ß-catenin immunopositivity associated with improved survival in the patients with good NAT-response (≤10% residual tumor cells) (Hazard ratio [HR] 0.26 95%, confidence interval [CI] 0.07-0.88 p = 0.030). Additionally, the combined moderate ß-catenin and PROX1 expression associated with improved survival (HR 0.20 95% CI 0.05-0-76 p = 0.018) among the good responders. Among the patients with a poor NAT-response (> 10% residual tumor cells), both strong ß-catenin immunopositivity and strong combined ß-catenin and PROX1 associated with shorter survival (HR 2.03 95% CI 1.16-3.55 p = 0.013, and HR 3.1 95% CI 1.08-8.94 p = 0.03, respectively). PROX1 alone was not associated with survival. CONCLUSIONS: Strong ß-catenin immunopositivity and combined strong or moderate ß-catenin and PROX1 immunopositivity associated with improved survival among the good NAT-responders and worse survival among the poor NAT-responders.

Long Term Results of Pancreatectomy With and Without Venous Resection: A Comparison of Safety and Complications of Spiral Graft, End-to-End and Tangential/Patch Reconstruction Techniques.

OBJECTIVE: Roughly 10% - 20% of pancreatic cancer patients are candidates for curative intent surgical treatment. In the 2000s, many studies showed similar survival rates comparing pancreatic surgery with or without vein resection and reconstruction. The aim was to identify the best method of venous reconstruction. METHODS: This was a retrospective cohort study. A total of 1 375 patients undergoing pancreatectomy between 2005 and 2018 were identified. Patients undergoing a combined pancreatic resection and venous reconstruction were included retrospectively. When tumour infiltration to the portal/superior mesenteric vein was detected, excision and reconstruction with tangential suturing/patch, end to end anastomosis, or a spiral graft from the great saphenous vein was performed. Next, 90 day and long term survival and outcomes across reconstruction techniques were analysed. RESULTS: Overall, 198 patients had venous involvement visible in pre-operative scans or detected during surgery, broken down as follows: 171 (86%) pancreaticoduodenectomy, 12 (6%) total pancreatectomy, and 15 (8%) distal pancreatectomy. In total, 69 (35%) spiral graft reconstructions, 77 (39%) end to end anastomoses, and 52 (26%) tangential/patch reconstructions were performed. Tumour histology revealed pancreatic adenocarcinomas in 162 (82%) patients, intraductal mucinous pancreatic neoplasia in 14 (7%), cholangiocarcinoma in five (3%), neuro-endocrine neoplasia in nine (5%), and eight other diagnoses. Overall, 183 (92%) were malignant and 15 (8%) benign. Two patients died within 90 days, one in hospital and one on post-operative day 38 due to thrombosis of the superior mesenteric vein and intestinal necrosis, a Clavien-Dindo grade 5 complication. In addition, 50 (23%) patients had Clavien-Dindo grade 3 - 4 complications. No differences in complications comparing vein reconstruction techniques or in the long term survival of pancreatectomy patients with or without venous reconstruction were detected. CONCLUSION: The spiral graft technique, used when more advanced venous infiltration occurs, does not increase complications, with outcomes mirroring those accompanying shorter venous resections.

Preoperative oncologic therapy and the prolonged risk of venous thromboembolism in resectable pancreatic cancer.

BACKGROUND: Pancreatic cancer is one of the most prothrombotic cancers. Among patients receiving preoperative chemotherapy followed by surgery, chemotherapy and surgery represent a compound risk for venous thromboembolism (VTE), rendering the postoperative time a period of interest. We aimed to analyze whether preoperative oncologic therapy increases the risk for VTE after surgery and identify which characteristics associate with VTE. METHODS: We first identified patients surgically treated for pancreatic cancer at Helsinki University Hospital between 2000 and 2017, collecting the following data: gender, age at surgery, preoperative medication, body mass index (BMI), preoperative chemo(radio)therapy, tumor size, positive node ratio, perineural and perivascular invasion, tumor grade, surgical technique, postoperative anticoagulation, adjuvant therapy, time of VTE, time of local disease recurrence, time of distant metastasis, and time of death. With a follow-up period of at least 2 years or until death, we compared a total of 93 preoperative oncologic therapy and 291 upfront surgery patients (n = 384, median age 66.5 years). RESULTS: Preoperative oncologic therapy increased the risk for thrombosis after surgery (hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.03-2.53). The VTE incidence rate remained high for up to 2 years after surgery. BMI ≥30 kg/m2 , prior anticoagulation, and disease recurrence (p < 0.05, respectively) associated with VTE. VTE is also associated with shorter overall survival (HR 3.25; 95% CI 2.36-4.44). In 71.6% (95% CI 60.5-81.1) of patients, VTE was diagnosed after disease recurrence. CONCLUSIONS: Preoperative oncologic therapy represents an independent risk factor for VTE, not only during the immediate postoperative period but up to 2 years after surgery. VTE is associated with obesity, prior anticoagulation, and disease recurrence and diminishes overall survival.

Impact of histological response after neoadjuvant therapy on podocalyxin as a prognostic marker in pancreatic cancer.

Podocalyxin overexpression associates with poor survival in pancreatic cancer (PDAC). We investigated whether podocalyxin expression correlates with treatment response or survival in neoadjuvant-treated PDAC. Through immunohistochemistry, we evaluated podocalyxin expression in 88 neoadjuvant and 143 upfront surgery patients using two antibodies. We developed a six-tier grading scheme for neoadjuvant responses evaluating the remaining tumor cells in surgical specimens. Strong podocalyxin immunopositivity associated with poor survival in the patients responding poorly to the neoadjuvant treatment (HR 4.16, 95% CI 1.56-11.01, p = 0.004), although neoadjuvant patients exhibited generally low podocalyxin expression (p = 0.017). Strong podocalyxin expression associated with perineural invasion (p = 0.003) and lack of radiation (p = 0.036). Two patients exhibited a complete neoadjuvant response, while a strong neoadjuvant response (≤ 5% of residual tumor cells) significantly associated with lower stage, pT-class and grade, less spread to the regional lymph nodes, less perineural invasion, and podocalyxin negativity (p < 0.05, respectively). A strong response predicted better survival (HR 0.28, 95% CI 0.09-0.94, p = 0.039). In conclusion, strong podocalyxin expression associates with poor survival among poorly responding neoadjuvant patients. A good response associates with podocalyxin negativity. A strong response associates with better outcome.