Transcriptomic and CRISPR/Cas9 technologies reveal FOXA2 as a tumor suppressor gene in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates and limited therapeutic options. Thus elucidation of signaling pathways involved in PDAC pathogenesis is essential for identifying novel potential therapeutic gene targets. Here, we used a systems approach to elucidate those pathways by integrating gene and microRNA profiling analyses together with CRISPR/Cas9 technology to identify novel transcription factors involved in PDAC pathogenesis. FOXA2 transcription factor was found to be significantly downregulated in PDAC relative to control pancreatic tissues. Functional experiments revealed that FOXA2 has a tumor suppressor function through inhibition of pancreatic cancer cell growth, migration, invasion, and colony formation. In situ hybridization analysis revealed miR-199a to be significantly upregulated in pancreatic cancer. Bioinformatics and luciferase analyses showed that miR-199a negatively but directly regulates FOXA2 expression through binding in its 3′-untranslated region (UTR). Evaluation of the functional importance of miR-199a on pancreatic cancer revealed that miR-199a acts as an inhibitor of FOXA2 expression, inducing an increase in pancreatic cancer cell proliferation, migration, and invasion. Additionally, gene ontology and network analyses in PANC-1 cells treated with a small interfering RNA (siRNA) against FOXA2 revealed an enrichment for cell invasion mechanisms through PLAUR and ERK activation. FOXA2 deletion (FOXA2Δ) by using two CRISPR/Cas9 vectors in PANC-1 cells induced tumor growth in vivo resulting in upregulation of PLAUR and ERK pathways in FOXA2Δ xenograft tumors. We have identified FOXA2 as a novel tumor suppressor in pancreatic cancer and it is regulated directly by miR-199a, thereby enhancing our understanding of how microRNAs interplay with the transcription factors to affect pancreatic oncogenesis

The impact of failure to achieve symptom control after resection of functional neuroendocrine tumors: An 8â institution study from the US Neuroendocrine Tumor Study Group

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147162/1/jso25306_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147162/2/jso25306.pd

Defining Long-Term Survivors Following Resection of Intrahepatic Cholangiocarcinoma

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive primary tumor of the liver. While surgery remains the cornerstone of therapy, long-term survival following curative-intent resection is generally poor. The aim of the current study was to define the incidence of actual long-term survivors, as well as identify clinicopathological factors associated with long-term survival. METHODS: Patients who underwent a curative-intent liver resection for ICC between 1990 and 2015 were identified using a multi-institutional database. Overall, 679 patients were alive with ≥ 5 years of follow-up or had died during follow-up. Prognostic factors among patients who were long-term survivors (LT) (overall survival (OS) ≥ 5) were compared with patients who were not non-long-term survivors (non-LT) (OS < 5). RESULTS: Among the 1154 patients who underwent liver resection for ICC, 5- and 10-year OS were 39.6 and 20.3% while the actual LT survival rate was 13.3%. After excluding 475 patients who survived  5 cm (OR 2.40, 95% CI, 1.54-3.74, p < 0.001), and direct invasion of an adjacent organ (OR 3.98, 95% CI, 1.18-13.4, p = 0.026). However, a subset of patients (< 10%) who had these pathological characteristics were LT. CONCLUSION: While ICC is generally associated with a poor prognosis, some patients will be LT. In fact, even a subset of patients with traditional adverse prognostic factors survived long term.info:eu-repo/semantics/publishedVersio

Long-Term Outcomes After Curative Resection of HCV-Positive Versus Non-Hepatitis Related Hepatocellular Carcinoma: an International Multi-Institutional Analysis

Background: To define the chronological changes of long-term survival among patients with non-hepatitis-related hepatocellular carcinoma (Non-Hep-HCC) versus hepatitis C-related HCC (HCV-HCC) over the last two decades. Methods: Patients who underwent curative-intent resection for HCC between 2000 and 2017 were identified from an international multi-institutional database. Overall (OS) and recurrence-free survival (RFS) were analyzed and compared among Non-Hep-HCC versus HCV-HCC patients. Propensity score matching (PSM) was utilized to mitigate residual bias. Results: Among 617 patients, 196 (31.8%) patients had HCV-HCC, whereas 421 (68.2%) patients had Non-Hep-HCC. While patients with HCV-HCC had an improvement in OS over time (5-year OS, 2000-2009 55% vs. 2010-2017 67%, p = 0.034), OS among patients with Non-Hep-HCC remain unchanged (5-year OS, 2000-2009 53% vs. 2010-2017 52%, p = 0.905). In the matched cohort, patients with HCV-HCC had a worse OS versus patients with Non-Hep-HCC during 2000 and 2009 (5-year OS, 12% vs. 63%, p = 0.029), but significantly better OS from 2010 to 2017 than patients with Non-Hep-HCC (5-year OS, 86% vs. 73%, p = 0.035). The recurrence timing, patterns and re-treatments were comparable among Non-Hep-HCC and HCV-HCC patients. Conclusion: While OS of patients with HCV-HCC improved over time, the long-term survival of patients with Non-Hep-HCC patients remained unchanged and was more unfavorable.info:eu-repo/semantics/publishedVersio

Proposed Modification of the Eighth Edition of the AJCC Staging System for Intrahepatic Cholangiocarcinoma

Background: To improve the prognostic accuracy of the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for intrahepatic cholangiocarcinoma (ICC) with establishment and validation of a modified TNM (mTNM) staging system. Methods: Data on patients who underwent curative-intent resection for ICC was collected from 15 high-volume centers worldwide (n = 643). An external validation dataset was obtained from the SEER registry (n = 797). The mTNM staging system was proposed by redefining T categories, and incorporating the recently proposed N status as N0 (no lymph node metastasis [LNM]), N1 (1-2 LNM) and N2 (≥3 LNM). Results: The 8th AJCC TNM staging system failed to stratify overall survival (OS) of stage II versus IIIA, stage IIIB versus IV, as well as overall stage III versus IV among all patients from the two databases, as well as stage I versus II, and stage III versus III among patients who had ≥6 LNs examined. There was a monotonic decrement in survival based on the proposed mTNM staging classification among patients derived from both the multi-institutional (Median OS, stage I 69.8 vs. II 37.1 vs. III 18.9 vs. IV 16.4 months, all p < 0.05), and SEER (Median OS, stage I 87.0 vs. II 29.3 vs. III 17.7 vs. IV 14.2 months, all p < 0.05) datasets, which was also verified among patients who had ≥6 lymph node harvested from both databases. Conclusion: The modified TNM staging system for ICC using the new T and N definitions provided an improved means to stratify patients relative to long-term OS versus the 8th AJCC staging.info:eu-repo/semantics/publishedVersio

Therapeutic index of lymphadenectomy among patients with pancreatic neuroendocrine tumors: A multi‐institutional analysis

BackgroundThe benefit derived from lymph node dissection (LND) in patients with pancreatic neuroendocrine tumors (pNETs) based on clinicopathological characteristics remains unclear.MethodsPatients undergoing surgery for pNET between 1997 and 2016 were identified using a multi‐institutional dataset. The therapeutic index of LND relative to patient characteristics was calculated.ResultsAmong 647 patients, the median number of lymph nodes (LNs) evaluated was 10 (interquartile range: 4‐16) and approximately one quarter of patients had lymph node metastasis (LNM) (N = 159, 24.6%). Among patients with LNM, 5‐year recurrence‐free survival was 56.0%, reflecting a therapeutic index value of 13.8. The therapeutic index was highest among patients with a moderately/poorly‐differentiated pNET (21.5), Ki‐67 ≥ 3% (20.1), tumor size ≥2.0 cm (20.0), and tumor location at the head of the pancreas (20.0). Patients with ≥8 LNs evaluated had a higher therapeutic index than patients who had 1 to 7 LNs evaluated (≥8: 17.9 vs 1‐7: 7.5; difference of index: 11.4).ConclusionLND was mostly beneficial among patients with pNETs >2 cm, Ki‐67 ≥ 3%, and lesions located at the pancreatic head as identification of LNM was most common among individuals with these tumor characteristics. Evaluation of ≥8 LNs was associated with a higher likelihood of identifying LNM as well as a higher therapeutic index, and therefore this number of LNs should be considered the goal.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151957/1/jso25689_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151957/2/jso25689.pd

Impact of Microvascular Invasion on Clinical Outcomes After Curative-Intent Resection for Intrahepatic Cholangiocarcinoma

Background: Microvascular invasion (MiVI) is a histological feature of intrahepatic cholangiocarcinoma (ICC) that may be associated with biological behavior. We sought to investigate the impact of MiVI on long-term survival of patients undergoing curative-intent resection for ICC. Methods: A total of 1089 patients undergoing curative-intent resection for ICC were identified. Data on clinicopathological characteristics, disease-free survival (DFS), and overall survival (OS) were compared among patients with no vascular invasion (NoVI), MiVI, and macrovascular invasion (MaVI). Results: A total of 249 (22.9%) patients had MiVI, while 149 (13.7%) patients had MaVI (±MiVI). MiVI was associated with higher incidence of perineural, biliary and adjacent organ invasion, and satellite lesions (all P 18 months) prognosis. Conclusions: Roughly 1 out of 5 patients with resected ICC had MiVI. MiVI was associated with advanced tumor characteristics and a higher risk of tumor recurrence.info:eu-repo/semantics/publishedVersio

Survival after Resection of Multiple Tumor Foci of Intrahepatic Cholangiocarcinoma

Background: Multiple tumor foci of intrahepatic cholangiocarcinoma (ICC) are often considered a contra-indication for resection. We sought to define long-term outcomes after resection of ICC in patients with multiple foci. Methods: Patients who underwent resection for ICC between 1990 and 2017 were identified from 12 major HPB centers. Outcomes of patients with solitary lesions, multiple lesions (ML), and oligometastases (OM) were compared. OM were defined as extrahepatic metastases spread to a single organ. Results: One thousand thirteen patients underwent resection of ICC. On final pathology, 185 patients (18.4%) had ML and 27 (2.7%) had OM. Median survival of patients with a solitary tumor was 43.2 months, while the median survival of patients with 2 tumors was 21.2 months; the median survival of patients with 3 or more tumors was 15.3 months (p < 0.001). Five-year survival was 43.3%, 28.0%, and 8.6%, respectively. The median survival of patients without OM was 37.8 months versus 14.9 months among patients with OM (p < 0.001); estimated 5-year survival was 39.3% and 10.6%, respectively. In multivariable analysis, the presence of two lesions was not an independent poor prognostic factor for OS (HR 1.19; 95%CI 0.90-1.57; p = 0.229). However, the presence of three or more tumors was an independent poor prognostic factor for OS (HR 1.97; 95%CI 1.48-2.64; p < 0.001). Conclusion: Resection of multiple liver tumors for patients with ICC did not preclude 5-year survival: in particular, estimated 5-year OS for resection of two tumors was 28.0%.info:eu-repo/semantics/publishedVersio

Evaluation of the ACS NSQIP Surgical Risk Calculator in Elderly Patients Undergoing Hepatectomy for Hepatocellular Carcinoma

Background: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) surgical risk calculator (SRC) aims to help predict patient-specific risk for morbidity and mortality. The performance of the SRC among an elderly population undergoing curative-intent hepatectomy for hepatocellular carcinoma (HCC) remains unknown. Methods: Patients > 70 years of age who underwent hepatectomy for HCC between 1998 and 2017 were identified using a multi-institutional international database. To estimate the performance of SRC, 12 observed postoperative outcomes were compared with median SRC-predicted risk, and C-statistics and Brier scores were calculated. Results: Among 500 patients, median age was 75 years (IQR 72-78). Most patients (n = 324, 64.8%) underwent a minor hepatectomy, while 35.2% underwent a major hepatectomy. The observed incidence of venous thromboembolism (VTE) (3.2%) and renal failure (RF) (4.4%) exceeded the median predicted risk (VTE, 1.8%; IQR 1.5-3.1 and RF, 1.0%; IQR 0.5-2.0). In contrast, the observed incidence of 30-day readmission (7.0%) and non-home discharge (2.5%) was lower than median-predicted risk (30-day readmission, 9.4%; IQR 7.4-12.8 and non-home discharge, 5.7%; IQR 3.3-11.7). Only 57.8% and 71.2% of patients who experienced readmission (C-statistic, 0.578; 95%CI 0.468-0.688) or mortality (C-statistic, 0.712; 95%CI 0.508-0.917) were correctly identified by the model. Conclusion: Among elderly patients undergoing hepatectomy for HCC, the SRC underestimated the risk of complications such as VTE and RF, while being no better than chance in estimating the risk of readmission. The ACS SRC has limited clinical applicability in estimating perioperative risk among elderly patients being considered for hepatic resection of HCC.info:eu-repo/semantics/publishedVersio

Recurrence Patterns and Timing Courses Following Curative-Intent Resection for Intrahepatic Cholangiocarcinoma

Background: Recurrence of intrahepatic cholangiocarcinoma (ICC) after curative resection is common. Objective: The aim of this study was to investigate the patterns, timing and risk factors of disease recurrence after curative-intent resection for ICC. Methods: Patients undergoing curative resection for ICC were identified from a multi-institutional database. Data on clinicopathological and initial operation information, timing and first sites of recurrence, recurrence management, and long-term outcomes were analyzed. Results: A total of 920 patients were included. With a median follow-up of 38 months, 607 patients (66.0%) experienced ICC recurrence. In the cohort, 145 patients (23.9%) recurred at the surgical margin, 178 (29.3%) recurred within the liver away from the surgical margin, 90 (14.8%) recurred at extraheptatic sites, and 194 (32.0%) developed both intrahepatic and extrahepatic recurrence. Intrahepatic margin recurrence (median 6.0 m) and extrahepatic-only recurrence (median 8.0 m) tended to occur early, while intrahepatic recurrence at non-margin sites occurred later (median 14.0 m; p < 0.05). On multivariate analysis, surgical margin < 10 mm was associated with increased margin recurrence (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.11-2.60; p = 0.014), whereas female sex (HR 2.12, 95% CI 1.40-3.22; p < 0.001) and liver cirrhosis (HR 2.36, 95% CI 1.31-4.25; p = 0.004) were both associated with an increased risk of intrahepatic recurrence at other sites. Median survival after recurrence was better among patients who underwent repeat curative-intent surgery (48.7 months) versus other treatments (9.7 months) [p < 0.001]. Conclusions: Different recurrence patterns and timing of recurrence suggest biological heterogeneity of ICC tumor recurrence. Understanding timing and risk factors associated with different types of recurrence can hopefully inform discussions around adjuvant therapy, surveillance, and treatment of recurrent disease.info:eu-repo/semantics/publishedVersio