Recurrence following Resection of Intraductal Papillary Mucinous Neoplasms: A Systematic Review to Guide Surveillance.

Patients who undergo resection for non-invasive IPMN are at risk for long-term recurrence. Further evidence is needed to identify evidence-based surveillance strategies based on the risk of recurrence. We performed a systematic review of the current literature regarding recurrence patterns following resection of non-invasive IPMN to summarize evidence-based recommendations for surveillance. Among the 61 studies reviewed, a total of 8779 patients underwent resection for non-invasive IPMN. The pooled overall median follow-up time was 49.5 months (IQR: 38.5-57.7) and ranged between 14.1 months and 114 months. The overall median recurrence rate for patients with resected non-invasive IPMN was 8.8% (IQR: 5.0, 15.6) and ranged from 0% to 27.6%. Among the 33 studies reporting the time to recurrence, the overall median time to recurrence was 24 months (IQR: 17, 46). Existing literature on recurrence rates and post-resection surveillance strategies for patients with resected non-invasive IPMN varies greatly. Patients with resected non-invasive IPMN appear to be at risk for long-term recurrence and should undergo routine surveillance.

KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer.

Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations affect the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed FOXA1-target genes and activated cell-cycle progression genes. Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability. SIGNIFICANCE: A gain-of-function epigenetic switch that disrupts differentiation is triggered by inactivating KDM6A mutations in bladder cancer and can serve as a potential target for novel therapies.

Pancreatogenic Diabetes after Partial Pancreatectomy: A Common and Understudied Cause of Morbidity.

BACKGROUND: Partial pancreatic resection is a known risk factor for new-onset pancreatogenic diabetes mellitus (P-DM). The long-term incidence of P-DM and its clinical impact after partial pancreatic resection remains unknown. The primary objective of this study is to determine the long-term incidence of P-DM and its clinical impact after partial pancreatic resection. STUDY DESIGN: The Medicare 100% Standard Analytic File (2013 to 2017) was queried for all patients who underwent partial pancreatic resection (pancreaticoduodenectomy, distal pancreatectomy). The primary outcome was the development of postoperative P-DM after surgery. RESULTS: Among 4,255 patients who underwent a pancreaticoduodenectomy or distal pancreatectomy, with a median follow-up of 10.8 months, the incidence of P-DM was 20.3% (n=863) and occurred at a median of 3.6 months after surgery. For patients with at least a 3-year follow-up, 32.2% of patients developed P-DM. Risk factors for developing P-DM included male sex (odds ratio [OR] 1.32, 95% CI 1.13 to 1.54), undergoing a distal pancreatectomy (OR 1.98, 95% CI 1.68 to 2.35), having a malignant diagnosis (OR 1.65, 95% CI 1.34 to 2.04), a family history of diabetes (OR 2.06, 95% CI 1.43 to 2.97; all p < 0.001), and being classified as prediabetic in the preoperative setting (OR 1.57, 95% CI 1.18 to 2.08; p = 0.002). Patients who developed P-DM were more commonly readmitted within 90 days of surgery and had higher postoperative healthcare expenditures in the year after surgery ($24,440 US dollars vs $16,130 US dollars; both p < 0.001) vs patients without P-DM. CONCLUSIONS: Approximately 1 in 5 Medicare beneficiaries who undergo a pancreatic resection develop P-DM after pancreatic resection. Appropriate screening and improved patient education should be conducted for these patients, in particular, for those with identified risk factors.

Surgical treatment of hepatic oligometastatic pancreatic ductal adenocarcinoma: An analysis of the National Cancer Database.

BACKGROUND: Patients with liver-only metastatic pancreatic adenocarcinoma have traditionally been offered palliative chemotherapy alone. Recent studies have explored the role of surgical resection among patients with limited metastatic disease. National practice patterns and the impact of surgery among these patients remains unknown. METHODS: The National Cancer Database was queried for all patients with pancreatic adenocarcinoma between 2010 and 2015. The primary outcome was overall survival from the time of diagnosis. Patients with liver-only metastatic disease were included. Univariable and multivariable logistic regression models were constructed to determine the association of patient, hospital, and regional factors with receipt of surgical resection. A propensity score-matched cohort (1:1) was generated by matching patient- and tumor-related factors (age, sex, race, comorbidity burden, primary tumor site, primary tumor size) among patients with liver-only stage IV pancreatic adenocarcinoma who received chemotherapy alone compared to those who received chemotherapy and underwent pancreatectomy and liver metastatectomy. RESULTS: Among 312,426 patients who met the study criteria, one half (n = 140,043, 50.4%) had stage IV disease; metastatic sites included bone (n = 5493, 3.1%), brain (n = 620, 0.4%), lung (n = 16,580, 9.5%), and liver (n = 62,444, 35.7%). Patients with stage IV disease were more likely to be younger (odds ratio: 1.10, 95% confidence interval: 1.0-1.2; P = .03) and have poorly (odds ratio: 2.1, 95% confidence interval: 1.8-2.5; P < .001) or undifferentiated (odds ratio: 3.1, 95% confidence interval: 2.3-4.1; P < .001) tumors. Among stage IV patients with liver-only disease (n = 47,785, 14.9%), 891 patients (1.9%) underwent pancreatic resection. Patients who underwent resection were more likely to be younger (odds ratio 1.4, 95% confidence interval: 1.0-1.8; P = .03) and treated at an academic/research center (odds ratio 2.1, 95% confidence interval: 1.2-3.5; P = .006). Median overall survival among patients who underwent resection was 10.74 months versus 3.4 months among patients who did not undergo resection. After controlling for patient and disease-related factors, patients who underwent surgical resection had a lower risk of death versus patients who did not undergo surgery (hazard ratio: 0.5, 95% confidence interval: 0.4-0.6; P < .001). After propensity score matching, patients who received multimodality treatment for liver-only metastatic pancreatic adenocarcinoma (surgery, chemotherapy) had a longer median overall survival (15.6 months vs 8.1 months) compared to those who received chemotherapy alone (P < .001). CONCLUSION: This study suggests that pancreatic resection in patients with liver metastases, in combination with chemotherapy and/or chemoradiation, may be associated with improved survival in well-selected patients. However, attempts at an aggressive surgical approach for patients with liver-only stage IV pancreatic adenocarcinoma patients should only be performed only under a well-designed prospective clinical trial.