Society: AGA

Abstract
Background and Aims: Currently, most patients with branch duct intraductal papillary mucinous neoplasms (BD-IPMN) are offered indefinite surveillance, resulting in health care costs with questionable benefits regarding cancer prevention. This study sought to identify patients where the risk of cancer is equivalent to an age-matched population, thereby justifying discontinuation of surveillance.

Methods: International multicenter study involving presumed BD-IPMN without worrisome features (WF) or high-risk stigmata (HRS) at diagnosis who underwent surveillance. Clusters of individuals at risk for cancer development were defined according to cyst size and stability for at least 5 years, and age-matched controls were used for comparison using standardized incidence ratios (SIRs) for pancreatic cancer.

Results: Of 3844 patients with presumed BD-IPMN, 843 (22%) developed a WF or HRS after a median surveillance of 53 (IQR 53) months and 164 patients (4.3%) underwent surgery. Of the overall cohort, 1617 patients (42%) remained stable without developing WF or HRS for at least 5 years. In patients 75 years or older, the SIR was 2.23 (95%CI 0.45-6.52), and in patients 65 year or older with stable lesions below 15mm in diameter after 5 years, the SIR was 1.77 (95%CI 0.20-6.39).

Conclusions: The risk of developing pancreatic malignancy in presumed BD-IPMN without WF or HRS after 5 years of surveillance is comparable to that of the general population depending on cyst size and patient age. Surveillance discontinuation could be justified after 5 years of stability in patients older than 75 years with cysts < 30 mm, and in patients 65 years or older who have cysts ≤ 15 mm.

<b>Standardized Incidence Ratio (SIR) for pancreatic cancer</b>

Standardized Incidence Ratio (SIR) for pancreatic cancer

Recommendations according to the new evidence provided by the paper

Recommendations according to the new evidence provided by the paper

Surgical management of Pancreatic neuroendocrine tumors (PNETs) has long been debated. Current NCCN guidelines state that non-functioning PNETs >2 centimeters (cm) should undergo primary surgical removal. Tumors < 2cm in size can be observed carefully and surgery is not always indicated. Recent NCDB based analysis suggests that surgical intervention for tumors 1-2 cms is beneficial while observation remains an option for tumors <1cm. In this analysis we seek to understand the influence of surgery on survival for smaller PNETS (</=2 cms).

Methods
The NCDB was used to identify 15,017 patients diagnosed with PNETs from 2004-2018 with known tumor size, surgical status, and survival outcomes. Variables included in this analysis are race, sex, age, rurality, Charlson-Deyo score, grade, surgery status, stage, site, and size of tumor. Variables were summarized with descriptive statistics including counts, percentages, and compared using Chi^2 analysis. Univariate Survival analysis was demonstrated through Kaplan Meyer survival curve analysis. Survival data was fit to an exponential curve and 60-month mortality estimates were reported. Cox-proportional hazards were used to conduct both whole cohort and stratified multivariate analysis. Hazard ratios and confidence intervals (95%) are reported.

Results
Tumor Size was separated into three categories (<1cm, 1-2cm, ≥2 cm). 950 (6.3%) were <1cm, 3043 (20.3%) were 1-2cm, and 11024 (73.4%) were ≥2cm in size. Of the 15017 patients included, 9911(66.1%) underwent surgical resection. Rates of surgical resection across tumor sizes differed with <1cm 680 (71.81%), 1-2 cm 2414 (79.46%) and ≥2 cm 6817 (61.9%). Five-year mortality estimates across all tumor sizes show a significant decrease in mortality with surgical resection. Survival curves show that patients across all tumor sizes that underwent surgical resection had improved survival outcomes. Multivariate analysis showed that patients not undergoing surgical resection, while controlling for effect of tumor size, had worse survival (HR: 2.41). Patients with increased tumor size (≥ 2cm) had worse survival outcomes compared to both smaller tumor size groups; 1-2 cm (HR 1.59) <1cm (1.34) while controlling for surgical status. Stratified Analysis showed that patients not undergoing surgical resection had worse survival across all tumor sizes; >2cm (HR: 2.46) 1-2 cm (HR: 2.22) <1cm (HR: 2.36).

Discussion
Our analysis suggest that surgical intervention across all tumor sizes is beneficial for overall survival. When controlling for other compounding factors, patients that underwent surgical intervention demonstrated increased survival. This analysis suggests that surgical or other ablative interventions should be considered across all PNET presentations regardless of tumor size and that current guidelines for watchful observation are not consistent with emerging survival data.

Background:
Pancreatic cyst biomarkers have been studied to risk-stratify neoplastic cysts for cancer, and previous studies have reported on the utility of measuring glucose and amphiregulin (AREG) to differentiate between mucinous from non-mucinous cysts. Glucose testing is relatively cheap and fast to obtain. Further validation studies with more rigorous study designs are needed.

Methods:
A total of 292 cyst samples with surgical histology, obtained from multiple centers, were sent to a central site for blinding. These blinded samples were then shipped to a separate site to measure cyst glucose and AREG. Glucose was measured using a Verio One Touch IQ Glucometer, and AREG was measured by ELISA. Cysts with glucose levels less than 50 mg/dl were classified as mucinous, and cysts with AREG levels greater than 112 pg/ml were classified as mucinous. The primary goal was to determine if glucose or AREG could reliably differentiate mucinous vs. non mucinous cysts, while secondary aims assessed their diagnostic performance in diagnosing mucinous cysts with advanced neoplasia (high-grade dysplasia or cancer).

Results:
Glucose differentiated mucinous vs. non-mucinous cysts with an AUC of 0.88 and sensitivity of 90% and specificity of 78% at pre-specified threshold. AREG differentiated mucinous vs. non-mucinous with an AUC of 0.60 and sensitivity of 65% and specificity of 47% at pre-specified threshold (Figure 1). Combining glucose and AREG did not improve diagnostic accuracy. CEA was used as the basis for comparison and had an AUC of 0.92 and sensitivity of 60% and specificity of 96%. Neither glucose nor AREG could meaningfully differentiate advanced neoplasia. Combining glucose and AREG did not improve overall diagnostic accuracy.

Conclusion:
In this multi-center blinded validation study, glucose demonstrated high diagnostic utility to differentiate mucinous from non-mucinous cysts. Glucose had greater sensitivity while CEA had greater specificity. AREG had less diagnostic accuracy in this validation study.

Randall Brand

University of Pittsburgh

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