Faculty Bibliography

OBJECTIVE:Previous nomogram models for patients undergoing resection of intraductal papillary mucinous neoplasms (IPMNs) have been relatively small single-institutional series. Our objective was to improve upon these studies by developing and independently validating a new model using a large multiinstitutional dataset. SUMMARY BACKGROUND DATA:IPMNs represent the most common radiographically identifiable precursor lesions of pancreatic cancer. They are a heterogenous group of neoplasms in which more accurate markers of high-grade dysplasia or early invasive carcinoma could help avoid unnecessary surgery in 1 case and support potentially curative intervention (resection) in another. METHODS:Prospectively maintained databases from 3 institutions were queried for patients who had undergone resection of IPMNs between 2005 and 2015. Patients were separated into main duct [main and mixed-type (MD)] and branch duct (BD) types based on preoperative imaging. Logistic regression modeling was used on a training subset to develop 2 independent nomograms (MD and BD) to predict low-risk (low- or intermediate-grade dysplasia) or high-risk (high-grade dysplasia or invasive carcinoma) disease. Model performance was then evaluated using an independent validation set. RESULTS:We identified 1028 patients who underwent resection for IPMNs [MD: n = 454 (44%), BD: n = 574 (56%)] during the 10-year study period. High-risk disease was present in 487 patients (47%). Patients with high-risk disease comprised 71% and 29% of MD and BD groups, respectively (P <0.0001). MD and BD nomograms were developed on the training set [70% of total (n = 720); MD: n = 318, BD: n = 402] and validated on the test set [30% (n = 308); MD: n = 136, BD: n = 172]. The presence of jaundice was almost exclusively associated with high-risk disease (57 of 58 patients, 98%). Cyst size >3.0 cm, solid component/mural nodule, pain symptoms, and weight loss were significantly associated with high-risk disease. C-indices were 0.82 and 0.81 on training and independent validation sets, respectively; Brier scores were 0.173 and 0.175, respectively. CONCLUSIONS:For patients with suspected IPMNs, we present an independently validated model for the prediction of high-risk disease.

Telomere end-to-end fusions are an important source of chromosomal instability that arise in cells with critically shortened telomeres. We developed a nested real-time quantitative PCR method for telomere fusion detection in pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms (IPMNs), and IPMN cyst fluids. Ninety-one pancreatic cancer cell lines and xenograft samples, 93 IPMNs, and 93 surgically aspirated IPMN cyst fluid samples were analyzed. The association between telomere shortening, telomerase activity, and telomere fusion detection was evaluated. Telomere fusions were detected in 56 of 91 pancreatic cancers (61.5%). Telomere fusion-positive cell lines had significantly shorter telomere lengths than fusion-negative lines (P = 0.003). Telomere fusions were undetectable in normal pancreas or IPMNs with low-grade dysplasia (0.0%) and were detected in IPMN with high-grade dysplasia (HGD; 48.0%) (P < 0.001). In IPMN cyst fluids, telomere fusions were more frequent in IPMNs with HGD (26.9%) or associated invasive cancer (42.9%) than IPMN with intermediate-grade dysplasia (15.4%) or low-grade dysplasia (0%) (P = 0.025). Telomerase activity levels were higher in cyst fluids with fusions than in those without (P = 0.0414). Cyst fluid telomere fusion status was an independent predictor of HGD/invasive cancer by multivariate analysis (odds ratio, 6.23; 95% CI, 1.61-28.0). Telomere fusions are detected in later stages of IPMN progression and can serve as a marker for predicting the presence of HGD and/or invasive cancer.

BACKGROUND:A standardized treatment regimen for unresectable isolated local recurrence (ILR) of pancreatic ductal adenocarcinoma has not been established. This study evaluated the outcomes for patients with ILR who underwent stereotactic body radiation therapy (SBRT). METHODS:The records of patients with ILR who underwent SBRT between 2010 and 2016 were retrospectively reviewed. Symptom palliation and treatment-related toxicity were recorded. Associations between patient or treatment characteristics and overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) were assessed. RESULTS:The study identified 51 patients who received SBRT for ILR. Of the 51 patients, 26 (51%) had not received radiation therapy before SBRT. The median OS was 36 months after diagnosis. From the first day of SBRT, the median OS, PFS, and LPFS were respectively 16, 7, and 10 months. Patients with a recurrence-free interval of 9 months or longer after surgery had superior OS (P = 0.019). Maintenance chemotherapy after SBRT was associated with superior OS (P < 0.001) and LPFS (P = 0.027). In the multivariable analysis, poorly differentiated tumor grade [hazard ratio (HR) 11.274], positive surgical margins (HR 0.126), and reception of maintenance chemotherapy (HR 0.141) were independently associated with OS. Positive surgical margins (HR 0.255) and maintenance chemotherapy (HR 0.299) were associated with improved LPFS. Of 16 patients, 10 (63%) experienced abdominal pain relief after SBRT. Four patients (8%) experienced grade 3 gastrointestinal toxicity, and one patient experienced grade 4 gastrointestinal toxicity. CONCLUSIONS:Use of SBRT for ILR improved pain for a majority of the patients with acceptable acute and late toxicity. The findings show that SBRT is a feasible treatment for select patients with ILR. For those who receive SBRT, maintenance chemotherapy should be considered.

Background/UNASSIGNED:Pancreatic ductal adenocarcinoma (PDAC) often presents with nonspecific symptoms and the workup is not standardized. To study the impact of delays in diagnosis and in the initiation of treatment, we investigated the relationship between length of diagnostic intervals and surgical resectability. Methods/UNASSIGNED:We performed a retrospective chart review of patients evaluated for PDAC at Johns Hopkins in 2014. Data were collected on the patient (date of first symptoms-first medical appointment), diagnostic (first medical appointment-diagnosis of PDAC), and treatment (diagnosis of PDAC-1st day of treatment) time intervals, and the upfront treatment received. Asymptomatic patients diagnosed incidentally, or for whom records were incomplete, were excluded from analysis. Results/UNASSIGNED:Of 453 charts reviewed, 116 patients met inclusion criteria. The median patient interval was 14 days [interquartile range (IQR): 6-30 days], the median diagnostic interval was 22 days (IQR: 8-46 days), and the median treatment interval was 26 days (IQR: 15-35 days). Thirty-eight patients (33%) received upfront surgery and 78 (67%) received nonsurgical treatment. After adjusting for multiple factors, the odds of receiving surgery significantly increased for individuals with a patient interval of 30 days or less [adjusted odds ratio (aOR): 3.41; 95% confidence interval (CI): 1.08-13.20; P=0.050] and with a diagnostic interval of 60 days or less (aOR: 15.68; 95% CI: 2.95-291.00, P=0.009). Conclusions/UNASSIGNED:A patient interval less than 1 month and a diagnostic interval less than 2 months for symptomatic PDAC are associated with increased odds of upfront surgical resection. These data provide initial evidence that reducing diagnostic delays may lead to improved outcomes in PDAC.