PURPOSE:Accurate staging of disease is vital in determining appropriate care for patients with pancreatic ductal adenocarcinoma (PDAC). It has been shown that the quality of scans and the experience of a radiologist can impact computed tomography (CT) based assessment of disease. The aim of the current study was to evaluate the impact of the rereading of outside hospital (OH) CT by an expert radiologist and a repeat pancreatic protocol CT (PPCT) on staging of disease.METHODS:Patients evaluated at the our institute's pancreatic multidisciplinary clinic (2006 to 2014) with OH scan and repeat PPCT performed within 30 days were included. In-house radiologists staged disease using OH scans and repeat PPCT, and factors associated with misstaging were determined.RESULTS:The study included 100 patients, with a median time between OH scan and PPCT of 19 days (IQR: 13-23 days.) Stage migration was mostly accounted for by upstaging of disease (58.8 % to 83.3 %) in all comparison groups. When OH scans were rereviewed, 21.5 % of the misstaging was due to missed metastases, however, when rereads were compared to the PPCT, occult metastases accounted for the majority of misstaged patients (62.5 %). Potential factors associated with misstaging were primarily related to imaging technique.CONCLUSION:A repeat PPCT results in increased detection of metastatic disease that rereviews of OH scans may otherwise miss. Accessible insurance coverage for repeat PPCT imaging even within 30 days of an OH scan could help optimize delivery of care and alleviate burdens associated with misstaging.

Patients with pancreatic ductal adenocarcinoma (PDAC) and liver metastasis are treated with palliative chemotherapy, whereas similar patients with metastatic colorectal cancer are considered for aggressive surgery.

Nodal disease is prognostic in pancreatic ductal adenocarcinoma (PDAC); however, optimal number of examined lymph nodes (ELNs) required to accurately stage nodal disease in the current era of neoadjuvant therapy remains unknown. The aim of the study was to evaluate the optimal number of ELNs in patients with neoadjuvantly treated PDAC. A retrospective study was performed on patients with PDAC undergoing resection following neoadjuvant treatment between 2011 and 2018. Clinicopathological data were extracted and analyzed. Of 546 patients included, 232 (42.5%) had lymph node metastases. The median recurrence free survival (RFS) was 10.6 months (95% confidence interval: 9.7–11.7) and nodal disease was independently associated with shorter RFS (9.1 vs 11.9 months; p < 0.001). A cutoff of 22 ELNs was identified that stratified patients by RFS. Patients with N1 and N2 disease had similar median RFS (9.1 vs 8.9 months; p = 0.410). On multivariable analysis, ELN of ≥ 22 was found to be significantly associated with longer RFS among patients with N0 disease (14.2 vs. 10.9 months, p = 0.046). However, ELN has no impact on RFS for patients with N1/N2 disease (9.5 vs. 8.4 months, p = 0.190). Adjuvant therapy was associated with RFS only in patients with residual nodal disease. Lymph node metastases remain prognostic in PDAC patients after neoadjuvant treatment. Among N0 patients, a cutoff of 22 ELN was associated with improved RFS and resulted in optimal nodal staging.

PURPOSE Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes, including familial pancreatic cancer. HR-DDR genes beyond BRCA1, BRCA2, ATM, and PALB2 may also mutate and confer the HR-DDR deficiency in pancreatic ductal adenocarcinoma (PDAC). METHODS We conducted a study to examine the genetic alterations using a companion diagnostic 15-gene HR-DDR panel in PDACs. HR-DDR gene mutations were identified and characterized by whole-exome sequencing and whole-genome sequencing. Different HR-DDR gene mutations are associated with variable homologous recombination deficiency (HRD) scores. RESULTS Eight of 50 PDACs with at least one HR-DDR gene mutation were identified. One tumor with BRCA2 mutations is associated with a high HRD score. However, another tumor with a CHEK2 mutation is associated with a zero HRD score. Notably, four of eight PDACs in this study harbor a RAD51B gene mutation. All four RAD51B gene mutations were germline mutations. However, currently, RAD51B is not the gene panel for germline tests. CONCLUSION The finding in this study thus supports including RAD51B in the germline test of HR-DDR pathway genes.

Background: Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that can result in developmental abnormalities of multiple organs with varying severity. In rare cases, patients with CdLS have been reported to develop malignant tumors. Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of tumors, and some of these are associated with syndromes. Case Description: A 27-year-old female with CdLS presented with epigastric pain and underwent diagnostic imaging via computed tomography (CT) and endoscopic ultrasound (US). Imaging demonstrated a pancreatic head mass, which was subsequently biopsied and confirmed to be a PNET. The patient underwent an uneventful pancreaticoduodenectomy. Histopathological examination revealed a 3.0 cm pancreatic mass involving the duodenum with local nodal involvement. At the 90-day follow-up, the patient was recovering well with no postoperative diabetes or pancreatic insufficiency. She was recommended routine imaging surveillance. In rare cases, patients with CdLS can develop tumors, possibly unrelated to the syndrome but of unclear etiology. Conclusions: Herein, we report the first case of a patient with CdLS developing a PNET. While evidence is limited, this report in conjunction with prior reports suggest that patients with CdLS might be at an increased risk of developing certain malignant tumors.

Parathyroid hormone receptor 1 (PTH1R) is a class B G-protein coupled receptor with key roles in bone development. The receptor signals through both the Gs and Gq G-proteins as well as through β-arrestin in a G-protein independent manner. Current treatments for bone disorders, such as osteoporosis, target the PTH1R but are suboptimal in their efficacy. Monoclonal antibodies represent a major growth area in therapeutics as a result of their superior specificity and long serum half-life. Here, we discovered antibodies against the extracellular domain (ECD) of PTH1R from a phage display library. One of these antibodies, ECD-ScFvhFc, binds PTH1R with high affinity and although it has little or no effect on G-protein dependent receptor signaling, it does reduce PTH1R mediated β-arrestin signaling. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) demonstrated that the ECD-ScFvhFc binding site overlapped partially with that of the cognate ligand, PTH. The results of this study demonstrate the suitability of PTH1R as a target for therapeutic antibody development.

Objective The aim of this study was to critically analyze the surgical experience of managing autoimmune pancreatitis (AIP) in an era of modern diagnostics and compare these patients with those who were managed conservatively. Methods Two prospectively maintained databases were used to retrospectively identify patients with AIP who were either managed conservatively or underwent pancreatectomy. Results Eighty-eight patients were included in the study, of which 56 (63.6%) underwent resection and 32 (36.4%) were managed conservatively. Patients who underwent resection were more likely to present with jaundice (64.3% vs 18.1%, P < 0.001) and weight loss (53.6% vs 15.6%, P = 0.005). The cohort who underwent resection had a significantly higher median carbohydrate antigen 19-9 (40.0 vs 18.6 U/mL, P = 0.034) and was less likely to have elevated immunoglobulin G4 (26.1% vs 50.0%, P < 0.001). The most frequent initial diagnosis in the cohort who underwent resection was ductal adenocarcinoma (82.1%). Nine patients (28.1%) in the conservatively managed cohort experienced AIP relapse compared with 6 patients (10.7%) in the cohort who underwent resection. Conclusions The most frequent reason for surgical resection of AIP is concern for malignancy. Carbohydrate antigen 19-9 elevations were more common than immunoglobulin G4 in our cohort, suggesting that this laboratory profile is suboptimal for this population.

Conventional radiotherapy is a widely used non-invasive form of treatment for many types of cancer. However, due to a low threshold in the lung for radiation-induced normal tissue damage, it is of less utility in treating lung cancer. For this reason, surgery is the preferred treatment for lung cancer, which has the detriment of being highly invasive. Non-conventional ultra-high dose rate (FLASH) radiotherapy is currently of great interest in the radiotherapy community due to demonstrations of reduced normal tissue toxicity in lung and other anatomy. This study investigates the effects of FLASH microbeam radiotherapy, which in addition to ultra-high dose rate incorporates a spatial segmentation of the radiation field, on the normal lung tissue of rats. With a focus on fibrotic damage, this work demonstrates that FLASH microbeam radiotherapy provides an order of magnitude increase in normal tissue radio-resistance compared to FLASH radiotherapy. This result suggests FLASH microbeam radiotherapy holds promise for much improved non-invasive control of lung cancer.

OBJECTIVE:The aim of this study was to critically analyze the surgical experience of managing autoimmune pancreatitis (AIP) in an era of modern diagnostics and compare these patients with those who were managed conservatively.METHODS:Two prospectively maintained databases were used to retrospectively identify patients with AIP who were either managed conservatively or underwent pancreatectomy.RESULTS:Eighty-eight patients were included in the study, of which 56 (63.6%) underwent resection and 32 (36.4%) were managed conservatively. Patients who underwent resection were more likely to present with jaundice (64.3% vs 18.1%, P < 0.001) and weight loss (53.6% vs 15.6%, P = 0.005). The cohort who underwent resection had a significantly higher median carbohydrate antigen 19-9 (40.0 vs 18.6 U/mL, P = 0.034) and was less likely to have elevated immunoglobulin G4 (26.1% vs 50.0%, P < 0.001). The most frequent initial diagnosis in the cohort who underwent resection was ductal adenocarcinoma (82.1%). Nine patients (28.1%) in the conservatively managed cohort experienced AIP relapse compared with 6 patients (10.7%) in the cohort who underwent resection.CONCLUSIONS:The most frequent reason for surgical resection of AIP is concern for malignancy. Carbohydrate antigen 19-9 elevations were more common than immunoglobulin G4 in our cohort, suggesting that this laboratory profile is suboptimal for this population.

PURPOSE:This study provides the first experimental application of multiscale 3-dimensional (3D) x-ray phase contrast imaging computed tomography (XPCI-CT) virtual histology for the inspection and quantitative assessment of the late-stage effects of radio-induced lesions on lungs in a small animal model. METHODS AND MATERIALS:Healthy male Fischer rats were irradiated with x-ray standard broad beams and microbeam radiation therapy, a high-dose rate (14 kGy/s), FLASH spatially fractionated x-ray therapy to avoid beamlet smearing owing to cardiosynchronous movements of the organs during the irradiation. After organ dissection, ex vivo XPCI-CT was applied to all the samples and the results were quantitatively analyzed and correlated to histologic data. RESULTS:XPCI-CT enables the 3D visualization of lung tissues with unprecedented contrast and sensitivity, allowing alveoli, vessel, and bronchi hierarchical visualization. XPCI-CT discriminates in 3D radio-induced lesions such as fibrotic scars and Ca/Fe deposits and allows full-organ accurate quantification of the fibrotic tissue within the irradiated organs. The radiation-induced fibrotic tissue content is less than 10% of the analyzed volume for all microbeam radiation therapy-treated organs and reaches 34% in the case of irradiations with 50 Gy using a broad beam. CONCLUSIONS:XPCI-CT is an effective imaging technique able to provide detailed 3D information for the assessment of lung pathology and treatment efficacy in a small animal model.

Objective To evaluate the impact of postoperative glycemic control on postoperative morbidity in patients undergoing a pancreaticoduodenectomy. Methods A retrospective study was performed on patients at The Johns Hopkins Hospital between April 2015 and April 2016. Data were collected on postoperative insulin regimens, blood glucose, rates of hyperglycemia and hypoglycemia, and postoperative complications and were evaluated. Results Out of 244 patients, 114 (46.7%) experienced at least 1 hyperglycemic (>180 mg/dL) episode and 16 (6.6%) experienced at least 1 hypoglycemic episode (<70 mg/dL) during the first postoperative 24 hours. Early postoperative hyperglycemia (>180 mg/dL) was associated with a significantly higher rate of surgical site infections (15.7% vs 7%; P = 0.031). Late postoperative hyperglycemia (>180 mg/dL) was associated with a significantly higher rate of fistulas (4.3% vs 14.6%; P = 0.021). Conclusions Early hyperglycemia (>180 mg/dL) is associated with a higher risk of surgical site infections while late hyperglycemia is associated with a higher risk of fistulas. Intensive glucose control (<150 mg/dL) was not demonstrated to decrease the risk of postoperative complications. Similar to other critically ill populations, targeting a glucose goal of <180 mg/dL may be an appropriate target to reduce morbidity without increasing the risk of hypoglycemia.

Supplemental digital content is available in the text. Objective The aim of this study was to critically analyze the surgical experience of managing autoimmune pancreatitis (AIP) in an era of modern diagnostics and compare these patients with those who were managed conservatively. Methods Two prospectively maintained databases were used to retrospectively identify patients with AIP who were either managed conservatively or underwent pancreatectomy. Results Eighty-eight patients were included in the study, of which 56 (63.6%) underwent resection and 32 (36.4%) were managed conservatively. Patients who underwent resection were more likely to present with jaundice (64.3% vs 18.1%, P < 0.001) and weight loss (53.6% vs 15.6%, P = 0.005). The cohort who underwent resection had a significantly higher median carbohydrate antigen 19-9 (40.0 vs 18.6 U/mL, P = 0.034) and was less likely to have elevated immunoglobulin G4 (26.1% vs 50.0%, P < 0.001). The most frequent initial diagnosis in the cohort who underwent resection was ductal adenocarcinoma (82.1%). Nine patients (28.1%) in the conservatively managed cohort experienced AIP relapse compared with 6 patients (10.7%) in the cohort who underwent resection. Conclusions The most frequent reason for surgical resection of AIP is concern for malignancy. Carbohydrate antigen 19-9 elevations were more common than immunoglobulin G4 in our cohort, suggesting that this laboratory profile is suboptimal for this population.

Presenter: Alina Hasanain MD | Johns Hopkins University School of Medicine Background: Outcomes in patients with pancreatic ductal adenocarcinoma (PDAC) remain poor and are predominantly driven by aggressive systemic disease. Despite improvements in treatment modalities, factors such as delay in the initiation of adjuvant therapy can still affect outcomes. Additionally, studies have reported that the presence and characteristics of circulating tumor cells (CTCs) are associated with outcomes. The aim of the current study was to assess whether CTC characteristics are associated with the impact of a delay in initiation of adjuvant therapy on patient outcomes. Methods: A retrospective study was performed on patients with PDAC enrolled in the prospective CLUSTER trial (NCT02974764) on CTC dynamics at the Johns Hopkins Hospital. CTCs were isolated based on size (ISET; Rarecells) from peripheral blood and counted and characterized using immunofluorescence. All patients who received adjuvant therapy were included. A delay in receipt of adjuvant therapy was defined as initiation >2 months after surgical resection. Clinicopathological features, CTC characteristics, and outcomes of these patients were analyzed. Results: A total of 84 patients were included in the study, of whom 43 (51.1%) experienced a delay in initiation of adjuvant therapy. Both cohorts of patients (delayed vs. timely initiation of adjuvant therapy) were well balanced in terms of their clinicopathological features (All p-values >0.05). In patients with timely initiation of therapy, the only factor independently associated with DFS on multivariable analysis was the receipt of neoadjuvant therapy (Hazard ratio [HR]: 2.38, 95% Confidence interval [95%CI]: 1.09-5.20, p=0.029). Postoperative transitional CTCs (mCTCs) positivity was not associated with DFS in this population (p=0.633). Contrastingly, in patients with a delay in initiation of adjuvant therapy, factors independently associated with poorer DFS on multivariable analysis included the presence of poorly differentiated or undifferentiated tumors (HR: 1.77, 95%CI: 1.13-2.76, p=0.013) and postoperative mCTCs positivity (HR: 2.72, 95%CI: 1.02-7.27, p=0.046). In patients with a delay in initiation of adjuvant therapy, those with postoperative mCTCs positivity had worse DFS compared to those without mCTCs (median DFS: 16.7 vs. 10.1 months, p=0.002) (Figure). Conclusion: Postoperative mCTCs positivity was associated with poorer DFS only in patients experiencing a delay in initiation of adjuvant therapy. This study is the first to propose a potential biological mechanism for the previously established observation that a delay in initiation of adjuvant therapy Results in worse survival. Future mechanistic studies are required to validate these findings and explore the underlying mechanisms involved.

Improvement in imaging has resulted in frequent diagnosis of benign and premalignant pancreatic tumors. Pancreatic nerve sheath (PNS) tumors are one of the rarest pancreatic tumors. Literature on PNS is limited and their biology is poorly understood. Here, we report the largest series of PNS tumors to date and review the literature to evaluate the current data available on PNS tumors.

Nodal involvement has been identified as one of the strongest prognostic factors in patients with nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). Sufficient lymphadenectomy and evaluation is vital for accurate staging. The purpose of this study was to identify the optimal number of examined lymph nodes (ELN) required for accurate staging. The SEER database was used to identify patients with resected NF-PanNETs between 2004 and 2014. The distributions of positive lymph nodes (PLN) ratio and total lymph nodes were used to develop a mathematical model. The sensitivity of detecting nodal disease at each cutoff of ELN was estimated and used to identify the optimal cutoff for ELN. A total of 1098 patients were included in the study of which 391 patients (35.6%) had nodal disease. The median ELN was 12 (interquartile range [IQR]: 7–19.5), and the median PLN was 2 (IQR: 1–4) for patients with nodal disease. With an increase in ELN, the sensitivity of detecting nodal disease increased from 12.0% (ELN: 1) to 92.2% (ELN: 20), plateauing at 20 ELN (< 1% increase in sensitivity with an additional ELN). This sensitivity increase pattern was similar in subgroup analyses with different T stages. The sensitivity of detecting nodal disease in patients with NF-PanNETs increases with an increase in the number of ELN. Cutoffs for adequate nodal assessment were defined for all T stages. Utilization of these cutoffs in clinical settings will help with patient prognostication and management.

Background Periampullary neuroendocrine tumors (NETs) arise from the duodenum, ampulla, and periampullary pancreas. Duodenal and ampullary NETs are rare and may have distinct biologic behavior from pancreatic NETs (P-NETs). We examined the outcomes of these entities. Methods An institutional database was queried for patients undergoing resection for pancreatic head, duodenal, or ampullary NETs from 2000 to 2018. Patients with MEN1 syndrome or follow up less than 12 months were excluded. Results Three hundred and ten patients were identified. Tumor locations were ampulla (n = 15), duodenum (n = 35) and pancreas (n = 260). Median follow-up and recurrence-free survival (RFS) were 60.9 (interquartile range [IQR]: 34.8-99.3) and 171.7 (IQR: 84.0-NR) months. Clinicopathologic data and survival outcomes were similar for duodenal and ampullary NETs (RFS: p = .347 and overall survival [OS]: p = .246) and were combined into an intestinal subtype (IS) group. There were no differences in OS or RFS when comparing IS-NET and P-NET. On multivariate analysis, tissue of origin was not associated with risk of recurrence. The current American Joint Committee on Cancer staging guidelines, which account for origin tissue, were predictive of outcomes for all subtypes. Conclusion Tissue of origin does not appear to impact long-term outcomes when comparing IS-NETs and P-NETs. The AJCC staging system offers good discriminatory capacity in the context of the tissue type.

Background Modern chemotherapeutics have led to improved systemic disease control for patients with locally advanced pancreatic cancer (LAPC). Surgical strategies such as distal pancreatectomy with celiac axis resection (DP-CAR) are increasingly entertained. Herein we review procedure-specific outcomes and assess biologic rationale for DP-CAR. Methods A prospectively maintained single-institution database of all pancreatectomies was queried for patients undergoing DP-CAR. We excluded all patients for whom complete data were not available and those who were not treated with contemporary multi-agent therapy. Data were supplemented with dedicated chart review and outreach for long-term oncologic outcomes. Results Fifty-four patients underwent DP-CAR between 2008 and 2018. The median age was 62.7 years. Ninety-eight percent received induction chemotherapy. Arterial reconstruction was performed in 17% and concomitant visceral resection in 30%. The R0 resection rate was 87%. Postoperative complications were common (43%) with chyle leak being the most frequent (17%). Length of stay was 8 days, readmission occurred in one-third, and 90-day mortality was 2%. Disease recurrence occurred in 74% during a median follow up of 17.4 months. Median recurrence-free (RFS) and overall survival (OS) were 9 and 25 months, respectively. Conclusions Following modern induction paradigms, DP-CAR can be performed with low mortality, manageable morbidity, and excellent rates of margin-negative resection in high-volume settings. The profile of complications of DP-CAR is distinct from pancreaticoduodenectomy and simple distal pancreatectomy. OS and RFS are similar to those undergoing resection of borderline resectable and resectable disease. Improved systemic disease control will likely lead to increasing utilization of aggressive surgical approaches to LAPC.

Presenter: Ding Ding MD, ScM | Johns Hopkins University School of Medicine Background: Circulating tumor cell (CTC) subtypes have been used as new biomarkers to predict early or late recurrence and response to treatment for pancreatic cancer. A subset of patient have persistent presence of CTCs beyond 6 months of resection. Since the estimated half-life of CTC are estimated to be 15 minutes, persistent CTC is presumed to be an indicator of minimal residual disease. The fate of this cohort of patients is unknown. Herein, we want to determine whether the presence of CTC subtypes found in recurrence free patients approximately 12 months post-surgery was associated with recurrence. Methods: The study included patients in our recently published prospective CLUSTER clinical trial who did not have clinical evidence of recurrence and had CTC testing Results between 9 and 15 months after surgery. Both epithelial CTC (eCTC) and epithelial/mesenchymal CTC (mCTC) subtypes were used to predict recurrence from the CTC testing time within 9-15months after surgery. Kaplan-Meier curve, log-rank test, and Cox model were used for survival analysis. Results: Of the 129 patients enrolled in CLUSTER trial, a total of 28 patients were included in this final study. The recurrence rate per person-month of follow-up was 14.8% (7 recurrences per 48.11.01 months) for the high eCTCs (≥5) group while only 4.2% (9 recurrences per 213.71 months) for the low eCTC ( < 5) group. Low eCTCs was associated with longer recurrence free survival since date of CTC testing compared to high eCTCs (median = not reached vs. 3.78 months, p=0.007). Furthermore, low eCTCs was associated with longer overall survival since CTCs testing date compared to high eCTC (median = not reached vs. 12.30, p=0.027). Negative mCTC (=0) was also associated with longer recurrence free survival (median = not reached vs. 4.23, p=0.015) since date of CTC testing. On multi-variable cox model including pathological covariates, neo-adjuvant, and adjuvant chemotherapy status, high eCTCs was a risk factor for recurrence since date of CTC testing(Hazard Ratio = 4.41; 95% CI [1.13, 17.23]; p=0.033). Positive mCTCs was also associated with a 10.25-fold risk (Hazard ratio = 10.25; 95% CI [1.83, 15.34]; p=0.008) of recurrence since date of CTC testing compared to negative mCTCs. Conclusion: Positive mCTCs and high eCTCs in recurrence free patients around 12 months after surgery were independent prognostic factors for earlier recurrence since date of CTC testing, which could be used a putative biomarker to guide prospective treatment.

Objective: This study seeks to evaluate the efficacy of negative pressure wound therapy for surgical-site infection (SSI) after open pancreaticoduodenectomy. Background: Despite improvement in infection control, SSIs remain a common cause of morbidity after abdominal surgery. SSI has been associated with an increased risk of reoperation, prolonged hospitalization, readmission, and higher costs. Recent retrospective studies have suggested that the use of negative pressure wound therapy can potentially prevent this complication. Methods: We conducted a single-center randomized, controlled trial evaluating surgical incision closure during pancreaticoduodenectomy using negative pressure wound therapy in patients at high risk for SSI. We randomly assigned patients to receive negative pressure wound therapy or a standard wound closure. The primary end point of the study was the occurrence of a postoperative SSI. We evaluated the economic impact of the intervention. Results: From January 2017 through February 2018, we randomized 123 patients at the time of closure of the surgical incision. SSI occurred in 9.7% (6/62) of patients in the negative pressure wound therapy group and in 31.1% (19/61) of patients in the standard closure group (relative risk = 0.31; 95% confidence interval, 0.13-0.73; P = 0.003). This corresponded to a relative risk reduction of 68.8%. SSIs were found to independently increase the cost of hospitalization by 23.8%. Conclusions: The use of negative pressure wound therapy resulted in a significantly lower risk of SSIs. Incorporating this intervention in surgical practice can help reduce a complication that significantly increases patient harm and healthcare costs.