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Purpose:Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment.Experimental Design:Harmonic motion imaging (HMI) is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens.Results:In mice, we learned that stiffness increased during progression from preneoplasia to adenocarcinoma and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2–mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients.Conclusions:These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in PDA.

Supplementary Methods

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SummaryTo identify novel drivers of malignancy in pancreatic ductal adenocarcinoma (PDAC), we employed regulatory network analysis, which calculates the activity of transcription factors and other regulatory proteins based on the integrated expression of their positive and negative target genes. We generated a regulatory network for the malignant epithelial cells of human PDAC using gene expression data from a set of 197 laser capture microdissected human PDAC samples and 45 low-grade precursors, for which we had matched histopathological, clinical, and epidemiological annotation. We then identified the most highly activated and repressed regulatory proteins (e.g. master regulators or MRs) associated with four malignancy phenotypes: precursors vs. PDAC (initiation), low-grade vs. high grade histopathology (progression), survival post resection, and association with KRAS activity. Integrating across these phenotypes, the top MR of PDAC malignancy was found to be BMAL2, a member of the PAS family of bHLH transcription factors. Although the canonical function of BMAL2 is linked to the circadian rhythm protein CLOCK, annotation of BMAL2 target genes highlighted a potential role in hypoxia response. We previously demonstrated that PDAC is hypovascularized and hypoperfused, and here show that PDAC from the genetically engineered KPC model exists in a state of extreme hypoxia, with a partial oxygen pressure of Statement of SignificanceThere is a surprising disconnect between the genomic alterations present in pancreatic ductal adenocarcinoma and key phenotypes of malignancy, suggesting that non-genetic factors must play a role. Here we analyze changes in regulatory state – calculated from network analysis of RNA expression data – to identify transcription factors and other regulatory proteins whose activities drive pancreatic cancer malignancy. We identified the top candidate, BMAL2, as a novel, KRAS-responsive regulator of hypoxic response in pancreatic cancer, serving as a switch between HIF1A and HIF2A expression. These data help explain how KRAS coordinates cell regulatory state to enable tumor cells to survive extreme hypoxia, and highlight the ability of regulatory network analysis to identify overlooked, key drivers of biological phenotypes.

Background While the frequency of pancreatic operations are increasing, understanding quality of life is still insufficient. The aim was to evaluate global health and quality of life of long-term survivors from a range of pancreatic operations using internationally validated instruments. Methods Patients surviving longer than 5 years after pancreatic operations were surveyed using the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Cancer-30 and Pancreatic Cancer-26 modules. Variables were analyzed according to demographic and clinical features. Results Eighty patients completed questionnaires. The median follow-up was 9.3 years from the time of operation. The mean scores of global health status/quality of life, physical function, role function, emotional function, cognitive function, and social functioning were 73.9, 83.7, 84.6, 81.1, 80.2, and 86.3, respectively. The participants’ reported quality of life was comparable or better than the general United States population. The summary score, which was defined as weighted average of function and symptom scores (excluding global health status/quality of life and financial impact scores), showed significant differences according to the level of education (70.1 no college vs 85.2 college and 85.7 grad school, P = .049), operation type (79.9 pancreatoduodenectomy vs 91.1 total, P = .043), additional endoscopic retrograde cholangiopancreatography (77.3 vs 86.0, P = .029), and additional abdominal operations related to the primary operation (79.0 vs 86.6, P = .026). Conclusion Long-term survivors of pancreatectomy had comparable or better global health status/quality of life, function scale, and lower symptom scores than the general population of the United States, though persistent gastrointestinal symptoms are common. These findings should help inform patients of the long-term consequences of pancreatectomy, so they can make better decisions especially when considering prophylactic operations.

Irreversible electroporation (IRE) expands the surgical options for patients with unresectable pancreatic cancer. This study evaluated for differences in survival stratified by type of IRE and receipt of adjuvant chemotherapy.Patients with locally advanced pancreatic cancer treated by IRE (2012-2020) were retrospectively included. Overall survival (OS) and recurrence-free survival (RFS) were compared by type of IRE (in situ for local tumor control or IRE of potentially positive margins with resection) and by receipt of adjuvant chemotherapy.Thirty-nine patients had IRE in situ, 61 had IRE for margin extension, and 19 received adjuvant chemotherapy. Most (97.00%) underwent induction chemotherapy. OS was 28.71 months (interquartile range [IQR] 19.17, 51.19) from diagnosis, with no difference by IRE type (hazard ratio [HR] 1.05 for margin extension [p = 0.85]) or adjuvant chemotherapy (HR 1.14 [p = 0.639]). RFS was 8.51 months (IQR 4.95, 20.17) with no difference by IRE type (HR 0.90 for margin extension [p = 0.694]) or adjuvant chemotherapy (HR 0.90 [p = 0.711]).These findings suggest that adjuvant therapy may have limited benefit for patients treated with induction chemotherapy followed by local control with IRE for unresectable pancreatic cancer. Further study of the duration and timing of systemic therapy is warranted to maximize benefit and limit toxicity.

Background Pancreatogenic diabetes is common after pancreatectomy, and the impact on quality of life (QOL) is poorly understood. The objective of this study was to investigate QOL between diabetic and non-diabetic patients at least five years after pancreatectomy. Methods Patients were recruited from a prospectively maintained institutional database. Participants were administered the Audit of Diabetes-Dependent Quality of Life (ADDQOL). Quality of life was compared between diabetics and non-diabetics using validated European Organization for Research and Treatment of Cancer questionnaires. Results 80 individuals completed surveys. 55% were female, 80% non-Hispanic white, 44% underwent Whipple, 48% were cystic neoplasms and 39% were adenocarcinoma. Diabetic patients (42.5%) reported comparable EORTC QLQ-C30 and Pan26 scores to non-diabetic patients. Pre-operative diabetic patients reported more dyspnea (p = 0.02) and greater pain (p = 0.02) than new-onset diabetics. Diabetic patients reported an overall ADDQOL quality of life score ‘very good’ (IQR: excellent, good) though felt life would be much better without diabetes (IQR: very much better, little better). While operation type was not influential, patients diagnosed with cystic neoplasms were almost twice as likely as those with other pathologies to report that life would be much better without diabetes (p Conclusion At a median of 9.3 years from pancreatic surgery, ADDQoL scores of patients were similar to cohorts of non-pancreatogenic diabetics in the general population. Patients without cancer were more likely to report that diabetes affected their overall QOL, regardless of operation. This study provides nuanced understanding of long-term QOL to improve the informed consent process and post-operative long-term care.

Background/aims The management of small, incidentally discovered nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) has been a matter of debate. Endoscopic ultrasound with fine-needle aspiration (EUS-FNA) is a tool used to identify and risk-stratify PNETs. This study investigates the concordance rate of Ki67 grading between EUS-FNA and surgical pathology specimens in NFPNETs and whether certain NF-PNET characteristics are associated with disease recurrence and disease-related death. Methods We retrospectively reviewed the clinical history, imaging, endoscopic findings, and pathology records of 37 cases of NFPNETs that underwent pre-operative EUS-FNA and surgical resection at a single academic medical center. Results There was 73% concordance between Ki67 obtained from EUS-FNA cytology and surgical pathology specimens; concordance was the highest for low- and high-grade NF-PNETs. High-grade Ki67 NF-PNETs based on cytology (p=0.028) and histology (p=0.028) were associated with disease recurrence and disease-related death. Additionally, tumors with high-grade mitotic rate (p=0.005), tumor size >22.5 mm (p=0.104), and lymphovascular invasion (p=0.103) were more likely to have poor prognosis. Conclusion NF-PNETs with high-grade Ki67 on EUS-FNA have poor prognosis despite surgical resection. NF-PNETs with intermediate-grade Ki67 on EUS-FNA should be strongly considered for surgical resection. NF-PNETs with low-grade Ki67 on EUSFNA can be monitored without surgical intervention, up to tumor size 20 mm.

Purpose: Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment. Experimental Design: Harmonic motion imaging (HMI) is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens. Results: In mice, we learned that stiffness increased during progression from preneoplasia to adenocarcinoma and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2–mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients. Conclusions: These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in PDA.

The evaluation of the malignancy risk of thyroid nodules involves clinical factors, sonographic characteristics, cytopathology, and molecular profiling. Altogether, this algorithm can be costly and time consuming. We evaluated the stepwise contribution of each diagnostic step toward an accurate prediction of malignancy.A retrospective study of dominant nodules of 137 patients who underwent surgical excision was performed. A baseline logistic regression model for predicting malignancy was regressed on clinical factors. In a stepwise fashion, the 2015 American Thyroid Association ultrasound risk stratification, Bethesda classification of fine-needle aspiration biopsies, and molecular profiling were added to the baseline model and the significance of each step analyzed using likelihood ratio test. Receiver operating characteristic curves were calculated for each model.The addition of American Thyroid Association risk stratification and Bethesda classification to preceding models were statistically significant (P.001). The addition of molecular profiling (as a strategy independent of a particular test) was not significant (P = .812). The areas under the curve of the baseline model and models sequentially including American Thyroid Association stratification, cytopathology, and molecular profiling were 0.76, 0.85, 0.91, and 0.91, respectively.Clinical factors, sonographic characteristics, and cytopathology are sufficiently accurate in predicting malignancy risk of most thyroid nodules.

This study aimed to determine the rate, timing, and predictors of diabetes and exocrine pancreatic insufficiency after pancreatectomy in order to inform preoperative patient counseling and risk management strategies.Using prescription claims as a surrogate for disease prevalence, IBM Watson Health MarketScan was queried for claims patterns pre- and post-pancreatectomy. Multivariable models explored associations between clinical characteristics and medication use within 2 years of surgery.In total, 18.96% of 2,848 pancreaticoduodenectomy (PD) patients and 18.95% of 1,858 distal pancreatectomy (DP) patients had preoperative diabetic medication prescription claims. Fewer (6.6% and 3.88%, respectively) had pancreatic enzyme replacement therapy (PERT) claims. Diabetic medication claims increased to 28.69% after PD and 38.59% after DP [adjusted relative risk (aRR) = 1.36 (95% CI 1.27, 1.46)]. Other associated factors included age 45, medical comorbidity, and obesity. The incidence of new diabetic medication claims among medication naïve patients was 13.78% for PD and 24.7% for DP (p 0.001) with a median 4.7 and 4.9 months post-operatively. The prevalence of PERT claims was 55.97% after PD and 17.06% after DP [aRR = 0.32 (0.29, 0.36)]. The incidence of postoperative PERT claims 53.98% (PD) and 14.84% (DP) (p 0.0001). The median time to new PERT claim was 3.0 (PD) and 3.2 (DP) months, respectively. Claims for both diabetic medications and PERT rose sharply after surgery and plateaued within 6 months.This study defines prevalence, timing, and predictors for post-pancreatectomy insufficiency to inform preoperative counseling, risk modification strategies, and interventions related to quality of life.

726 Background: The development of new treatments in oncology is a long, costly, and, too often, unsuccessful process. Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials are needed. Methods: We used a mathematical model of tumor growth kinetics fit to serial radiographic tumor measurements or CA19-9 values to estimate rates of exponential tumor growth [g] and decay [d] during treatment for pancreatic ductal adenocarcinoma (PDAC). Results: We retrospectively collected and analyzed data from 2691 patients with stage III-IV PDAC who were enrolled in five clinical trials or were included in two large real-world data sets from Columbia University Irving Medical Center and Veterans Administration Medical Centers. Using log-rank comparison of Kaplan-Meier plots by quartile of g, we found that in patients with metastatic PDAC g correlates highly with overall (OS) and progression-free survival (PFS) (p

Cytoreductive surgery with intraoperative hyperthermic intraperitoneal chemotherapy is standard of care for diffuse malignant peritoneal mesothelioma (DMPM), but there is variability among institutions in the administration of adjuvant chemotherapy. Characterization of the largest series of DMPM patients treated at a single institution and identification of the demographic, disease, and treatment factors associated with overall survival were sought. All DMPM patients who underwent initial cytoreductive surgery with the intention to undergo intraperitoneal chemotherapy and a second-look operation from 1995 to 2016 at our institution were retrospectively reviewed. The primary endpoint was overall survival. A total of 204 DMPM patients underwent initial cytoreduction. Median overall survival was 32 months from initial cytoreduction. Independent baseline prognostic factors of improved overall survival were female sex, age

Retroperitoneal laparoscopic adrenalectomy is gaining traction as a minimally invasive technique. One of the purported relative contraindications is BMI given the smaller working space. We hypothesize that other anthropometric measurements may be better predictors of operative time. An IRB-approved, single-institution, retrospective study of 83 patients who underwent laparoscopic retroperitoneal adrenalectomy evaluated the association of anthropometric measurements taken from cross-sectional imaging and the primary outcome of operative time. Descriptive statistics were performed with Wilcoxon rank-sum test for continuous variables (median; IQR) and Chi-square (n; %) for categorical variables. A linear random effects model was used to model operative time. The majority of the patients were white (40; 48.2%) women (46; 55.4%) with a median age of 54 with interquartile range (IQR) of 43–63 and a median BMI of 27.8 (IQR 21.2–38.6). On univariable analysis, factors that led to longer operative time included right-sided operation (p = 0.04), male gender (p

Recently, normocalcemic (NC) and normohormonal (NH) variants of primary hyperparathyroidism (pHPT) have been described, with distinct biochemical profiles from the typical high serum calcium and parathyroid hormone (PTH) levels. Here, we investigate whether biochemical profile affects cure rate, as well as the kinetics of intraoperative PTH (IOPTH). This is a single-center, retrospective study of pHPT patients undergoing parathyroidectomy. Patients were grouped based on preoperative calcium and PTH levels into typical, NC (normal calcium, elevated PTH, no evidence of secondary hyperparathyroidism), and NH (elevated calcium, unsuppressed PTH) biochemical profiles. All patients had IOPTH monitoring and ≥6-month post-op serum studies to confirm surgical cure. Patient variables were analyzed with Kruskal–Wallis test and Chi-square analysis. IOPTH kinetic curves were analyzed using a linear mixed model. From June 2006 to October 2014, 646 patients met inclusion criteria. Biochemical profile was typical in 460 patients (71%), NC in 101 (16%), and NH in 85 (13%). IOPTH levels were higher at all time points in typical patients, p

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options and exceedingly high mortality rates. Currently, cure can only be achieved through resection, however the vast majority of patients present with advanced disease for which upfront surgery is not an option. In an effort to improve surgical candidacy, neoadjuvant chemotherapy, with or without radiation therapy, is often used in an effort to downstage borderline resectable and locally advanced tumors, and some argue for its use even in patients with resectable tumors. Underlying this thinking is the recognition that pancreatic cancer is simultaneously both a locally invasive and systemic disease, even in patients without evidence of metastasis on imaging. Current evidence to date is largely retrospective, but suggests that neoadjuvant therapy can increase R0 (pathologically negative margin) resection rates and improve overall survival. The standard approach to neoadjuvant treatment involves choosing between the two most active combination regimens for metastatic disease, namely modified FOLFIRNOX and gemcitabine/nab-paclitaxel. Nonrandomized data indicate that these regimens can yield resection rates up to 68% and 36%, in borderline resectable and locally advanced PDAC, respectively. Furthermore, randomized data in patients with resectable PDAC treated with gemcitabine-based neoadjuvant therapy suggests that despite an approximate 10% drop in resection rates, there is a significant improvement in median overall survival. Herein, we will discuss the rationale for neoadjuvant therapy, current and former treatment regimens, common issues faced by clinicians when using these combinations, and several ongoing clinical trials.

Background Bone mineral density (BMD) has been found to improve after parathyroidectomy (PTX) in patients with primary hyperparathyroidism. There are few data on the effect of PTX on BMD in normocalcemic and normohormonal primary hyperparathyroidism. Methods A retrospective analysis of 92 primary hyperparathyroidism patients who underwent PTX between 2004 and 2012 with pre- and post-PTX dual-energy x-ray absorptiometry was performed. Within-person changes in BMD pre- and post-PTX were analyzed using log linear mixed models, stratified by biochemical status. Results Bone mineral density increased post-PTX in the whole cohort at the lumbar spine (+2.5%), femoral neck (+2.1%), and total hip (+1.9%) and decreased at the one-third radius (–0.9%). On comparison of BMD changes by profile, BMD increased in those with the typical profile at the lumbar spine (3.2%), femoral neck (2.9%), and total hip (2.9%) but declined at the one-third radius (–1.5%). In contrast, BMD improved only at the femoral neck (4.3%) in the normohormonal group and did not change at any site in the normocalcemic group. The typical group had a greater increase in BMD over time at the femoral neck and total hip compared with normocalcemic patients. Conclusion Our results indicate that the skeletal benefit of PTX was attenuated in normocalcemic and normohormonal patients, suggesting that skeletal changes after PTX may depend on biochemical profile.

Background Opioids are central to analgesia for pancreatic diseases. Individuals undergoing pancreatectomy have largely been excluded from studies of opioid use, because of malignancy or chronic use. Surgeons need to understand usage patterns, and practices that may incline patients toward persistent post-operative use. Methods A retrospective study using IBM Watson Health MarketScan database examined patterns of peri-pancreatectomy opioid use between 2009 and 2017. Patients were grouped by opioid use 12 months to 31 days prior to pancreatectomy and followed for persistent use (refills 90–180 days postoperatively). Morphine milligram equivalents (MME) were calculated. Multivariable models explored associations between clinical characteristics, perioperative use and persistent use. Results Opioids were used within the year prior to surgery by 35.6% of 8325 patients. The median MME for opioid naive patients (400 mg) was a fraction of the 1800 mg prescribed to chronic opioid users for peri-operative analgesia. The rate of persistent opioid use was 15.1% among naive, 27.2% among intermittent and 77.3% among chronic opioid users. Multivariable models demonstrated naive and intermittent users who filled a prescription within 30 days prior to pancreatectomy, those who were prescribed total MME ≥1500 mg, and a ≥14 day supply were most at risk of persistent opioid use. Almost 23% of chronic users stopped using opioids post-operatively, suggesting surgery can provide relief. Conclusion Preoperative and persistent opioid use after pancreatectomy is substantially greater than expected based on other operations. Providers may mitigate this by recognizing the issue, managing expectations, and altering the timing and quantities of opioids prescribed.

Pancreas ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of 10%. Currently, chemotherapy remains the standard of care for systemic treatment. Immunotherapy with checkpoint inhibitors unfortunately has not been found to be effective in the treatment of PDAC to date, likely due to the highly desmoplastic and immunosuppressive tumor microenvironment (TME). Treatment targeting pathways against the immunosuppressive mechanisms of PDAC are of mounting interest to improve outcomes in PDAC. In this review, we discuss prior efforts and the current state of immunotherapy in PDAC. We will also review the emerging targets and treatments with significant clinical potential for the treatment of PDAC such as: CD40 pathway, the adenosine pathway, the CXCR4/CXCL12 axis, the CCR2/CCL2 axis, IDO pathway, and others.

Background & Aims There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. Methods CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. Results In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection. Conclusion CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.

Patients with low-risk lesions require ongoing surveillance since the rate of progression to pancreatic cancer (PC), while small, is much greater than in the general population. Our objective was to study the relationship between new onset diabetes (NODM) and progression in patients with low risk mucinous cysts.We evaluated a prospectively maintained cohort of 442 patients with a suspected mucinous cyst without worrisome features (WF) or high-risk stigmata (HRS). Multivariable Cox models were developed for progression to WF and HRS, with diabetes status formulated as both time independent and dependent covariates. The adjusted cumulative risk of progression was calculated using the corrected group prognosis method.The 5-year cumulative progression rates to WFs and HRS were 12.8 and 3.6%, respectively. After controlling for other risk factors, the development of NODM was strongly associated with progression to HRS (HR = 11.6; 95%CI, 3.5-57.7%), but not WF. Among patients with the smallest cysts (10 mm) at baseline, those who developed NODM had a 5-year adjusted cumulative risk of progression to HRS of 8.6% (95%CI, 0.0%-20.2%), compared to only 0.8% (95%CI, 0.0%-2.3%) for patients without NODM. Among patients with the largest cysts (20-29 mm), those who developed NODM during surveillance had a 5-year adjusted cumulative risk of progression of 53.5% (95%CI, 19.6%-89.9%) compared to only 7.5% (95%CI, 1.6%-15.2%) for patients without NODM.New onset diabetes may predict progression in patients with low risk mucinous cysts. Pending validation with large-scale studies, these findings support regular diabetes screening among patients surveilled for suspected IPMNs or MCNs.

608 Background: Recurrence rates after resection of pancreatic ductal adenocarcinoma (PDA) can be up to 80%. Prior data suggests that initial site of recurrence influences prognosis. This study aims to compare survival of patients (pts) with resected PDA by initial site of recurrence. Methods: We retrospectively reviewed the demographics, treatments, recurrence and survival of 717 pts with PDA who underwent resection at Columbia University Irving Medical Center from 2011 to 2020 and were part of a tumor registry. Analyses were performed using Kaplan-Meier and paired T-tests. Results: Of 717 pts with resected PDA, 320 had confirmed recurrence. Median age at diagnosis was 67 years (yrs). Among pts with a single initial recurrence site, 36 recurred in lung, 97 in liver, 95 locally, and 23 in peritoneum. 58 pts had initial recurrence at 2 or more sites. Neoadjuvant treatment had been administered in 42%, 36%, 40%, 35%, and 22% of pts with lung, liver, local, peritoneal, and multiple sites at initial recurrence, respectively (p=0.21). Adjuvant treatment had been administered in 72%, 69%, 76%, 70%, and 72% of pts with lung, liver, local, peritoneal, and multiple sites at initial recurrence, respectively (p=0.88). Pts with initial lung recurrence had a significantly longer median overall survival (mOS), 4.39 yrs, compared to initial recurrence in the liver (1.98 yrs, p=0.02), peritoneum (2.19 yrs, p=0.0002), and at multiple sites (2.66 yrs, p=0.03). A significantly longer time from diagnosis to recurrence was observed in pts who had initial lung recurrence, compared to pts who had initial hepatic, peritoneal or multiple site recurrences. Pts with initial lung recurrence had a significantly longer time from first recurrence to death compared to pts with initial peritoneal recurrence. See Table for summary. Conclusions: Pts with resected PDA with initial pulmonary recurrence experience improved survival compared to those who recur at other distinct or multiple sites. The underlying pathways contributing to this improved survival need to be investigated further.[Table: see text]

565 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a minority of patients (pts) eligible for curative resection. Currently, systemic treatment options for down-staging pts with borderline resectable or locally advanced PDAC is extrapolated from the metastatic setting and modified FOLFIRINOX (FFX) +/- radiation (RT) is the most widely used regimen. Herein, we report the outcomes of combination gemcitabine, docetaxel, and capecitabine (GTX) +RT as compared to FFX +RT in the neoadjuvant (NA) setting via a single institution retrospective cohort review. Methods: We retrospectively reviewed the outcomes of pts with PDAC who underwent surgical resection at Columbia University Irving Medical Center (CUIMC) between 2011-2020. We evaluated demographics, treatment, clinical, surgical, and pathological outcomes. Statistical analysis includes Kaplan-Meier analysis and paired t-tests. Results: We reviewed 717 pts who underwent surgical resection at CUIMC of which 227 pts were confirmed to have received NA chemotherapy. Of those 227 patients, 133 pts also received RT. In total, 39 pts received GTX+RT and 42 pts received FFX+RT. Median age at diagnosis of pts who received NA GTX+RT or FFX+RT was 65 and 63 years, respectively. All pts were AJCC stage III at diagnosis and ECOG 0 or 1. There was a significantly greater percentage of pts who achieved R0 resection after GTX+RT as compared to FFX+RT, 35 (89.7%) vs 29 (69.0%), respectively (p=0.022). Significantly more pts achieved N0 lymph node status after GTX+RT as compared to FFX+RT, 29 (74.4%) vs 22 (52.4%), respectively (p=0.041). No statistically significant difference was detected in recurrence-free survival (RFS) or median overall survival (mOS) in pts who received GTX+RT and achieved R0 resection as compared to FFX+RT. See Table for summary. Conclusions: GTX appears to be a viable and active NA regimen in Stage III PDAC. In our small cohort study, more patients who received GTX+RT achieved R0 resection and N0 status as compared to FFX+RT. No difference in survival was detected but this may be due to inadequate power or choice of subsequent therapies. Larger prospective studies evaluating GTX+RT as an alternative treatment in the NA setting are warranted.[Table: see text]

Introduction Neuroendocrine tumors (NETs) represent a small proportion of cancers, but are increasing in incidence due to incidental diagnosis. We examined NET incidence and survival over time in a population-based registry. Materials/Methods We identified all NET cases diagnosed between 1995 and 2014 in the Surveillance, Epidemiology, and End Results database, November 2016 submission. We determined incidence rates and calculated overall and cancer-specific survival curves in different subgroups stratified by grade, stage, and age at diagnosis. Results We identified 85,133 patients with a diagnosis of NET between 1995 and 2014. Patients with grade 1, localized NETs had the best median overall survival (233 months, 95% confidence intervals [CI] not estimable) and 5-year cancer-specific survival (97.6%; 95% CI, 97.4%, 97.8%). The median overall survival decreased with age across the entire spectrum of ages, with patients >70 years having a particularly poor prognosis (28.0 months; 95% CI, 26.5, 29.5). Patients >70 years old often had distant (34.3%) or grade 3 disease (40.8%), but even elderly patients with lower grade and/or stage disease had worse median overall survival compared with younger subjects. Conclusions Age appears to be associated with a worse prognosis independent of NET stage, and grade at the time of diagnosis. Patients with grade 1, localized NETs have an excellent long-term prognosis. Further research is warranted on reducing intensity of surveillance in these patients.

Large-scale sequencing studies have identified a limited number of genetic drivers of PDAC malignancy, with only four genes found mutated a high penetrance across human pancreatic tumors. This suggests that the cell-autonomous ability to progress, dedifferentiate and metastasize is determined by non-genetic alterations to transcriptional regulation. Regulatory network analysis is a computational means of identifying changes in the activity of transcription factors on a genome-wide scale. Briefly, the approach calculates the activity of each regulatory protein (i.e. transcription factors, co-factors, and other proteins that regulate RNA transcript abundance) based on the expression of its positive and negative transcriptional targets (which are inferred de novo in a context-specific manner using the ARACNe algorithm). In this way, it is possible to identify the most hyper-activated and hyper-repressed regulatory proteins between groups of samples that represent different phenotypes – i.e. the “master regulators” (MRs) of those phenotypes. We applied regulatory network analysis to identify MRs of PDAC malignancy by comparing groups of samples representing several phenotypes. First, we performed laser capture microdissection and RNA sequencing (LCM-RNAseq) on 199 human PDAC samples, 26 low-grade PanIN, and 19 low-grade IPMN, isolating just the epithelial cells for transcriptional profiling. We then identified MRs of four different phenotypes among these samples: 1) precursor versus PDAC; 2) low-grade versus high-grade PDAC (based on histopathology); 3) low versus high Kras signaling; and long versus short overall survival. Integrating these analyses, the most highly activated regulatory protein in the genome across these four phenotypes was ARNTL2, an understudied member of the ARNT (HIF1β) superfamily. Notably, this protein was only modestly differentially expressed at the RNA level, indicating that its activation occurs primarily at a post-translational level. Computational analysis of the function of ARNTL2 indicated an enrichment of pathways involved in hypoxia responsiveness. Experimental analysis found that ARNTL2 had little impact in proliferation or survival under normoxic conditions, but drove increased invasiveness under hypoxic conditions. The functional associations of ARNTL2 in cultured cells expanded substantially under hypoxic conditions. Together, these findings suggest that ARNTL2 may serve as a Kras-associated, hypoxia-responsive driver of PDAC malignancy. Citation Format: Alvaro Curiel-Garcia, Carlo H. Maurer, Pasquale Laise, Irina Sagalovskiy, John A. Chabot, Gulam A. Manji, Alina Iuga, Kristen Johnson, Andrea Califano, Kenneth P. Olive. ARNTL2 is a hypoxia-responsive master regulator of PDAC malignancy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-001.

The prognosis for patients with diffuse malignant peritoneal mesothelioma has dramatically improved with cytoreductive surgery and intraperitoneal chemotherapy. Little is known about disease recurrence after treatment. We analyzed the time to and predictors of recurrence in a large cohort of optimally treated patients. We examined 113 patients completing a two-stage cytoreduction and intraperitoneal chemotherapy protocol. All patients achieved optimal surgical resection with completeness of cytoreduction (CC) score ≤ 1 and were divided into two groups based on absence (Group A) or presence (Group B) of gross disease at the outset of the second operation. Predictors of disease recurrence and recurrence-free survival (RFS) were determined using Cox proportional hazard regression modeling, and estimates were obtained by using the Kaplan–Meier method. Forty-six percent of patients had no gross evidence of disease at the second operation; the remaining 54% were cytoreduced to CC ≤ 1 (Group B). Forty-two percent of patients developed disease recurrence with a median recurrence-free survival of 38.5 months for the cohort; 79% of these received a form of iterative treatment. There was no statistically significant difference in recurrence-free survival between Group A (median RFS: 44.6 months) and B (median RFS: 35.5 months) (log-rank test, p = 0.06). Additionally, the only variable significantly associated with RFS was male gender (hazard ratio [HR] 1.98, 95% confidence interval [CI] 1.16–3.38). Absence of gross disease at the second operation was not statistically protective against recurrence compared with presence of quantifiable residual disease (Group B) that was effectively cytoreduced. Long-term disease surveillance is recommended, because recurrence continues years after treatment. Where a question of recurrence arises on surveillance, males may benefit from a higher degree of suspicion.

Modern-era systemic therapy for locally advanced pancreatic adenocarcinoma (LAPC) offers improved survival relative to historical regimens but not necessarily improved radiographic downstaging to allow more patients to undergo resection. The aim of this study was to evaluate the survival, progression, and pathologic outcomes after resection of LAPC that did not regress from > 180 degrees arterial encasement after neoadjuvant therapy. Sixty-one LAPC patients were brought to the operating room after neoadjuvant therapy for NCCN-defined unresectable pancreatic cancer between 2012 and 2017. Pts were explored with intent of pancreatectomy and irreversible electroporation for margin extension; 5 (8%) had metastatic lesions on exploratory laparoscopy and were excluded from analyses. Imaging was re-examined to confirm LAPC prior to surgery. Data were analyzed from a prospective pancreatic cancer database. Patients had arterial involvement of the celiac axis (37.5%) and/or superior mesenteric artery (42.9%) and/or an extended length of the common hepatic (n = 44.6%) artery. Twenty-nine males and 27 females, median 65 years of age, received neoadjuvant gemcitabine-based (58.9%) or FOLFIRINOX (35.7%) chemotherapy and stereotactic body (42.9%) or intensity-modulated (51.8%) radiation therapy. Median months from initiation of neoadjuvant therapy to surgery was 7.5. Sixty-one percent underwent Whipple, 21% distal, and 18% modified Appleby procedures; 57% patients underwent venous reconstruction. Ninety-day mortality was 2%. An R0 margin was achieved in 80%, and 53% were N0. Median overall and progression-free survival was 18.5 (95%CI 12.27–32.33) and 8.5 months (95%CI 6.0–15.0), respectively. One- and 3-year survival from surgery was 68.5% (95%CI 53.0–79.7) and 39.0% (95%CI 23.7–53.8), respectively. With modern-era neoadjuvant therapy, R0 resections can be achieved in a majority of non-metastatic patients with locally advanced, unresectable disease based on cross-sectional imaging.

Purpose To assess the relationship between diffusion-weighted imaging (DWI) and intravoxel incoherent motion (IVIM)-derived quantitative parameters (apparent diffusion coefficient [ADC], perfusion fraction [f], Dslow, diffusion coefficient [D], and Dfast, pseudodiffusion coefficient [D*]) and histopathology in pancreatic adenocarcinoma (PAC). Materials and Methods Subjects with suspected surgically resectable PAC were prospectively enrolled in this Health Insurance Portability and Accountability Act (HIPAA)-compliant, Institutional Review Board-approved study. Imaging was performed at 1.5T with a respiratory-triggered echo planar DWI sequence using 10 b values. Two readers drew regions of interest (ROIs) over the tumor and adjacent nontumoral tissue. Monoexponential and biexponential fits were used to derive ADC2b, ADCall, f, D, and D*, which were compared to quantitative histopathology of fibrosis, mean vascular density, and cellularity. Two biexponential IVIM models were investigated and compared: 1) nonlinear least-square fitting based on the Levenberg–Marquardt algorithm, and 2) linear fit using a fixed D* (20 mm2/s). Statistical analysis included Student's t-test, Pearson correlation (P < 0.05 was considered significant), intraclass correlation, and coefficients of variance. Results Twenty subjects with PAC were included in the final cohort. Negative correlation between D and fibrosis (Reader 2: r = –0.57 P = 0.01; pooled P = –0.46, P = 0.04) was observed with a trend toward positive correlation between f and fibrosis (r = 0.44, P = 0.05). ADC2b was significantly lower in PAC with dense fibrosis than with loose fibrosis ADC2b (P = 0.03). Inter- and intrareader agreement was excellent for ADC, D, and f. Conclusion In PAC, D negatively correlates with fibrosis, with a trend toward positive correlation with f suggesting both perfusion and diffusion effects contribute to stromal desmoplasia. ADC2b is significantly lower in tumors with dense fibrosis and may serve as a biomarker of fibrosis architecture. Level of Evidence: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:393–402

Primary hyperparathyroidism is characterized by increased levels of serum calcium and parathyroid hormone. Recently, 2 additional mild biochemical profiles have emerged, normocalcemic and normohormonal primary hyperparathyroidism. We reviewed our surgical experience of mild biochemical profile patients and compared them with classic primary hyperparathyroidism patients.This is a single institution, retrospective cohort review of all patients who underwent parathyroidectomy for primary hyperparathyroidism from 2006-2012. Preoperative and intraoperative variables were analyzed. Univariable analysis was performed with analysis of variance and the χA total of 573 patients underwent parathyroidectomy for primary hyperparathyroidism (classic, n = 405; normohormonal, n = 96; normocalcemic, n = 72). Normocalcemic primary hyperparathyroidism was associated with multigland disease in 43 (45%, P .001) patients as compared with the normohormonal (7, 10%) and classic (36, 9%) groups. On logistic regression, significant predictors for multigland disease were the normocalcemic subtype and positive family history. Twelve month biochemical normalization rates after operative treatment were98% in all 3 groups.Our series shows that normocalcemic primary hyperparathyroidism is associated with a high incidence of multigland disease. Normohormonal disease is similar to classic disease patients with90% presenting with single adenomas. Excellent rates of biochemical normalization can be obtained by operative treatment in all 3 groups.

There is substantial evidence that resecting adrenal metastases can be safely accomplished and extend overall survival in select patients. However, patient access to this operation has not been studied at the population level. The purpose of this study was to determine differences in utilization rates of adrenal metastasectomy (ADMX) across patient populations. The Healthcare Utilization Project National Inpatient Sample was used to identify patients who had adrenal metastases (ADM) and who underwent ADMX from 2007 to 2011. Patients were identified by ICD-9-CM diagnosis and procedure codes. Predictor variables included sex, race, median household income, and primary insurance payer. Primary outcomes included receiving an ADMX and same hospitalization mortality. Secondary outcomes included length of stay, infection, cardiac, pulmonary, and renal complications. Univariable and multivariable logistic regression models were used to identify statistical associations. 32,331 ADM and 1070 ADMX patients identified in the database. Despite similar comorbidities, Black patients had 0.30 (95% CI 0.21–0.41) lower odds to receive an ADMX compared to White patients. Medicaid patients had 0.38 (0.28–0.52) less odds and Private Insurance patients 1.18 (1.00–1.39) more odds to receive an ADMX compared to Medicare patients. Women had a 1.39 (1.22–1.58) higher odds ratio of undergoing ADMX compared to men. Of the ADMX cohort, there was no difference in same hospitalization mortality or surgical complications. Black and Medicaid patients underwent fewer adrenal metastasectomies despite similar comorbidities and postoperative outcomes. This suggests a potential disparity in access to this treatment that disproportionately affects Black and low-income patients, and prompts further study, outreach attempts, as well as, research into improving access.

Background and aims: Poor specificity and predictive values of current cross-sectional radiological imaging methods in evaluation of pancreatic adenocarcinoma (PDAC) limit the clinical capability to accurately stage the tumor pre-operatively and provide optimal surgical treatment and improve patient outcomes. Methods: In this study, we applied Harmonic Motion Elastography (HME), a quantitative ultrasound-based imaging method to calculate Young's modulus (YM) in PDAC mouse models (n = 30) and human pancreatic resection specimens of PDAC (n=32). We compared the YM to the collagen assessment by Picrosirius red (PSR) stain on corresponding histologic sections. Results: HME is capable of differentiating between different levels of fibrosis in transgenic mice. In mice without pancreatic fibrosis, the measured YM was 4.2 ± 1.3 kPa, in fibrotic murine pancreata, YM was 5.5 ± 2.0 kPa and in murine PDAC tumors, YM was 11.3 ± 1.7 kPa. The corresponding PSR values were 2.0 ± 0.8 %, 9.8 ± 3.4 %, and 13.2 ± 1.2%, respectively. In addition, three regions within each human surgical PDAC specimen were assessed: tumor, which had both the highest Young's modulus (YM > 40 kPa) and collagen density (PSR > 40 %); non-neoplastic adjacent pancreas, which had the lowest Young's modulus (YM < 15 kPa) and collagen density (PSR < 10%) and a transitional peri-lesional region between the tumor and non-neoplastic pancreas with an intermediate value of measured Young's modulus (15 kPa < YM < 40 kPa) and collagen density (15% < PSR < 35 %). Conclusion: In conclusion, a non-invasive, quantitative imaging tool for detecting, staging and delineating PDAC tumor margins based on the change in collagen density was developed.

Quantitative metrics to objectively assess the fidelity of cancer models, such as cell lines, organoids, or patient-derived xenografts (PDXs), remain elusive, with histological criteria or the presence of specific mutations often used as driving principles. We show that molecular criteria, based on the regulatory proteins responsible for maintaining transcriptional cell state and its regulatory network, are effective in identifying models that can recapitulate drug mechanism of action and drug sensitivity, independent of histological consideration.

ObjectivePancreatic ductal adenocarcinoma (PDA) has among the highest stromal fractions of any cancer and this has complicated attempts at expression-based molecular classification. The goal of this work is to profile purified samples of human PDA epithelium and stroma and examine their respective contributions to gene expression in bulk PDA samples.DesignWe used laser capture microdissection (LCM) and RNA sequencing to profile the expression of 60 matched pairs of human PDA malignant epithelium and stroma samples. We then used these data to train a computational model that allowed us to infer tissue composition and generate virtual compartment-specific expression profiles from bulk gene expression cohorts.ResultsOur analysis found significant variation in the tissue composition of pancreatic tumours from different public cohorts. Computational removal of stromal gene expression resulted in the reclassification of some tumours, reconciling functional differences between different cohorts. Furthermore, we established a novel classification signature from a total of 110 purified human PDA stroma samples, finding two groups that differ in the extracellular matrix-associated and immune-associated processes. Lastly, a systematic evaluation of cross-compartment subtypes spanning four patient cohorts indicated partial dependence between epithelial and stromal molecular subtypes.ConclusionOur findings add clarity to the nature and number of molecular subtypes in PDA, expand our understanding of global transcriptional programmes in the stroma and harmonise the results of molecular subtyping efforts across independent cohorts.

Aims: We sought to re-examine the incidence of thyroid cancer among breast cancer survivors by performing a population-based, cohort analysis using the SEER-9 database. Methods: We identified 704,370 breast cancer patients, 49,663 thyroid cancer patients and 1526 patients who developed thyroid cancer after breast cancer (B1T). Results: Risk for developing thyroid cancer is greatest among survivors diagnosed with breast cancer at age less than 50 years. In general, B1T patients are younger with smaller tumors, and have a greater percentage of invasive ductal carcinoma. They develop thyroid cancer at an older age, and have a greater percentage of aggressive subtypes. Conclusion: Recognition of this association between thyroid and breast cancer should prompt increased awareness in these cancer patient populations.