Browsing by Author "Zyromski, Nicholas J."

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    Adipocytes enhance murine pancreatic cancer growth via a hepatocyte growth factor (HGF)-mediated mechanism
    (Elsevier, 2016-04) Ziegler, Kathryn M.; Considine, Robert V.; True, Eben; Swartz-Basile, Deborah A.; Pitt, Henry A.; Zyromski, Nicholas J.; Department of Surgery, IU School of Medicine
    INTRODUCTION: Obesity accelerates the development and progression of pancreatic cancer, though the mechanisms underlying this association are unclear. Adipocytes are biologically active, producing factors such as hepatocyte growth factor (HGF) that may influence tumor progression. We therefore sought to test the hypothesis that adipocyte-secreted factors including HGF accelerate pancreatic cancer cell proliferation. MATERIAL AND METHODS: Murine pancreatic cancer cells (Pan02 and TGP-47) were grown in a) conditioned medium (CM) from murine F442A preadipocytes, b) HGF-knockdown preadipocyte CM, c) recombinant murine HGF at increasing doses, and d) CM plus HGF-receptor (c-met) inhibitor. Cell proliferation was measured using the MTT assay. ANOVA and t-test were applied; p < 0.05 considered significant. RESULTS: Wild-type preadipocyte CM accelerated Pan02 and TGP-47 cell proliferation relative to control (59 ± 12% and 34 ± 12%, p < 0.01, respectively). Knockdown of preadipocyte HGF resulted in attenuated proliferation vs. wild type CM in Pan02 cells (35 ± 5% vs. 68 ± 14% greater than control; p < 0.05), but proliferation in TGP-47 cells remained unchanged. Recombinant HGF dose-dependently increased Pan02, but not TGP-47, proliferation (p < 0.05). Inhibition of HGF receptor, c-met, resulted in attenuated proliferation versus control in Pan02 cells, but not TGP-47 cells. CONCLUSIONS: These experiments demonstrate that adipocyte-derived factors accelerate murine pancreatic cancer proliferation. In the case of Pan02 cells, HGF is responsible, in part, for this proliferation.
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    Annular pancreas: endoscopic and pancreatographic findings from a tertiary referral ERCP center
    (Elsevier, 2019-02) Gromski, Mark A.; Lehman, Glen A.; Zyromski, Nicholas J.; Watkins, James L.; El Hajj, Ihab I.; Tan, Damien; McHenry, Lee; Easler, Jeffrey J.; Tirkes, Temel; Sherman, Stuart; Fogel, Evan L.; Medicine, School of Medicine
    Background and Aims Annular pancreas is a congenital anomaly whereby pancreatic tissue encircles the duodenum. Current knowledge of endoscopic findings of annular pancreas is limited to small case series. The aim of this study was to describe the endoscopic and pancreatographic findings of patients with annular pancreas at a large tertiary care ERCP center. Methods This is a retrospective observational study. Our Institutional Review Board–approved, prospectively collected ERCP database was queried for cases of annular pancreas. The electronic medical records were searched for patient and procedure-related data. Results From January 1, 1994, to December 31, 2016, 46 patients with annular pancreas underwent ERCP at our institution. Index ERCP was technically successful in 42 patients (91.3%), and technical success was achieved in all 46 patients (100%) after 2 attempts, when required. A duodenal narrowing or ring was found in most patients (n = 39, 84.8%), yet only 2 (4.3%) had retained gastric contents. Pancreas divisum was found in 21 patients (45.7%), 18 of which were complete divisum. Pancreatobiliary neoplasia was the indication for ERCP in 7 patients (15.2%). Pancreatographic findings consistent with chronic pancreatitis were noted in 15 patients (32.6%) at the index ERCP. Conclusion This is the largest series describing the endoscopic and pancreatographic findings of patients with annular pancreas. We found that 45.7% of patients had concurrent pancreas divisum. Endoscopic therapy was successful in most patients at our institution after 1 ERCP, and in all patients after a second ERCP. Nearly one-third of patients had findings consistent with chronic pancreatitis at the time of index ERCP. It is unclear whether this may be a feature of the natural history of annular pancreas.
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    Biliary Stricture after Necrotizing Pancreatitis: An Underappreciated Challenge
    (Wolters Kluwer, 2020-10) Maatman, Thomas K.; Ceppa, Eugene P.; Fogel, Evan L.; Easler, Jeffrey J.; Gromski, Mark A.; House, Michael G.; Nakeeb, Attila; Schmidt, C. Max; Sherman, Stuart; Zyromski, Nicholas J.; Surgery, School of Medicine
    Objective: Biliary stricture in necrotizing pancreatitis (NP) has not been systematically categorized; therefore, we sought to define the incidence and natural history of biliary stricture caused by NP. Summary/Background Data: Benign biliary stricture occurs secondary to bile duct injury, anastomotic narrowing, or chronic inflammation and fibrosis. The profound loco-regional inflammatory response of NP creates challenging biliary strictures. Methods: NP patients treated between 2005–2019 were reviewed. Biliary stricture was identified on cholangiography as narrowing of the extrahepatic biliary tree to < 75% of the diameter of the unaffected duct. Biliary stricture risk factors and outcomes were evaluated. Results: Among 743 NP patients, 64 died, 13 were lost to follow up; therefore, a total of 666 patients were included in the final cohort. Biliary stricture developed in 108 (16%) patients. Mean follow up was 3.5 ± 3.3 years. Median time from NP onset to biliary stricture diagnosis was 4.2 months (IQR, 1.8–10.9). Presentation was commonly clinical or biochemical jaundice, n = 30 (28%) each. Risk factors for stricture development were splanchnic vein thrombosis and pancreatic head parenchymal necrosis. Median time to stricture resolution was 6.0 months after onset (2.8–9.8). A mean of 3.3 ± 2.3 procedures were performed. Surgical intervention was required in 22 (20%) patients. Endoscopic treatment failed in 17% (17/99) of patients and was not associated with stricture length. Operative treatment of biliary stricture was more likely in patients with infected necrosis or NP disease duration ≥6 months. Conclusion: Biliary stricture occurs frequently after necrotizing pancreatitis and is associated with splanchnic vein thrombosis and pancreatic head necrosis. Surgical correction was performed in 20%.
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    Cancer History: A Predictor of IPMN Subtype and Dysplastic Status?
    (Elsevier, 2017) Carr, Rosalie A.; Kiel, Brandon A.; Roch, Alexandra M.; Ceppa, Eugene P.; House, Michael G.; Zyromski, Nicholas J.; Nakeeb, Attila; Schmidt, C. Max; Surgery, School of Medicine
    Introduction The aim of this study was to determine the association of PMH and FH of pancreatic (PDAC) and non-pancreatic cancers with IPMN malignant risk. Methods A retrospective review of a prospective database of IPMN patients undergoing resection was performed to assess FH and PMH. Results FH of PDAC was present in 13% of 362 included patients. Of these, 8% had at least one first degree relative (FDR) with PDAC. The rate of PDAC positive FH in non-invasive versus invasive IPMN patients was 14% and 8%, respectively (p = 0.3). In main duct IPMN patients, FH (44%) and PMH of non-pancreatic cancer (16%) was higher than that seen in branch duct IPMN (FH 29%; PMH 6%; p = 0.004 and 0.008). Conclusions FH of PDAC is not associated with IPMN malignant progression. FH and PMH of non-pancreatic cancer is associated with main duct IPMN, the subtype with the highest rate of invasive transformation.
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    The continuum of complications in survivors of necrotizing pancreatitis
    (Elsevier, 2020-12) Maatman, Thomas K.; Roch, Alexandra M.; Ceppa, Eugene P.; Easler, Jeffrey J.; Gromski, Mark A.; House, Michael G.; Nakeeb, Attila; Schmidt, C. Max; Sherman, Stuart; Zyromski, Nicholas J.; Surgery, School of Medicine
    Background: Necrotizing pancreatitis survivors develop complications beyond infected necrosis that often require invasive intervention. Remarkably few data have cataloged these late complications after acute necrotizing pancreatitis resolution. We sought to identify the types and incidence of complications after necrotizing pancreatitis. Design: An observational study was performed evaluating 647 patients with necrotizing pancreatitis captured in a single-institution database between 2005 and 2017 at a tertiary care hospital. Retrospective review and analysis of newly diagnosed conditions attributable to necrotizing pancreatitis was performed. Exclusion criteria included the following: death before disease resolution (n = 57, 9%) and patients lost to follow-up (n = 12, 2%). Results: A total of 578 patients were followed for a median of 46 months (range, 8 months to 15 y) after necrotizing pancreatitis. In 489 (85%) patients 1 or more complications developed and included symptomatic disconnected pancreatic duct syndrome (285 of 578, 49%), splanchnic vein thrombosis (257 of 572, 45%), new endocrine insufficiency (195 of 549, 35%), new exocrine insufficiency (108 of 571, 19%), symptomatic chronic pancreatitis (93 of 571, 16%), incisional hernia (89 of 420, 21%), biliary stricture (90 of 576, 16%), chronic pain (44 of 575, 8%), gastrointestinal fistula (44 of 578, 8%), pancreatic duct stricture (30 of 578, 5%), and duodenal stricture (28 of 578, 5%). During the follow-up period, a total of 340 (59%) patients required an invasive intervention after necrotizing pancreatitis resolution. Invasive pancreatobiliary intervention was required in 230 (40%) patients. Conclusion: Late complications are common in necrotizing pancreatitis survivors. A broad variety of problems manifest themselves after resolution of the acute disease process and often require invasive intervention. Necrotizing pancreatitis patients should be followed lifelong by experienced clinicians.
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    The Dilemma of the Dilated Main Pancreatic Duct in the Distal Pancreatic Remnant After Proximal Pancreatectomy for IPMN
    (Springer, 2019-08) Simpson, Rachel E.; Ceppa, Eugene P.; Wu, Howard H.; Akisik, Fatih; House, Michael G.; Zyromski, Nicholas J.; Nakeeb, Attila; Al-Haddad, Mohammad A.; DeWitt, John M.; Sherman, Stuart; Schmidt, C. Max; Surgery, School of Medicine
    Objective(s) A dilated main pancreatic duct in the distal remnant after proximal pancreatectomy for intraductal papillary mucinous neoplasms (IPMN) poses a diagnostic dilemma. We sought to determine parameters predictive of remnant main-duct IPMN and malignancy during surveillance. Methods Three hundred seventeen patients underwent proximal pancreatectomy for IPMN (Indiana University, 1991–2016). Main-duct dilation included those ≥ 5 mm or “dilated” on radiographic reports. Statistics compared groups using Student’s T/Mann-Whitney U tests for continuous variables or chi-square/Fisher’s exact test for categorical variables with P < 0.05 considered significant. Results High-grade/invasive IPMN or adenocarcinoma at proximal pancreatectomy predicted malignant outcomes (100.0% malignant outcomes; P < 0.001) in remnant surveillance. Low/moderate-grade lesions revealed benign outcomes at last surveillance regardless of duct diameter. Twenty of 21 patients undergoing distal remnant reoperation had a dilated main duct. Seven had main-duct IPMN on remnant pathology; these patients had greater mean maximum main-duct diameter prior to reoperation (9.5 vs 6.2 mm, P = 0.072), but this did not reach statistical significance. Several features showed high sensitivity/specificity for remnant main-duct IPMN. Conclusions Remnant main-duct dilation after proximal pancreatectomy for IPMN remains a diagnostic dilemma. Several parameters show a promise in accurately diagnosing main-duct IPMN in the remnant.
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    DNA profile components predict malignant outcomes in select cases of intraductal papillary mucinous neoplasm with negative cytology
    (Elsevier, 2018-10) Simpson, Rachel E.; Cockerill, Nathan J.; Yip-Schneider, Michele T.; Ceppa, Eugene P.; House, Michael G.; Zyromski, Nicholas J.; Nakeeb, Attila; Al-Haddad, Mohammad A.; Schmidt, C. Max; Surgery, School of Medicine
    Predicting malignancy in intraductal papillary mucinous neoplasm remains challenging. Integrated molecular pathology combines pancreatic fluid DNA and clinical factors into a malignant potential score. We sought to determine the utility of DNA components alone in predicting high-grade dysplasia/invasive disease. Methods We reviewed prospectively the records from 1,106 patients with intraductal papillary mucinous neoplasm. We excluded non-intraductal papillary mucinous neoplasm cases and cases with definitive malignant cytology. A total 225 patients had 283 DNA profiles (98 followed by surgery, 185 followed by ≥23-month surveillance). High-grade dysplasia/invasive outcomes were high-grade dysplasia, intraductal papillary mucinous neoplasm-invasive, and adenocarcinoma on surgical pathology or mesenteric or vascular invasion, metastases, or biopsy with high-grade dysplasia or adenocarcinoma during surveillance. Results High-quantity DNA predicted (P = .004) high-grade dysplasia/invasive disease outcomes with sensitivity of 78.3%, but 52.7% specificity, indicating benign cases may exhibit high-quantity DNA. High clonality loss of heterozygosity of tumor suppressor genes was 98.0% specific, strongly predicted high-grade dysplasia/invasive disease but lacked sensitivity (20.0%). High-quantity DNA + high clonality loss of heterozygosity had 99.0% specificity for high-grade dysplasia/invasive disease. KRAS mutation alone did not predict high-grade dysplasia/invasive disease, but, when combined with high-quantity DNA (specificity 84.7%) and high clonality loss of heterozygosity (specificity 99.0%) strongly predicted high-grade dysplasia/invasive outcomes. Conclusion Certain DNA components are highly specific for high-grade dysplasia/invasive disease and may indicate aggressive lesions, requiring resection when cytology fails.
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    Evolving treatment of necrotizing pancreatitis
    (Elsevier, 2017) Roch, Alexandra M.; Maatman, Thomas; Carr, Rose A.; Easler, Jeffrey J.; Schmidt, C. Max; House, Michael G.; Nakeeb, Attila; Ceppa, Eugene P.; Zyromski, Nicholas J.; Surgery, School of Medicine
    Background Over the past decade, the treatment of necrotizing pancreatitis (NP) has incorporated greater use of minimally invasive techniques, including percutaneous drainage and endoscopic debridement. No study has yet compared outcomes of patients treated with all available techniques. We sought to evaluate the evolution of NP treatment at our high volume pancreas center. We hypothesized that minimally invasive techniques (medical only, percutaneous, and endoscopic) were used more frequently in later years. Methods Treatment strategy of NP patients at a single academic medical center between 2005 and 2014 was reviewed. Definitive management of pancreatic necrosis was categorized as: 1) medical treatment only; 2) surgical only; 3) percutaneous (interventional radiology – IR) only; 4) endoscopic only; and 5) combination (Surgery ± IR ± Endoscopy). Results 526 NP patients included biliary (45%), alcoholic (17%), and idiopathic (20%) etiology. Select patients were managed exclusively by medical, IR, or endoscopic treatment; use of these therapies remained relatively consistent over time. A combination of therapies was used in about 30% of patients. Over time, the percentage of NP patients managed without operation increased from 28% to 41%. 247 (47%) of patients had operation as the only NP treatment; an additional 143 (27%) required surgery as part of a multidisciplinary management. Conclusion Select NP patients may be managed exclusively by medical, IR, or endoscopic treatment. Combination treatment is necessary in many NP patients, and surgical treatment continues to play an important role in the definitive therapy of necrotizing pancreatitis patients.
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    High Rates of Readmission in Necrotizing Pancreatitis: Natural History or Opportunity for Improvement?
    (Springer, 2019-09) Maatman, Thomas K.; Mahajan, Sarakshi; Roch, Alexandra M.; Lewellen, Kyle A.; Heimberger, Mark A.; Colgate, Cameron L.; Ceppa, Eugene P.; House, Michael G.; Nakeeb, Attila; Schmidt, C. Max; Zyromski, Nicholas J.; Surgery, School of Medicine
    Background Necrotizing pancreatitis (NP) is a complex and heterogeneous disease with a protracted disease course. Hospital readmission is extremely common; however, few data exist regarding the cause of readmission in NP. Methods A retrospective review of NP patients treated between 2005 and 2017 identified patients readmitted both locally and to our hospital. All patients with unplanned hospital readmissions were evaluated to determine the cause for readmission. Clinical and demographic factors of all patients were recorded. As appropriate, two independent group t tests and Pearson’s correlation or Fisher’s exact tests were performed to analyze the relationship between index admission clinical factors and readmission. p values of < 0.05 were accepted as statistically significant. Results Six hundred one NP patients were reviewed. Median age was 52 years (13–96). Median index admission length of stay was 19 days (2–176). The most common etiology was biliary (49.9%) followed by alcohol (20.0%). Unplanned readmission occurred in 432 patients (72%) accounting for a total of 971 unique readmissions (mean readmissions/patient, 2.3). The most common readmission indications were symptomatic necrosis requiring supportive care and/or intervention (31.2%), infected necrosis requiring antibiotics and/or intervention (26.6%), failure to thrive (9.7%), and non-necrosis infection (6.6%). Patients requiring readmission had increased incidence of index admission renal failure (21.3% vs. 14.2%, p = 0.05) and cardiovascular failure (12.5% vs. 4.7%, p = 0.01). Discussion Readmission in NP is extremely common. Significant portions of readmissions are a result of the disease natural history; however, a percentage of readmissions appear to be preventable. Patients with organ failure are at increased risk for unplanned readmission and will benefit from close follow-up.
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    Histopathologic correlation of pancreatic fibrosis with pancreatic magnetic resonance imaging quantitative metrics and Cambridge classification
    (Springer, 2022) Tirkes, Temel; Saeed, Omer A.; Osuji, Vitalis C.; Kranz, Carsyn E.; Roth, Adam A.; Patel, Aashish A.; Zyromski, Nicholas J.; Fogel, Evan L.; Radiology and Imaging Sciences, School of Medicine
    Purpose: To determine the correlation of the T1-weighted signal intensity ratio (T1 SIR, or T1 Score) and arterial-to-delayed venous enhancement ratio (ADV ratio) of the pancreas with pancreatic fibrosis on histopathology. Methods: Sixty consecutive adult CP patients who had an MRI/MRCP study prior to pancreatic surgery were analyzed. Three blinded observers measured T1 SIR of pancreas to spleen (T1 SIR p/s), pancreas-to-paraspinal muscle (T1 SIR p/m), ADV ratio, and Cambridge grade. Histopathologic grades were given by a gastrointestinal pathologist using Ammann's fibrosis score. Statistical analysis included Spearman's correlation coefficient of the T1 SIR, ADV ratio, Cambridge grade with the fibrosis score, and weighted kappa for interobserver agreement. Results: The study population included 31 female and 29 male patients, with an average age of 52.1 (26-78 years). Correlations between fibrosis score and T1 SIR p/s, T1 SIR p/m, and ADV ratio were ρ = - 0.54 (p = 0.0001), ρ = - 0.19 (p = 0.19), and ρ = - 0.39 (p = 0.003), respectively. The correlation of Cambridge grade with fibrosis score was ρ = 0.26 (p = 0.07). There was substantial interobserver agreement (weighted kappa) for T1 SIR p/s (0.78), T1 SIR p/m (0.71), and ADV ratio (0.64). T1 SIR p/s of ≤ 1.20 provided a sensitivity of 74% and specificity of 50% (AUC: 0.74), while ADV ratio of ≤ 1.10 provided a sensitivity of 75% and specificity of 55% (AUC: 0.68) to detect a fibrosis score of ≥ 6. Conclusion: There is a moderate negative correlation between the T1 Score (SIR p/s) and ADV ratio with pancreatic fibrosis and a substantial interobserver agreement. These parenchymal metrics show a higher correlation than the Cambridge grade.