The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A ...secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
The aim of the study was to compare the outcomes of patients with pancreatic or peripancreatic walled‐off necrosis by endoscopy using the conventional approach versus an algorithmic ...approach based on the collection size, location and stepwise response to intervention.
Methods
This was an observational before–after study of consecutive patients managed over two time intervals. In the initial period (2004–2009) symptomatic patients with walled‐off necrosis underwent conventional single transmural drainage with placement of two stents and a nasocystic catheter, followed by direct endoscopic necrosectomy, if required. In the later period (2010–2013) an algorithmic approach was adopted based on size and extent of the walled‐off necrosis and stepwise response to intervention. The main outcome was treatment success, defined as a reduction in walled‐off necrosis size to 2 cm or less on CT after 8 weeks.
Results
Forty‐seven patients were treated in the first interval and 53 in the second. There was no difference in patient demographics, clinical or walled‐off necrosis characteristics and laboratory parameters between the groups, apart from a higher proportion of women and Caucasians in the later period. The treatment success rate was higher for the algorithmic approach compared with conventional treatment (91 versus 60 per cent respectively; P < 0·001). On multivariable logistic regression, management based on the algorithm was the only predictor of treatment success (odds ratio 6·51, 95 per cent c.i. 2·19 to 19·37; P = 0·001).
Conclusion
An algorithmic approach to pancreatic and peripancreatic walled‐off necrosis, based on the collection size, location and stepwise response to intervention, resulted in an improved rate of treatment success compared with conventional endoscopic management.
Tailored approach improves outcomes
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The study goal was to analyze outcome after distal pancreatectomy for three subtypes of adenocarcinoma to determine the role of en bloc resection in surgical management. A secondary aim was to ...identify those clinicopathologic factors correlating with survival in an analysis limited to ductal adenocarcinoma. Medical records of consecutive patients undergoing distal pancreatectomy for adenocarcinoma between 1987 and 2003 were reviewed. A comparative analysis was undertaken of the safety and outcome of patients undergoing standard and en bloc resections. Clinicopathologic factors for patients undergoing distal pancreatectomy for ductal adenocarcinoma were subjected to both univariate and multivariate survival analyses. Ninety-three patients underwent resection for ductal adenocarcinoma (66, 71%), mucinous cystadenocarcinoma (18, 19%), or adenocarcinoma associated with intraductal papillary mucinous neoplasm (IPMN) (9, 10%). En bloc resection was required in 33 (35%) patients. There was no operative mortality. Median survival was 15.5 months, 30.2 months, and 50.7 months for ductal adenocarcinoma, mucinous cystadenocarcinoma, and adenocarcinoma associated with IPMN, respectively. Patients undergoing en bloc resection had a higher overall complication rate, required more transfusions and more intensive care unit admissions, and had a higher rate of positive margins; however, there were no deaths. For ductal adenocarcinoma, tumor size greater than 3.5 cm, age greater than 60 years, and stage were factors that correlated with survival on a univariate analysis. None were significant on multivariate analysis. Four patients with ductal adenocarcinoma were actual 5-year survivors. While en bloc resections are associated with a higher rate of complications, the majority are self-limited and mortality is low. Resection, including adjacent organs, should be performed when appropriate. Long-term survival for patients with cystadenocarcinoma or IPMN-associated adenocarcinoma can be anticipated. While rare, long-term survival for patients with ductal adenocarcinoma after distal pancreatectomy can be achieved.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
A retrospective study of patients with surgically resectable adenocarcinoma of the pancreatic head was undertaken to determine which prognostic factors are independently associated with improved ...survival. Thirty-four men and 41 women (mean age, 61.9 years) had resection for adenocarcinoma of the pancreatic head between 1980 and 1997 at Rush-Presbyterian-St. Luke's Medical Center. Surgical resections included 15 total pancreatectomies, 43 pyloric-preserving procedures, and 17 standard Whipple procedures. Thirty-six patients received adjuvant radiation and/or chemotherapy. Overall median survival was 13 months, with a 5-year survival of 17 per cent. Thirty-day surgical mortality was 1.3 per cent. Significant factors that negatively influenced survival using univariate Kaplan-Meier analysis were: positive resection margin (P = 0.01), intraoperative blood transfusion (P = 0.01), and lymph node metastases (P = 0.01). Presenting signs and symptoms, patient demographics, operative procedure, tumor size, histologic differentiation, and adjuvant therapy did not have a significant impact on survival. Using multivariate Cox regression analysis, the only significant independent factors improving survival were the absence of intraoperative blood transfusion (P = 0.02) and a negative resection margin (P = 0.04). Performing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas with negative microscopic margins of resection and without intraoperative transfusion significantly improves survival.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
While selected pancreatic diseases may be best treated by total pancreatectomy (TP), the anticipated sequelae of pancreatic insufficiency make TP an undesirable alternative. Our aim was to determine ...if patients undergoing TP have a worse quality of life (QoL) than age- and gender-matched controls and poor long-term glycemic control. Ninety-nine patients undergoing TP from 1985 through 2002 were identified. The 34 survivors with no recurrent malignancy were surveyed with the Short Form-36 (SF-36), the Audit of Diabetes Dependent QoL (ADD QoL), the European Organization for Research and Treatment in Cancer Pancreas 26 (EORTC PAN 26), and our institutional questionnaire. Operative morbidity and mortality were 32% and 5%, respectively. Three late postoperative deaths (3%) were attributed to hypoglycemia. Of the 34 surviving patients, 27 (79%) agreed to participate at a mean of 7.5 years postoperatively. Seven patients had required 12 hospitalizations for poor glycemic control. Per the SF-36, two domains (role physical and general health) were decreased compared with an age- and gender-matched national population (
P < .05). The ADD QoL demonstrated an overall decrease in QoL related specifically to the diabetes mellitus (
P < .01), but comparison with insulin-dependent diabetics from other causes showed no significant difference in QoL. The EORTC PAN 26 instrument also showed measurable effects on QoL. Total pancreatectomy can be performed safely. QoL after TP is decreased compared with age- and gender-matched controls but not with diabetes from other causes; however, the changes are not overwhelming. TP should remain a viable option but in selected patients.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
(1) To determine the safety of the epidermal growth factor receptor (EGFR) antibody cetuximab with concurrent gemcitabine and abdominal radiation in the treatment of patients with locally ...advanced adenocarcinoma of the pancreas. (2) To evaluate the feasibility of pancreatic cancer cell epithelial–mesenchymal transition (EMT) molecular profiling as a potential predictor of response to anti-EGFR treatment.
Methods
Patients with non-metastatic, locally advanced pancreatic cancer were treated in this dose escalation study with gemcitabine (0–300 mg/m
2
/week) given concurrently with cetuximab (400 mg/m
2
loading dose, 250 mg/m
2
weekly maintenance dose) and abdominal irradiation (50.4 Gy). Expression of E-cadherin and vimentin was assessed by immunohistochemistry in diagnostic endoscopic ultrasound fine-needle aspiration (EUS-FNA) specimens.
Results
Sixteen patients were enrolled in 4 treatment cohorts with escalating doses of gemcitabine. Incidence of grade 1–2 adverse events was 96%, and incidence of 3–4 adverse events was 9%. There were no treatment-related mortalities. Two patients who exhibited favorable treatment response underwent surgical exploration and were intraoperatively confirmed to have unresectable tumors. Median overall survival was 10.5 months. Pancreatic cancer cell expression of E-cadherin and vimentin was successfully determined in EUS-FNA specimens from 4 patients.
Conclusions
Cetuximab can be safely administered with abdominal radiation and concurrent gemcitabine (up to 300 mg/m
2
/week) in patients with locally advanced adenocarcinoma of the pancreas. This combined therapy modality exhibited limited activity. Diagnostic EUS-FNA specimens could be analyzed for molecular markers of EMT in a minority of patients with pancreatic cancer.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
OBJECTIVE:To identify a clinical fistula risk score following distal pancreatectomy.
BACKGROUND:Clinically relevant pancreatic fistula (CR-POPF) following distal pancreatectomy (DP) is a dominant ...contributor to procedural morbidity, yet risk factors attributable to CR-POPF and effective practices to reduce its occurrence remain elusive.
METHODS:This multinational, retrospective study of 2026 DPs involved 52 surgeons at 10 institutions (2001–2016). CR-POPFs were defined by 2016 International Study Group criteria, and risk models generated using stepwise logistic regression analysis were evaluated by c-statistic. Mitigation strategies were assessed by regression modeling while controlling for identified risk factors and treating institution.
RESULTS:CR-POPF occurred following 306 (15.1%) DPs. Risk factors independently associated with CR-POPF includedage (<60 yrsOR 1.42, 95% CI 1.05–1.82), obesity (OR 1.54, 95% CI 1.19–2.12), hypoalbuminenia (OR 1.63, 95% CI 1.06–2.51), the absence of epidural anesthesia (OR 1.59, 95% CI 1.17–2.16), neuroendocrine or nonmalignant pathology (OR 1.56, 95% CI 1.18–2.06), concomitant splenectomy (OR 1.99, 95% CI 1.25–3.17), and vascular resection (OR 2.29, 95% CI 1.25–3.17). After adjusting for inherent risk between cases by multivariable regression, the following were not independently associated with CR-POPFmethod of transection, suture ligation of the pancreatic duct, staple size, the use of staple line reinforcement, tissue patches, biologic sealants, or prophylactic octreotide. Intraoperative drainage was associated with a greater fistula rate (OR 2.09, 95% CI 1.51–3.78) but reduced fistula severity (P < 0.001).
CONCLUSIONS:From this large analysis of pancreatic fistula following DP, CR-POPF occurrence cannot be reliably predicted. Opportunities for developing a risk score model are limited for performing risk-adjusted analyses of mitigation strategies and surgeon performance.
Introduction
International Study Group of Pancreatic Fistula (ISGPF) grade C postoperative pancreatic fistulas (POPF) are the greatest contributor to major morbidity and mortality following ...pancreatoduodenectomy (PD); however, their infrequent occurrence has hindered deeper analysis. This study sought to develop a predictive algorithm, which could facilitate effective management of this challenging complication.
Methods
Data were accrued from 4301 PDs worldwide. Demographics, postoperative management, and microbiological characteristics of grade C POPFs were evaluated. American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) preoperative and intraoperative variables were compared between grade C POPFs and a 639-case sample of non-grade C POPFs. Risk factors for grade C POPF formation were identified using regression analysis.
Results
Grade C POPFs developed in 79 patients (1.8 %). Deaths (90 days) occurred in 2.0 % (
N
= 88) of the overall series, with 35 % (
N
= 25) occurring in the presence of a grade C POPF. Reoperations occurred 72.2 % of the time. The rates of single- and multi-system organ failure were 28.2 and 39.7 %, respectively. Mortality rates escalated with pulmonary, renal, and neurologic organ failure, but they were unaffected by reoperation(s). The median number of complications incurred was four (IQR: 2–5), and the median duration of hospital stay was 32 (IQR: 21–54) days. Warning signs for impending grade C POPFs most often presented on postoperative day (POD) 6. Adjuvant chemotherapy might have benefited 55.7 % of grade C POPF patients, yet it was delayed in 25.6 % and never delivered in 67.4 % of these patients. Predictive models for grade C POPF occurrence based on preoperative factors alone and preoperative and intraoperative factors yielded areas under the receiver operating characteristic curve of 0.73 and 0.84 (both
P
< 0.000001), respectively.
Conclusion
This global study represents the largest analysis of grade C POPFs following PD. It describes the severe burden that grade C POPFs incur on patients, with high rates of reoperation and infection, while also potentially worsening overall survival by causing death and delay/omission of adjuvant therapy. Additionally, aggressive clinical management for these POPFs did not improve or worsen 90-day mortality. Predictive tools developed through these data may provide value in managing this difficult complication.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Serum-biomarker based screening for pancreatic cancer could greatly improve survival in appropriately targeted high-risk populations.
Eighty-three circulating proteins were analyzed in sera of ...patients diagnosed with pancreatic ductal adenocarcinoma (PDAC, n = 333), benign pancreatic conditions (n = 144), and healthy control individuals (n = 227). Samples from each group were split randomly into training and blinded validation sets prior to analysis. A Metropolis algorithm with Monte Carlo simulation (MMC) was used to identify discriminatory biomarker panels in the training set. Identified panels were evaluated in the validation set and in patients diagnosed with colon (n = 33), lung (n = 62), and breast (n = 108) cancers.
Several robust profiles of protein alterations were present in sera of PDAC patients compared to the Healthy and Benign groups. In the training set (n = 160 PDAC, 74 Benign, 107 Healthy), the panel of CA 19-9, ICAM-1, and OPG discriminated PDAC patients from Healthy controls with a sensitivity/specificity (SN/SP) of 88/90%, while the panel of CA 19-9, CEA, and TIMP-1 discriminated PDAC patients from Benign subjects with an SN/SP of 76/90%. In an independent validation set (n = 173 PDAC, 70 Benign, 120 Healthy), the panel of CA 19-9, ICAM-1 and OPG demonstrated an SN/SP of 78/94% while the panel of CA19-9, CEA, and TIMP-1 demonstrated an SN/SP of 71/89%. The CA19-9, ICAM-1, OPG panel is selective for PDAC and does not recognize breast (SP = 100%), lung (SP = 97%), or colon (SP = 97%) cancer.
The PDAC-specific biomarker panels identified in this investigation warrant additional clinical validation to determine their role in screening targeted high-risk populations.
To evaluate surgical performance in pancreatoduodenectomy using clinically relevant postoperative pancreatic fistula (CR-POPF) occurrence as a quality indicator.
Accurate assessment of surgeon and ...institutional performance requires (1) standardized definitions for the outcome of interest and (2) a comprehensive risk-adjustment process to control for differences in patient risk.
This multinational, retrospective study of 4301 pancreatoduodenectomies involved 55 surgeons at 15 institutions. Risk for CR-POPF was assessed using the previously validated Fistula Risk Score, and pancreatic fistulas were stratified by International Study Group criteria. CR-POPF variability was evaluated and hierarchical regression analysis assessed individual surgeon and institutional performance.
There was considerable variability in both CR-POPF risk and occurrence. Factors increasing the risk for CR-POPF development included increasing Fistula Risk Score (odds ratio 1.49 per point, P < 0.00001) and octreotide (odds ratio 3.30, P < 0.00001). When adjusting for risk, performance outliers were identified at the surgeon and institutional levels. Of the top 10 surgeons (≥15 cases) for nonrisk-adjusted performance, only 6 remained in this high-performing category following risk adjustment.
This analysis of pancreatic fistulas following pancreatoduodenectomy demonstrates considerable variability in both the risk and occurrence of CR-POPF among surgeons and institutions. Disparities in patient risk between providers reinforce the need for comprehensive, risk-adjusted modeling when assessing performance based on procedure-specific complications. Furthermore, beyond inherent patient risk factors, surgical decision-making influences fistula outcomes.
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