Background
The present study aims to evaluate the long-term outcome and metastatic pattern of patients who underwent resection of a pancreatic ductal adenocarcinoma (PDAC) with portal or superior ...mesenteric vein (PV/SMV) resection.
Methods
Patients who underwent a partial pancreatoduodenectomy or total pancreatectomy for PDAC between 2005 and 2015 were retrospectively analyzed. Three subgroups were generated, depending on PV/SMV resection (P
+
) and pathohistological PV/SMV tumor infiltration (I
+
): P
+
I
+
, P
+
I
−
, and P
−
I
−
. Statistical analysis was performed using the R software package.
Results
The study cohort included 179 patients, 113 of whom underwent simultaneous PV/SMV resection. Thirty-six patients (31.9 %) had pathohistological tumor infiltration of the PV/SMV (P
+
I
+
), and were matched with 66 cases without PV/SMV infiltration (P
−
I
−
). The study revealed differences in overall median survival (11.9 P
+
I
+
vs. 16.1 P
+
I
−
vs. 20.1 P
−
I
−
months;
p
= 0.01). Multivariate survival analysis identified true invasion of the PV/SMV as the only significant, negative prognostic factor (
p
= 0.01). Whereas the incidence of local recurrence was comparable (
p
= 0.96), the proportion of patients with distant metastasis showed significant differences (75 % P
+
I
+
vs. 45.8 % P
+
I
−
vs. 54.7 % P
−
I
−
,
p
= 0.01). Furthermore, the median time to progression was significantly shorter if the PV/SMV was involved (7.4 months P
+
I
+
vs. 10.9 months P
+
I
−
vs. 11.6 months P
−
I
−
). Initial liver metastases occurred in 33 % of the patients.
Conclusions
True invasion of the PV/SMV is an independent risk factor for overall survival, and is associated with a higher incidence of distant metastasis and shorter progressive-free survival. Radical vascular resection cannot compensate for aggressive tumor biology.
Ampullary cancer represents approximately 6% of the malignant periampullary tumors. An early occurrence of symptoms leads to a 5-year survival rate after curative surgery of 30 to 67%. In addition to ...the tumor stage, the immunohistological subtypes appear to be important for postoperative prognosis. The aim of this study was to analyze the different subtypes regarding their prognostic relevance. A total of 170 patients with ampullary cancer were retrospectively analyzed between 1999 until 2016 after pancreatic resection. Patients were grouped according to their pathohistological subtype of ampullary cancer (pancreatobiliary, intestinal, mixed). Characteristics among the groups were analyzed using univariate and multivariate models. Survival probability was analyzed by the Kaplan-Meier method. An exact subtyping was possible in 119 patients. A pancreatobiliary subtype was diagnosed in 69 patients (58%), intestinal in 41 patients (34.5%), and a mixed subtype in 9 patients (7.6%). Survival analysis showed a significantly worse 5-year survival rate for the pancreatobiliary subtype compared with the intestinal subtype (27.5% versus 61%, p < 0.001). The mean overall survival of patients with pancreatobiliary, intestinal, and mixed subtype was 52.5, 115 and 94.7 months, respectively (p < 0.001). The pathohistological subtypes of ampullary cancer allows a prediction of the postoperative prognosis.
Predicting the clinical outcome of cancer patients based on the expression of marker genes in their tumors has received increasing interest in the past decade. Accurate predictors of outcome and ...response to therapy could be used to personalize and thereby improve therapy. However, state of the art methods used so far often found marker genes with limited prediction accuracy, limited reproducibility, and unclear biological relevance. To address this problem, we developed a novel computational approach to identify genes prognostic for outcome that couples gene expression measurements from primary tumor samples with a network of known relationships between the genes. Our approach ranks genes according to their prognostic relevance using both expression and network information in a manner similar to Google's PageRank. We applied this method to gene expression profiles which we obtained from 30 patients with pancreatic cancer, and identified seven candidate marker genes prognostic for outcome. Compared to genes found with state of the art methods, such as Pearson correlation of gene expression with survival time, we improve the prediction accuracy by up to 7%. Accuracies were assessed using support vector machine classifiers and Monte Carlo cross-validation. We then validated the prognostic value of our seven candidate markers using immunohistochemistry on an independent set of 412 pancreatic cancer samples. Notably, signatures derived from our candidate markers were independently predictive of outcome and superior to established clinical prognostic factors such as grade, tumor size, and nodal status. As the amount of genomic data of individual tumors grows rapidly, our algorithm meets the need for powerful computational approaches that are key to exploit these data for personalized cancer therapies in clinical practice.
Background
Pancreatic cancer is a devastating disease with a 5-year survival rate of 20–25%. As approximately only 20% of patients diagnosed with pancreatic cancer are initially staged as resectable, ...it is necessary to evaluate new therapeutic approaches. Hence, neoadjuvant (radio)chemotherapy is a promising therapeutic option, especially in patients with a borderline resectable tumor. The aim of this non-randomized, monocentric, prospective, phase II clinical study was to assess the prognostic value of functional imaging techniques, i.e.,
18
F2-fluoro-2-deoxy-
d
-glucose positron emission tomography/computed tomography (FDG-PET/CT) and diffusion weighted magnetic resonance imaging (DW-MRI), prior to and during neoadjuvant radiochemotherapy.
Methods
Patients with histologically proven resectable, borderline resectable or unresectable non-metastatic pancreatic adenocarcinoma received induction chemotherapy followed by neoadjuvant radiochemotherapy. Patients underwent FDG-PET/CT and DW-MRI including T1- and T2-weighted sequences prior to and after neoadjuvant chemotherapy as well as following induction radiochemotherapy. The primary endpoint was the evaluation of the response as quantified by the standardized uptake value (SUV) measured with FDG-PET. Response to treatment was evaluated by FDG-PET and DW-MRI during and after the neoadjuvant course. Morphologic staging was performed using contrast-enhanced CT and contrast-enhanced MRI to decide inclusion of patients and resectability after neoadjuvant therapy. In those patients undergoing subsequent surgery, imaging findings were correlated with those of the pathologic resection specimen.
Results
A total of 25 patients were enrolled in the study. The response rate measured by FDG-PET was 85% with a statistically significant decrease of the maximal SUV (SUV
max
) during therapy (
p
< 0.001). Using the mean apparent diffusion coefficient (ADC), response was not detectable with DW-MRI. After neoadjuvant treatment 16 patients underwent surgery. In 12 (48%) patients tumor resection could be performed. The median overall survival of all patients was 25 months (range: 7–38 months).
Conclusion
Based on these limited patient numbers, it was possible to show that this trial design is feasible and that the neoadjuvant therapy regime was well tolerated. FDG-PET/CT may be a reliable method to evaluate response to the combined therapy. In contrast, when evaluating the response using mean ADC, DW-MRI did not show conclusive results.
The forkhead transcription factor Foxp3 is highly expressed in CD4+CD25+ regulatory T cells (Treg) and was recently identified as a key player in mediating their inhibitory functions. Here, we ...describe for the first time the expression and function of Foxp3 in pancreatic ductal adenocarcinoma cells and tumors. Foxp3 expression was induced by transforming growth factor-beta2 (TGF-beta2), but not TGF-beta1 stimulation in these cells, and was partially suppressed following antibody-mediated neutralization of TGF-beta2. The TGF-beta2 effect could be mimicked by ectopic expression of a constitutively active TGF-beta type I receptor/ALK5 mutant. Down-regulation of Foxp3 with small interfering RNA (siRNA) in pancreatic carcinoma cells resulted in the up-regulation of interleukin 6 (IL-6) and IL-8 expression, providing evidence for a negative transcriptional activity of Foxp3 also in these epithelial cells. Coculture of Foxp3-expressing tumor cells with naive T cells completely inhibited T-cell proliferation, but not activation, and this antiproliferative effect was partially abrogated following specific inhibition of Foxp3 expression. These findings indicate that pancreatic carcinoma cells share growth-suppressive effects with Treg and suggest that mimicking Treg function may represent a new mechanism of immune evasion in pancreatic cancer.
Background Although postpancreatectomy hemorrhage (PPH) is observed infrequently after pancreatic surgery, it remains a serious complication with a high rate of mortality. Recently, the International ...Study Group of Pancreatic Surgery (ISGPS) issued a new definition for PPH. To evaluate and validate this new definition, we analyzed data retrospectively from our center. Methods Data from 945 patients who underwent pancreatic surgery in our department between October 1993 and December 2009 were identified retrospectively from our prospective database with regard to the occurrences of PPH. We graded the hemorrhages recorded in our database according to the ISGPS consensus definition. We assessed the clinical course, morbidity, mortality, and duration of hospital stay for patients with grade B and C PPHs in comparison with patients who underwent pancreatic resections without hemorrhage. Results Grade B PPH after pancreatic surgery occurred in 16 patients (1.7%), and grade C PPH occurred in 38 patients (4.0%). Mortality was significantly increased in PPH grades B and C compared with control patients (25.9% vs 2.0%; P < .001) and contributed to nearly one-half of the mortality in the present series. Morbidity was also increased in patients with grade B (76.5%) and C (94.6%) PPH compared with control patients (59.6%; P < .001). Grade B and C PPH correlated significantly with the incidence of grade C postoperative pancreatic fistula (14.8% vs 1.9%), grade C delayed gastric emptying (18.5% vs 4.0%), and wound infection (38.9% vs 13.5%) compared with control patients. Conclusion This is the first clinical evaluation of the ISGPS PPH definition. Our data indicate that the new definition correlates well with morbidity, mortality, and duration of hospital stay. The definition, therefore, seems suitable for clinical and scientific applications.
Background & Aims Preoperative differential diagnosis of pancreatic ductal adenocarcinoma (PDAC) and focal masses in patients with chronic pancreatitis (CP) can be challenging. There are fine ...differences in the vascularization of these lesions; ultrasound contrast agents can aid in their differentiation. We evaluated the value of software-aided quantitative analysis of transabdominal contrast-enhanced ultrasonography for differential diagnosis of PDAC vs focal masses. Methods Sixty patients for whom it was not possible to differentiate between an inflammatory focal lesion of the pancreas and a pancreatic carcinoma underwent contrast-enhanced ultrasonography with a second-generation contrast agent. Time-intensity curves were obtained for all exams in 2 regions of interest within the lesion and within the normal pancreatic tissue. Images were processed using Axius ACQ software; the following parameters were obtained: maximum intensity, arrival time, time-to-peak, and area under the curve. Absolute values and differences between the lesion and the normal tissue were evaluated. Results Histology analysis revealed 45 PDACs and 15 inflammatory masses in patients with CP. Time-dependent parameters (arrival time and time to peak) were significantly longer in PDACs compared to focal masses. Although markedly lower than in healthy pancreata, the maximum intensity and area under the curve parameters were not significantly different between PDACs and focal lesions in patients with CP. Conclusions In cases of CP, PDAC and focal masses exhibit different perfusion patterns at a capillary level that can be visualized using the small microbubbles of ultrasound contrast agents. Contrast quantification software supplements a subjective visual assessment with objective criteria to facilitate the differential diagnosis of focal lesions in pancreatic cancer and chronic pancreatitis.
Background: Patient outcome after resection of colorectal liver metastases can be predicted by various prognostic factors.
Aims: Development of a model for risk stratification based on analysis of ...prognostic factors.
Methods: Data of 201 patients were collected prospectively and included in a single‐centre trial. A total of 20 factors were analysed as to their influence on recurrence‐free and overall survival. Independent prognostic factors were entered into a model of a clinical risk score.
Results: Median recurrence‐free survival reached 24 months for all patients; median overall survival was 50 months. Only a synchronous manifestation of primary colorectal carcinoma and liver metastases, the presence of four or more metastases and a carcino‐embryonic antigen level of 200 ng/ml or more significantly influenced recurrence‐free and overall survival in the multivariate analysis. The derived risk stratification grouped the patients according to the following criteria: low risk, zero prognostic factors (n=112); intermediate risk, one factor (n=74); high risk, two or more factors (n=15). The median recurrence‐free survival for low, intermediate and high risk were 30.0, 23.0 and 11.0 months, respectively; the median overall survival was 94.0, 40.0 and 33.0 months. Compared with the low‐risk group, patients with intermediate risk demonstrated an increased hazard ratio (HR) of 1.57‐fold for recurrence (P=0.018) and 1.91‐fold for mortality (P=0.007). For the high‐risk group, the HR rose significantly to 3.26 for recurrence (P<0.0005) and to 3.10 for mortality (P=0.001).
Conclusions: The presented clinical score may allow for patients with colorectal liver metastases to be stratified appropriately and for optimization of their subsequent therapeutic management.
To investigate different subtypes of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and their prognostic value.
IPMNs of the pancreas are estimated to have a better prognosis than ...pancreatic ductal adenocarcinomas (PDACs). In addition to the different growth types (ie, main duct vs. branch duct types), the histological subtypes of IPMNs (ie, intestinal, pancreatobiliary, gastric, and oncocytic type) are prognostically relevant. These subtypes can be characterized by different mucin (MUC) expression patterns. In this study, we analyzed the IPMNs from 2 pancreatic cancer referral centers by correlating the MUC expression, histological subtype, and clinical outcome.
We re-evaluated all resections due to a pancreatic tumor over a period of 15 years. Cases with IPMNs were identified, and the subtypes were distinguished using histopathological analysis, including the immunohistochemical analysis of MUC (ie, MUC1, MUC2, and MUC5AC) expression. Furthermore, we determined clinical characteristics and patient outcome.
A total of 103 IPMNs were identified. On the basis of the MUC profile, histopathological subtypes were classified into the following categories: intestinal type n = 45 (44%), pancreatobiliary type n = 41 (40%), gastric type n = 13 (12%), and oncocytic type n = 4 (4%). The following types of resections were performed: pancreatic head resections n = 77 (75%), tail resections n = 16 (15%), total pancreatectomies n = 5 (5%), and segment resections n = 5 (5%). The 5-year survival of patients with intestinal IPMNs was significantly better than pancreatobiliary IPMNs (86.6% vs. 35.6%; P < 0.001). The pancreatobiliary subtype was strongly associated with malignancy odds ratio (OR): 6.76, recurrence (P < 0.001), and long-term survival comparable with that of PDAC patients.
Evaluation of IPMN subtypes supports postoperative patient prognosis prediction. Therefore, subtype differentiation could lead to improvements in clinical management. Potentially identifying subgroups with the need for adjuvant therapy may be possible.
Aims/hypothesis
Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: ...Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium (
www.imidia.org
) established a comprehensive, unique multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP).
Methods
Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells.
Results
Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate ≤0.05, fold change ≥1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included
TMEM37
, which inhibited Ca
2+
-influx and insulin secretion in beta cells, and
ARG2
and
PPP1R1A
, which promoted insulin secretion. Systems biology approaches identified
HNF1A
,
PDX1
and
REST
as drivers of gene co-expression modules correlated with impaired insulin secretion or glucose tolerance, and 14 out of 19 differentially expressed type 2 diabetic islet signature genes were enriched in these modules. None of these signature genes was significantly dysregulated in islets of PPP with impaired glucose tolerance or type 3c diabetes.
Conclusions/interpretation
These studies enabled the stringent definition of a novel transcriptomic signature of type 2 diabetic islets, regardless of islet source and isolation procedure. Lack of this signature in islets from PPP with IGT or type 3c diabetes indicates differences possibly due to peculiarities of these hyperglycaemic conditions and/or a role for duration and severity of hyperglycaemia. Alternatively, these transcriptomic changes capture, but may not precede, beta cell failure.
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