Background
The prognostic role of resection margins in pancreatic ductal adenocarcinoma (PDAC) is debated. This study aimed to investigate the impact that global and individual resection margin ...status after pancreatic head resection for PDAC has on disease-free survival (DFS) and disease-specific survival (DSS).
Methods
Surgical specimens of pancreaticoduodenectomy/total pancreatectomy performed for PDAC were examined with a standardized protocol. Surgical margin status (biliary, pancreatic neck, duodenal, anterior and posterior pancreatic, superior mesenteric vein groove and superior mesenteric artery margins) was classified as the presence of malignant cells (1) directly at the inked surface (
R
1 direct), (2) within less than 1 mm (
R
1 ≤ 1 mm), or (3) with a distance greater than 1 mm (
R
0). Patients with a positive neck margin at the final histology were excluded from the study.
Results
Of the 362 patients included in the study, 179 patients (49.4 %) had an
R
0 resection, 123 patients (34 %) had an
R
1 ≤ 1 mm resection, and 60 patients (16.6 %) had an
R
1 direct resection. The independent predictors of DFS were
R
1 direct resection (hazard ratio HR, 1.49),
R
1 ≤ 1 mm resection (HR, 1.38), involvement of one margin (HR, 1.36), and involvement of two margins or more (HR, 1.55). When surgical margins were analyzed separately, only
R
1 ≤ 1 mm superior mesenteric vein margin (HR, 1.58) and
R
1 direct posterior margin (HR, 1.69) were independently associated with DFS.
Conclusions
Positive
R
status is an independent predictor of DFS (
R
1 direct and
R
1 ≤ 1 mm definitions) and of DSS (
R
1 direct). The presence of multiple positive margins is a risk factor for cancer recurrence and poor survival. Different surgical margins could have different prognostic roles.
The aim of this study is to provide a comprehensive characterization of stemness in pancreatic ductal adenocarcinoma (PDAC) cell lines. Seventeen cell lines were evaluated for the expression of ...cancer stem cell (CSC) markers. The two putative pancreatic CSC phenotypes were expressed heterogeneously ranging from 0 to 99.35% (median 3.46) for ESA+CD24+CD44+ and 0 to 1.94% (median 0.13) for CXCR4+CD133+. Cell lines were classified according to ESA+CD24+CD44+ expression as: Low-Stemness (LS; <5%, n = 9, median 0.31%); Medium-Stemness (MS; 6−20%, n = 4, median 12.4%); and High-Stemness (HS; >20%, n = 4, median 95.8%) cell lines. Higher degree of stemness was associated with in vivo tumorigenicity but not with in vitro growth kinetics, clonogenicity, and chemo-resistance. A wide characterization (chemokine receptors, factors involved in pancreatic organogenesis, markers of epithelial−mesenchymal transition, and secretome) revealed that the degree of stemness was associated with KRT19 and NKX2.2 mRNA expression, with CD49a and CA19.9/Tie2 protein expression, and with the secretion of VEGF, IL-7, IL-12p70, IL-6, CCL3, IL-10, and CXCL9. The expression of stem cell markers was also evaluated on primary tumor cells from 55 PDAC patients who underwent pancreatectomy with radical intent, revealing that CXCR4+/CD133+ and CD24+ cells, but not ESA+CD24+CD44+, are independent predictors of mortality.
Objectives
To assess the incidence (1 year) and the cumulative incidence (3 years) of the condition of patients accruing cumulative effective doses (CED) of ≥ 100 mSv and their variability among ...different hospitals.
To establish and validate a reference level for the CED in patients with recurrent exposures (RERL) and provide a RERL value.
Methods
Data of CT exposure was collected in 9 similar hospitals. The database included 294,222 patient*years who underwent 442,278 CT exams in 3 years. The incidence proportion of patients with CED ≥ 100 mSv in a given year (
I
100;1
) and the 3-year cumulative incidence of patients with CED ≥ 100 mSv over 3 consecutive years (
I
100;3
) were calculated and compared among different institutions.
Results
I
100;1
ranged from a minimum of 0.1% to a maximum of 5.1%. The percentage of recurrent patients was quite uniform among centres ranging from 23 to 38%. The
I
100;3
ranged from a minimum of 1.1 to 11.4%. There was a strong positive correlation between the third quartile values of yearly CED and yearly incidence (
r
= 0.90;
R
2
= 0.81;
p
< 0.0001). RERL value in our study was found at 34.0 mSv.
Conclusion
The management of patients with recurrent exposures is highly variable among hospitals leading to a 50-fold variation in
I
100;1
and to a tenfold variation in
I
100;3
.
RERL could be established and used by taking as a RERL quantity the CED and as a RERL value the 75th percentile of the third quartiles of the distribution of the yearly CED obtained by surveying different hospitals.
Clinical relevance statement
This is the first ever multicentre study that quantifies recurrent exposures in terms of incidence and cumulative incidence of patients with CED ≥ 100 mSv. RERL establishment and use could benefit the optimisation of radioprotection of patients with recurrent exposures.
Key points
This is the first multicentre study estimating yearly incidence and 3-year cumulative incidence of patients with cumulative effective doses ≥ 100 mSv.
In this study, a 50-fold inter centre variation between the maximum (5.1%) and the minimum value (0.1%) of yearly incidence of patients with cumulative effective doses ≥ 100 mSv was reported. The range of the 3-year cumulative incidence extended from 1.1 to 11.4% (a tenfold variation)
The third quartile of the yearly cumulative effective doses in a centre showed a strong positive correlation with the yearly incidence of patients with cumulative effective doses ≥ 100 mSv, with a potential of being used to set reference levels for recurrent exposures.
Background
A recent RCT showed similar postoperative outcomes and a reduced time to functional recovery in patients undergoing minimally invasive distal pancreatectomy (DP) compared to open approach. ...However, it reported very-high post-discharge readmission rates, calling for further investigation. The aim of our study was to evaluate the extent to which minimally invasive surgery impacts on postoperative readmissions following DP.
Methods
Clinical data for patients undergoing DP between 2011 and 2018 were reviewed. Primary outcome was hospital readmission at 90 days after surgery. Secondary outcomes included post-discharge emergency department (ED) visits and time to functional recovery. Regression analyses were performed to evaluate the impact of the laparoscopic approach and other perioperative factors.
Results
Overall, 376 consecutive patients underwent DP during the study period. Laparoscopy was successfully performed in 219 (58%) patients. Overall, 62 patients (16.5%) returned to the ED after discharge, 41 (18.7%) of laparoscopically operated patients, and 21 (13.4%) of those undergoing open surgery (
p
= 0.162). Forty-six (12.2%) of them required readmission, 31 (14.2%) after laparoscopic, and 15 (9.6%) after open procedures (
p
= 0.179). At multivariate regression, a low preoperative physical status (OR 2.3, 95% CI 1.2–4.7;
p
= 0.017), occurrence of pancreatic fistula (OR 6.8, 95% CI 2.9–15.9;
p
< 0.001), and post-pancreatectomy hemorrhage (OR 3.9, 95% CI 1.2–13.1;
p
= 0.025) were significantly associated with 90-day readmission, while laparoscopy had no impact. Median time to reach functional recovery was 5 (IQR 4–6) days. At multivariate analysis, laparoscopy reduced time to functional recovery by 13% (95% CI − 19 to − 6%;
p
< 0.001), time to adequate oral intake by 19% (95% CI − 27 to − 10%;
p
< 0.001), and time to adequate pain control by 12% (95% CI − 18 to − 5%;
p
< 0.001).
Conclusion
Hospital readmissions and ED visits following DP were not influenced by the surgical approach. A low preoperative physical status, occurrence of postoperative pancreatic fistula and hemorrhage were significantly associated with post-discharge readmission within 90 days. Laparoscopy reduced time to functional recovery.
Background
Defining optimal treatment duration in patients with resectable pancreatic ductal adenocarcinoma (PDAC) receiving primary chemotherapy is an unmet need. The role of time to CA19-9 nadir ...and of nadir magnitude was explored in this study.
Patients and methods
The databases of our institution’s prospective trials were queried to speculate on the time to maximum chemotherapy response. Patients with pathologically proven, metastatic (
N
= 356) or non-metastatic non-resected (
N
= 163) PDAC and elevated baseline (> 34 UI/mL) CA19-9 were analyzed. Survival curves were estimated using the Kaplan–Meier method and compared by means of the log-rank test for analyses including at least 45 patients. Multivariable Cox proportional hazards model was used to estimate clinical features for their association with OS. All probability values were from two-sided tests.
Results
Time to CA19-9 nadir was ≥ 4 months in 184 of 346 (53%) metastatic and 121 of 163 (74%) non-metastatic patients (
p
= 0.002). The likelihood of a later nadir was higher with taxane-based chemotherapy as compared to taxane-free combinations (73% versus 56%;
p
= 0.02). Both metastatic and non-metastatic patients had significantly longer survival when nadir occurred later. Patients with a larger CA19-9 nadir magnitude had significantly longer survival. Metastatic patients with CA19-9 reduced by < 50%, 50–89%, or > 89% and had a median survival of 7.4, 9.8, and 14.7 months, respectively (
p
≤ 0.001 for all comparisons). The corresponding figures for non-metastatic patients were 10.6; 17.0; and 18.7 months, respectively (
p
≤ 0.02 for < 50% versus 50–89% or > 89%;
p
= 0.14 for 50–89% versus > 89%). Multivariable analyses showed that time to CA19-9 nadir but not CA19-9 nadir magnitude was independently predictive of survival.
Conclusion
The present study suggests that a 4–6 months program might be a more suitable candidate for prospective assessment in comparison to shorter pre-defined period in patients who are candidates to surgery after primary chemotherapy.
Background New therapies are needed for pancreatic cancer. Objective To determine the feasibility and safety of a new endoscopic treatment. Secondary endpoints were to determine effects on tumor ...growth measured with CT scan and to find the overall survival. Design A cohort study of patients with local progression of advanced pancreatic adenocarcinoma after neoadjuvant therapy. The cryotherm probe (CTP), a flexible bipolar device that combines radiofrequency with cryogenic cooling, was used under EUS guidance. Setting San Raffaele Hospital, Milan, Italy; University Medical Center, Hamburg-Eppendorf, Germany. Patients A total of 22 patients (male/female 11/11; mean age 61.9 years) were enrolled from September 2009 to May 2011. Intervention Radiofrequency heating: 18 W; pressure for cooling: 650 psi (Pounds per Square Inch); application time: depending on tumor size. Main Outcome Measurements Feasibility was evaluated during the procedure. A clinical and radiologic follow-up was planned. Results The CTP was successfully applied in 16 patients (72.8%); in 6 it was not possible because of stiffness of the GI wall and of the tumor. Amylase arose in 3 of 16 patients; none had clinical signs of pancreatitis. Late complications arose in 4 cases: 3 were mostly related to tumor progression. Median postablation survival time was 6 months. A CT scan was performed in all patients, but only in 6 of 16 was it possible to clearly define the tumor margins after ablation. In these patients, the tumor appeared smaller compared with the initial mass ( P = .07). Limitations Small sample of patients, difficulty of objectifying the size of the ablated zone by CT scan. Conclusion EUS-guided CTP ablation is feasible and safe. Further investigations are needed to demonstrate progression-free survival and local control.
We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers ...associated with sensitivity to metformin antineoplastic action.
We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population.
Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% 95% confidence interval (CI), 33-69 in the control group and 42% (95% CI, 24-59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin.
Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. See related commentary by Yang and Rustgi, p. 1031.
This paper proposes a data-based approach for a robust fault detection (FD) of the inertial measurement unit (IMU) sensors of an aircraft. Fuzzy interval models (FIMs) have been introduced for coping ...with the significant modeling uncertainties caused by poorly modeled aerodynamics. The proposed FIMs are used to compute robust prediction intervals for the measurements provided by the IMU sensors. Specifically, a nonlinear neural network (NN) model is used as central prediction of the sensor response while the uncertainty around the central estimation is captured by the FIM model. The uncertainty has been also modelled using a conventional linear Interval Model (IM) approach; this allows a quantitative evaluation of the benefits provided by the FIM approach. The identification of the IMs and of the FIMs was formalized as a linear matrix inequality (LMI) optimization problem using as cost function the (mean) amplitude of the prediction interval and as optimization variables the parameters defining the amplitudes of the intervals of the IMs and FIMs. Based on the identified models, FD validation tests have been successfully conducted using actual flight data of a P92 Tecnam aircraft by artificially injecting additive fault signals on the fault free IMU readings.
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