Abstract Background The majority of patients who have undergone a pancreatic resection for pancreatic cancer develop disease recurrence within two years. In around 30% of these patients, isolated ...local recurrence (ILR) is found. The aim of this study was to systematically review treatment options for this subgroup of patients. Methods A systematic search was performed in PubMed, Embase and the Cochrane Library. Studies reporting on the treatment of ILR after initial curative-intent resection of primary pancreatic cancer were included. Primary endpoints were morbidity, mortality and survival after ILR treatment. Results After screening 1152 studies, 18 studies reporting on 313 patients undergoing treatment for ILR were included. Treatment options for ILR included surgical re-resection (8 studies, 100 patients), chemoradiotherapy (7 studies, 153 patients) and stereotactic body radiation therapy (SBRT) (4 studies, 60 patients). Morbidity and mortality were reported for re-resection (29% and 1%, respectively), chemoradiotherapy (54% and 0%) and SBRT (3% and 1%). Most patients had a prolonged disease-free interval before recurrence. Median survival after treatment of ILR of up to 32, 19 and 16 months was reported for re-resection, chemoradiotherapy and SBRT, respectively. Conclusion In selected patients, treatment of ILR following pancreatic resection for pancreatic cancer seems safe, feasible and associated with relatively good survival.
Background & Aims Colon tumors contain a fraction of undifferentiated stem cell−like cancer cells with high tumorigenic potential. Little is known about the signals that maintain these stem-like ...cells. We investigated whether differentiated tumor cells provide support. Methods We established undifferentiated colonosphere cultures from human colon tumors and used them to generate stably differentiated cell lines. Antibody arrays were used to identify secreted factors. Expression of genes involved in stemness, differentiation, and the epithelial to mesenchymal transition was measured using reverse transcription quantitative polymerase chain reaction. Expression of KIT in human tumors was analyzed with gene expression arrays and by immunohistochemistry. Colonospheres were injected into the livers of CBy.Cg-Foxn1nu/J mice. After liver tumors had formed, hypoxia was induced by vascular clamping. Results Differentiated cells from various tumors, or medium conditioned by them, increased the clonogenic capacity of colonospheres. Stem cell factor (SCF) was secreted by differentiated tumor cells and supported the clonogenic capacity of KIT+ colonosphere cells. Differentiated tumor cells induced the epithelial to mesenchymal transition in colonosperes; this was prevented by inhibition of KIT or SCF. SCF prevented loss of clonogenic potential under differentiation-inducing conditions. Suppression of SCF or KIT signaling greatly reduced the expression of genes that regulate stemness and the epithelial to mesenchymal transition and inhibited clonogenicity and tumor initiation. Bioinformatic and immunohistochemical analyses revealed a correlation between expression of KIT- and hypoxia-related genes in colon tumors, which was highest in relapse-prone mesenchymal-type tumors. Hypoxia induced expression of KIT in cultured cells and in human colon tumor xenografts and this contributed to the clonogenic capacity of the tumor cells. Conclusions Paracrine signaling from SCF to KIT, between differentiated tumor cells and undifferentiated stem-like tumor cells, helps maintain the stem-like features of tumor cells, predominantly under conditions of hypoxia.
Irreversible electroporation (IRE) with needle electrodes is being explored as treatment option in locally advanced pancreatic cancer. Several studies have shown promising results with IRE needles, ...positioned around the tumor to achieve tumor ablation. Disadvantages are the technical difficulties for needle placement, the time needed to achieve tumor ablation, the risk of needle track seeding and most important the possible occurrence of postoperative pancreatic fistula via the needle tracks. The aim of this experimental study was to evaluate the feasibility of a new IRE-technique using two parallel plate electrodes, in a porcine model.
Twelve healthy pigs underwent laparotomy. The pancreas was mobilized to enable positioning of the paddles. A standard monophasic external cardiac defibrillator was used to perform an ablation in 3 separate parts of the pancreas; either a single application of 50 or 100J or a serial application of 4x50J. After 6 hours, pancreatectomy was performed for histology and pigs were terminated.
Histology showed necrosis of pancreatic parenchyma with neutrophil influx in 5/12, 11/12 and 12/12 of the ablated areas at 50, 100, and 4x50J respectively. The electric current density threshold to achieve necrosis was 4.3, 5.1 and 3.4 A/cm2 respectively. The ablation threshold was significantly lower for the serial compared to the single applications (p = 0.003). The content of the ablated areas differed between the applications: areas treated with a single application of 50 J often contained vital areas without obvious necrosis, whereas half of the sections treated with 100 J showed small islands of normal looking cells surrounded by necrosis, while all sections receiving 4x 50 J showed a homogeneous necrotic lesion.
Pancreatic tissue can be successfully ablated using two parallel paddles around the tissue. A serial application of 4x50J was most effective in creating a homogeneous necrotic lesion.
Background
Preoperative differentiation between malignant and benign pancreatic tumors can be difficult. Consequently, a proportion of patients undergoing pancreatoduodenectomy for suspected ...malignancy will ultimately have benign disease. The aim of this study was to compare preoperative clinical and diagnostic characteristics of patients with unexpected benign disease after pancreatoduodenectomy with those of patients with confirmed (pre)malignant disease.
Methods
We performed a multicenter retrospective cohort study in 1,629 consecutive patients undergoing pancreatoduodenectomy for suspected malignancy between 2003 and 2010 in 11 Dutch centers. Preoperative characteristics were compared in a benign:malignant ratio of 1:3. Malignant cases were selected from the entire cohort by using a random number list. A multivariable logistic regression prediction model was constructed to predict benign disease.
Results
Of 107 patients (6.6 %) with unexpected benign disease after pancreatoduodenectomy, 86 fulfilled the inclusion criteria and were compared with 258 patients with (pre)malignant disease. Patients with benign disease presented more often with pain (56 vs. 38 %;
P
= 0.004), but less frequently with jaundice (60 vs. 80 %;
P
< 0.01), a pancreatic mass (13 vs. 54 %,
P
< 0.001), or a double duct sign on computed tomography (21 vs. 47 %;
P
< 0.001). In a prediction model using these parameters, only 19 % of patients with benign disease were correctly predicted, and 1.4 % of patients with malignant disease were missed.
Conclusions
Nearly 7 % of patients undergoing pancreatoduodenectomy for suspected malignancy were ultimately diagnosed with benign disease. Although some preoperative clinical and imaging characteristics might indicate absence of malignancy, their discriminatory value is insufficient for clinical use.
Pancreatic resection is a major abdominal operation with 50% risk of postoperative complications. A common complication is pancreatic fistula, which may have severe clinical consequences such as ...postoperative bleeding, organ failure and death. The objective of this study is to investigate whether implementation of an algorithm for early detection and minimally invasive management of pancreatic fistula may improve outcomes after pancreatic resection.
This is a nationwide stepped-wedge, cluster-randomized, superiority trial, designed in adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. During a period of 22 months, all Dutch centers performing pancreatic surgery will cross over in a randomized order from current practice to best practice according to the algorithm. This evidence-based and consensus-based algorithm will provide daily multilevel advice on the management of patients after pancreatic resection (i.e. indication for abdominal imaging, antibiotic treatment, percutaneous drainage and removal of abdominal drains). The algorithm is designed to aid early detection and minimally invasive step-up management of postoperative pancreatic fistula. Outcomes of current practice will be compared with outcomes after implementation of the algorithm. The primary outcome is a composite of major complications (i.e. post-pancreatectomy bleeding, new-onset organ failure and death) and will be measured in a sample size of at least 1600 patients undergoing pancreatic resection. Secondary endpoints include the individual components of the primary endpoint and other clinical outcomes, healthcare resource utilization and costs analysis. Follow up will be up to 90 days after pancreatic resection.
It is hypothesized that a structured nationwide implementation of a dedicated algorithm for early detection and minimally invasive step-up management of postoperative pancreatic fistula will reduce the risk of major complications and death after pancreatic resection, as compared to current practice.
Netherlands Trial Register: NL 6671. Registered on 16 December 2017.
Consensus molecular subtype 4 (CMS4) is a recently identified aggressive colon cancer subtype for which platelet-derived growth factor receptors (PDGFRs) and KIT are potential therapeutic targets. We ...aimed to develop a clinically applicable CMS4 reverse transcription polymerase chain reaction (RT-qPCR) test to select patients for PDGFR/KIT-targeted therapy.
We used logistic regression to develop a CMS4 prediction rule based on microarray expression values of PDGFRA , PDGFRB , PDGFC , and KIT (566 training and 1259 test samples, using the 273-gene random forest classifier as CMS4 reference standard). We next translated the prediction rule into a single-sample RT-qPCR test, which we independently validated in 29 fresh tumor samples. To study intratumor CMS4 heterogeneity, we used the RT-qPCR test to analyze five random regions of 20 colon tumors.
The microarray-based prediction rule diagnosed CMS4-type tumors extremely well in both training and independent test samples (training: area under the curve AUC = 0.95, 95% confidence interval CI = 0.94 to 0.97; test: AUC = 0.95, 95% CI = 0.94 to 0.96), with excellent calibration and approximately 80% overall net benefit over a large threshold range. Translation into an RT-qPCR test did not affect discrimination (AUC = 0.97, 95% CI = 0.93 to 1.00, independent validation). RT-qPCR analysis of five random tumor regions revealed extensive intratumor CMS4 heterogeneity in nine out of 20 tumors. At least two regions likely have to be analyzed to identify patients that are predominantly CMS4 positive (>50% average CMS4 chance).
The CMS4 RT-qPCR test is a promising clinical tool for selecting individual patients for CMS4-subtype-targeted therapy.
Abstract Context Only a minority of thyroid nodules is malignant; nevertheless, many invasive diagnostic procedures are performed to distinguish between benign and malignant nodules. Qualitative ...ultrasound elastography is a non-invasive technique to evaluate thyroid nodules. Objective To investigate the diagnostic value of qualitative elastography in distinguishing benign from malignant thyroid nodules in patients referred for fine-needle aspiration (FNA). Data sources A systematic literature search (PubMed, Embase and Cochrane Library) was performed. Study selection Included studies reported thyroid nodule elastography color scores and the related cytologic or histologic findings in patients with a thyroid nodule referred for FNA. Data extraction Two independent reviewers extracted study data and assessed study quality. Pooled sensitivities and specificities of different populations were calculated using a bivariate Bayesian framework. Data Synthesis Twenty studies including thyroid nodules were analyzed. Pooled results of elastography indicate a summary sensitivity of 85% (95% confidence interval CI, 79–90%) and specificity of 80% (95% CI, 73–86%). The respective pooled negative predictive and positive predictive values were 97% (95% CI, 94–98%) and 40% (95% CI, 34–48%). The pretest probability of a benign nodule was 82%. Only 3.7% of the false-negative nodules was a follicular thyroid carcinoma. A pooled negative predictive value of 99% (95% CI, 97–100%) was found when only complete soft nodules (Asteria elastography 1) were classified as benign, which included 14% of the studied population. Conclusions Elastography has a fair specificity and sensitivity for diagnostic accuracy. Its major strength entails the detection of benignity, especially when only completely soft nodules are qualified as benign. The outcomes of our analysis show that FNA could safely be omitted in patients referred for analysis of their thyroid nodule when elastography shows it to be completely soft (Asteria elastography 1). This could prevent unnecessary invasive diagnostic procedures in a substantial portion of patients.
Drug-resistant cancer stem cells (CSCs) have been implicated in tumor recurrence following chemotherapy. However, the contribution of CSCs to drug-resistance in colorectal cancer is unclear and ...CSC-intrinsic drug-resistance mechanisms are ill-defined. Here, we address these issues by proteomic analysis of the secretomes of CSCs and isogenic differentiated tumor cells (DTCs) isolated from three distinct metastasized colon tumors.
Mass spectrometry-based proteomics identified 1254 unique proteins in the conditioned media of the paired CSC and DTC cultures. Ingenuity Pathway Analysis revealed that proteins governing ‘Cell Death’ were most significantly enriched in the CSC secretome. The vast majority of these (37/43) promote cell survival. The CSC secretome is also characterized by a pro-survival Nrf2 antioxidant signature. Interestingly, proteome-maintenance networks are highly enriched in the CSC secretome. CSCs also secrete high levels of drug-metabolizing enzymes, including aldehyde dehydrogenase 1 (ALDH1A1) and bleomycin hydrolase (BLMH). We show that these enzymes cause extracellular detoxification of maphosphamide and bleomycin respectively.
We conclude that colorectal CSCs are characterized by extensive survival and anti-oxidant networks, which are likely to contribute to CSC-intrinsic drug-resistance. In addition, CSCs may modulate drug responses in nearby tumor cells by detoxifying chemotherapeutic drugs in the extracellular space.
Cancer stem cells are thought to play an important role in mediating drug resistance and tumor recurrence following chemotherapy. Therefore, it is important to identify the factors that are secreted by them. Our results provide novel insights into the pathways that govern the intrinsic resistance of CSCs to chemotherapy and, furthermore, demonstrate that they can also inactivate chemotherapeutic drugs in the extracellular space. A better understanding of the pathways that govern drug resistance in CSCs may help in developing effective CSC-targeting drugs.
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•Secretome analysis of cancer stem cells and differentiated tumor cells•Survival proteins are enriched in the cancer stem cell secretome.•Cancer stem cells secrete high levels of drug-metabolizing enzymes.•Secreted drug-metabolizing enzymes detoxify drugs in the extracellular space.•Cancer stem cells may protect nearby non-CSCs from cytotoxic chemotherapy.
Decrease in blood pressure (BP) is the major goal of adrenalectomy for primary aldosteronism. Nevertheless, the optimal timing to assess these outcomes and the needed duration of follow-up are ...uncertain. We systematically reviewed the literature regarding trends in BP-related outcomes during follow-up after adrenalectomy.
A systematic literature search of medical literature from PubMed, Embase and the Cochrane Library regarding BP-related outcomes (i.e. cure of hypertension rates, BP and antihypertensives) was performed. The Quality In Prognosis Studies risk of bias tool was used.
Of the 2057 identified records, 13 articles met the inclusion criteria. Overall study quality was low. In multiple studies, the biggest decrease in BP was shown within the first month(s) after adrenalectomy and afterwards BP often remained stable during long-term follow-up.
Based on the available studies one might suggest that long follow-up is unnecessary, since outcomes seem to stabilize within the first months.
•The needed follow-up duration after surgery for primary aldosteronism is not clear.•This systematic review clarifies the course of blood pressure decrease post surgery.•Studies show that blood pressure seems to decrease the most within the first months.•Long follow-up after surgery might be unnecessary.
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