AIM: To systematically characterize specific pain patterns in the most frequent pancreatic diseases.
METHODS: Pain in patients with chronic pancreatitis (n = 314), pancreatic cancer (n = 469), and other pancreatic tumors (n = 249) including mucinous (n = 20) and serous cystadenoma (n = 31), invasive (n = 37) and non-invasive intraductal papillary mucinous neoplasia (IPMN; n = 48), low stage (n = 18) and high stage neuroendocrine neoplasia (n = 44), and ampullary cancer (n = 51) was registered and correlated with clinicopathological data. Survival times were estimated by the Kaplan-Meier method. Patients alive at the follow-up time were censored. Survival curves were compared statistically using the log-rank test.
RESULTS: Forty-nine point one percent of pancreatic cancer patients revealed no pain, whereas in chronic pancreatitis only 18.3% were pain free. In contrary, moderate/severe pain was registered in 15.1% in pancreatic cancer patients that was increased in chronic pancreatitis with up to 34.2%. Serous cystadenoma was asymptomatic in most cases (58.1%), whereas 78.9% of all mucinous cystadenoma patients suffered pain. In neuroendocrine neoplasia pain was not a key clinical symptom since 64% of low stage neuroendocrine neoplasia and 59% of high stage neuroendocrine neoplasia patients were pain free. Cancer localization in the pancreatic body and patients with malignant pancreatic neoplasms were associated with more severe pain. Tumor grading and stage did not show any impact on pain. Only in pancreatic cancer, pain was directly associated with impaired survival.
CONCLUSION: Pancreatic pain depicts different patterns of abdominal pain sensation according to the respective pancreatic disorder and does not allow a unification of the term pancreatic pain.
Abdominal pain; Pancreatic neoplasm; Chronic pancreatitis; Intraductal papillary mucinous neoplasia; Pancreatic cancer
Pancreatic cancer is characterized by frequently delayed diagnosis and aggressive tumor growth which hampers most of the current treatment modalities. This review aims to summarize the available evidence about the diagnostic and therapeutic aspects of resectable and non-resectable pancreatic cancer therapy.
Embedded in the concept of multimodal therapy, surgery plays the central role in the treatment of pancreatic cancer. With advantageous tumor characteristics and complete tumor resection as the most relevant positive prognostic factors, the detection of premalignant or early invasive lesions combined with safe and oncologic adequate surgery is the major therapeutic aim. Most pancreatic adenocarcinomas are locally advanced or metastatic when diagnosed and need to be treated by the combination of surgery and (radio)chemotherapy or by palliative chemotherapy.
Diagnostics; Multimodal therapy; Palliative therapy; Pancreatic ductal adenocarcinoma; Surgery
AIM: To evaluate quality of life (QoL) after curative liver resection and identify variables associated with decreased QoL.
METHODS: From October 2001 to July 2004, 323 patients underwent liver resection. At 3-36 mo after discharge, 188 patients were disease free. QoL was assessed using the Short Form (SF)-12 Health Survey with mental and physical component scales (SF-12 MCS and PCS), supplemented with generic questions concerning pain and liver-specific items.
RESULTS: Sixty-eight percent (128/188) returned the questionnaire, which was completed in 75% (96/128) of cases. Median SF-12 PCS and MCS were 46.7 (interquartile range: 34.2-53.9) and 54.1 (42.8-58.2). Fifty percent were pain free with a median symptom score of 1.75 (1.38-2.13). PCS was higher after major hepatectomy [57% (55/96)] compared to minor resection (P = 0.0049), which represented an improved QoL. QoL was not affected by sex but by age compared to the general German population. MCS was higher after liver surgery for metastatic disease [55.9 (47.5-58.8)] compared to primary carcinoma [49.6 (36.5-55.1)] and benign disease [49.2 (37.7-56.3)] (P = 0.0317). There was no correlation between length of postoperative period and QoL. Pain, deficiencies in everyday life and a high symptom score significantly decreased MCS and PCS.
CONCLUSION: Most patients were only marginally affected even after major liver resection; however, minor complications were associated with decreased SF-12 MCS and PCS and need careful attention.
Quality of life; Liver resection
Transforming growth factors βs (TGF‐βs) are implicated in pancreatic tissue repair but their role in acute pancreatitis is not known. To determine whether endogenous TGF‐βs modulate the course of caerulein induced acute pancreatitis, caerulein was administered to wild‐type (FVB−/−) and transgenic mice that are heterozygous (FVB+/−) for expression of a dominant negative type II TGF‐β receptor.
After 7 hourly supramaximal injections of caerulein, the pancreas was evaluated histologically and serum was assayed for amylase and lipase levels. Next, the effects of caerulein on amylase secretion were determined in mouse pancreatic acini, and cholecystokinin (CCK) receptor expression was assessed.
The normal mouse pancreas was devoid of inflammatory cells whereas the pancreas from transgenic mice contained lymphocytic infiltrates. Caerulein injection in wild‐type mice resulted in 6‐ and 36‐fold increases in serum amylase and lipase levels, respectively, increased serum trypsinogen activation peptide (TAP) levels, gross oedema and a marked inflammatory response in the pancreas that consisted mainly of neutrophils and macrophages. By contrast, FVB+/− mice exhibited minimal alterations in response to caerulein with attenuated neutrophil–macrophage infiltrates. Moreover, acini from FVB+/− mice did not exhibit restricted stimulation at high caerulein concentrations, even though CCK receptor mRNA levels were not decreased.
Our findings indicate that a functional TGF‐β signalling pathway may be required for caerulein to induce acute pancreatitis and for the CCK receptor to induce acinar cell damage at high ligand concentrations. Our results also support the concept that restricted stimulation at high caerulein concentrations contributes to the ability of caerulein to induce acute pancreatitis.
Pancreatic cancer (PDAC) is the fourth leading cause of cancer-related mortality in the Western world and, even in 2014, a therapeutic challenge. The only chance for long-term survival is radical surgical resection followed by adjuvant chemotherapy which can be performed in about 20% of all PDAC patients by the time of diagnosis. As pancreatic surgery has significantly changed during the past years, extended operations, including vascular resections, have become more frequently performed in specialized centres and the border of resectability has been pushed forward to achieve a potentially curative approach in the respective patients in combination with neoadjuvant and adjuvant treatment strategies. In contrast to adjuvant treatment which has to be regarded as a cornerstone to achieve long-term survival after resection, neoadjuvant treatment strategies for locally advanced findings are currently under debate. This overview summarizes the possibilities and evidence of vascular, namely, venous and arterial, resections in PDAC surgery.
Surgical management of renal secondary hyperparathyroidism (sHPT) is varying. Total parathyroidectomy with heterotopic autotransplantation (TPTX + AT) is one of the standard surgical procedures in sHPT, but there is no consensus about the optimal site for graft insertion. At the surgical department of the University Hospital of Heidelberg we prefer the autotransplantation into the tibialis anterior muscle. The aim of this study was to assess the long-term function of the auto-transplanted parathyroid tissue in this type of surgical procedure.
The function of the autograft of 42 patients was assessed 8.2 ± 2.5 years after surgery, using a modified Casanova-test of the leg bearing the parathyroid tissue. Ischemic blockage was induced by tourniquet and the levels of parathyroid hormone (PTH) were assessed during the test.
At the point of assessment, the ischemic blockage led to a significant reduction in the concentration of PTH (≥50 % of the baseline value) in 19 patients (45 %) indicating well-functioning autografts. In 11 patients (26 %), ischemic blockage did not cause any change in the concentration of PTH (≤20 % of the baseline value), indicating functioning residual parathyroid tissue from another site. The source of PTH production was classified as unidentifiable in five patients (12 %). Two patients had developed graft-dependent recurrent HPT (5 %) without therapeutic consequences and three patients suffered from persistent symptomatic hypoparathyroidism (7 %).
These results indicate that TPTX + AT into the tibialis anterior muscle is a successful surgical treatment for renal HPT and that the modified Casanova-test is a suitable diagnostic tool for autografts function.
Renal hyperparathyroidism; Parathyroidectomy; Autotransplantation; Casanova-test
Mesh augmentation seems to reduce recurrences following laparoscopic paraesophageal hernia repair (LPHR). However, there is an uncertain risk of mesh-associated complications. Risk-benefit analysis might solve the dilemma.
Materials and Methods
A systematic literature search was performed to identify randomized controlled trials (RCTs) and observational clinical studies (OCSs) comparing laparoscopic mesh-augmented hiatoplasty (LMAH) with laparoscopic mesh-free hiatoplasty (LH) with regard to recurrences and complications. Random effects meta-analyses were performed to determine potential benefits of LMAH. All data regarding LMAH were used to estimate risk of mesh-associated complications. Risk-benefit analysis was performed using a Markov Monte Carlo decision-analytic model.
Meta-analysis of 3 RCTs and 9 OCSs including 915 patients revealed a significantly lower recurrence rate for LMAH compared to LH (pooled proportions, 12.1% vs. 20.5%; odds ratio (OR), 0.55; 95% confidence interval (CI), 0.34 to 0.89; p = 0.04). Complication rates were comparable in both groups (pooled proportions, 15.3% vs. 14.2%; OR, 1.02; 95% CI, 0.63 to 1.65; p = 0.94). The systematic review of LMAH data yielded a mesh-associated complication rate of 1.9% (41/2121; 95% CI, 1.3% to 2.5%) for those series reporting at least one mesh-associated complication. The Markov Monte Carlo decision-analytic model revealed a procedure-related mortality rate of 1.6% for LMAH and 1.8% for LH.
Mesh application should be considered for LPHR because it reduces recurrences at least in the mid-term. Overall procedure-related complications and mortality seem to not be increased despite of potential mesh-associated complications.
Sarcoidosis is a chronic multisystemic granulomatous disease of unknown origin, which can involve nearly all organs. In the case of an infrequent gastrointestinal tract involvement in systemic sarcoidosis, granulomas of the liver are most commonly described while isolated pancreatic sarcoid lesions are rarely seen. We report a case of systemic sarcoidosis with exclusive extrapulmonal involvement of the liver and the pancreas in a 71-year-old white man. The diagnosis of liver involvement was confirmed by biopsy. Pancreatic surgery was needed because preoperative evaluation could not exclude pancreatic cancer and for biliary decompression. An extensive literature review of systemic sarcoidosis, focusing on reported cases with unusual presentation of sarcoidosis in the liver and the pancreas, its diagnosis, treatment, and prognosis was made.
Systemic; Sarcoidosis; Extrapulmonary; Liver; Pancreas
Pancreatic cystic lesions comprise various entities with different histopathological characteristics and their differential diagnosis is often a challenge for clinicians. Autoimmune pancreatitis (AIP) is usually not considered in the differential diagnosis of cystic lesions, but often mimics the morphological aspects of pancreatic neoplasm. We report the case of a 64-year-old male patient with a cystic pancreatic head lesion (diameter 5 cm) and stenosis of the distal bile duct requiring repeated stenting. Because of the clinical presentation together with moderate elevation of serum CA19-9 and massive elevation of cyst fluid CA19-9 (122.695 U/L; normal range: < 37.0 U/L), the patient underwent explorative laparotomy and pylorus preserving partial pancreaticoduodenectomy. Histology revealed surprisingly AIP with an inflammatory pseudocyst. In conclusion, cyst fluid analysis of tumor markers and cyst fluid cytology lack high accuracy to clearly differentiate cystic pancreatic lesions. Although AIP is rarely associated with pseudocysts, the disease has to be considered in the differential diagnosis of cystic pancreatic lesions. Early examination of serum IgG, IgG4 and auto-antibodies might save these patients from unnecessary endoscopical and surgical procedures.
Pseudocyst; Autoimmune pancreatitis; Pancreatic cancer; Tumor marker; CEA; CA19-9
Angiosarcoma is a rare primary malignant neoplasm of the liver with a poor prognosis. Here, we report a case of a patient with a ruptured hepatic angiosarcoma which was treated by emergency catheter-directed embolization, followed by left-sided hemihepatectomy.
Ruptured angiosarcoma; Liver; Embolization
The introduction of transjugular intrahepatic portal-systemic stent-shunt (TIPSS) has been a major breakthrough in the treatment of portal hypertension, which has evolved to a large extent, into a routine procedure. A 21-year-old male patient with progressive graft fibrosis/cirrhosis requiring TIPSS for variceal hemorrhage in the esophagus due to portal hypertension was unresponsive to conventional measures two years after living related liver transplantation (LDLT). Subsequently, variceal hemorrhage was controlled, however, liver function decreased dramatically with consecutive multi organ failure. CT scan revealed substantial necrosis in the liver. The patient underwent successful “high urgent” cadaveric liver transplantation and was discharged on postoperative d 20 in a stable condition.
Portal hypertension; Liver necrosis; Fibrosis; Cirrhosis
Tracheostomy is one of the most frequently performed procedures in intensive care medicine. The two main approaches to form a tracheostoma are the open surgical tracheotomy (ST) and the interventional strategy of percutaneous dilatational tracheotomy (PDT). It is particularly important to the critically ill patients that both procedures are performed with high success rates and low complication frequencies. Therefore, the aim of this systematic review is to summarize and analyze existing and relevant evidence for peri- and postoperative parameters of safety.
A systematic literature search will be conducted in The Cochrane Library, MEDLINE, LILACS, and Embase to identify all randomized controlled trials (RCTs) comparing peri- and postoperative complications between the two strategies and to define the strategy with the lower risk of potentially life-threatening events. A priori defined data will be extracted from included studies, and methodological quality will be assessed according to the recommendations of the Cochrane Collaboration.
The findings of this systematic review with proportional meta-analysis will help to identify the strategy with the lowest frequency of potentially life-threatening events. This may influence daily practice, and the data may be implemented in treatment guidelines or serve as the basis for planning further randomized controlled trials. Considering the critical health of these patients, they will particularly benefit from evidence-based treatment.
Systematic review registration
Tracheostomy; Percutaneous dilatational tracheostomy; Surgical tracheostomy; Systematic review with meta-analysis
AIM: To determine whether IFN-α is the agent that turns a slightly effective treatment (radiochemotherapy) into a potent therapy, we tested IFN-α for its synergistic properties.
METHODS: Eight pancreatic carcinoma cell lines were treated with the single agents and combinations of these. The role of IFN-α regarding a) direct inhibitory effects; b) radio and chemosensitizing effects; c) anti-angiogenic properties and d) enhancement of immunogenicity was investigated.
RESULTS: Our results show that IFN-α has direct inhibitory properties and some synergistic influence as determined by AnnexinV/PI stain and cell count. IFN-α is also able to prevent the increase in proliferation rate and VEGF secretion of CDDP resistant cells. Having taken the results from immunogenicity experiments together, we found cells that can be influenced by IFN-α but were less susceptible against T cells. Furthermore, high expression of MHC molecules, CD118, EGF-R and Fas was predictive for a good response.
CONCLUSION: In conclusion, IFN-α has direct cytotoxic effects, acts as a radiosensitizer and circumvents tumor cell-regrowth after CDDP treatment. These mechanisms may be responsible for the good clinical outcome of CapRI.
Interferon-alpha; Pancreatic adenocarcinoma; Synergistic effects; Combination therapy
AIM: To present a case of methicillin-resistant Staphylococcus aureus (MRSA) infection following bile duct stenting in a patient with malignant biliary obstruction.
METHODS: A 78-year-old male patient was admitted to a community hospital with progredient painless jaundice lasting over two weeks, weight loss and sweating at night. Whether a stent should be implanted pre-operatively in jaundiced patients or whether these patients should directly undergo surgical resection, was discussed.
RESULTS: ERC and a biopsy from the papilla of Vater revealed an adenocarcinoma. In addition, a 7-Ch plastic stent was placed into the common bile duct. Persistent abdominal pain, increasing jaundice, weakness and indigestion led to the transfer of the patient to our hospital. A pylorus-preserving pancreatoduodenectomy was performed. Intraoperatively, bile leaked out of the transected choledochus and the stent was found to be dislocated in the duodenum. A smear of the bile revealed an infection with MRSA, leading to post-operative isolation of the patient.
CONCLUSION: As biliary stents can cause severe infection of the bile, the need for pre-operative placement of biliary stents should be carefully evaluated in each individual case.
Methicillin-resistant Staphylococcus aureus; Bile; Infection; Stent; Biliary obstruction; Malignancy; Surgery
Roux-en-Ygastric bypass (RYGB) and sleeve gastrectomy (SG) rank among the most frequently applied bariatric procedures worldwide due to their positive risk/benefit correlation. A systematic review revealed a similar excess weight loss (EWL) 2 years postoperatively between SG and RYGB. However, there is a lack of randomized controlled multi-centre trials comparing SG and RYGB, not only concerning EWL, but also in terms of remission of obesity-related co-morbidities, gastroesophageal reflux disease (GERD) and quality of life (QoL) in the mid- and long-term.
The BariSurg trial was designed as a multi-centre, randomized controlled patient and observer blind trial. The trial protocol was approved by the corresponding ethics committees of the centres. To demonstrate EWL non-inferiority of SG compared to RYGB, power calculation was performed according to a non-inferiority study design. Morbidity, mortality, remission of obesity-related co-morbidities, GERD course and QoL are major secondary endpoints. 248 patients between 18 and 70 years, with a body mass index (BMI) between 35–60 kg/m2 and indication for bariatric surgery according to the most recent German S3-guidelines will be randomized. The primary and secondary endpoints will be assessed prior to surgery and afterwards at discharge and at the time points 3–6, 12, 24, 36, 48 and 60 months postoperatively.
With its five year follow-up, the BariSurg-trial will provide further evidence based data concerning the impact of SG and RYGB on EWL, remission of obesity-related co-morbidities, the course of GERD and QoL.
The trial protocol has been registered in the German Clinical Trials Register DRKS00004766.
Sleeve gastrectomy; Roux-en-Ygastric bypass; Randomized controlled trial; Patient and observer blind trial; Long-term excess weight loss; Obesity related co-morbidity; Gastroesophageal reflux disease; Quality of life; Morbidity; Mortality
AIM: The structural and functional characteristics of cells are dependent on the specific gene expression profile. The ability to study and compare gene expression at the cellular level will therefore provide valuable insights into cell physiology and pathophysiology.
METHODS: Individual cells were isolated from frozen colon tissue sections using laser microdissection. DNA as well as RNA were extracted, and total RNA was reversely transcribed to complementary DNA (cDNA). Both DNA and cDNA were analyzed by nested polymerase chain reaction (PCR). The quality of isolated DNA and RNA was satisfactory.
RESULTS: Single cells were successfully microdissected using an ultraviolet laser micromanipulator. Nested PCR amplification products of DNA and cDNA of single cells could clearly be visualized by agarose gel electrophoresis.
CONCLUSION: The combined use of laser microdissection and nested-PCR provides an opportunity to analyze gene expression in single cells. This method allows the analysis and identification of specific genes which are involved in physiological and pathophysiological processes in a complex of variable cell phenotypes.
Isolated pancreatic metastases or pancreatic metastases with limited extrapancreatic disease are uncommon and account for only 2-4% of resected malignant pancreatic lesions in surgical series. However, clear-cell renal cell carcinoma is the predominant primary tumor and accounts for more than 60% of cases with isolated pancreatic metastases. Pancreatectomy is the treatment of choice for most patients with isolated pancreatic metastases from renal cell cancer.
This review provides an overview of clinical presentation and diagnosis as well as surgical management, including patient selection for surgery and surgical technique for pancreatic metastases of renal cell carcinoma.
Although there is no high-level evidence that surgical resection of pancreatic metastases improves survival, the survival results of several observational series and of systematic reviews are promising and support pancreatic resection as part of a multimodal treatment. The reported median survival and 5-year survival rates after pancreatic resection range from 6 to 10 years and from 55 to 75%, respectively. Pancreatic resection is effective for local control. However, extrapancreatic progression frequently occurs. With the introduction of novel systemic therapy options such as tyrosine kinase inhibitors, the prognosis of metastatic renal cell carcinoma has improved, and this will affect the role of pancreatic resection for metastases.
Pancreatic resection for isolated renal cell carcinoma is safe and effective, may confer a survival benefit and should, therefore, be considered in patients for whom no contraindication for surgery exists.
Pancreatic metastases; Urogenital tract; Surgical resection
Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT.
Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT).
The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs.
The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group.
Hepatocellular carcinoma; Liver transplantation; Sorafenib; Transarterial chemoembolization
The composition of tumor-targeted T cell infiltrates is a major prognostic factor in colorectal cancer (CRC) outcome; however, the functional role of these populations in prolonging patient survival remains unclear. Here, we evaluated 190 patients with CRC for the presence of functionally active tumor-infiltrating lymphocytes (TILs), the tumor specificity of these TILs, and the correlation between patient TILs and long-term survival. Using intracytoplasmic cytokine staining in conjunction with HLA multimers loaded with tumor peptide and antigen-specific cytokine secretion assays, we determined that TNF-α expression delineates a population of tumor antigen–specific (TA-specific) cytotoxic T lymphocytes (CTLs) present within tumors from patients with CRC. Upregulation of TNF-α expression in TILs strongly correlated with an increase in the total amount of intratumoral TNF-α, which is indicative of tumor-specific CTL activity. Moreover, a retrospective multivariate analysis of 102 patients with CRC, which had multiple immune parameters evaluated, revealed that increased TNF-α concentration was an independent prognostic factor. Together, these results indicate that the prognostic impact of T cell infiltrates for CRC maybe largely based on subpopulations of active TA-specific T cells within the tumor, suggesting causal implication for these cells in patient survival. Additionally, these results support the use of intratumoral TNF-α, which is indicative of T cell function, as a prognostic parameter for CRC.
The purpose of the study was to evaluate the effect of radiation therapy and chemoradiation with gemcitabine (GEM) after R1 resection in patients with pancreatic adenocarcinoma (PAC).
We performed a retrospective analysis of 25 patients who were treated with postoperative radiotherapy (RT) or chemoradiation (CRT) after surgery with microscopically positive resection margins for primary pancreatic cancer (PAC). Median age was 60 years (range 34 to 74 years), and there were 17 male and 8 female patients. Fractionated RT was applied with a median dose of 49.6 Gy (range 36 to 54 Gy). Eight patients received additional intraoperative radiotherapy (IORT) with a median dose of 12 Gy.
Median overall survival (mOS) of all treated patients was 22 months (95% confidence interval (CI) 7.9 to 36.1 months) after date of resection and 21.1 months (95% CI 7.6 to 34.6 months) after start of (C)RT. Median progression-free survival (mPFS) was 13.0 months (95% CI 0.93 to 25 months). Grading (G2 vs. G3, P = 0.005) and gender (female vs. male, P = 0.01) were significantly correlated with OS. There was a significant difference in mPFS between male and female patients (P = 0.008). A total of 11 from 25 patients experienced local tumour progression, and 19 patients were diagnosed with either locoregional or distant failure.
We demonstrated that GEM-based CRT can be applied in analogy to neoadjuvant protocols in the adjuvant setting for PAC patients at high risk for disease recurrence after incomplete resection. Patients undergoing additive CRT have a rather good OS and PFS compared to historical control patient groups.
Radiotherapy; Pancreatic cancer; Adjuvant radiotherapy; Incomplete resection; R1 resection
The insertion of central venous access devices, such as totally implantable venous access ports (TIVAPs), is routine in patients who need a safe and permanent venous access. The number of port implantations is increasing due to the development of innovative adjuvant and neo-adjuvant therapies. Currently, two different strategies are being routinely used: surgical cut-down of the cephalic vein (vena section) and direct puncture of the subclavian vein. The aim of this trial is to identify the strategy for the implantation of TIVAPs with the lowest risk of pneumothorax and haemothorax.
The PORTAS-3 trial is designed as a multicentre, randomised controlled trial to compare two implantation strategies. A total of 1,154 patients will be randomised after giving written informed consent. Patients must be over 18 years of age and scheduled for primary implantation of a TIVAP on the designated side. The primary endpoint will be the frequency of pneumothorax and haemothorax after insertion of a TIVAP by one of two different strategies. The experimental intervention is as follows: open strategy, defined as surgical cut-down of the cephalic vein, supported by a rescue technique if necessary, and in the case of failure, direct puncture of the subclavian vein. The control intervention is as follows: direct puncture of the subclavian vein using the Seldinger technique guided by sonography, fluoroscopy or landmark technique. The trial duration is approximately 36 months, with a recruitment period of 18 months and a follow-up period of 30 days.
The PORTAS-3 trial will compare two different TIVAP implantation strategies with regard to their individual risk of postoperative pneumothorax and haemothorax. Since TIVAP implantation is one of the most common procedures in general surgery, the results will be of interest for a large community of surgeons as well as oncologists and general practitioners. The pragmatic trial design ensures that the results will be generalizable to a wide range of patients.
The trial protocol was registered on 28 August 2014 with the German Clinical Trials Register (DRKS00004900). The World Health Organization’s Universal Trial Number is U1111-1142-4420.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0643-z) contains supplementary material, which is available to authorized users.
Venous access ports; Implantation strategies; Pneumothorax; Haemothorax
We performed a multistage genome-wide association study (GWAS) including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT; per-allele odds ratio [OR] = 0.79; 95% confidence interval [CI] = 0.74–0.84; P = 3.0×10−12), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2; OR = 1.46; 95% CI = 1.30–1.65; P = 1.1×10−10), rs9581943 at 13q12.2 (PDX1; OR = 1.15; 95% CI = 1.10–1.20; P = 2.4×10−9), and rs16986825 at 22q12.1 (ZNRF3; OR = 1.18; 95% CI = 1.12–1.25; P = 1.2×10−8). An independent signal was identified in exon 2 of TERT at the established region 5p15.33 (rs2736098; OR = 0.80; 95% CI = 0.76–0.85; P = 9.8×10−14). We also identified a locus at 8q24.21 (rs1561927; P = 1.3×10−7) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study has identified multiple new susceptibility alleles for pancreatic cancer worthy of follow-up studies.
In colorectal cancer (CoCa) EpCAM is frequently associated with claudin-7. There is evidence that tumor-promoting EpCAM activities are modulated by the association with claudin-7. To support this hypothesis, claudin-7 was knocked-down (kd) in HT29 and SW948 cells.
HT29-cld7kd and SW948-cld7kd cells display decreased anchorage-independent growth and the capacity for holoclone-, respectively, sphere-formation is reduced. Tumor growth is delayed and cld7kd cells poorly metastasize. In line with this, migratory and invasive potential of cld7kd clones is strongly impaired, migration being inhibited by anti-CD49c, but not anti-EpCAM, although motility is reduced in EpCAM siRNA-treated cells. This is due to claudin-7 recruiting EpCAM in glycolipid-enriched membrane fractions towards claudin-7-associated TACE and presenilin2, which cleave EpCAM. The cleaved intracellular domain, EpIC, promotes epithelial-mesenchymal transition (EMT)-associated transcription factor expression, which together with fibronectin and vimentin are reduced in claudin-7kd cells. But, uptake of HT29wt and SW948wt exosomes by the claudin-7kd lines sufficed for transcription factor upregulation and for restoring motility.
Thus, claudin-7 contributes to motility and invasion and is required for recruiting EpCAM towards TACE/presenilin2. EpIC generation further supports motility by promoting a shift towards EMT. Notably, EMT features of cld7-competent metastatic CoCa cells can be transferred via exosomes to poorly metastatic cells.
Colorectal cancer; claudin 7; EpCAM; cancer initiating cells; metastasis
Identification of a single molecular trait that is determinant of common malignancies may serve as a powerful diagnostic supplement to cancer type-specific markers. Here, we report a DNA methylation mark that is characteristic of seven studied malignancies, namely cancers of lung, breast, prostate, pancreas, colorectum, glioblastoma and B cell chronic lymphocytic leukaemia (CLL) (n = 137). This mark was defined by substantial hypermethylation at the promoter and first exon of growth hormone secretagouge receptor (GHSR) through bisulfite pyrosequencing. The degree of aberrant methylation was capable of accurate discrimination between cancer and control samples. The highest sensitivity and specificity of cancer detection was achieved for cancers of pancreas, lung, breast and CLL yielding the area under the curve (AUC) values of 1.0000, 0.9952, 0.9800 and 0.9400, respectively. Narrowing to a single CpG site within the gene's promoter or four consecutive CpG units of the highest methylation levels within the first exon improved the detection power. GHSR hypermethylation was detected already at the early stage tumors. The accurate performance of this marker was further replicated in an independent set of pancreatic cancer and control samples (n = 78). These findings support the candidature of GHSR methylation as a highly accurate pan-cancer marker.
DNA methylation; Cancer; Diagnosis; GHSR; Epigenetics