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1.  Preoperative inspiratory muscle training to prevent postoperative pulmonary complications in patients undergoing esophageal resection (PREPARE study): study protocol for a randomized controlled trial 
Trials  2014;15:144.
Background
Esophageal resection is associated with a high incidence of postoperative pneumonia. Respiratory complications account for almost half of the readmissions to the critical care unit. Postoperative complications can result in prolonged hospital stay and consequently increase healthcare costs. In cardiac surgery a preoperative inspiratory muscle training program has shown to prevent postoperative pneumonia and reduce length of hospital stay. While in some surgical centers inspiratory muscle training is already used in the preoperative phase in patients undergoing esophageal resection, the added value of this intervention on the reduction of pulmonary complications has not yet been investigated in large surgical populations other than cardiac surgery in a randomized and controlled study design.
Methods/Design
The effect of a preoperative inspiratory muscle training program on the incidence of postoperative pneumonia in patients undergoing esophageal resection will be studied in a single blind multicenter randomized controlled trial (the PREPARE study). In total 248 patients (age >18 years) undergoing esophageal resection for esophageal cancer will be included in this study. They are randomized to either usual care or usual care with an additional inspiratory muscle training intervention according to a high-intensity protocol which is performed with a tapered flow resistive inspiratory loading device. Patients have to complete 30 dynamic inspiratory efforts twice daily for 7 days a week until surgery with a minimum of 2 weeks. The starting training load will be aimed to be 60% of maximal inspiratory pressure and will be increased based on the rate of perceived exertion.
The main study endpoint is the incidence of postoperative pneumonia. Secondary objectives are to evaluate the effect of preoperative inspiratory muscle training on length of hospital stay, duration of mechanical ventilation, incidence of other postoperative (pulmonary) complications, quality of life, and on postoperative respiratory muscle function and lung function.
Discussion
The PREPARE study is the first multicenter randomized controlled trial to evaluate the hypothesis that preoperative inspiratory muscle training leads to decreased pulmonary complications in patients undergoing esophageal resection.
Trial registration
NCT01893008.
doi:10.1186/1745-6215-15-144
PMCID: PMC4019558  PMID: 24767575
Inspiratory muscle training; Physical therapy; Preoperative; Esophageal resection; Pneumonia
2.  Imagine a world without cancer 
BMC Cancer  2014;14:186.
Background
Since the “War on Cancer” was declared in 1971, the United States alone has expended some $300 billion on research, with a heavy focus on the role of genomics in anticancer therapy. Voluminous data have been collected and analyzed. However, in hindsight, any achievements made have not been realized in clinical practice in terms of overall survival or quality of life extended. This might be justified because cancer is not one disease but a conglomeration of multiple diseases, with widespread heterogeneity even within a single tumor type.
Discussion
Only a few types of cancer have been described that are associated with one major signaling pathway. This enabled the initial successful deployment of targeted therapy for such cancers. However, soon after this targeted approach was initiated, it was subverted as cancer cells learned and reacted to the initial treatments, oftentimes rendering the treatment less effective or even completely ineffective. During the past 30 plus years, the cancer classification used had, as its primary aim, the facilitation of communication and the exchange of information amongst those caring for cancer patients with the end goal of establishing a standardized approach for the diagnosis and treatment of cancers. This approach should be modified based on the recent research to affect a change from a service-based to an outcome-based approach. The vision of achieving long-term control and/or eradicating or curing cancer is far from being realized, but not impossible. In order to meet the challenges in getting there, any newly proposed anticancer strategy must integrate a personalized treatment outcome approach. This concept is predicated on tumor- and patient-associated variables, combined with an individualized response assessment strategy for therapy modification as suggested by the patient’s own results. As combined strategies may be outcome-orientated and integrate tumor-, patient- as well as cancer-preventive variables, this approach is likely to result in an optimized anticancer strategy.
Summary
Herein, we introduce such an anticancer strategy for all cancer patients, experts, and organizations: Imagine a World without Cancer.
doi:10.1186/1471-2407-14-186
PMCID: PMC3995593  PMID: 24629025
Cancer; Carcinogenesis; Multimodal therapy; Cancer classification; Personalized anticancer therapy; Individualized anticancer therapy
3.  Adding Preoperative Radiotherapy Plus Cetuximab to Perioperative Chemotherapy for Resectable Esophageal Adenocarcinoma: A Single-Center Prospective Phase II Trial 
The Oncologist  2013;19(1):32-33.
Background.
Local and systemic recurrence are important sources of treatment failure following surgical resection of esophageal adenocarcinoma. We hypothesized that adding preoperative cetuximab and radiotherapy (cetux-RT) to perioperative chemotherapy would increase treatment efficacy with acceptable toxicity.
Methods.
In this prospective phase II trial, patients were treated with three cycles of epirubicin, cisplatin, and capecitabine (ECX), followed by cetux-RT. After surgery with curative intent, patients received three more cycles of ECX. Primary endpoints were efficacy, determined by histopathological complete response (pCR) rate, and safety, which was assessed with resectability rate.
Results.
Of the 12 patients enrolled in this trial, six received at least one dose of cetux-RT. In five patients, cetux-RT was not started because of adverse events (AEs) related to preoperative chemotherapy; one patient had progressive disease. Addition of cetux-RT was well tolerated and did not interfere with the resectability rate (100%). However, the pCR rate was 0, and 50% of patients experienced serious adverse events (SAEs) postoperatively.
Conclusion.
With 12 patients enrolled, the lack of initial signs of efficacy and a high incidence of postoperative SAEs prompted us to end this study prematurely. Perioperative ECX was associated with considerable toxicity, and further treatment intensification is problematic.
doi:10.1634/theoncologist.2013-0254
PMCID: PMC3903062  PMID: 24335595
4.  Strategies to reduce pulmonary complications after esophagectomy 
Esophagectomy, the surgical removal of all or part of the esophagus, is a surgical procedure that is associated with high morbidity and mortality. Pulmonary complications are an especially important postoperative problem. Therefore, many perioperative strategies to prevent pulmonary complications after esophagectomy have been investigated and introduced in daily clinical practice. Here, we review these strategies, including improvement of patient performance and technical advances such as minimally invasive surgery that have been implemented in recent years. Furthermore, interventions such as methylprednisolone, neutrophil elastase inhibitor and epidural analgesia, which have been shown to reduce pulmonary complications, are discussed. Benefits of the commonly applied routine nasogastric decompression, delay of oral intake and prophylactic mechanical ventilation are unclear, and many of these strategies are also evaluated here. Finally, we will discuss recent insights and new developments aimed to improve pulmonary outcomes after esophagectomy.
doi:10.3748/wjg.v19.i39.6509
PMCID: PMC3801361  PMID: 24151374
Esophagectomy; Complications; Pneumonia; Acute lung injury; Acute respiratory distress syndrome
5.  Early severe mediastinal bleeding after esophagectomy: a potentially lethal complication 
Journal of Thoracic Disease  2013;5(2):E58-E60.
Background
Anastomotic leakage after cervical oesophagogastrostomy is a common and difficult problem. Mediastinal manifestation of anastomotic leakage may lead to mediastinitis with dramatic and potentially lethal outcome. Contamination of the mediastinum can be controlled by endoscopic placement of an expandable metal stent. We present two cases of severe haemorrhage after mediastinal manifestation of anastomotic leakage in patients with and without expandable metal stent (EMS).
Cases
This case report describes two cases of severe haemorrhage after thoracolaparoscopic esophagectomy with cervical oesophagogastrostomy. The recovery of both patients was complicated by anastomotic leakage with mediastinal manifestation. In one case, 11 days after placement of an EMS for anastomotic leakage a bleeding occurred in the cervical wound. Angiography during surgery showed contrast leakage in the aortic arch. Despite sternotomy and endovascular catheterization, there were no surgical options to treat this condition and the patient died of exsanguination. In the other case the patient presented with severe hematemesis 11 days after surgery. Shortly after this hematemesis the patient became hemodynamic instable. The patient was taken to the operation theatre, but before any intervention could take place resuscitation was needed and the patient died of exsanguination.
Conclusions
Severe haemorrhage is a rare and potentially lethal complication after esophagectomy. This condition is related to anastomotic leakage with mediastinal manifestation. Awareness of this potentially lethal complication is important for early recognition and treatment of this condition. The role of endoscopic stenting of the cervical anastomosis is controversial and potentially dangerous.
doi:10.3978/j.issn.2072-1439.2012.10.12
PMCID: PMC3621925  PMID: 23585960
Severe haemorrhage; expandable metal stent; anastomotic leakage; mediastinitis
6.  Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer, a randomized controlled trial (ROBOT trial) 
Trials  2012;13:230.
Background
For esophageal cancer patients, radical esophagolymphadenectomy is the cornerstone of multimodality treatment with curative intent. Transthoracic esophagectomy is the preferred surgical approach worldwide allowing for en-bloc resection of the tumor with the surrounding lymph nodes. However, the percentage of cardiopulmonary complications associated with the transthoracic approach is high (50 to 70%).
Recent studies have shown that robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RATE) is at least equivalent to the open transthoracic approach for esophageal cancer in terms of short-term oncological outcomes. RATE was accompanied with reduced blood loss, shorter ICU stay and improved lymph node retrieval compared with open esophagectomy, and the pulmonary complication rate, hospital stay and perioperative mortality were comparable. The objective is to evaluate the efficacy, risks, quality of life and cost-effectiveness of RATE as an alternative to open transthoracic esophagectomy for treatment of esophageal cancer.
Methods/design
This is an investigator-initiated and investigator-driven monocenter randomized controlled parallel-group, superiority trial. All adult patients (age ≥18 and ≤80 years) with histologically proven, surgically resectable (cT1-4a, N0-3, M0) esophageal carcinoma of the intrathoracic esophagus and with European Clinical Oncology Group performance status 0, 1 or 2 will be assessed for eligibility and included after obtaining informed consent. Patients (n = 112) with resectable esophageal cancer are randomized in the outpatient department to either RATE (n = 56) or open three-stage transthoracic esophageal resection (n = 56). The primary outcome of this study is the percentage of overall complications (grade 2 and higher) as stated by the modified Clavien–Dindo classification of surgical complications.
Discussion
This is the first randomized controlled trial designed to compare RATE with open transthoracic esophagectomy as surgical treatment for resectable esophageal cancer. If our hypothesis is proven correct, RATE will result in a lower percentage of postoperative complications, lower blood loss, and shorter hospital stay, but with at least similar oncologic outcomes and better postoperative quality of life compared with open transthoracic esophagectomy. The study started in January 2012. Follow-up will be 5 years. Short-term results will be analyzed and published after discharge of the last randomized patient.
Trial registration
Dutch trial register: NTR3291 ClinicalTrial.gov: NCT01544790
doi:10.1186/1745-6215-13-230
PMCID: PMC3564860  PMID: 23199187
7.  Exploring Gene Expression Signatures for Predicting Disease Free Survival after Resection of Colorectal Cancer Liver Metastases 
PLoS ONE  2012;7(11):e49442.
Background and Objectives
This study was designed to identify and validate gene signatures that can predict disease free survival (DFS) in patients undergoing a radical resection for their colorectal liver metastases (CRLM).
Methods
Tumor gene expression profiles were collected from 119 patients undergoing surgery for their CRLM in the Paul Brousse Hospital (France) and the University Medical Center Utrecht (The Netherlands). Patients were divided into high and low risk groups. A randomly selected training set was used to find predictive gene signatures. The ability of these gene signatures to predict DFS was tested in an independent validation set comprising the remaining patients. Furthermore, 5 known clinical risk scores were tested in our complete patient cohort.
Result
No gene signature was found that significantly predicted DFS in the validation set. In contrast, three out of five clinical risk scores were able to predict DFS in our patient cohort.
Conclusions
No gene signature was found that could predict DFS in patients undergoing CRLM resection. Three out of five clinical risk scores were able to predict DFS in our patient cohort. These results emphasize the need for validating risk scores in independent patient groups and suggest improved designs for future studies.
doi:10.1371/journal.pone.0049442
PMCID: PMC3504021  PMID: 23185333
8.  Efficacy and Complications of Nasojejunal, Jejunostomy and Parenteral Feeding After Pancreaticoduodenectomy 
Journal of Gastrointestinal Surgery  2012;16(6):1144-1151.
Background
European nutritional guidelines recommend routine use of enteral feeding after pancreaticoduodenectomy (PD) whereas American guidelines do not. Data on the efficacy and, especially, complications of the various feeding strategies after PD are scarce.
Methods
Retrospective monocenter cohort study in 144 consecutive patients who underwent PD during a period wherein the routine post-PD feeding strategy changed twice. Patients not receiving nutritional support (n=15) were excluded. Complications were graded according to the Clavien-Dindo classification and the International Study Group of Pancreatic Surgery (ISGPS) definitions. Analysis was by intention-to-treat. Primary endpoint was the time to resumption of normal oral intake.
Results
129 patients undergoing PD (111 pylorus preserving) were included. 44 patients (34%) received enteral nutrition via nasojejunal tube (NJT), 48 patients (37%) via jejunostomy tube (JT) and 37 patients (29%) received total parenteral nutrition (TPN). Groups were comparable with respect to baseline characteristics, Clavien ≥II complications (P=0.99), in-hospital stay (P=0.83) and mortality (P=0.21). There were no differences in time to resumption of normal oral intake (primary endpoint; NJT/JT/TPN: median 13, 16 and 14 days, P=0.15) and incidence of delayed gastric emptying (P=0.30). Duration of enteral nutrition was shorter in the NJT- compared to the JT- group (median 8 vs. 12 days, P=0.02). Tube related complications occurred mainly in the NJT-group (34% dislodgement). In the JT-group, relaparotomy was performed in three patients (6%) because of JT-leakage or strangulation leading to death in one patient (2%). Wound infections were most common in the TPN group (NJT/JT/TPN: 16%, 6% and 30%, P=0.02).
Conclusion
None of the analysed feeding strategies was found superior with respect to time to resumption of normal oral intake, morbidity and mortality. Each strategy was associated with specific complications. Nasojejunal tubes dislodged in a third of patients, jejunostomy tubes caused few but potentially life-threatening bowel strangulation and TPN doubled the risk of infections.
doi:10.1007/s11605-012-1887-5
PMCID: PMC3354327  PMID: 22528573
Pancreas; Surgery; Feeding; Nutrition; Complications
9.  Preoperative Imaging of Colorectal Liver Metastases After Neoadjuvant Chemotherapy: A Meta-Analysis 
Annals of Surgical Oncology  2012;19(9):2805-2813.
Background
Chemotherapy treatment induces parenchymal changes that potentially affect imaging of CRLM. The purpose of this meta-analysis was to provide values of diagnostic performance of magnetic resonance imaging (MRI), computed tomography (CT), fluorodeoxyglucose positron emission tomography (FDG-PET), and FDG-PET/CT for preoperative detection of colorectal liver metastases (CRLM) in patients treated with neoadjuvant chemotherapy.
Methods
A comprehensive search was performed for original articles published from inception to 2011 assessing diagnostic performance of MRI, CT, FDG-PET, or FDG-PET/CT for preoperative evaluation of CRLM following chemotherapy. Intraoperative findings and/or histology were used as reference standard. For each imaging modality we calculated pooled sensitivities for patients who received neoadjuvant chemotherapy as well as for chemonaive patients, defined as number of malignant lesions detected divided by number of malignant lesions as confirmed by the reference standard.
Results
A total of 11 papers, comprising 223 patients with 906 lesions, were included. Substantial variation in study design, patient characteristics, imaging features, and reference tests was observed. Pooled sensitivity estimates of MRI, CT, FDG-PET, and FDG-PET/CT were 85.7% (69.7–94.0%), 69.9% (65.6–73.9%), 54.5% (46.7–62.1%), and 51.7% (37.8–65.4%), respectively. In chemonaive patients, sensitivity rates were 80.5% (67.0–89.4%) for CT, 81.3% (64.1–91.4%) for FDG-PET, and 71.0% (64.3–76.9%) for FDG-PET/CT. Specificity could not be calculated because of non-reporting of “true negative lesions.”
Conclusion
In the neoadjuvant setting, MRI appears to be the most appropriate imaging modality for preoperative assessment of patients with CRLM. CT is the second-best diagnostic modality and should be used in the absence of MRI. Diagnostic accuracy of FDG-PET and PET-CT is strongly affected by chemotherapy.
doi:10.1245/s10434-012-2300-z
PMCID: PMC3433675  PMID: 22396005
10.  Primary lymphoma of the liver - A complex diagnosis 
World Journal of Radiology  2012;4(2):53-57.
A 59-year-old woman presented with the clinical symptoms and radiologic investigations of a liver lesion suspect of metastasis. However, postoperative histopathology revealed a primary hepatic lymphoma (PHL). The case of a patient with a solitary PHL, which was treated by resection and subsequent chemotherapy, will be discussed with a short overview of the literature.
doi:10.4329/wjr.v4.i2.53
PMCID: PMC3304094  PMID: 22423319
Primary; Hepatic; Lymphoma; Liver; Diagnosis; Computed tomography; Magnetic resonance imaging
12.  Risk of Thromboembolic Events after Perioperative Chemotherapy Versus Surgery Alone for Esophageal Adenocarcinoma 
Annals of Surgical Oncology  2011;19(2):684-692.
Background
Major oncologic surgery is associated with a high incidence of thromboembolic events (TEE). Addition of perioperative chemotherapy in esophageal cancer surgery may increase the risk of TEE.
Methods
The thromboembolic toxicity profile was analyzed in patients with esophageal adenocarcinoma (EAC). Two groups were identified: patients who underwent esophagectomy and received perioperative chemotherapy with epirubicin, cisplatin, and capecitabine (ECC; n = 52), and patients who were treated with surgery alone (n = 35).
Results
A total of 22 TEEs was observed in 17 patients (32.7%) in the chemotherapy group and 3 patients (7.5%) in the surgery-alone group (P < .01). The relative risk of developing a TEE for patients receiving perioperative chemotherapy during the whole treatment period was 3.8 (95% confidence interval 1.2–12.0). A preoperatively occurring TEE did not increase the risk of postoperative TEE, nor did it increase postoperative hospital stay (P = .325). Median postoperative hospital stay was 23 days (range 14–78) for patients with a postoperative TEE and 15 days (range 10–105) for patients without TEE (P = .126). Perioperative chemotherapy with the epirubicin, cisplatin, and capecitabine regimen was independently associated with the development of TEE in the combined preoperative and postoperative period (P = .034).
Conclusions
Perioperative chemotherapy improves survival for operable esophageal cancer but comes at the price of toxicity. Perioperative chemotherapy for EAC increases the risk of TEE. However, chemotherapy-related preoperative TEE did not increase the risk of postoperative TEE, nor did it increase postoperative hospital stay, justifying its use in clinical practice.
doi:10.1245/s10434-011-2005-8
PMCID: PMC3264865  PMID: 21837523
13.  Viable Tumor Tissue Adherent to Needle Applicators after Local Ablation: A Risk Factor for Local Tumor Progression 
Annals of Surgical Oncology  2011;18(13):3702-3710.
Background
Local tumor progression (LTP) is a serious complication after local ablation of malignant liver tumors, negatively influencing patient survival. LTP may be the result of incomplete ablation of the treated tumor. In this study, we determined whether viable tumor cells attached to the needle applicator after ablation was associated with LTP and disease-free survival.
Methods
In this prospective study, tissue was collected of 96 consecutive patients who underwent local liver ablations for 130 liver malignancies. Cells and tissue attached to the needle applicators were analyzed for viability using glucose-6-phosphate-dehydrogenase staining and autofluorescence intensity levels of H&E stained sections. Patients were followed-up until disease progression.
Results
Viable tumor cells were found on the needle applicators after local ablation in 26.7% of patients. The type of needle applicator used, an open approach, and the omission of track ablation were significantly correlated with viable tumor tissue adherent to the needle applicator. The presence of viable cells was an independent predictor of LTP. The attachment of viable cells to the needle applicators was associated with a shorter time to LTP.
Conclusions
Viable tumor cells adherent to the needle applicators were found after ablation of 26.7% of patients. An independent risk factor for viable cells adherent to the needle applicators is the omission of track ablation. We recommend using only RFA devices that have track ablation functionality. Adherence of viable tumor cells to the needle applicator after local ablation was an independent risk factor for LTP.
doi:10.1245/s10434-011-1762-8
PMCID: PMC3222809  PMID: 21590455
14.  Behavioral and psychosocial effects of rapid genetic counseling and testing in newly diagnosed breast cancer patients: Design of a multicenter randomized clinical trial 
BMC Cancer  2011;11:6.
Background
It has been estimated that between 5% and 10% of women diagnosed with breast cancer have a hereditary form of the disease, primarily caused by a BRCA1 or BRCA2 gene mutation. Such women have an increased risk of developing a new primary breast and/or ovarian tumor, and may therefore opt for preventive surgery (e.g., bilateral mastectomy, oophorectomy). It is common practice to offer high-risk patients genetic counseling and DNA testing after their primary treatment, with genetic test results being available within 4-6 months. However, some non-commercial laboratories can currently generate test results within 3 to 6 weeks, and thus make it possible to provide rapid genetic counseling and testing (RGCT) prior to primary treatment. The aim of this study is to determine the effect of RGCT on treatment decisions and on psychosocial health.
Methods/Design
In this randomized controlled trial, 255 newly diagnosed breast cancer patients with at least a 10% risk of carrying a BRCA gene mutation are being recruited from 12 hospitals in the Netherlands. Participants are randomized in a 2:1 ratio to either a RGCT intervention group (the offer of RGCT directly following diagnosis with tests results available before surgical treatment) or to a usual care control group. The primary behavioral outcome is the uptake of direct bilateral mastectomy or delayed prophylactic contralateral mastectomy. Psychosocial outcomes include cancer risk perception, cancer-related worry and distress, health-related quality of life, decisional satisfaction and the perceived need for and use of additional decisional counseling and psychosocial support. Data are collected via medical chart audits and self-report questionnaires administered prior to randomization, and at 6 month and at 12 month follow-up.
Discussion
This trial will provide essential information on the impact of RGCT on the choice of primary surgical treatment among women with breast cancer with an increased risk of hereditary cancer. This study will also provide data on the psychosocial consequences of RGCT and of risk-reducing behavior.
Trial registration
The study is registered at the Netherlands Trial Register (NTR1493) and ClinicalTrials.gov (NCT00783822).
doi:10.1186/1471-2407-11-6
PMCID: PMC3022885  PMID: 21219598
15.  Axillary Staging in Breast Cancer Patients with Exclusive Lymphoscintigraphic Drainage to the Internal Mammary Chain 
World Journal of Surgery  2010;35(1):159-164.
Background
The aim of this study was to evaluate the need of axillary staging in breast cancer patients showing exclusive lymphatic drainage to the internal mammary chain (IMC).
Methods
A total of 2203 patients treated for breast carcinoma in three participating hospitals between July 2001 and July 2008 were analyzed. Only patients showing drainage to the IMC on preoperative lymphoscintigraphy were included. The number of harvested IMC sentinel lymph nodes (SLNs), axillary SLNs, and metastases were recorded. Finally, the follow-up of this group of patients was analyzed.
Results
In 25/426 patients, drainage was exclusively to the IMC. Exploration of the axilla resulted in the harvesting of blue SLNs in 9 patients (36%) and the retrieval of an enlarged lymph node in 1 patient. In 4 of the remaining 15 patients, an axillary lymph node dissection (ALND) was done. Lymph node metastases were found in 3 patients who had blue axillary SLNs and in 1 patient who underwent ALND. In the 11 patients who had no blue SLNs and no ALND, no axillary recurrences were observed during follow-up (median = 26 months).
Conclusions
Proper staging of the axilla remains crucial in patients showing exclusive drainage to the IMC. When no axillary node can be retrieved, ALND remains subject to discussion.
doi:10.1007/s00268-010-0795-7
PMCID: PMC3006651  PMID: 20936283
16.  Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma: What is the evidence today? 
Insights into Imaging  2010;1(3):167-181.
Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Only 10–15% of HCC patients are suitable candidates for hepatic resection and liver transplantation due to the advanced stage of the disease at time of diagnosis and shortage of donors. Therefore, several minimally invasive image-guided therapies for locoregional treatment have been developed. Tumor ablative techniques are either based on thermal tumor destruction, as in radiofrequency ablation, cryoablation, microwave ablation, laser ablation and high-intensity focused ultrasound, or chemical tumor destruction, as in percutaneous ethanol injection. Image-guided catheter-based techniques rely on intra-arterial delivery of embolic, chemoembolic or radioembolic agents. These minimally invasive image-guided therapies have revolutionized the management of inoperable HCC. This review provides a description of all minimally invasive image-guided therapies currently available, an up-to-date overview of the scientific evidence for their clinical use, and thoughts for future directions.
doi:10.1007/s13244-010-0027-6
PMCID: PMC3288853  PMID: 23100194
Hepatocellular carcinoma; Liver cancer; Ablation techniques; Intra-arterial infusion; Embolization
18.  Feasibility of MRI-guided large-core-needle biopsy of suspiscious breast lesions at 3 T 
European Radiology  2009;19(7):1639-1644.
The feasibility of large-core-needle magnetic resonance imaging (MRI)-guided breast biopsy at 3 T was assessed. Thirty-one suspicious breast lesions shown only by MRI were detected in 30 patients. Biopsy procedures were performed in a closed-bore 3-T clinical MR system on a dedicated phased-array breast coil with a commercially available add-on stereotactic biopsy device. Tissue sampling was technically successful in 29/31 (94%) lesions. Median lesion size (n = 29) was 9 mm. Histopathological analysis showed 19 benign lesions (66%) and one inconclusive biopsy result (3%). At follow-up of these lesions, 15 lesions showed no malignancy, no information was available in three patients and two lesions turned out to be malignant (one lesion at surgical excision 1 month after biopsy and one lesion at a second biopsy because of a more malignant enhancement curve at 12-months follow-up MRI). Nine biopsy results showed a malignant lesion (31%) which were all surgically removed. No complications occurred. MRI-guided biopsy at 3 T is a safe and effective method for breast biopsy in lesions that are occult on mammography and ultrasound. Follow-up MRI at 6 months after the biopsy should be performed in case of a benign biopsy result.
doi:10.1007/s00330-009-1310-0
PMCID: PMC2691521  PMID: 19214520
Breast neoplasms; Magnetic resonance imaging; Biopsy; High field
19.  Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-trial) 
BMC Surgery  2008;8:15.
Background
With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction.
The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs.
Methods/design
The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007.
Discussion
The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease.
Trial registration
Nederlands Trial Register NTR1150
doi:10.1186/1471-2482-8-15
PMCID: PMC2533646  PMID: 18721465
20.  The efficacy of 'Radio guided Occult Lesion Localization' (ROLL) versus 'Wire-guided Localization' (WGL) in breast conserving surgery for non-palpable breast cancer: A randomized clinical trial – ROLL study 
BMC Surgery  2008;8:9.
Background
With the increasing number of non palpable breast carcinomas, the need of a good and reliable localization method increases. Currently the wire guided localization (WGL) is the standard of care in most countries. Radio guided occult lesion localization (ROLL) is a new technique that may improve the oncological outcome, cost effectiveness, patient comfort and cosmetic outcome. However, the studies published hitherto are of poor quality providing less than convincing evidence to change the current standard of care.
The aim of this study is to compare the ROLL technique with the standard of care (WGL) regarding the percentage of tumour free margins, cost effectiveness, patient comfort and cosmetic outcome.
Methods/design
The ROLL trial is a multi center randomized clinical trial. Over a period of 2–3 years 316 patients will be randomized between the ROLL and the WGL technique. With this number, the expected 15% difference in tumour free margins can be detected with a power of 80%. Other endpoints include cosmetic outcome, cost effectiveness, patient (dis)comfort, degree of difficulty of the procedures and the success rate of the sentinel node procedure.
The rationale, study design and planned analyses are described.
Trial Registration
(, study protocol number NCT00539474)
doi:10.1186/1471-2482-8-9
PMCID: PMC2409294  PMID: 18495027
21.  Validation of tissue microarray technology in squamous cell carcinoma of the esophagus 
Virchows Archiv  2008;452(5):507-514.
Tissue microarray (TMA) technology has been developed to facilitate high-throughput immunohistochemical and in situ hybridization analysis of tissues by inserting small tissue biopsy cores into a single paraffin block. Several studies have revealed novel prognostic biomarkers in esophageal squamous cell carcinoma (ESCC) by means of TMA technology, although this technique has not yet been validated for these tumors. Because representativeness of the donor tissue cores may be a disadvantage compared to full sections, the aim of this study was to assess if TMA technology provides representative immunohistochemical results in ESCC. A TMA was constructed containing triplicate cores of 108 formalin-fixed, paraffin-embedded squamous cell carcinomas of the esophagus. The agreement in the differentiation grade and immunohistochemical staining scores of CK5/6, CK14, E-cadherin, Ki-67, and p53 between TMA cores and a subset of 64 randomly selected donor paraffin blocks was determined using kappa statistics. The concurrence between TMA cores and donor blocks was moderate for Ki-67 (κ = 0.42) and E-cadherin (κ = 0.47), substantial for differentiation grade (κ = 0.65) and CK14 (κ = 0.71), and almost perfect for p53 (κ = 0.86) and CK5/6 (κ = 0.93). TMA technology appears to be a valid method for immunohistochemical analysis of molecular markers in ESCC provided that the staining pattern in the tumor is homogeneous.
doi:10.1007/s00428-008-0602-0
PMCID: PMC2329733  PMID: 18392848
Biological markers; Esophageal neoplasms; Protein microarray analysis; Squamous cell carcinoma; Validation studies
22.  The Microanatomic Location of Metastatic Breast Cancer in Sentinel Lymph Nodes Predicts Nonsentinel Lymph Node Involvement 
Annals of Surgical Oncology  2008;15(5):1309-1315.
Background
The majority of sentinel node (SN) positive breast cancer patients do not have additional non-SN involvement and may not benefit from axillary lymph node dissection (ALND). Previous studies in melanoma have suggested that microanatomic localization of SN metastases may predict non-SN involvement. The present study was designed to assess whether these criteria might also be used to be more restrictive in selecting breast cancer patients who would benefit from an ALND.
Methods
A consecutive series of 357 patients with invasive breast cancer and a tumor-positive axillary SN, followed by an ALND, was reviewed. Microanatomic SN tumor features (subcapsular, combined subcapsular and parenchymal, parenchymal, extensive localization, multifocality, and the penetrative depth from the SN capsule) were evaluated for their predictive value for non-SN involvement.
Results
Non-SN metastases were found in 136/357 cases (38%). Microanatomic location and penetrative depth of SN metastases were significant predictors for non-SN involvement (<0.001); limited penetrative depth was associated with a low frequency of non-SN involvement with a minimal of 10%.
Conclusions
Microanatomic location and penetrative depth of breast cancer SN metastases predict non-SN involvement. However, based on these features no subgroup of patients could be selected with less than 10% non-SN involvement.
doi:10.1245/s10434-007-9803-z
PMCID: PMC2277442  PMID: 18253802
Breast cancer; Sentinel node; Axillary lymph node metastases; Morphometry
23.  Combining partial liver resection and local ablation of liver tumours: a preliminary Dutch experience 
Background
The combination of partial liver resection and radiofrequency ablation (RFA) is a novel concept in the treatment of unresectable liver malignancies. The aim of this study is to evaluate the results of this combined strategy in the Netherlands.
Methods
Thirty-five patients treated with a combination of partial liver resection and RFA were identified from a prospectively registered pooled multicentre database. All patients were operated between June 1999 and November 2003 in 8 medical centres in the Netherlands. Main outcome parameters were morbidity, mortality, local success rate, and survival.
Results
Thirty-seven operations were performed in 35 patients. The group consisted of 20 male and 15 female patients with a median age of 59 years (range 41–76). Seventy-six lesions were resected and RFA was performed to ablate 82 unresectable liver tumours. Twelve patients developed a total of 24 complications, resulting in an overall perioperative morbidity rate of 32%. In two patients major complications resulted in postoperative death (postoperative mortality rate 5.4%). Local success rate after RFA was 88% and the estimated 1-, 2- and 3-year overall survival rates were 84%, 70% and 43%, respectively.
Conclusion
This strategy should only be performed following strict patient selection and within the context of prospective clinical trials.
doi:10.1186/1477-7819-4-46
PMCID: PMC1553444  PMID: 16846515
24.  Liver metastases of neuroendocrine tumours; early reduction of tumour load to improve life expectancy 
Background
Neuroendocrine tumours frequently metastasize to the liver. Although generally slowly progressing, hepatic metastases are the major cause of carcinoid syndrome and ultimately lead to liver dysfunction, cardiac insufficiency and finally death.
Methods
A literature review was performed to define the optimal treatment strategy and work-up in patients with neuroendocrine hepatic metastases. Based on this, an algorithm for the management of these patients was established.
Results
Platelet serotonin and chromogranin A are useful biomarkers for detection and follow-up of neuroendocrine tumour. Helical computed tomography and somatostatin receptor scintigraphy are the most sensitive diagnostic modalities. Surgical debulking is an accepted approach for reducing hormonal symptoms and to establish better conditions for medical treatment, but is frequently impossible due to the extent of disease. A novel approach is the local ablation of tumour by thermal coagulation using therapies such as radiofrequency ablation (RFA) or laser induced thermotherapy (LITT). These techniques preserve normal liver tissue. There is a tendency to destroy metastases early in the course of disease, thereby postponing or eliminating the surgically untreatable stage. This can be combined with postoperative radioactive octreotide to eliminate small multiple metastases. In patients with extensive metastases who are not suitable for local destruction, systemic therapy by octreotide, 131I-MIBG treatment or targeted chemo- and radiotherapy should be attempted. A final option for selective patients is orthotopic liver transplantation.
Conclusion
Treatment for patients with neuroendocrine hepatic metastases must be tailored for each individual patient. When local ablative therapies are used early in the course of the disease, the occurrence of carcinoid syndrome with end stage hepatic disease can be postponed or prevented.
doi:10.1186/1477-7819-4-35
PMCID: PMC1524962  PMID: 16800893
25.  Local treatment in unresectable hepatic metastases of carcinoid tumors: Experiences with hepatic artery embolization and radiofrequency ablation 
Background
Hepatic metastases of carcinoid tumors cause incapacitating symptoms, but are usually diffuse and therefore unresectable. In this article we evaluate our experiences with local treatment techniques in the management of carcinoid patients with hepatic metastases and failing systemic treatment.
Methods
Fifteen consecutive carcinoid patients (11 men and 4 women; median age 60 years; range 45–71 years) were treated with either hepatic artery embolization (HAE) with Ivalon particles or radiofrequency ablation (RFA) (percutaneously or intra-operatively). Follow-up evaluation was performed by CT scan and 24-hours urinary 5-HIAA excretions.
Results
A total of 18 HAE's was performed in 13 patients, while 10 lesions in 3 patients were treated with RFA. Median follow-up was 12.5 months (2 – 25 months). Median duration of symptoms was 22 months (8 – 193 months). Median overall decrease of 5-HIAA excretion 2 months after HAE was 32% with tumor regression on CT-scan in 4 patients (30%) and improvement of symptoms with a median duration of 15 months in 3 of them (23%). Embolization led to fatal hepatic failure in one patient. The 3 patients treated with RFA showed a decrease of urinary 5-HIAA values of 34, 81 and 93% respectively, with tumor regression in all of them. Improvement of symptoms was reported in 2 patients up to 25 months.
Conclusion
Liver embolization performed late in the clinical course had limited effect on symptoms and biochemical and radiological parameters. First experiences with RFA are favorable and might encourage to apply RFA more widely in metastatic carcinoid.
doi:10.1186/1477-7819-3-75
PMCID: PMC1325231  PMID: 16293186

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