Richard van Hillegersberg

Selective Accumulation of Endogenously Produced Porphyrins in a Liver Metastasis Model in Rats

The possibility of using the porphyrin precursor 5-aminolevulinic acid to cause selective porphyrin accumulation in tumors was examined. Syngeneic colon carcinomas CC531 were implanted in the livers of Wag/Rij rats. Groups of three to six animals each were given 2 mg/mL of 5-aminolevulinic acid in drinking water from the 8th, 14th, or 17th day after tumor implantation. Two other groups received either 2.5 or 5 mg/kg of Photofrin II (Photomedica Inc., Raritan, NJ) intravenously on day 17. On day 19 the livers were removed and porphyrin concentrations were measured in normal livers and tumors by solvent extraction and high-performance liquid chromatography. Protoporphyrin accumulated progressively in tumors with increasing duration of 5-aminolevulinic acid administration (P = 0.0001), whereas no increase was found in normal livers. After 11 days of 5-aminolevulinic acid administration the porphyrin concentration ratio between tumors and livers was 4:1. In contrast, after Photofrin II administration the concentration was higher in normal livers than in tumors (1:3 ratio, tumor to liver). Enzyme measurements showed a threefold decrease in ferrochelatase activity in tumors compared with livers (P less than 0.001). In conclusion, oral administration of 5-aminolevulinic acid results in progressive accumulation of protoporphyrin in a transplantable colon carcinoma without accumulation in the surrounding liver tissue. This selective accumulation of porphyrins appears to be caused by a relative ferrochelatase deficiency in malignant tissue. 5-Aminolevulinic acid administration may be a suitable approach to photosensitizing liver tumors for photodynamic therapy or to early detection of tumors by fluorescence in ultraviolet light.

Endoscopic ablation therapy for Barrett’s esophagus with high-grade dysplasia: a review

ABSTRACTBesides esophagectomy and antireflux therapy with intensive endoscopic surveillance, endoscopic ablation therapy is a new treatment modality for Barretts esophagus (BE) with high-grade dysplasia (HGD). Endoscopic surgical ablation can be performed by either a thermal, chemical, or mechanical method. This article describes the current management of patients with BE and HGD and the various methods of endoscopic ablation, including multipolar electrocoagulation, argon plasma beam coagulation, contact laser photoablation, and photodynamic therapy. It also summarizes the results of 37 patient studies, case reports, and abstracts on experimental endoscopic therapies for BE. The advantages and disadvantages of the various treatment possibilities are considered, and the future direction of the management of BE is discussed.

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patients perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.

Factors Influencing the Local Failure Rate of Radiofrequency Ablation of Colorectal Liver Metastases

BackgroundThe prognosis of patients with colorectal cancer is poor, especially when there is distant metastatic disease. Local ablation of tumor by radiofrequency ablation (RFA) has emerged as a safe and effective new treatment modality, but its long-term efficacy may be hindered by renewed local tumor growth at the site of RFA. The objectives of this study were to identify risk factors for local RFA failure and to define exclusion criteria for RFA treatment of colorectal liver metastases.MethodsA total of 199 lesions in 87 patients were ablated with RFA. Factors influencing local failure rates were identified and compared with data from the literature.ResultsThe local failure rate was 47.2%, and the average time to local disease progression was 6.5 months. Factors that significantly correlated with increased failure rates were metachronous occurrence of liver metastases, large mean lesion size, and central tumor location.ConclusionsBecause accurate electrode placement is pivotal in achieving adequate tumor necrosis, RFA should not be performed percutaneously when electrode placement is impaired. We suggest that lesions >5 cm and lesions located near great vessels or adjacent organs should be treated with open RFA, thus allowing vascular inflow occlusion and complete mobilization of the liver. Lesions that are difficult to reach by electrodes should be approached by an open procedure.

Current Status of Photodynamic Therapy in Oncology

SummaryPhotodynamic therapy (PDT) is a cancer treatment based on the accumulation in malignant tissue of a photosensitiser with low systemic toxicity. Subsequent illumination induces a type II photochemical reaction with singlet oxygen production that results in destruction of biomolecules and subcellular organelles.The first full clinical report of PDT dates from 1976. Haematoporphyrin derivative, a complex mixture of porphyrins, was initially used as a photosensitiser. An enriched fraction (porfimer sodium) is now the most commonly used clinical agent. After systemic administration porphyrins bind to albumin and lipoproteins. Accumulation occurs mainly in tumours and organs of the reticuloendothelial system. The light of an argon-dye laser can be tuned to the appropriate wavelength and delivered either superficially, interstitially or intraluminally. Light distribution can be assessed by using a radiation transport model and tissue optical properties, or direct measurement with light detectors.The effects of PDT depend in a complex way on: characteristics, tissue concentration and localisation of the photosensitiser; the target tissue optical properties and oxygenation; activation wavelength, power density and treatment regimen. Future research is directed towards: better photosensitisers (i.e. phthalocyanines, chlorins or protoporphyrin IX endogenously produced from 5-aminolevulinic acid); improved light generation and delivery; and combination with hyperthermia, chemotherapy, radiotherapy or surgery. Adjuvant intraoperative PDT is a promising approach to destroying residual tumour after surgery.

Primary Colorectal Cancers and Their Subsequent Hepatic Metastases Are Genetically Different: Implications for Selection of Patients for Targeted Treatment

Purpose: In the era of DNA-guided personalized cancer treatment, it is essential to conduct predictive analysis on the tissue that matters. Here, we analyzed genetic differences between primary colorectal adenocarcinomas (CRC) and their respective hepatic metastasis. Experimental Design: The primary CRC and the subsequent hepatic metastasis of 21 patients with CRC were analyzed using targeted deep-sequencing of DNA isolated from formalin-fixed, paraffin-embedded archived material. Results: We have interrogated the genetic constitution of a designed “Cancer Mini-Genome” consisting of all exons of 1,264 genes associated with pathways relevant to cancer. In total, 6,696 known and 1,305 novel variations were identified in 1,174 and 667 genes, respectively, including 817 variants that potentially altered protein function. On average, 83 (SD = 69) potentially function-impairing variations were gained in the metastasis and 70 (SD = 48) variations were lost, showing that the primary tumor and hepatic metastasis are genetically significantly different. Besides novel and known variations in genes such as KRAS, BRAF, KDR, FLT1, PTEN, and PI3KCA, aberrations in the up/downstream genes of EGFR/PI3K/VEGF-pathways and other pathways (mTOR, TGFβ, etc.) were also detected, potentially influencing therapeutic responsiveness. Chemotherapy between removal of the primary tumor and the metastasis (N = 11) did not further increase the amount of genetic variation. Conclusion: Our study indicates that the genetic characteristics of the hepatic metastases are different from those of the primary CRC tumor. As a consequence, the choice of treatment in studies investigating targeted therapies should ideally be based on the genetic properties of the metastasis rather than on those of the primary tumor. Clin Cancer Res; 18(3); 688–99. ©2011 AACR.

Robot-assisted minimally invasive thoraco-laparoscopic esophagectomy versus open transthoracic esophagectomy for resectable esophageal cancer, a randomized controlled trial (ROBOT trial)

BackgroundFor 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/designThis 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.DiscussionThis 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 registrationDutch trial register: NTR3291 ClinicalTrial.gov: NCT01544790

5-Aminolaevulinic acid-induced protoporphyrin IX accumulation in tissues: Pharmacokinetics after oral or intravenous administration

UNLABELLED In this study, the biodistribution of 5-aminolaevulinic acid (ALA) and accumulation of protoporphyrin IX (PpIX) in rats have been examined. Two groups of 21 WAG/Rij rats are given 200 mg/kg ALA orally or intravenously. Six rats serve as controls. At 1, 2, 3, 4, 6, 12 and 24 h after ALA administration, ALA and porphyrin concentrations are measured in 18 tissues and fluids. Liver enzymes and renal-function tests are measured to determine ALA toxicity. In both groups ALA concentration is highest in kidney, bladder and urine. After oral administration, high concentrations are also found in duodenal aspirate and jejunum. Mild, short-lasting elevation of creatinine is seen in both treatment groups. Porphyrins, especially PpIX, accumulate mainly in duodenal aspirate, jejunum, liver and kidney (> 10 nmol/g tissue), less in oesophagus, stomach, colon, spleen, bladder, heart, lung and nerve (2-10 nmol/g tissue), and only slightly in plasma, muscle, fat, skin and brain (< 2 nmol/g tissue). In situ synthesis of porphyrins rather than enterohepatic circulation contributes to the PpIX accumulation. Confocal laser scanning microscopy shows selective porphyrin fluorescence in epithelial layers. Peak levels and total production of porphyrins are equal after oral and intravenous ALA administration. IN CONCLUSION administration of 200 mg/kg ALA results in accumulation of photosensitive concentrations of PpIX, 1 to 6 h after ALA administration, in all tissues except muscle, fat, skin and brain. Knowledge of the time-concentration relationship should be helpful in selecting dosages, routes of administration and timing of ALA photodynamic therapy.

Preoperative Imaging of Colorectal Liver Metastases After Neoadjuvant Chemotherapy: A Meta-Analysis

BackgroundChemotherapy 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.MethodsA 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.ResultsA 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.”ConclusionIn 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.

Robot-Assisted Endoscopic Surgery: A Four-Year Single-Center Experience

Background: Robotic systems were introduced in the late 1990s with the objective to overcome the technical limitations of endoscopic surgery. In this prospective cohort study the potential safety, feasibility, pitfalls and challenges of robotic systems in gastrointestinal endoscopic surgery are assessed and our vision on future perspectives is presented. Methods:Between August 2000 and December 2004, 208 procedures were performed with support of the Intuitive Surgical da Vinci™ robotic system. We started with cholecystectomies (40) and Nissen fundoplications (41) to gain experience with robot-assisted surgery. In the following years more complex procedures were carried out, i.e. colorectal procedures (7), type III/IV paraesophageal hernia repair (32), redo Nissen fundoplications (9), Heller myotomies (24), esophageal resections (22), rectopexies (16) and aortobifemoral bypasses (3). Results:The median robotic set-up time was 13 min, and 7 min in the last 50 procedures. The median operating time for the total of procedures was 120 min (45–420) and the median blood loss was 30 ml (0–800). Fourteen procedures were converted to open surgery (6.7%). Equipment-related problems, such as start-up failures and positioning difficulties of the robotic arms, were encountered in 11 cases (5.3%). Postoperative complications were seen in 11 patients (11/176, 6.3%) after robot-assisted laparoscopic procedures. Pulmonary complications occurred in 11 patients, cardiac in 3, anastomic leakage in 3, chylous leakage in 3 and vocal cord paralysis in 3 after thoracoscopic esophagolymphadenectomy for esophageal cancer. One patient died 12 days after esophageal resection (0.5%). Conclusion:During the implementation of this robotic system, we experienced an obvious learning curve, particularly with regard to the positioning of the robot cart and communication between the surgeon and operating team. After 4 years, we have experienced that the merits of the current generation of this technology probably is preserved to complex endoscopic procedures with delicate dissection and suturing. In the nearby future we will focus on the treatment of motility disorders and malignancies of the esophagus and stomach. The position of the robot in the endoscopic operating room will have to be clarified by the outcome of prospective research. Furthermore, priorities have to be acclaimed on technical sophistication and cost reduction of these systems.