S. Kruijff

Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: a single-centre feasibility study

BACKGROUND Optimum cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is essential for the curative treatment of peritoneal carcinomatosis of colorectal origin. At present, surgeons depend on visual inspection and palpation for tumour detection. Improved detection of tumour tissue using molecular fluorescence-guided surgery could not only help attain a complete cytoreduction of metastatic lesions, but might also prevent overtreatment by avoiding resection of benign lesions. METHODS For this non-randomised, single-centre feasibility study, we enrolled patients with colorectal peritoneal metastases scheduled for cytoreductive surgery and HIPEC. 2 days before surgery, 4·5 mg of the near-infrared fluorescent tracer bevacizumab-IRDye800CW was administered intravenously. The primary objectives were to determine the safety and feasibility of molecular fluorescence-guided surgery using bevacizumab-IRDye800CW. Molecular fluorescence-guided surgery was deemed safe if no allergic or anaphylactic reactions were recorded and no serious adverse events were attributed to bevacizumab-IRDye800CW. The technique was deemed feasible if bevacizumab-IRDye800CW enabled detection of fluorescence signals intraoperatively. Secondary objectives were correlation of fluorescence with histopathology by back-table imaging of the fresh surgical specimen and semi-quantitative ex-vivo analyses of formalin-fixed paraffin embedded (FFPE) tissue on all peritoneal lesions. Additionally, VEGF-α staining and fluorescence microscopy was done. This study is registered with the Netherlands Trial Registry, number NTR4632. FINDINGS Between July 3, 2014, and March 2, 2015, seven patients were enrolled in the study. One patient developed an abdominal sepsis 5 days postoperatively and another died from an asystole 4 days postoperatively, most probably due to a cardiovascular thromboembolic event. However, both serious adverse events were attributed to the surgical cytoreductive surgery and HIPEC procedure. No serious adverse events related to bevacizumab-IRDye800CW occurred in any of the patients. Intraoperatively, fluorescence was seen in all patients. In two patients, additional tumour tissue was detected by molecular fluorescence-guided surgery that was initially missed by the surgeons. During back-table imaging of fresh surgical specimens, a total of 80 areas were imaged, marked, and analysed. All of the 29 non-fluorescent areas were found to contain only benign tissue, whereas tumour tissue was detected in 27 of 51 fluorescent areas (53%). Ex-vivo semi-quantification of 79 FFPE peritoneal lesions showed a tumour-to-normal ratio of 6·92 (SD 2·47). INTERPRETATION Molecular fluorescence-guided surgery using the near-infrared fluorescent tracer bevacizumab-IRDye800CW is safe and feasible. This technique might be of added value for the treatment of patients with colorectal peritoneal metastases through improved patient selection and optimisation of cytoreductive surgery. A subsequent multicentre phase 2 trial is needed to make a definitive assessment of the diagnostic accuracy and the effect on clinical decision making of molecular fluorescence-guided surgery. FUNDING FP-7 Framework Programme BetaCure and SurgVision BV.

Breslow thickness in the Netherlands: a population-based study of 40 880 patients comparing young and elderly patients

Background:Melanoma incidence has increased rapidly in the last decades, and predictions show a continuing increase in the years to come. The aim of this study was to assess trends in melanoma incidence, Breslow thickness (BT), and melanoma survival among young and elderly patients in the Netherlands.Methods:Patients diagnosed with invasive melanoma between 1994 and 2008 were selected from the Netherlands Cancer Registry. Incidence (per 100 000) over time was calculated for young (<65 years) and elderly patients (⩾65 years). Distribution of BT for young and elderly males and females was assessed. Regression analysis of the log-transformed BT was used to assess changes over time. Relative survival was calculated as the ratio of observed survival to expected survival.Results:Overall, 40 880 patients were included (42.3% male and 57.7% female). Melanoma incidence increased more rapidly among the elderly (5.4% estimated annual percentage change (EAPC), P<0.0001) than among younger patients (3.9% EAPC, P<0.0001). The overall BT declined significantly over time (P<0.001). Among younger patients, BT decreased for almost all locations. Among elderly males, BT decreased for melanomas in the head and neck region (P=0.001) and trunk (P<0.001), but did not decrease significantly for the other regions. Among elderly females, BT only decreased for melanomas at the trunk (P=0.01). The relative survival of elderly patients was worse compared with that of younger patients (P<0.001).Conclusion:Melanoma incidence increases more rapidly for elderly than for younger patients and the decline in BT is less prominent among elderly patients than among young patients. Campaigns in the Netherlands should focus more on early melanoma detection in the elderly.

The value of pre operative S-100B and SUV in clinically stage III melanoma patients undergoing therapeutic lymph node dissection.

INTRODUCTION High preoperative serum S-100B values and Standardized Uptake Values (SUV) of Fluorodeoxyglucose (FDG) in PET for clinically stage III melanoma patients could be indicators of recurrence after surgical treatment. Aim was to assess the correlation and the prognostic value of these markers. METHODS All melanoma patients with palpable nodal metastases, without distant metastases, were included from February 2004 to December 2007. Preoperative SUV and S-100B was determined. The correlation between SUV and S-100B and their relations with DFS and DSS were calculated by Cox Proportional Hazard Analysis. RESULTS 62 Patients, median age 56.9 years, were included in the study. An elevated S-100B was found in 31 patients (50%) and elevated SUV in 24 patients (38.7%). No relation was found between S-100B and SUV. DFS was reduced (31.1%) for patients with an elevated S-100B (HR = 3.1; p = 0.02) in comparison to a normal S-100B (44.6%). The DFS was 42.0% for patients with a SUV below the cut-off point and 29.0% for patients with an elevated SUV (HR = 1.1; p = 0.8). DSS was 60.7% in a normal S-100B and 44.7% for patients with an elevated S-100B (HR = 2.2; p = 0.07). DSS was 59.1% for patients with a normal SUV and 43.5% for patients with elevated SUV (HR = 1.1; p = 0.8). CONCLUSION S-100B and SUV in stage III melanoma are not correlated and each have different associations with various histopathological factors. S-100B, in contrast with SUV, is associated with nodal tumor load, and when elevated, predicts a shorter DFS. SYNOPSIS Preoperative serum S-100B and Fluorodeoxyglucose (FDG) Standardized Uptake Value (SUV) in clinically stage III melanoma are not correlated. S-100B is a strong predictor for Disease Free Survival (DFS) in stage III melanoma.

The predictive power of serum S-100B for non-sentinel node positivity in melanoma patients.

BACKGROUND Completion lymph node dissection (CLND) in sentinel node (SN) positive melanoma patients leads to substantial morbidity and costs, while only approximately 20% have a metastasis in non-sentinel nodes (NSNs). The aim of this study was to investigate if the biomarkers S-100B and Lactate Dehydrogenase (LDH) are associated with NSN positivity, to identify patients in whom CLND could safely be omitted. METHODS All SN positive patients who underwent CLND at the University Medical Centre Groningen between January 2004 and January 2015 were analysed. Patient and tumor characteristics, and serum S-100B and LDH values measured the day before CLND were statistically tested for their association with NSN positivity. RESULTS NSN positivity was found in 20.6% of the 107 patients undergoing CLND. Univariate analysis revealed male gender (p = 0.02), melanoma of the lower extremity (p = 0.05), Breslow thickness (p = 0.004), ulceration (p = 0.04), proportion of involved SNs (p = 0.045) and S-100B value (p = 0.01) to be associated with NSN positivity. LDH level was not significantly associated with positive NSNs (p = 0.39). In multivariable analysis, S-100B showed to have the strongest association with NSN positivity, within its reference interval of 0.20 μg/l (p = 0.02, odds ratio 5.71, 95% confidence interval 1.37-23.87). CONCLUSION In this study, the preoperatively measured S-100B value is the strongest predictor for NSN positivity in patients planned for CLND. Fluctuations of the S-100B level within the reference interval might give important clues about residual tumor load. Although further validation will be needed, this new closer look of S-100B could be of value in patient selection for CLND in the future.

Expression of HIF-1α in medullary thyroid cancer identifies a subgroup with poor prognosis

Background Medullary thyroid cancer (MTC) comprises only 4% of all thyroid cancers and originates from the parafollicular C-cells. HIF-1α expression has been implied as an indicator of worse prognosis in various solid tumors. However, whether expression of HIF-1α is a prognosticator in MTC remained unclear. Our aim was to evaluate the prognostic value of HIF-1α in patients with MTC. Methods All patients with MTC who were operated on between 1988 and 2014 in five tertiary referral centers in The Netherlands were included. A tissue microarray was constructed in which 111 primary tumors could be analyzed for expression of HIF-1α, CAIX, Glut-1, VEGF and CD31 and correlated with clinicopathologic variables and survival. Results The mean age of patients was 46.3 years (SD 15.6), 59 (53.2%) were male. Of the 111 primary tumors, 49 (44.1%) were HIF-1α negative and 62 (55.9%) were HIF-1α positive. Positive HIF-1α expression was an independent negative indicator for progression free survival (PFS) in multivariate cox regression analysis (HR 3.1; 95% CI 1.3 – 7.3). Five-years survival decreased from 94.0% to 65.9% for the HIF-1α positive group (p=0.007). Even within the group of patients with TNM-stage IV disease, HIF-1α positivity was associated with a worse prognosis, shown by a decrease in 5-years survival of 88.0% to 49.3% (p=0.020). Conclusion Expression of HIF-1α is strongly correlated with adverse prognosis of MTC. This could open up new ways for targeted systemic therapy of MTC.

Identification of novel therapeutic targets in anaplastic thyroid carcinoma using functional genomic mRNA-profiling: Paving the way for new avenues?

Background. Currently, anaplastic thyroid carcinoma has a very poor prognosis and there is an unmet need for new therapeutic options. Therefore, this study aims to identify upregulated genes in anaplastic thyroid carcinoma with known drug interactions that could serve as new therapeutic targets. Methods. Publicly available microarray expression profiles of anaplastic thyroid carcinoma and normal thyroid tissue were collected. FGmRNA‐profiling was applied, which is a recently developed method that enhances the ability to capture the downstream effects of genomic alterations on gene expression levels. Next, a comparison between FGmRNA‐profiles of anaplastic thyroid carcinoma and normal thyroid samples was performed. Significantly upregulated genes in ATC were prioritized based on: 1) known interaction with antineoplastic drugs, 2) current drug development status in human, and 3) association with biologic pathways known to be involved in anaplastic thyroid carcinoma carcinogenesis. Results. In the study, 25 anaplastic thyroid carcinoma and 80 normal thyroid samples were included for FGmRNA‐profiling. Class comparison identified 301 significantly upregulated genes. Following prioritization, MTOR, MET, WEE1, PSMD1, MERTK, FGFR3, RARG, and ESR2 were identified as potential therapeutic targets. Conclusion. We prioritized 8 potential therapeutic druggable targets in anaplastic thyroid carcinoma. Ultimately, inhibition of these therapeutic targets might improve patient outcome in anaplastic thyroid carcinoma by reducing locoregional disease and distant metastases.

Liver Metastases in Thyroid Cancer

Liver metastases from well-differentiated thyroid cancer (WDTC) are rare, with a reported frequency of less than 1 %. Despite this, in the treatment of liver metastases in general, recently the benefit-risk ratio has dramatically improved toward a lower risk for patients with liver metastases when treated by minimal invasive locoregional liver-directed treatments. Although the various thyroid cancer disease entities (papillary, follicular, medullary, and Hurthle cell thyroid cancer) have different biological characteristics, thyroid cancer liver metastases can thus increasingly be considered for curative or palliative treatment. Without doubts, in the following decade the ongoing development of liver-directed therapies will benefit the outcome of patients with liver metastases from any organ and thus also for patients with liver metastases in thyroid carcinoma.

Considerations in minimally invasive adrenal surgery : The frontdoor or the backdoor?

Over the last few decades, in the field of minimally invasive adrenal surgery, retroperitoneoscopic adrenalectomy (PRA) has shown favorable results when compared to laparoscopic transperitoneal adrenalectomy (LTA). However, for many endocrine surgeons it is unclear if, when, and how to transition from LTA to PRA. Although the length of the learning curve for both approaches is comparable, the LTA is a technically more challenging procedure whilst PRA demands an orientation in a new environment in a patient that is positioned upside down. Visiting a proctor is crucial for successfully adopting the PRA procedure, and continued mentorship in a surgeons own hospital during the first procedures is preferable. There are several other aspects related to the decision to transition to PRA; the caseload of adrenal patients, learning aspects of other members of the team, technical considerations, case selection, and a well-developed emergency plan in case of complications during surgery. In a dedicated endocrine center with a considerable annual case load of approximately 30 procedures, we recommend to transition to PRA in order to provide the highest quality of care to adrenal patients.

Molecular fluorescence-guided surgery of peritoneal carcinomatosis of colorectal origin: A narrative review

Patients with peritoneal carcinomatosis (PC) from colorectal origin may undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as a curative approach. One major prognostic factor that affects survival is completeness of cytoreduction. Molecular Fluorescence Guided Surgery (MFGS) is a novel intraoperative imaging technique that may improve tumor identification in the future, potentially preventing over‐ and under‐treatment in these patients. This narrative review outlines a chronological overview of MFGS development in patients with PC of colorectal origin.

The theranostic target prostate-specific membrane antigen is expressed in medullary thyroid cancer

Summary Medullary thyroid cancer (MTC) accounts for 4% of all thyroid cancers and originates from the parafollicular C-cells. Prostate-specific membrane antigen (PSMA) is known for its expression in the epithelium of prostate cancer and has been demonstrated to be useful both for therapeutic and diagnostic purposes as a so-called theranostic target. As PSMA is also expressed in the neovasculature of other solid tumor types, our aim was to assess PSMA expression and its prognostic role in MTC. Tissues from patients that underwent surgery for MTC between 1988 and 2014 in five tertiary referral centers in The Netherlands were included in a tissue microarray. Using immunohistochemistry, total numbers of PSMA and CD31-positive microvessels were evaluated. Results showed that 92% of MTC expressed PSMA in the neovasculature, whereas the tumor cells were consistently negative. The average number of PSMA-positive microvessels did not differ significantly between the primary tumor and initial lymph node metastases (P = .09), nor between initial and recurrent lymph node metastases (P = 1.00). The PSMA score was found to be correlated with progression-free survival and overall survival. In multivariate analysis, a higher number of PSMA-positive microvessels was associated with favorable prognosis (odds ratio 3.6; 95% confidence interval 1.0–12.8; P = .05). In conclusion, over 90% of MTC appears to express PSMA in the neovasculature. A higher number of PSMA-positive microvessels is prognostically favorable. Since it is highly expressed in MTC, PSMA is an interesting novel target for imaging and potentially also as a target for peptide radioligand therapy in MTC.