Lukas B. Been

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.

Hyperthermic isolated limb perfusion, preoperative radiotherapy, and surgery (PRS) a new limb saving treatment strategy for locally advanced sarcomas

This feasibility study presents the results of a new intensive treatment regimen for locally advanced extremity soft tissue sarcomas (ESTS), consisting of hyperthermic isolated limb perfusion (HILP), preoperative external beam radiotherapy (EBRT), and surgical resection.

Amputations for extremity soft tissue sarcoma in an era of limb salvage treatment: Local control and survival

Despite multimodality limb salvage treatment (LST) for locally advanced extremity soft tissue sarcoma (ESTS), some patients still need an amputation. Indications for amputation and oncological outcome for these patients are described.

Reply to comment on: Incidence and predictors of postoperative delirium after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy

Dear Editor, We appreciate the interest in our work and the opportunity to respond to the comments andmatters raised byWeng et al. regarding our article on “Incidence and predictors of postoperative delirium after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy.” The study was conducted among a consecutive series of 136 prospectively included patients who underwent CRS-HIPEC at our hospital. Twenty-eight percent of our patients developed a postoperative delirium. Excluding patients with sepsis (n = 7), having three or more organs resected and the CRP serum levels were the main predictors. Given the relatively small sample size, the confidence intervals were rather wide. Weng et al. questioned whether multicollinearity might be an alternative explanation for these wide confidence intervals. However, as all variance inflation factors (data not reported) were close to one, this is not an explanation. We agree with the authors that in this study we did not focus on model performance by evaluation of the Area under the Curve (AUC), the Net Reclassification Improvement (NRI), the Integrated Discrimination Improvement (IDI) or due to our relatively small sample size by cross-validation or bootstrapping. Our main argument for this is that the main focus of this analysis was to evaluate factors associated with the occurrence of postoperative delirium and not to propose a predictive model. As a consequence, our conclusion is that future research is needed to evaluate whether a postoperative delirium increases the risk for other postoperative complications or whether a postoperative delirium is a symptom of other complications which can occur after surgery.

RETRACTED: Diagnosis and Treatment of Intestinal Melanoma Metastases in the Era of Effective Systemic Treatment

OBJECTIVE The aim of the present study was to describe different presentations, diagnostic tools, and available treatments for melanoma metastasized to the intestines. BACKGROUND The intestine is a frequent site of metastases in melanoma patients. In the current era, with long-term survival after systemic treatment, there is a need for a timely diagnosis and optimal treatment of intestinal metastases. METHODS Patients diagnosed between 2011 and 2015 with intestinal metastases of melanoma were included. Diagnostic procedures, treatment strategies, and their outcome were analyzed for all patients. RESULTS A total of 22 patients were included. Twenty patients received systemic therapy for widely disseminated disease. Fourteen of these twenty patients received local treatment for symptomatic intestinal metastases. Median overall survival after detection of intestinal metastasis in patients receiving systemic treatment was 22 months. On the basis of this cohort, a treatment algorithm for treatment of patients with symptomatic intestinal melanoma metastases was constructed. CONCLUSIONS The treatment of intestinal melanoma metastases has changed due to the introduction of novel systemic treatments that can result in long-term survival of patients with widely metastatic melanoma. Surgeons and other clinicians should be aware of these changes in clinical practice as well as the diverse presentation of intestinal melanoma metastases and the diagnostic and therapeutic dilemmas involved.

Preoperative BRAF inhibition in patients with irresectable locally advanced stage III melanoma

Aim: Neoadjuvant treatment of locally advanced disease with BRAF inhibitors is expected to increase the likelihood of a R0 resection. We present six patients with stage III unresectable melanoma, neoadjuvantly treated with BRAF inhibitors. Methods: Patients with unresectable, BRAF-mutated, stage III melanoma, were treated with BRAF inhibitors between 2012 and 2015. Unresectability was determined based on clinical and/or radiological findings. At maximal response, resection was performed. The specimen was reviewed to determine the degree of response. Results: In five of six patients a radical resection was achieved. Postoperative complications were unremarkable. In five of six resected specimens, vital tumor tissue was found. Conclusion: Neoadjuvant BRAF inhibitor treatment of locally advanced melanoma is feasible and has the potential to facilitate an R0 resection.

Incidence and predictors of postoperative delirium after cytoreduction surgery-hyperthermic intraperitoneal chemotherapy

Incidence of, and baseline characteristics associated with delirium in patients after cytoreduction surgery‐hyperthermic intraperitoneal chemotherapy (CRS‐HIPEC), were subject of investigation.

Volume of interest delineation techniques for F-18-FDG PET-CT scans during neoadjuvant extremity soft tissue sarcoma treatment in adults : a feasibility study

BackgroundThis study explores various volume of interest (VOI) delineation techniques for fluorine-18-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET-CT) scans during neoadjuvant extremity soft tissue sarcoma (ESTS) treatment.ResultsDuring neoadjuvant treatment, hyperthermic isolated limb perfusion (HILP) and preoperative external beam radiotherapy (EBRT), 11 patients underwent three 18F-FDG PET-CT scans. The first scan was made prior to the HILP, the second after the HILP but prior to the start of the EBRT, and the third prior to surgical resection. An automatically drawn VOIauto, a manually drawn VOIman, and two gradient-based semi-automatically drawn VOIs (VOIgrad and VOIgrad+) were obtained. Maximum standardized uptake value (SUVmax), SUVpeak, SUVmean, metabolically active tumor volume (MATV), and total lesion glycolysis (TLG) were calculated from each VOI. The correlation and level of agreement between VOI delineation techniques was explored. Lastly, the changes in metabolic tumor activity were related to the histopathologic response. The strongest correlation and an acceptable level of agreement was found between the VOIman and the VOIgrad+ delineation techniques. A decline (VOIman) in SUVmax, SUVpeak, SUVmean, TLG, and MATV (all p < 0.05) was found between the three scans. A > 75% decline in TLG between scan 1 and scan 3 possibly identifies histopathologic response.ConclusionsThe VOIgrad+ delineation technique was identified as most reliable considering reproducibility when compared with the other VOI delineation techniques during the multimodality neoadjuvant treatment of locally advanced ESTS. A significant decline in metabolic tumor activity during the treatment was found. TLG deserves further exploration as predictor for histopathologic response after multimodality ESTS treatment.

Chirurgische behandeling melanomen

SamenvattingWevers KP, Been LB, Hoekstra HJ. Chirurgische behandeling van melanomen. Huisarts Wet 2013;56(6):290-4.De incidentie van het melanoom blijft stijgen in Nederland. In diagnostiek en behandeling speelt chirurgie een belangrijke rol. De eerste diagnostische excisie, die meestal in de eerste lijn wordt uitgevoerd, is van groot belang voor het verdere beleid. Bij vastgestelde maligniteit volgt in de tweede lijn altijd een therapeutische re-excisie. De resectiemarge die de chirurg daarbij aanhoudt, hangt af van de zogeheten breslowdikte.Bij een breslowdikte > 1 mm vindt re-excisie plaats in combinatie met een schildwachtklierprocedure. Bij een ‘positieve’ schildwachtklier volgt in principe een aanvullende lymfeklierdissectie. Het moet echter nog komen vast te staan of deze procedure ook daadwerkelijk de overleving verbetert. Als er al hematogene metastasen zijn, is chirurgisch ingrijpen (metastasectomie) in sommige gevallen nog mogelijk, maar de vijfjaarsoverleving van deze procedure is slechts 20-40%.In de follow-up kijkt men vooral naar complicaties van de behandeling (wondinfectie, seroom, wondrandnecrose) en naar mogelijke locoregionale recidieven (de meeste worden ontdekt bij zelfcontrole door de patiënt). Vooral liesklierdissectie en aanvullende radiotherapie kunnen leiden tot complicaties die een snelle behandeling vereisen.AbstractWevers KP, Been LB, Hoekstra HJ. Chirurgische behandeling van melanomen. Huisarts Wet 2013;56(6):290-4.The incidence of cutaneous melanoma is rising in the Netherlands. Surgery is the cornerstone in the treatment (and staging) of melanoma. The diagnostic excision is often performed by the general practitioner, in which adequate effectuation is very important. A therapeutic re-excision is performed to increase local control. The resection margins are based on the Breslow thickness of the primary melanoma. In melanomas with a Breslow thickness of > 1 mm, a sentinel lymph node biopsy can be performed, providing the patient and physician with valuable prognostic information. In case of a positive sentinel lymph node or clinically apparent lymph node metastases, a lymph node dissection is performed. In sentinel-node positive patients, the pending MSLT-II trial should establish whether lymph node dissection improves survival compared to nodal observation using ultrasound. In case of hematogenous dissemination, highly selected patients with resectable metastases can undergo complete metastasectomy, which can lead to a 5-year survival of 20-40%. Follow-up of melanoma patients is aimed at postoperative complications (infection, seroma, necrosis), and detection of recurrent disease. For the general practitioner it is important to know that postoperative wound complications after lymph node dissections (with or without radiation therapy) are frequent and need prompt treatment.