Patrick H. J. Hemmer

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.

Results of Surgery for Perforated Gastroduodenal Ulcers in a Dutch Population

Objective: Despite improvements in anesthesiology and intensive care medicine, mortality for perforated gastroduodenal ulcer disease remains high. This study was designed to evaluate the results of surgery for perforated ulcer disease and to identify prognostic factors for mortality in order to optimize treatment. Patients and Methods: The medical records of 272 patients undergoing emergency surgery for perforated ulcer disease from 2000 to 2005 in two large teaching hospitals and one university hospital in the Netherlands were retrospectively analyzed. Information on 89 pre-, peri- and postoperative data were recorded. Statistical analysis was performed using multiple logistic regression analysis. The primary endpoint was 30-day mortality. Results: The 30-day mortality rate was 16%. Variables associated with 30-day mortality were age, shock, tachycardia, anemia and ASA class. Conclusions: A relatively low 30-day mortality rate was achieved. Age, shock, tachycardia and anemia were significantly associated with 30-day mortality. Finding that shock, tachycardia and anemia are independently associated with 30-day mortality could indicate that patients are septic upon admission. Improvements in survival might be achieved by early sepsis treatment.

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.

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.

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.

Hypertherme intraperitoneale chemotherapie (HIPEC)

SamenvattingHemmer PHJ, Van Leeuwen BL. Hypertherme intraperitoneale chemotherapie (HIPEC). Huisarts Wet 2013;56(1):36-9. Chirurgie vormt de basis van de behandeling van kanker. Ook bij uitzaaiingen kan chirurgische resectie de overleving soms verbeteren. Een voorbeeld van dat laatste is cytoreductieve chirurgie gevolgd door hypertherme intraperitoneale chemotherapie (HIPEC). Hierbij maakt de chirurg de buikholte chirurgisch tumorvrij en spoelt deze vervolgens na met een verwarmde chemotherapieoplossing. Als de patiënt hersteld is, volgt aanvullende chemotherapie. De techniek is begin jaren negentig geïntroduceerd ter behandeling van pseudomyxoma peritonei en wordt inmiddels ook toegepast bij peritonitis carcinomatosa en bij maligne peritoneaal mesothelioom. Er zijn zes HIPEC-centra in Nederland.HIPEC is een zware, maar effectieve behandeling. Patiënten met peritoneale metastasen van een coloncarcinoom hebben normaliter een slechte prognose. Met HIPEC is de vijfjaarsoverleving 30% en in bepaalde groepen zelfs 50%. De mortaliteit van de procedure zelf is 4% en daalt nog steeds. Ook patiënten met een maligne peritoneaal mesothelioom komen in aanmerking voor HIPEC.Tijdens het hele behandeltraject is er veel aandacht nodig voor de lichamelijke en geestelijke begeleiding van de patiënt. De huisarts speelt daarin een belangrijke rol, met name bij de begeleiding buiten de ziekenhuisopnamen en bij het signaleren van lichamelijke problemen door de behandeling. Speciale aandacht verdienen psychosociale problemen, stoma, koorts, sondevoeding, splenectomie, enterocutane fistel en recidief.AbstractHemmer PHJ, Van Leeuwen BL. Hyperthermic intraperitoneal chemotherapy (HIPEC). Huisarts Wet 2013;56(1):36-9. Surgery forms the basis of cancer therapy, and surgical resection sometimes improves survival in metastatic disease. One such surgical approach is cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC). In this procedure, the surgeon removes all visible tumour from the abdominal cavity and then flushes the cavity with a warmed solution of chemotherapy agents. Once the patient has recovered, adjunct chemotherapy is started. The technique was introduced in the 1990s for the treatment of pseudomyxoma peritonei but is now also used for peritoneal carcinomatosis and malignant peritoneal mesothelioma. Six centres in the Netherlands provide HIPEC.It is an aggressive and taxing, but effective, procedure. Patients with peritoneal metastases from colon cancer usually have a poor prognosis, but after HIPEC the 5-year survival rate is 30% and even 50% in certain patient groups. Procedure mortality is 4% but is decreasing. Throughout treatment, considerable attention should be paid to managing the physical and mental health of the patient, and in this the general practitioner has an essential role in detecting treatment-related physical problems. Special attention should be paid to psychosocial problems, stoma, fever, tube feeding, splenectomy, enterocutaneous fistula, and tumour recurrence.