Characterisation and mitigation of gas leaks at laparoscopy: an international prospective, multi-center cohort clinical trial.

INTRODUCTION: Gas leaks polluting the operating room are common in laparoscopy. Studies defining methods for sensitive leak characterisation and mechanical mitigation in real world settings are, however, lacking. METHODS: Mobile optical gas imagers (both a miniaturised Schlieren system and sensitive tripod-mounted near-infrared carbon dioxide camera (GF343, FLIR)) prospectively defined trocar-related gas leaks occurring either spontaneously or with instrumentation during planned laparoscopic surgery at three hospitals. A boutique Matlab-based analyser using sequential frame subtraction categorised leaks (class 0-no observable leak; class 1-marginally detectable leak; class 2-short-lived plume; class 3-energetic, turbulent jet). Concurrently, the usefulness of a novel vacuum-ring device (LeakTrap™, Palliare, Ireland) designed as a universal adjunct for existing standard laparoscopic ports at both abdominal wall and port valve level was determined similarly in a phase I/11 clinical trial along with the device's useability through procedural observation and surgeon questionnaire. RESULTS: With ethical and regulatory approval, 40 typical patients (mean age 58.6 years, 20 males) undergoing planned laparoscopic cholecystectomy (n = 36) and hernia repair (n = 4) were studied comprising both control (n = 20) and intervention (n = 20) cohorts. Dual optical gas imaging was successfully performed across all procedures with minimal impact on procedural flow. In total, 1643 trocar instrumentations were examined, 819 in the control group (mean 41 trocar instrumentations/procedure) and 824 in the intervention group (mean 41.2 trocar instrumentations/procedure). Gas leaks were detected during 948(62.6%) visualised trocar instrumentations (in 129-7.8%-the imaging was obscured). 14.8% (110/742) and 60% (445/742) of leaks in control patients were class 0 and 3, respectively, versus 59.1% (456/770) and 8.7% (67/772) in the interventional group (class 3 v non-class 3, p < 0.0001, χ2). The Leaktrap proved surgically acceptable without significant workflow disruption. CONCLUSION: Laparoscopic gas leaks can be sensitively detected and consistently, effectively mitigated using straightforward available-now technology with most impact on the commonest, highest energy instrument exchange leaks.

Deep sedation versus orotracheal intubation for endoscopic sleeve gastroplasty (ESG): preliminary experience.

BACKGROUND: Endoscopic sleeve gastroplasty (ESG) is an emerging bariatric procedure currently performed under general anaesthesia with orotracheal intubation (OTI). Several studies have shown the feasibility of advanced endoscopic procedures under deep sedation (DS) without impacting patient outcomes or adverse event rates. Our goal was to perform an initial comparative analysis of ESG in DS with ESG under OTI. METHODS: A prospective institutional registry was reviewed for ESG patients between 12/2016 and 1/2021. Patients were stratified into OTI or DS cohorts, and the 1st 50 cases performed in each cohort were included for comparability. Univariate analysis was performed on demographics, intraoperative, and postoperative outcomes (up to 90 days). Multivariate analyses evaluated the relationship between anesthesia type, preclinical and clinical variables. RESULTS: Of the 50 DS patients, 21(42%) underwent primary and 29 (58%) revisional surgery. There was no significant differences in Mallampati score across groups. No DS patient required intubation. DS patients were younger (p = 0.006) and lower BMI (p = 0.002) than OTI. As expected, DS patients overall and in the primary subgroup had shorter operative time (p ≤ 0.001 and p = 0.003, respectively) and higher rates (84% DS vs. 20% OTI, p ≤ 0.001) of ambulatory procedures. There were no significant differences in the sutures used between groups (p = 0.616). DS patients required less postoperative opioids (p ≤ 0.001) and antiemetics (p = 0.006) than OTI. There were no significant differences in 3-month postoperative weight loss across cohorts. There was no rehospitalization in either group. In primary ESG cases, we found DS patients were more likely younger (p = 0.006), female (p = 0.001), and had a lower BMI (p = 0.0027). CONCLUSIONS: ESG under DS is safe and feasible in select patients. We found DS safely increased rates of outpatient care, reduced use of opioids and antiemetics, and provided the same results of postoperative weight loss. Patient selection for DS may be more clearer for durable weight loss.

Partial Hepatic Vein Occlusion and Venous Congestion in Liver Exploration Using a Hyperspectral Camera: A Proposal for Monitoring Intraoperative Liver Perfusion.

INTRODUCTION: The changes occurring in the liver in cases of outflow deprivation have rarely been investigated, and no measurements of this phenomenon are available. This investigation explored outflow occlusion in a pig model using a hyperspectral camera. METHODS: Six pigs were enrolled. The right hepatic vein was clamped for 30 min. The oxygen saturation (StO2%), deoxygenated hemoglobin level (de-Hb), near-infrared perfusion (NIR), and total hemoglobin index (THI) were investigated at different time points in four perfused lobes using a hyperspectral camera measuring light absorbance between 500 nm and 995 nm. Differences among lobes at different time points were estimated by mixed-effect linear regression. RESULTS: StO2% decreased over time in the right lateral lobe (RLL, totally occluded) when compared to the left lateral (LLL, outflow preserved) and the right medial (RML, partially occluded) lobes (p < 0.05). De-Hb significantly increased after clamping in RLL when compared to RML and LLL (p < 0.05). RML was further analyzed considering the right portion (totally occluded) and the left portion of the lobe (with an autonomous draining vein). StO2% decreased and de-Hb increased more smoothly when compared to the totally occluded RLL (p < 0.05). CONCLUSIONS: The variations of StO2% and deoxy-Hb could be considered good markers of venous liver congestion.

Educational Scoring System in Laparoscopic Cholecystectomy: Is It the Right Time to Standardize?

Background and Objectives: Laparoscopic cholecystectomy (LC) is one of the most performed surgeries worldwide. Procedure difficulty and patient outcomes depend on several factors which are not considered in the current literature, including the learning curve, generating confusing and subjective results. This study aims to create a scoring system to calculate the learning curve of LC based on hepatobiliopancreatic (HPB) experts' opinions during an educational course. Materials and Methods: A questionnaire was submitted to the panel of experts attending the HPB course at Research Institute against Digestive Cancer-IRCAD (Strasbourg, France) from 27-29 October 2022. Experts scored the proposed variables according to their degree of importance in the learning curve using a Likert scale from 1 (not useful) to 5 (very useful). Variables were included in the composite scoring system only if more than 75% of experts ranked its relevance in the learning curve assessment ≥4. A positive or negative value was assigned to each variable based on its effect on the learning curve. Results: Fifteen experts from six different countries attended the IRCAD HPB course and filled out the questionnaire. Ten variables were finally included in the learning curve scoring system (i.e., patient body weight/BMI, patient previous open surgery, emergency setting, increased inflammatory levels, presence of anatomical bile duct variation(s), and appropriate critical view of safety (CVS) identification), which were all assigned positive values. Minor or major intraoperative injuries to the biliary tract, development of postoperative complications related to biliary injuries, and mortality were assigned negative values. Conclusions: This is the first scoring system on the learning curve of LC based on variables selected through the experts' opinions. Although the score needs to be validated through future studies, it could be a useful tool to assess its efficacy within educational programs and surgical courses.

Fluorescence-based bowel anastomosis perfusion evaluation: results from the IHU-IRCAD-EAES EURO-FIGS registry.

BACKGROUND: Anastomotic leakage (AL) is one of the dreaded complications following surgery in the digestive tract. Near-infrared fluorescence (NIRF) imaging is a means to intraoperatively visualize anastomotic perfusion, facilitating fluorescence image-guided surgery (FIGS) with the purpose to reduce the incidence of AL. The aim of this study was to analyze the current practices and results of NIRF imaging of the anastomosis in digestive tract surgery through the EURO-FIGS registry. METHODS: Analysis of data prospectively collected by the registry members provided patient and procedural data along with the ICG dose, timing, and consequences of NIRF imaging. Among the included upper-GI, colorectal, and bariatric surgeries, subgroup analysis was performed to identify risk factors associated with complications. RESULTS: A total of 1240 patients were included in the study. The included patients, 74.8% of whom were operated on for cancer, originated from 8 European countries and 30 hospitals. A total of 54 surgeons performed the procedures. In 83.8% of cases, a pre-anastomotic ICG dose was administered, and in 60.1% of cases, a post-anastomotic ICG dose was administered. A significant difference (p < 0.001) was found in the ICG dose given in the four pathology groups registered (range: 0.013-0.89 mg/kg) and a significant (p < 0.001) negative correlation was found between the ICG dose and BMI. In 27.3% of the procedures, the choice of the anastomotic level was guided by means of NIRF imaging which means that in these cases NIRF imaging changed the level of anastomosis which was first decided based on visual findings in conventional white light imaging. In 98.7% of the procedures, the use of ICG partly or strongly provided a sense of confidence about the anastomosis. A total of 133 complications occurred, without any statistical significance in the incidence of complications in the anastomoses, whether they were ICG-guided or not. CONCLUSION: The EURO-FIGS registry provides an insight into the current clinical practice across Europe with respect to NIRF imaging of anastomotic perfusion during digestive tract surgery.

A curriculum to democratize and standardize flexible endoscopy fundamental knowledge and skills: a critical review of the first 5 years of a surgical endoscopy university diploma.

BACKGROUND: As flexible endoscopy offers many advantages to patients, access to training should be aggressively encouraged. In 2014, the IRCAD-IHU-Strasbourg launched a year-long university diploma using advanced education methods to offer surgeons and gastroenterologists high-quality, personalized training in flexible endoscopy. This paper describes and critically reviews the first 5 years of the University Diploma in Surgical Endoscopy (UDSE). METHODS: The UDSE aims to progressively transmit theoretical knowledge, clinical judgment, and practical skills on basic and advanced flexible endoscopy. The 300-h year-long curriculum is composed of 100 h of online lectures with tests, 150 h of clinical rotations and 50 h of hands-on sessions. The hands-on training is delivered through validated mechanical simulators, virtual reality simulators, and specifically designed ex vivo and in vivo animal models. Participants' demographics, training, and clinical experience were recorded. Trainees' evaluations of each online lecture, hands-on training, and clinical rotations were assessed using a Likert scale from 1 (not satisfactory) to 5 (outstanding). Trainees' skill progression was evaluated using the Global Assessment of Gastrointestinal Endoscopic Skills (GAGES) proficiency test. Finally, clinical uptake was surveyed. RESULTS: 162 (79.01% males) trainees from 38 countries enrolled and successfully completed the first 5 courses. The vast majority of the trainees were surgeons and 19.14% were gastroenterologist. Sixty-nine (42.59%) participants were residents and 97 (56.79%) had no prior experience in flexible endoscopy. The online lectures, on-site sessions, and clinical rotations were highly appreciated receiving an overall average score of 4.33/5, 4.56/5, 4.43/5, respectively. Trainees' endoscopic skills improved significantly (16.68 vs. 20.53 GAGES scores; p = 0.016). At an average of 18.83 months following the course, 31 alumni (77.50% of repliers) started to use a flexible endoscope in their practice. CONCLUSIONS: Over its 5-year evolution, the UDSE has proven to be a valid means to ease access to the fundamental knowledge, practical skills, and clinical judgment necessary to achieve proficiency in surgical endoscopy.

Effects of Warmed and Humidified CO2 Surgical Site Insufflation in a Novel Experimental Model of Magnetic Compression Colonic Anastomosis.

Background. Pneumoperitoneum insufflation with warmed and humidified carbon dioxide (WH-CO2) can prevent heat loss and increase tissue oxygenation. We evaluated the impact of localized WH-CO2 insufflation on the anastomotic healing process. Methods. Sixty male Wistar rats were randomized: Group 1 (control, n = 12), Group 2 (cold and dry CO2, CD-CO2, n = 24), and Group 3 (WH-CO2, n = 24). A magnetic compression side-to-side colonic anastomosis was performed under 60-minute local abdominal CO2 flow insufflation. Animal temperature was recorded. IL-1, IL-6, and CRP levels were assessed before and after insufflation and on postoperative day (POD) 7 and POD 10. Endoscopic follow-up was performed on POD 7 and POD 10. A burst pressure (BP) test of the specimen was performed on POD 10, and histopathological analysis was then performed. Metabolomics of the anastomotic site was determined. Results. Seven rats (5 CD-CO2 group, 1 WH-CO2 group, and 1 control group) died during the survival period. Necropsies revealed intestinal occlusions (n = 2). One additional rat from the CD-CO2 group was sacrificed on POD 7 due to intestinal perforation. The postoperative course was uneventful in the remaining cases. There was no difference in BP among the groups. Thermal monitoring confirmed that WH-CO2 insufflation was effective to reduce heat loss. IL-1 levels were statistically and significantly lower on POD 10 in the WH-CO2 group than the CD-CO2 group but not lower than the control group. CRP levels, histopathology, and metabolomics did not show any difference between the 3 groups. Conclusions. WH-CO2 was effective to preserve core temperature. However, it did not improve anastomotic healing.

Management of Liver Oligometastatic Esophageal Cancer: Overview and Critical Analysis of the Different Loco-Regional Treatments.

Esophageal cancer (EC) is an aggressive disease that is associated with a poor prognosis. Since metastastic EC is usually considered suitable only for palliative therapy with an estimated 5-year overall survival (OS) less than 5%, the optimal management of patients with liver oligometastatic EC (LOEC) is still undefined. The aim of this review is to provide an overview of the different treatment options for LOEC. A literature search was conducted using PubMed, Embase, and Cochrane to identify articles evaluating different treatment strategies for LOEC. Among 828 records that were identified, 20 articles met the inclusion criteria. These studies included patients who have undergone any type of surgical procedure and/or loco-regional therapy. Liver resection resulted in the best survival for patients with low tumor burden (3 lesions): 5-year OS 30-50% versus 8-12% after only chemotherapy (CHT). The 5-year OS of loco-regional therapies was 23% with a local recurrence risk ranging 0-8% for small lesions (2 to 3 cm). An aggressive multidisciplinary approach for LOEC patients may improve survival. Surgery seems to be the treatment of choice for resectable LOEC. If unfeasible, loco-regional therapies may be considered. In order to better select these patients and offer a chance of cure, prospective trials and a definition of treatment protocols are needed.

Gastric tube cancer after esophagectomy for cancer: a systematic review.

Gastric conduit used for reconstruction after esophagectomy for cancer has the potential to develop a metachronous neoplasm known as gastric tube cancer (GTC). The aim of this study was to review literature and evaluate outcomes and possible treatment strategies for GTC. A comprehensive systematic literature search was conducted using PubMed, EMBASE, Scopus, and the Cochrane Library Central Register of Controlled Trials. No restriction was set for the type of publication, number, age, or sex of the patients. The search was limited to articles in English. Characteristics of esophageal cancer (EC) and its treatment and GTC and its treatment were analyzed. A total of 28 studies were analyzed, 12 retrospective analyses and 16 case reports, involving 229 patients with 250 GTCs in total. The majority of ECs (88.2%) were squamous cell carcinomas. In 120 patients (52.4%) a posterior mediastinal reconstructive route was used when esophagectomy was performed. The mean interval between esophagectomy and diagnosis of GTC was 55.8 months, with a median interval of 56.8 months (4-236 months). One hundred and twenty-four GTCs (49.6%) were located in the lower part of the gastric tube. One hundred and forty patients were endoscopically treated. Eighty-five patients underwent surgery. Thirty-six total gastrectomies with lymphadenectomy with colon or jejunal interposition were performed. Forty-three subtotal gastrectomies and 6 wedge resections were performed. The main reported postoperative complications were anastomotic leak, vocal cord palsy, and respiratory failure. Twenty-five patients were treated with palliative chemotherapy. Three-year survival rates were 69.3% for endoscopically treated patients, 58.8% for surgically resected patients, and 4% for patients who underwent palliative treatment. The feasibility of endoscopic resections in patients diagnosed with superficial GTC has been reported. Surgical treatment represented the preferred treatment method in operable patients with locally invasive tumor. Patients treated with conservative therapy have a scarce prognosis. The development of GTC should be taken into consideration during the extended follow-up of patients undergoing esophagectomy for cancer. Total gastrectomy plus lymphadenectomy should be considered the preferred treatment modality in operable patients with locally invasive tumor, when endoscopy is contraindicated. Long-term yearly endoscopic follow-up is recommended.

Which method of distal pancreatectomy is cost-effective among open, laparoscopic, or robotic surgery?

BACKGROUND: The aim of this study was to analyze the clinical and economic impact of robotic distal pancreatectomy, laparoscopic distal pancreatectomy, and open distal pancreatectomy. METHODS: All consecutive patients who underwent distal pancreatic resection for benign and malignant diseases between January 2012 and December 2015 were prospectively included. Cost analysis was performed; all charges from patient admission to discharge were considered. RESULTS: There were 21 robotic (RDP), 25 laparoscopic (LDP), and 43 open (ODP) procedures. Operative time was longer in the RDP group (RDP =345 minutes, LDP =306 min, ODP =251 min, P=0.01). Blood loss was higher in the ODP group (RDP =192 mL, LDP =356 mL, ODP =573 mL, P=0.0002). Spleen preservation was more frequent in the RDP group (RDP =66.6%, LDP =61.9%, ODP =9.3%, P=0.001). The rate of patients with Clavien-Dindo > grade III was higher in the ODP group (RDP =0%, LDP =12%, ODP =23%, P=0.01), especially for non-surgical complications, which were more frequent in the ODP group (RDP =9.5%, LDP =24%, ODP =41.8%, P=0.02). Length of hospital stay was increased in the ODP group (ODP =19 days, LDP =13 days, RDP =11 days, P=0.007). The total cost of the procedure, including the surgical procedure and postoperative course was higher in the ODP group (ODP =30,929 Euros, LDP =22,150 Euros, RDP =21,219 Euros, P=0.02). CONCLUSIONS: Cost-effective results of RDP seem to be similar to LDP with some better short-term outcomes.

Injectable Hybrid Hydrogels, with Cell-Responsive Degradation, for Tumor Resection.

Biocompatible soft materials have recently found applications in interventional endoscopy to facilitate resection of mucosal tumors. When neoplastic lesions are in organs that can be easily damaged by perforation, such as stomach, intestine, and esophagus, the formation of a submucosal fluid cushion (SFC) is needed to lift the tumor from the underlying muscle during the resection of neoplasias. Such procedure is called endoscopic submucosal dissection (ESD). We describe an injectable, biodegradable, hybrid hydrogel able to form a SFC and to facilitate ESD. The hydrogel, based on polyamidoamines, contains breakable silica nanocapsules covalently bound to its network and able to release biomolecules. To promote degradation, the hydrogel is composed of cleavable disulfide moieties that are reduced by the cells through secretion of glutathione. The same stimulus triggers the breaking of the silica nanocapsules; therefore, the entire hybrid material can be completely degraded and its decomposition depends entirely on the presence of cells. Interestingly, the hydrogel precursor solution showed rapid gelation when injected in vivo and afforded a long-lasting high mucosal elevation, keeping the cushion volume constant during the dissection. This novel material can provide a solution to ESD limitations and promote healing of tissues after surgery.

Weight regain following RYGB can be effectively treated using a combination of endoscopic suturing and sclerotherapy.

BACKGROUND: Obesity is a leading cause of morbidity and healthcare utilization. At the moment, the best treatment for obesity has shown to be laparoscopic gastric bypass. However, about a quarter of the patients experience substantial weight regain, which is difficult to treat, as revision surgery has higher risks than primary procedures. Endoscopic procedures, such as endoscopic suturing, are effective, safe and less invasive in addressing weight regain. METHODS: We conducted a retrospective analysis on 22 consecutive patients operated between 2011 and 2013 who had a significant weight regain after RYGB (mean follow-up 22 months), in order to evaluate the long-term outcomes of endoscopic gastro-jejunal revision after weight regain post-bypass surgery. Mucosal ablation around the anastomosis was performed in all patients, and the endoscopic suturing device was used to perform suture stoma reduction. We also evaluated, in a group of 11 patients, the effect of combining sclerotherapy and endoscopic suturing. RESULTS: We showed good efficacy of the endoluminal procedure, with 100 % of patients achieving weight loss. Maximum weight loss was noted at a mean of 18-month follow-up (average of 60.3 % excess weight loss; n = 19), while the mean weight loss regained percentage was 5 % ± 39. 4/22 patients (all four in non-sclerotherapy group, all of them had an anastomosis >10 mm) regained some of this lost weight by the time of the longest follow-up. There was an actual correlation between final stoma diameter (<10 mm) and weight loss. CONCLUSIONS: A larger randomized sample of patients with a longer follow-up would be needed to support the effectiveness of the combination of the two therapies. Although almost 20 % of the patients regained weight during the follow-up period, the endoluminal approach offers the advantage of being repeatable after weight regain without adding morbidity risks.

Expression of tenascin-C in various human brain tumors and its relevance for survival in patients with astrocytoma.

BACKGROUND: Tenascin-C (TN-C), a large extracellular matrix (ECM) glycoprotein with a molecular weight of 180-250 kilodaltons, is present in several normal adult tissues. TN-C is up-regulated during embryogenesis, in wound healing, and in tumor tissues. Glioblastoma multiforme (GBM) is the most frequent and malignant astrocytic tumor comprised of poorly differentiated, neoplastic astrocytes. Recently, TN-C-based radioimmunotherapy was administered to patients with GBM. METHODS: In the current study, the authors used immunohistochemistry to conduct a systematic investigation of TN-C distribution patterns in normal human brain tissue and in a large variety of brain tumors (n = 485 tumors). Immunoreactivity for TN-C was assessed with regard to its localization within tumor cells, blood vessels, and ECM using three different monoclonal antibodies (clones BC2, BC4, and TN2). RESULTS: In control human brains, a significant difference was noted in the expression of TN-C when comparing gray with white matter using either Western blot analysis or immunohistochemistry. TN-C was found in the white matter of the frontal, temporal, parietal, and occipital lobes and in the hippocampus, where the immunoreaction was especially strong in the hippocampal formation. In 181 astrocytomas of different grades (World Health Organization [WHO] Grade 2-4), TN-C immunopositivity was seen to varying degrees in the cellular and stromal components of the tumor and in tumor-associated vessels. Glioblastomas (n = 113 tumors) showed strong immunopositivity in the vessels and moderate immunopositivity of the ECM. A statistically significant reduction of TN-C immunopositivity in tumor-associated vessels or ECM was observed in anaplastic astrocytomas (WHO Grade 3) compared with GBM (WHO Grade 4). A Kaplan-Meier analysis showed that patients who had GBM lesions that lacked TN-C immunopositivity in the ECM had a significantly longer survival (median, 28 months; standard error, 7.8 months) (n = 12 patients) compared with patients who had GBM lesions with TN-C immunopositivity (median, 12 months; standard error, 1.6 months) (n = 87 patients). In meningiomas (n = 24 tumors), the neoplastic cells, the ECM of the tumor, and the vessels were TN-C negative. In schwannomas (n = 31 tumors), the tumor cells were TN-C negative; whereas, in > 50% of tumors, the vessels and the ECM of regressively altered tumor areas were positive. In metastatic carcinomas (n = 53 tumors), the tumor cells were negative; seldom were vessels stained positive for TN-C. Focal areas of the ECM, often accompanied with fibrotic changes, were immunopositive for TN-C. CONCLUSIONS: The most constant TN-C immunopositivity was noted in the ECM of the fibrotic stroma in highly malignant brain tumors and along the tumor border, especially in high-grade astrocytomas. The current results suggest that TN-C expression may be correlated with the grade of malignancy in astrocytic tumors and that the presence or absence of TN-C expression in the stroma of astrocytic tumors may play a not yet clearly understood role in shortening or prolonging, respectively, the survival of patients.

Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer.

PURPOSE: ED-B fibronectin is expressed only during angiogenic processes and in tissues undergoing growth and/or extensive remodeling. We demonstrated previously the possibility to target and selectively deliver therapeutic substances to tumor vasculature in experimental animal models using a human recombinant antibody fragment, L19, specific for the ED-B domain of fibronectin. Here we evaluate the possibility of targeting primary tumors and metastatic lesions in cancer patients through immunoscintigraphy using (123)I-labeled dimeric L19 [L19(scFv)(2)]. EXPERIMENTAL DESIGN: Twenty patients (34-79 years of age) with lung, colorectal, or brain cancer, whose tumors had been confirmed by imaging techniques and/or histologically, were admitted to the immunoscintigraphic investigation. RESULTS: The dimeric L19 antibody selectively localized in tumor lesions in aggressive types of lung cancer and colorectal cancer. Because ED-B fibronectin is expressed only during angiogenic processes and in tissues undergoing growth and/or extensive remodeling, L19(scFv)(2) is able to distinguish between quiescent and actively growing lesions. No side effects were observed. CONCLUSIONS: The ability of L19(scFv)(2) to target tumors in patients provides the foundations for new therapeutic applications, in which the L19 antibody is engineered to selectively deliver bioactive molecules to primary tumors as well as to metastases.

In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS trial.

The high-level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled peptide analogues as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress one or the other of 5 distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress human(h) SSTR2, intestinal adenocarcinomas frequently express hSSTR3 or hSSTR4, or both of these hSSTRs. In contrast to (111)In-diethylenetriamine pentaacetic acid (DTPA)-(D)he(1)-octreotide (OctreoScan; Mallinckrodt, Petten, NL), which binds to hSSTR2 and 5 with high affinity (K(d)0.1-5 nmol/L), to hSSTR3 with moderate affinity (K(d)10-100 nmol/L), and does not bind to hSSTR1 and hSSTR4, (111)In /(90)Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (K(d)200 nmol/L). Based on its unique hSSTR binding profile, (111)In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and (90)Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. When directly compared with (111)In-DTPA-(D)he(1)-octreotide and (111)In-DOTA-(D)he(1)-Tyr(3)-octreotide, discrepancies in the scintigraphic imaging pattern are seen in about one third of tumor patients concerning both the tumor uptake as well as the detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a higher high-affinity binding affinity of (111)In-DOTA-(D)he(1)-Tyr(3)-octreotide for hSSTR2 (K(d)0.1-1 nmol/L). Beneficial results of receptor-mediated experimental radionuclide therapy were first reported for high-dose treatment with (111)In-DTPA-(D)he(1)-octreotide, based on the emission of Auger electrons. Phase IIa of the Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a European Study (MAURITIUS), shows in progressive cancer patients (therapy entry criteria) with a calculated tumor dose > 10 Gy/GBq (90)Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with peptide receptor imaging agents. In the MAURITIUS study, cumulative treatment doses up to 232 mCi (90)Y-DOTA-lanreotide were given as short-term intravenous infusion. Preliminary treatment results in 154 patients indicate stable tumor disease in 41% (63 of 154) of patients and regressive tumor disease in 14% (22 of 154) of tumor patients with different tumor entities expressing hSSTR. No severe acute or chronic hematologic toxicity, change in renal or liver function parameters caused by (90)Y-DOTA-lanreotide treatment were reported for patients in the MAURITIUS trial. In two thirds of patients with neuroendocrine tumor lesions, (90)Y-DOTA-(D)he(1)-Tyr(3)-octreotide showed a higher tumor uptake and should therefore be considered the first choice for experimental receptor-based therapy. Potential indications for (90)Y-DOTA-lanreotide treatment are radioiodine-negative thyroid cancer, hepatocellular cancer, lung cancer, some brain tumors, and possibly melanomas. In conclusion, preclinical data and clinical studies confirm the potential usefulness of radiolabeled lanreotide for tumor diagnosis and therapy. However, careful consideration of the type of radiotracer used for receptor-mediated therapy should be made for the individual patient. Whole-body dosimetry should always be performed to predict doses for tumors and the critical organs, which are kidney and bone marrow.