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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.

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). 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. 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. 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.

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: 0.013–0.89mg/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.

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.

New onset atrial fibrillation (AF) is observed in up to 37% of patients after esophagectomy for esophageal and esophago-gastric junction (EGJ) cancer. Little is known about risk factors for AF in this cohort of patients. Current literature describes an association between postoperative AF and other complications, notably anastomotic leaks and infective or pulmonary complications. The aim of this paper is to determine which factors relate to an increased risk of new-onset AF after esophagectomy. Methods We retrospectively analyzed a prospectively collected database in a high-volume, tertiary referral center for esophageal disease. All consecutive patients who underwent hybrid Ivor-Lewis (IL) esophagectomy for esophageal or EGJ cancer at the Upper GI surgery unit in Humanitas Research Hospital from January 2018 to august 2019 were evaluated for inclusion. Patients with a history of paroxysmal or chronic AF were excluded from the analysis. Complications were reported according to the ECCG classification. Association between variables and onset of AF was studied with univariable and multivariable logistic regression analysis. Results 89 IL cases among 125 esophagectomies were included for analysis. Overall complication rate was 29.2%. AF accounted for 9 cases (10.1%) and was the only complication in these patients. Anastomotic leak occurred in 2 patients (2.25%) both ECCG type 1, 3 developed significant pleural effusion (3.37%), 6 other infective conditions (6.7%). No postoperative deaths occurred. Significantly increased risk of AF was found in patients who underwent chemoradiotherapy(CRT) compared to those who received chemotherapy(CT) or no treatment(OR = 8.4, p = 0.02). If we compare only patients who received neoadjuvant treatment, a higher risk for CRT versus CT alone was found(OR = 5.5), with a trending significance(p = 0.08). Conclusion In this study, we did not find any association between AF and other complications. New-onset AF always presented as the only complication and it was significantly associated to neoadjuvant chemoradiotherapy. On the basis of this findings, we are designing a protocol with the aim of studying potential preventive intervention for postoperative FA after esophagectomy.

Minimally Invasive esophagectomy has been introduced to reduce the trauma associated with open surgery while keeping the same oncological outcome. Robotic platforms could facilitate this. Even with the increasing availability of surgical robots and the standardization of the technique, it can be difficult to convince high volume centers to change their surgical approach. Our aim is to assess the impact of the learning curve for robotic surgery in a high-volume laparoscopic center. Methods We retrospectively analyzed a prospectively collected database in a tertiary referral center for esophagogastric surgery. We identified two groups composed by the patients who underwent Ivor-Lewis (IL) esophagectomy by a hybrid laparoscopic (HL) approach (standard laparoscopy + open thoracotomy) and those who underwent a hybrid robotic (HR) approach (robotic abdominal part + open thoracotomy) with the Davinci Xi surgical platform for lower esophageal or EGJ cancer from November 2018 to September 2019. Data regarding post-operative stay, complications, leaks, total number of lymph nodes and length of surgery were analyzed. Complications were reported according to the ECCG classification. Results We selected 50 consecutive IL cases among which there were our first 17 HR cases. There were no differences in terms of demographics, comorbidities and neoadjuvant treatments between the two groups. No statistical difference was observed in post-operative stay(median 12 vs 10 days in HL and HR respectively, p = 0.09), overall complication rate was 33% in HL and 35% in HR(p = 0.9), patients with leaks 1(3.03%) in HL and 1(5.88%) in HR(p = 0.6), total lymph nodes median of 38 in HL vs 30 in HR(p = 0.4). Only the total length of surgery was statistically longer in the HR group (median 446 vs 478 min, p = 0.01). Conclusion We showed that in the setting of a high-volume center with no previous robotic surgery expertise, robotically performing only the abdominal phase could represent an effective alternative to familiarize with the robotic system without compromising the clinical outcome and workflow. We understand that the main advantages would be seen when using the robot during the thoracic part. After these first cases we will proceed to adopt it during the most demanding part of the operation.

International audience; 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.

Aim We evaluated short-term outcomes of esophagectomy for esophageal and esophagogastric carcinoma without routine postoperative admission to Intensive Care Unit (ICU). Background & Methods esophagectomy is subject to high rates of complications and mortality even when performed in high-volume centers and conventional postoperative management often involves routine ICU admission according to recent guidelines and recommendations1 . From January 2018 to June 2019 a total of 112 esophagectomies were performed in the Upper GI Surgery division of Humanitas Research Hospital. We included the 83 patients that underwent transthoracic esophagectomy with a hybrid technique (laparoscopy + right thoracotomy) and high intrathoracic anastomosis for esophageal and esophagogastric junction cancer. Preoperative assessment included a prehabilitation program (nutritional evaluation, respiratory physiotherapy and adjustment of cardiologic therapy). Postoperatively, patients were managed by surgical team members. We retrospectively recorded data on necessity of ICU, operative times, complication rate (according to ECCG)2,3, length of hospital stay, in-hospital, 30-day and 90-day mortality. Results 68 patients were males and 15 females. Mean age was 65 years old (range 29-82). 67 patients underwent neoadjuvant therapy (49 chemo-radiotherapy, 18 chemotherapy alone). Postoperative ICU admission was necessary in 6 patients (9,5%), reasons for admission were necessity of ventilatory weaning in 2 patients, high lactate levels in one patient, glottic oedema following oro-tracheal intubation in one patient, while in the other cases ICU admission was planned for severe comorbidities. Mean duration of prehabilitation was 20.3 days (1-107). Mean surgery duration was 452.4 minutes (337-549). Overall complication rate was 33.8%, with the most common complications being atrial fibrillation (50% of all complications) and urinary retention (20%). There were two type I anastomotic leaks. Median length of hospital stay was 11 days (range 8-29). All patients were alive at 30 and 90 days after surgery. Conclusion routine ICU admission is not necessary after transthoracic esophagectomy for cancer in over 90% of patients. Careful patients’ evaluation, stratification of the surgical risk and systematic use of a prehabilitation program, along with adequate peri-operative management, can narrow the need for postoperative ICU admission in the setting of a high-volume centre without any impact on short-term outcomes.

SUMMARY 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.

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. 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. 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 (

Description Giant esophageal leiomyomas (GEL) are challenging benign conditions to treat in a total minimally invasive way. Here we show the management of a complete thoracoscopic enucleation (TE) of three giant esophageal masses in three different patients. Not only the size of these masses but mostly the position of them made the indication for TE borderline. Methods Every patient underwent a full diagnostic pre-op workup with CT scan, PET and EUS guided biopsies to rule out any malignancy. In this video, we show a full thoracoscopic approach with the patient on the left flank in a semi-prone/prone position and under general anesthesia without lung exclusion. We use a 3 trocars approach and low pressure(8mmHg) CO2 insufflation during the whole procedure. The dissection of the mass is carefully performed to keep the whole mucosal layer undamaged and minimizing the incision in the muscular layer. Careful reconstruction of the muscular layer is a mandatory step at the end of the procedure. Azygos vein resection is performed depending on the mass location. We extract the mass in a bag by enlarging the incision of the inferior scapular trocar. The integrity of the mucosal layer was constantly checked during the procedure either by direct endoscopic vision or by insufflation of air through a nasogastric tube. Results All the patients had an uneventful post-operative course, upper-GI series showed no leak, no stricture nor dilatation of the esophagus. On POD 4 a soft diet was administered. Conclusions Esophageal leiomyomas are a rare condition; the ones larger than 10cm are defined as GEL and they represent the 17% of the total. While, in advanced centers, Total TE for small leiomyomas is a standard of care, GELs are usually managed by open surgery, and in many cases, esophagectomy has to be performed. In our series of five consecutive GELs, located in the upper esophagus, TE proved to be safe and effective in all the patients. Disclosure All authors have declared no conflicts of interest.

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.

Background Gastric conduit used for reconstruction after esophagectomy for esophageal cancer (EC) has the potential to develop a metachronous cancer known as gastric tube cancer (GTC). The aim of our study was to review literature and evaluate outcomes and possible treatment strategies for GTC. Methods A comprehensive systematic literature search was conducted using PubMed. No restriction was set for type of publication, number, age and sex of patients. Study language was limited to English. Characteristics of EC and its treatment and GTC and its treatment were analyzed. Results A total of 26 studies were analyzed, 10 retrospective analysis and 16 case reports, involving 170 patients, 17 patients (10%) were affected by multifocal GTC. 143 ECs (84,1%) were squamous cell carcinomas. In 95 patients (55,9%) a posterior-mediastinal reconstructive route was used at the time of esophagectomy for EC. Mean interval between esophagectomy and diagnosis of GTC was 67,18 months (4–236 months). 184 GTCs were metachronous lesions (98,4%). 164 GTCs were adenocarcinomas (98,2%). 84 GTCs were located in the lower part of the gastric tube. 88 patients were endoscopically treated. 63 patients underwent surgery. 30 total gastrectomies + limphoadenectomy with colon or jejunal interposition were performed. 27 subtotal gastrectomies and 6 wedge resections were performed. Main reported post-operative complications were: anastomotic leak, vocal cord palsy and respiratory failure. 19 patients were treated with chemoradiotherapy and palliative care. 68,2% of endoscopically treated patients, 63,5% of surgically resected patients and 5,2% of patients who underwent chemoradiotherapy were alive at a mean follow-up of 25,5 months. Feasibility of endoscopic resections in patients diagnosed with superficial GTC has been established. Surgical treatment represents the preferred treatment modality in operable patients with locally invasive tumor. Patients treated with conservative therapy have a scarce prognosis. Conclusion Yearly endoscopic follow-up is of paramount importance in patients who underwent esophagectomy for EC with gastric tube reconstruction. At least, a 10-year endoscopic surveillance is recommended. Disclosure All authors have declared no conflicts of interest.

Collis gastroplasty was originally designed to deal with the increasing incidence of short esophagus (SE) associated with the new epidemic of gastroesophageal reflux disease (GERD) and hiatal hernias. In following years, a fundoplication was added to the procedure in an attempt to correct the underlying cause of the disease. Nowadays Collis gastroplasty with fundoplication is the standard treatment for patients in whom, even after an extensive surgical dissection of the distal esophagus, the gastroesophageal junction (GEJ) cannot be brought at least 2.5 cm below the diaphragmatic hiatus without tension. The real incidence of SE is controversial in the era of laparoscopic fundoplication, with some groups proposing that all short esophagi can be solved with adequate mediastinal dissection of the esophagus prior to fundoplication, and others advocating frequent use of the Collis. Still others have tried to identify predictive factors linked to the presence of a true SE. However, studies suggest that a significant percentage of failures of primary antireflux surgery might be due to axial tension on the repair from intrinsic shortening of the esophagus that was not properly addressed. With the advent of the laparoscopic era new tools and new approaches were described to asses and to treat this condition. We describe both thoracoscopic/laparoscopic and totally laparoscopic techniques for minimally invasive Collis gastroplasty. While symptomatic results are good, the procedure is non-physiologic and many patients have esophagitis from ectopic gastric mucosa. While the true incidence of SE is unknown, what is undeniable is that chronic reflux disease can lead to foreshortening of the esophagus and, although in the proton pump inhibitor (PPI) era the presence of a SE is a relatively rare finding, the foregut surgeon must be prepared to identify and treat this condition.

BACKGROUND Infusion of radiolabeled monoclonal antibodies (MAbs) directly into a tumor or into the site of disease after surgery concentrates a high quantity of antibody and radioisotope in the neoplastic tissue. The strong irradiation delivered by this method can result in control of high grade malignant gliomas. METHODS Antitenascin MAbs BC-2 and BC-4 labeled with 131I (mean dose, 1998 MBq) were injected into 105 patients with malignant glioma by means of an indwelling catheter. Multiple courses (up to six) were given. The patients underwent MAb treatment after their tumors were minimized by surgery, radiotherapy, and, in recurrent lesions, a second operation. Data is presented in this article for 62 evaluable patients with high grade malignant gliomas (58 glioblastomas and 4 anaplastic astrocytomas), of which 31 were newly diagnosed tumors and 31 were recurrent lesions. In 40 cases the disease was minimal at the time of MAb injection, and in 22 cases a macroscopic remnant was present. RESULTS There were very few adverse effects, all of which were minor. The treatment yielded a significant extension of patients' median survival (23 months) and of the disease free time to relapse (12 months). Favorable objective responses were recorded as follows: 9 partial responses, 3 complete responses, and 20 with no evidence of disease. A response rate of 51.6% was calculated for all assessable patients. The most important factor in obtaining beneficial outcomes was limited extension of the neoplasm at the time of therapy. CONCLUSIONS In selected patients, locoregional radioimmunotherapy can be included in a multimodal strategy to control high grade malignant gliomas and produce favorable results. Cancer 1997; 80:2733-42. © 1997 American Cancer Society.

Background. Using a wide range of interferon (IFN) doses and schedules, a number of authors have found them to be active against neuroendocrine tumors. Methods. To verify the clinical activity of IFN, 49 evaluable patients with advanced stage low- and intermediate-grade neuroendocrine tumors were treated with recombinant IFN-alpha-2a at a daily dose of 6 × 106 IU intramuscularly for 8 weeks, and 3 times weekly thereafter. The predominant histotype was carcinoid, although a few cases had malignant islet cell tumors, medullary thyroid carcinoma, Merkel cell carcinoma, or other neuroendocrine tumors. All of the patients had measurable lesions and most had multiple sites. Carcinoid syndrome was present in 14 cases. Results. After a median treatment duration of 6 months, complete regression was achieved in 1 of the 7 cases of medullary thyroid carcinoma, and partial response was observed in 4 of 34 carcinoids. Response duration ranged from 1–11 months. Control of the syndrome was obtained in nine patients and a greater than or equal to 50% reduction of 5-hydroxyindoleacetic acid in eight patients. The treatment was well-tolerated. The most frequently observed side effects were fever, flu-like syndrome, and leukopenia. After 12 months of recombinant IFN-alpha-2a, 15 cases in progression and 4 with stable disease or partial response received another treatment (either radiometabolic therapy with I131 metaiodobenzylguanidine or polychemotherapy with streptozotocin plus epirubicin). Conclusions. The use of recombinant IFN-alpha-2a at these doses is well-tolerated and effective in controlling carcinoid syndrome (complete remission plus partial remission, 64%), although it has limited activity on tumor growth inhibition. No definitive data can be given for the other protocol treatments.

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. Cancer 2003. © 2003 American Cancer Society.

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)].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.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.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.

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 dose10 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.

Locoregional radioimmunotherapy (LR-RIT) was administered to 111 patients (20 were recruited in a phase I and 91 in a phase II study) with malignant gliomas: 1 patient with oligodendroglioma, 7 patients with anaplastic oligodendroglioma, 2 with grade II astrocytoma, 10 with anaplastic astrocytoma and 91 with glioblastoma, amounting to 58 newly diagnosed and 53 recurrent tumours. The 131I-labelled monoclonal antibodies BC-2 and BC-4 were used in order to recognize stromal and intracellular glycoprotein tenascin, an antigen present particularly in glioblastoma. The patients were enrolled between February 1990 and December 1997 after conventional therapy. The radiopharmaceutical was injected directly into the tumour site. Sequential scintigraphies demonstrated a high and enduring uptake in the tumour. The mean irradiation dose in the tumour was 300 Gy per cycle. In the group of 74 phase II glioblastoma patients the clinical responses were as follows: 10 patients with stable disease (SD), 9 with partial responses (PR), 23 with no evidence of disease (NED) and 1 patient with complete response (CR). The median survival was 19 months. The response rate (CR + PR + NED) was 17.8% for those patients with bulky lesions, with a median survival of 17 months, but 66.6% for patients with small lesions, with a median survival of 25 months. Better outcomes were recorded in cases with less aggressive diseases: oligodendroglioma, anaplastic oligodendroglioma and anaplastic astrocytoma. We conclude that fractionated LR-RIT can be safely performed, with promising results especially in patients with minimal disease.

BC-2 and BC-4 Mabs labelled with 1-131, were given directly in the tumoral bed. 81 glioblastoma evaluable cases were treated. Adverse effects were very few. The treatment lengthened the patients’ median survival (22 months in total). 11 PR, 1 CR and 24 NED (No Evidence of Disease) were recorded. The response rate was 44.4 %. Then a new isotope, Y-90, has been employed. Following a phase I trial, a phase II study was initiated in 22 cases with malignant glioma (anaplastic astrocytoma n.6 and glioblastoma n.16). In 16evaluable patients (12 glioblastoma and 4 anaplastic astrocytoma) the objective response consisted in 1 PD, 4 SD,7 PR,2 CR and 2 NED.The global response rate (PR+ CR+NED) was 68.75% (66.6% in glioblastoma and 75% in anaplastic astrocytoma group).

Intralesional radioimmunotherapy (RAIT) may improve the management of malignant gliomas whose prognosis is, at present, very poor. Current treatment modalities (e.g., surgery, radiotherapy, and chemotherapy) may prolong survival by a few months but cannot prevent tumor recurrence.Following one or more surgical operations, radiotherapy, and chemotherapy, 24 patients with recurrent malignant gliomas (23 brain and 1 spinal cord) underwent RAIT with 2 murine monoclonal antibodies (MoAb), BC-2 and BC-4, raised against tenascin (TN). This antigen is expressed in large amounts in the stroma of glial tumors but not normal brain tissue. The isotope used was iodine-131 (131I). The radiolabelled antibodies were injected directly into the tumor by means of a removable catheter or an indwelling catheter placed in the site of disease at the time of craniotomy. The patients were admitted to the protocol if histochemical analysis of their tumors demonstrated the presence of TN in high abundance. Biodistribution and dosimetry of an intralesional tracer dose (1 mg MoAb and 37 MBq 131I) were studied. RAIT was performed by the administration of escalating doses of radioiodine, ranging from 15 mCi to 57 mCi. In many cases, RAIT was was repeated two, three, or four times (on 8, 3 and 4 patients, respectively).Pharmacokinetic data resulted, on average, as follows: the 24-hour tumor/background ratio was 16.6; the percentage of injected dose concentrated per gram of tumor at 24 hours was 2.4%; and the effective half-life of the MoAb at the tumor was 74.5 hours. The mean radiation dose to the tumor was 36.48 cGy per MBq of 131I injected. Both systemic and brain toxicities were absent, while human anti-mouse antibody production after MoAb administration occurred in only a few cases. At present, 17 patients are assessable, with a median survival time of 16 months. Objective responses consisted of 5 tumor stabilizations (median time, 9 months), 3 partial remissions (11 months), and 3 complete remissions (15 months).

Alternative routes of administration of radiolabelled antitumor monoclonal antibodies were investigated in order to try to overcome some of the limitations of the immunoscintigraphic method observed by using the intravenous route of administration. Such limitations are: a) the high vascular background due to circulating radiolabelled antibodies and possibly to circulating immunocomplexes; b) the high accumulation of radioactivity in liver, spleen and bone marrow, due to nonspecific uptake of antibodies and immunocomplexes, and possibly of degradation products which develop in vivo after the injection; and c) the catabolic degradation of monoclonal antibodies with consequent release of free isotopes that are picked up by their respective critical organs — thyroid, salivary glands, stomach, liver, bone marrow, etc. All these phenomena give rise to a lowering of the signal coming from the target tumor which cannot be easily differentiated from the surrounding tissues. We are then forced in some instances to use dual tracer subtraction techniques, which are particularly useful when I-131 is employed as a label.