11-Year Experience with Laparoscopic Adjustable Gastric Banding for Morbid Obesity—What Happened to the First 123 Patients?

Background Few long-term studies regarding the outcome of laparoscopic adjustable gastric banding for morbid obesity have so far been published. We report our 11-year experience with the technique by looking closely at the first 123 patients that have at least 5 years (mean 86 months) of follow-up. Methods Data have been collected prospectively among 280 patients operated since March 1996. Until March 2002 (minimum 5-year follow-up), 123 patients have been operated laparoscopically with the Swedish band. We report major late complications, reoperations, excess weight losses (EWL) and failure rates among these patients, with a mean (range) follow-up time of 86 months (60–132). EWL < 25% or major reoperation was considered as a failure. EWL > 50% was considered a success. Results Mean (range) age of the patients (male/female ratio 31:92) was 43 years (21–44). Mean (range) preoperative weight was 130 kg (92–191). Mean (range) preoperative body mass index was 49.28 kg/m² (35.01–66.60). Patients lost to follow-up was nearly 20% at 5 years and 30% at 8 years. Major late complications (including band erosions 3.3%, slippage 6.5%, leakage 9.8%) leading to major reoperation occurred in 30 patients (24.4%). Nearly 40% of the reoperations was performed during the third year after the operation. The mean EWL at 7 years was 56% in patients with the band in place, but 46% in all patients. The failure rates increased from about 15% during years 1 to 3 to nearly 40% during years 8 and 9. The success rate declined from nearly 60% at 3 years to 35% at 8 and 9 years. Conclusions Complications requiring reoperations are common during the third year after the operation, and almost 25% of the patients will need at least one reoperation. Mean EWL in all patients does not exceed 50% in 7 years or 40% in 9 years and failure rates increase with time, up to 40% at 9 years.     

Selective retrograde venous revascularization of the myocardium when PCI or CABG is impossible: investigation in a porcine model

We investigated the possibility of nourishing the myocardium through selective retrograde coronary venous bypass grafting (CVBG) with an off-pump technique and evaluated various methods of monitoring the physiological effects of this procedure. In a porcine model, the left internal mammary artery (LIMA) was anastomosed to the left anterior descending coronary vein (LAD vein) in an off-pump procedure. The LAD vein was ligated proximal to the anastomosis. The LAD artery was ligated proximally. The physiological effects were monitored using microdialysis, tissue oxygen tension, blood flow in LIMA, blood samples, and hemodynamic and histological analyses. As controls, 5 pigs underwent surgery involving only LAD artery ligation without CVBG. CVBG with LAD ligation was performed in 16 pigs; 12 survived CVBG and were monitored for 2-2.5 hours while in sinus rhythm, a 75% salvage rate after an otherwise lethal LAD artery occlusion. Immediately after LAD artery ligation, the anterior wall of the left ventricle became cyanotic and hypokinetic. Over time it regained color and contractility as flow in the LIMA increased. Microdialysis showed a significant increase in lactate. Initially tissue oxygen tension decreased, but with time some recovery was seen. Cardiac troponin T was elevated. Histological analysis showed ischemic changes. In control pigs, microdialysis was performed for 1.5 hours up to LAD artery ligation, after which all pigs died in ventricular fibrillation arrest. No increase in lactate was observed. These results indicate that after LAD artery occlusion, CVBG can nourish the myocardium to a certain extent and prevent death in the majority of cases, although varying degrees of ischemia remain.     

Environmental cues from CNS, PNS, and ENS cells regulate CNS progenitor differentiation

Cellular origin and environmental cues regulate stem cell fate determination. Neuroepithelial stem cells form the central nervous system (CNS), whereas neural crest stem cells generate the peripheral (PNS) and enteric nervous system (ENS). CNS neural stem/progenitor cell (NSPC) fate determination was investigated in combination with dissociated cultures or conditioned media from CNS, PNS, or ENS. Cells or media from ENS or PNS cultures efficiently promoted NSPC differentiation into neurons, glia, and smooth muscle cells with a similar morphology as the feeder culture. Together with CNS cells or its conditioned medium, NSPC differentiation was partly inhibited and cells remained immature. Here, we demonstrate that secreted factors from the environment can influence CNS progenitor cells to choose a PNS-like cell fate.     

Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis

OBJECTIVE: To investigate the role of the collagen receptor discoidin domain receptor 2 (DDR-2) in the pathogenesis of osteoarthritis (OA). METHODS: Histologic and immunohistochemical analyses were performed to characterize femoral head cartilage from 7 patients with OA and 4 patients with fracture, as well as articular cartilage from the knee joints of mice with surgically induced OA. Gene constructs encoding human Raf kinase inhibitor protein (RKIP), DDR-2 lacking the discoidin (DS) domain (DeltaDS-DDR-2) or the protein tyrosine kinase (PTK) core (DeltaPTK-DDR-2), DDR-2 containing a substitution of tyrosine for alanine at position 740 (Y740A), and luciferase driven by the matrix metalloproteinase 13 (MMP-13) promoter were transfected into human chondrocyte cell lines. Activated and neutralized alpha2beta1 integrin polyclonal antibodies, interleukin-1 receptor antagonist, and the chemical inhibitors SB203580, for p38, and SP600125, for JNKs, were used in cell cultures. Real-time polymerase chain reaction was performed to examine MMP-13 and DDR-2 messenger RNA (mRNA). RESULTS: Increased immunostaining for DDR-2, MMP-13, and MMP-derived type II collagen fragments was detected in cartilage from patients with OA and from mice with surgically induced OA. The discoidin domain and PTK core of DDR-2 were essential for signal transmission and the resulting increased expression of MMP-13 in chondrocytes. Y740A mutation of DDR-2 reduced levels of mRNA for MMP-13 and endogenous DDR-2. The overexpression of RKIP or preincubation with the p38 inhibitor reduced MMP-13 mRNA levels. DDR-2 signaling was independent of the alpha2beta1 integrin and the interleukin-1-induced signaling pathways in chondrocytes. CONCLUSION: These findings suggest that increased expression of DDR-2, resulting in the elevated expression of MMP-13, may be one of the common events in OA progression.     

Basal-like phenotype is not associated with patient survival in estrogen-receptor-negative breast cancers

Introduction

Basal-phenotype or basal-like breast cancers are characterized by basal epithelium cytokeratin (CK5/14/17) expression, negative estrogen receptor (ER) status and distinct gene expression signature. We studied the clinical and biological features of the basal-phenotype tumors determined by immunohistochemistry (IHC) and cDNA microarrays especially within the ER-negative subgroup.

Methods

IHC was used to evaluate the CK5/14 status of 445 stage II breast cancers. The gene expression signature of the CK5/14 immunopositive tumors was investigated within a subset (100) of the breast tumors (including 50 ER-negative tumors) with a cDNA microarray. Survival for basal-phenotype tumors as determined by CK5/14 IHC and gene expression signature was assessed.

Results

From the 375 analyzable tumor specimens, 48 (13%) were immunohistochemically positive for CK5/14. We found adverse distant disease-free survival for the CK5/14-positive tumors during the first years (3 years hazard ratio (HR) 2.23, 95% confidence interval (CI) 1.17 to 4.24, p = 0.01; 5 years HR 1.80, 95% CI 1.02 to 3.15, p = 0.04) but the significance was lost at the end of the follow-up period (10 years HR 1.43, 95% CI 0.84 to 2.43, p = 0.19). Gene expression profiles of immunohistochemically determined CK5/14-positive tumors within the ER-negative tumor group implicated 1,713 differently expressed genes (p < 0.05). Hierarchical clustering analysis with the top 500 of these genes formed one basal-like and a non-basal-like cluster also within the ER-negative tumor entity. A highly concordant classification could be constructed with a published gene set (Sorlie's intrinsic gene set, concordance 90%). Both gene sets identified a basal-like cluster that included most of the CK5/14-positive tumors, but also immunohistochemically CK5/14-negative tumors. Within the ER-negative tumor entity there was no survival difference between the non-basal and basal-like tumors as identified by immunohistochemical or gene-expression-based classification.

Conclusion

Basal cytokeratin-positive tumors have a biologically distinct gene expression signature from other ER-negative tumors. Even if basal cytokeratin expression predicts early relapse among non-selected tumors, the clinical outcome of basal tumors is similar to non-basal ER-negative tumors. Immunohistochemically basal cytokeratin-positive tumors almost always belong to the basal-like gene expression profile, but this cluster also includes few basal cytokeratin-negative tumors.     

Glucagon-like peptide-2 improves both acute and late experimental radiation enteritis in the rat

PURPOSE: Acute and/or chronic radiation enteritis can develop after radiotherapy for pelvic cancers. Experimental and clinical observations have provided evidence of a role played by acute mucosal disruption in the appearance of late effects. The therapeutic potential of acute administration of glucagon-like peptide-2 (GLP-2) against acute and chronic intestinal injury was investigated in this study. METHODS AND MATERIALS: Intestinal segments were surgically exteriorized and exposed to 16.7 or 19 Gy X-rays. The rats were treated once daily with vehicle or a protease-resistant GLP-2 derivative for 14 days before irradiation, with or without 7 days of GLP-2 after treatment. Macroscopic and microscopic observations were made 2 and 15 weeks after radiation exposure. RESULTS: In the control animals, GLP-2 induced an increase in intestinal mucosal mass, along with an increase in villus height and crypt depth. GLP-2 administration before and after irradiation completely prevented the acute radiation-induced mucosal ulcerations observed after exposure to 16.7 Gy. GLP-2 treatment strikingly reduced the late radiation damage observed after 19 Gy irradiation. Microscopic observations revealed an improved organization of the intestinal wall and an efficient wound healing process, especially in the smooth muscle layers. CONCLUSION: GLP-2 has a clear therapeutic potential against both acute and chronic radiation enteritis. This therapeutic effect is mediated through an increased mucosal mass before tissue injury and the stimulation of still unknown mechanisms of tissue response to radiation damage. Although these preliminary results still need to be confirmed, GLP-2 might be a way to limit patient discomfort during radiotherapy and reduce the risk of consequential late effects.     

Radiotherapy adapted to spatial and temporal variability in tumor hypoxia

PURPOSE: To explore the feasibility and clinical potential of adapting radiotherapy to temporal and spatial variations in tumor oxygenation. METHODS AND MATERIALS: Repeated dynamic contrast enhanced magnetic resonance (DCEMR) images were taken of a canine sarcoma during the course of fractionated radiation therapy. The tumor contrast enhancement was assumed to represent the oxygen distribution. The IMRT plans were retrospectively adapted to the DCEMR images by employing tumor dose redistribution. Optimized nonuniform tumor dose distributions were calculated and compared with a uniform dose distribution delivering the same integral dose to the tumor. Clinical outcome was estimated from tumor control probability (TCP) and normal tissue complication probability (NTCP) modeling. RESULTS: The biologically adapted treatment was found to give a substantial increase in TCP compared with conventional radiotherapy, even when only pretreatment images were used as basis for the treatment planning. The TCP was further increased by repeated replanning during the course of treatment, and replanning twice a week was found to give near optimal TCP. Random errors in patient positioning were found to give a small decrease in TCP, whereas systematic errors were found to reduce TCP substantially. NTCP for the adapted treatment was similar to or lower than for the conventional treatment, both for parallel and serial normal tissue structures. CONCLUSION: Biologically adapted radiotherapy is estimated to improve treatment outcome of tumors having spatial and temporal variations in radiosensitivity.