IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction.

BACKGROUND & AIMS: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could affect the efficacy of immunotherapy in vivo. METHODS: To induce spontaneous or forced liver metastasis in mice, murine cancer cells (MC38) or colon tumor organoids were injected into the cecum or the spleen, respectively. Mice with complete and cell type-specific deletion of IL-10 and IL-10 receptor alpha were used to identify the source and the target of IL-10 during metastasis formation. Programmed death ligand 1 (PD-L1)-deficient mice were used to test the role of this checkpoint. Flow cytometry was applied to characterize the regulation of PD-L1 by IL-10. RESULTS: We found that Il10-deficient mice and mice treated with IL-10 receptor alpha antibodies were protected against liver metastasis formation. Furthermore, by using IL-10 reporter mice, we demonstrated that Foxp3+ regulatory T cells (Tregs) were the major cellular source of IL-10 in liver metastatic sites. Accordingly, deletion of IL-10 in Tregs, but not in myeloid cells, led to reduced liver metastasis. Mechanistically, IL-10 acted on Tregs in an autocrine manner, thereby further amplifying IL-10 production. Furthermore, IL-10 acted on myeloid cells, i.e. monocytes, and induced the upregulation of the immune checkpoint protein PD-L1. Finally, the PD-L1/PD-1 axis attenuated CD8-dependent cytotoxicity against metastatic lesions. CONCLUSIONS: Treg-derived IL-10 upregulates PD-L1 expression in monocytes, which in turn reduces CD8+ T-cell infiltration and related antitumor immunity in the context of colorectal cancer-derived liver metastases. These findings provide the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastases. IMPACT AND IMPLICATIONS: Liver metastasis diminishes the effectiveness of immunotherapy and increases the mortality rate in patients with colorectal cancer. We investigated the role of IL-10 in liver metastasis formation and assessed its impact on the effectiveness of immunotherapy. Our data show that IL-10 is a pro-metastatic factor involved in liver metastasis formation and that it acts as a regulator of PD-L1. This provides the basis for future monitoring and targeting of IL-10 in colorectal cancer-derived liver metastasis.

Protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies.

The transplantation model provides the opportunity to assess the relevance of a molecule of interest for tumor cell extravasation by using a respective genetically modified donor animal. Here, we present a protocol for orthotopic single-lung transplantation in mice as a tool for lung metastasis studies. We describe steps for animal preparation, lung transplantation, and tumor cell injection. We then detail procedures for the direct comparison of tumor cell spreading between the genetically modified left lung and the naive right lung parenchyma. For complete details on the use and execution of this protocol, please refer to Giannou et al. (2023).1.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

Minimally invasive intrathoracic negative-pressure therapy and flexible thoracoscopy (FlexVATS) for patients with pleural empyema.

To determine whether a new surgical method using a flexible endoscope (FlexVATS) to perform sparing debridement and apply negative-pressure therapy without extensive decortication may be an alternative treatment option for empyema. Surgical treatment of pleural empyema is associated with considerable postoperative complications and mortality rates, and alternative treatment options are being explored to improve patient outcomes. This was a prospective case series. Seventeen consecutive patients treated with FlexVATS between February 2021 and August 2022 were included in the study. Only patients for whom FlexVATS was the first therapeutic intervention for pleural empyema were included. Treatment success, defined as infection resolution, was the primary endpoint of the study. The secondary endpoints were length of hospital stay, 90-day mortality, and empyema cavity volume reduction. Patients who had previously been treated for pleural empyema by either drainage or surgery were excluded. The trial was performed as a single-centre study at a tertiary medical centre in Germany. In total, 17 patients with pleural empyema were included in the study. The median (IQR) duration of vacuum treatment was 15 days (8-35 days). Twelve of the 17 (71%) patients were successfully treated, and a significant reduction in the empyema cavity volume was observed. 41% of the dressing changes were performed outside the operating room. Compared with a historic cohort of conventionally treated patients (decortication via VATS or thoracotomy), the 90-day mortality rates tended to be lower without reaching statistical significance. Three patients (18%) died in hospital during treatment. No negative pressure-therapy-related complications were observed. FlexVATS therapy is a promising alternative therapy for both healthy and debilitated patients with pleural empyema. Larger randomised trials are required to validate this treatment option.

Thyroid-stimulating hormone levels in euthyroid patients 8 years following bariatric surgery.

BACKGROUND: Bariatric surgery (BS) was shown to promote a decline in thyroid-stimulating hormone (TSH) in euthyroid patients with severe obesity in the short-term. Aim of the present study was to assess the effect of weight loss on thyroid function in euthyroid patients in the long-term following different bariatric procedures. METHODS: In a retrospective cohort study including 135 patients at baseline, thyroid function was assessed at six time points up to 8 years after surgery. Patients were stratified by TSH levels at baseline and divided into two groups to compare the change in TSH at long-time. We used log-linear regression to assess the relation between thyroid hormones and TSH and linear regression analyses to identify variables that were thought to determine TSH and fT3/fT4-ratio as well as their change long-term. RESULTS: Over a mean follow-up of 8 years, TSH and fT3/fT4-ratio declined (both p < 0.001). Patients with high-normal TSH showed a greater decline in TSH than those with normal TSH compared to baseline. Thyroid hormones and TSH displayed a negative log-linear correlation at long-term follow-up. Change in TSH at long-time showed a negative correlation with TSH at baseline (B = -0.55; p < 0.001). With regard to type of surgery, there were no significant differences in TSH. CONCLUSION: BS promotes a decline of TSH in euthyroid patients up to 8 years after intervention despite weight regain. The greatest change in TSH was seen among patients with high-normal baseline-TSH. Results of log-linear regression suggest recovery of the pituitary-thyroid axis. Type of surgery did not affect the change in TSH levels over time.

[Sepsis after cat bite-How medical history, physical examination and interdisciplinary cooperation influence disease progression]. / Sepsis nach Katzenbiss ­ Wie Anamnese, körperliche Untersuchung und eine interdisziplinäre Zusammenarbeit den Krankheitsverlauf beeinflussen.

A 67-year-old woman with symptoms of shock was admitted to hospital with a suspected diagnosis of acute pulmonary artery embolism. After ruling out a thromboembolic event, sepsis was diagnosed by using the SOFA score. A CT scan of the chest with contrast revealed phlegmonous inflammation of the subcutis at the level of the right upper arm. After taking two pairs of peripheral blood samples, calculated antibiotic therapy with piperacillin/tazobactam was administered. After administration of an initial volume bolus, the patient could be transferred to the general medical ward in a stable condition with normal serum lactate level. On day one after hospital admission, blood cultures were positive for Pasteurella multocida, a gramnegative rod that belongs to the oral flora of dogs and cats. Intensified history revealed that the patient had been bitten on the forearm by her cat 2 weeks earlier. The patient did not present to a general practitioner. Despite antibiotic therapy, the patient developed increasing leukocytosis with progressive pain and swelling in the area of the right upper arm and the right ankle. On recommendation of the department of infectious diseases antibiotic therapy was escalated to imipenem and transesophageal echocardiography was performed. Endocarditic vegetations could be ruled out. Despite further escalation of the antibiotic regimen, spontaneous pus discharge occurred at the right ankle. A CT scan of the chest as well as the foot and the right ankle with contrast showed new abscess formations in the right thoracic wall between the pectoralis major and minor muscles as well as extensive abscesses in the extensor compartment of the right lower leg. On day 12 after admission, surgical drainage of multiple abscesses was performed, with rapid improvement in general condition and normalized leukocytes. A further six operations were necessary before the patient could be discharged home after 7 weeks of inpatient treatment.

Long-Term Improvement of Chronic Low-Grade Inflammation After Bariatric Surgery.

PURPOSE: Bariatric surgery (BS) was shown to improve inflammatory markers in previous short-term follow-up studies. The aim of the present study was to assess the long-term effects of BS on chronic low-grade inflammation markers related to severe obesity. Moreover, the meaning of the type of BS procedure as well as the remission of type 2 diabetes (T2D) for inflammatory status up to 4 years after BS was analyzed. MATERIALS AND METHODS: In a retrospective cohort study including 163 patients at baseline, inflammatory and metabolic parameters were assessed at 4 time points: before surgery (baseline), 6 months after surgery (visit 1), 2 years after surgery (visit 2), and 4 years after surgery (visit 3). Univariate regression analysis was used to identify variables that were thought to determine change in inflammatory parameters. RESULTS: CRP, hs-CRP, leucocytes, and ferritin significantly declined in the mid- and long-term according to the U-shaped curve of weight loss (p<0.001). Change in body mass index (BMI) at long-time follow-up showed a significant linear effect on change in leucocytes (B=0.082; p<0.001) and change in hs-CRP (B=0.03; p<0.05). There was a strong, positive correlation between T2D and hs-CRP at visit 2 (rs=0.195; p<0.05) and visit 3 (rs=0.36; p=0.001). With regard to type of surgery and gender, there were no significant differences in inflammatory parameters. CONCLUSION: BS is able to reduce obesity-related chronic low-grade inflammation up to 4 years after surgical intervention. The improvement in metaflammation is related to the change in BMI and remission of T2D in the long-term.

Bariatric Surgery Is Protective Against Renal Function Decline in Severely Obese Patients in the Long-Term.

PURPOSE: This study aims to assess the long-term renal effects of bariatric surgery (BS) in severely obese patients over a follow-up period of up to 11 years. MATERIALS AND METHODS: In a retrospective cohort study including 102 patients, patients were stratified by eGFR at baseline and divided into three groups: (1) reduced, (2) normal, and (3) increased filtration rate. Adjustments for age- and sex-related decline in eGFR were performed. We used uni- and multivariate regression analysis to identify variables that were thought to determine change in eGFR. RESULTS: Over a median follow-up of 8.5 years (interquartile range 2.7), eGFR declined from 96.1 ± 20.7 to 84.9 ± 21.0 ml/min (p < 0.001). Among patients with (1), eGFR remained stable (69.1 ± 19.3 ml/min). Among patients with (2), eGFR declined from 99.7 ± 13.3 ml/min to 88.7 ± 19.4 ml/min (p < 0.001). Among patients with (3), eGFR decreased to normal levels (94.2 ± 17.7 ml/min, p < 0.001). Age- and sex-adjusted eGFR increased (6.4 ± 14.4 ml/min; p < 0.05) among patients with reduced filtration rate. Among patients with normal filtration rate, adjusted eGFR remained stable during follow-up (-1.3 ± 15.2 ml/min; n.s.). Among patients with increased filtration rate, adjusted eGFR decreased and remained within the normal range (-13.2 ± 12.2 ml/min; p < 0.001). Change in eGFR showed a negative correlation with eGFR at baseline (B = -0.31; p < 0.001), change in LDL-cholesterol (B = -0.09; p < 0.05), and a negative correlation with treatment requiring hypertension (B = -9.36; p = 0.001). CONCLUSION: BS is protective against renal function decline in severely obese patients in the long term.

Mentorship Programs in Bariatric Surgery Reduce Perioperative Complication Rate at Equal Short-Term Outcome-Results from the OPTIMIZE Trial.

OBJECTIVES: The aim of this study was to determine the efficacy of coaching on outcome in low volume centers of excellence and to evaluate the influence of mentorship programs on the center development. BACKGROUND: The number of bariatric procedures has increased steadily in the last years. Providing nationwide bariatric care on a high professional level needs structures to train and guide upcoming centers and ensure high quality in patient care. METHODS: A prospective multicentered, observational study including laparoscopic sleeve gastrectomies (SG) and Roux-en-Y gastric bypass (RYGB) procedures was performed. Twelve emerging bariatric centers were coached by five experienced bariatric centers. Surgeons of the mentor centers gave guidance on pre- and postsurgical management of their patients including complications and proctored the first interventions. The results were compared regarding operative outcomes, percentage of excess weight loss, complications, and resolution of comorbidities. RESULTS: A total of 214 of 293 patients (73.0%) completed the study. The most frequently reported complications were wound infection (4.4%), disorder of emptying stomach/new reflux (2.4%), anastomotic leaks, intra-abdominal secondary hemorrhage, and dumping syndrome (2.0% each). The mortality rate was zero. We found no difference in overall complication rates or resolution of obesity-related comorbidities when comparing experienced surgeons with less experienced surgeons. CONCLUSIONS: Our results suggest that under the conditions of the practices of this study, coaching and mentoring were associated with comparable outcomes both in experienced and emerging centers. In addition, mentorship programs ensure equal outcome quality in terms of improvement of obesity-associated comorbidities. TRIAL REGISTRATION: NCT Number: NCT01754194 .

Perioperative Short-Term Outcome in Super-Super-Obese Patients Undergoing Bariatric Surgery.

BACKGROUND: Prevalence of obesity is increasing with a pandemic magnitude worldwide. Incidence of super-super-obesity (> 60 kg/m2) is expanding by the same means. While bariatric surgery is the only approach with proven long-term results, surgical outcome in super-super-obesity is still discussed controversially. OBJECTIVE: This retrospective study examined bariatric surgery patients' short-term outcome in relation to their degree of obesity. SETTING: Data collection was performed in a German university medical center between March 2010 and November 2013. METHODS: This study analyzes a cohort of 715 patients in a single institution. Patients were subdivided into three groups, obese (≤ 49.9 kg/m2), super-obese (≥ 50 kg/m2), and super-super-obese (≥ 60 kg/m2), and evaluated regarding perioperative outcome. RESULTS: Three hundred eighty-one patients were included into obese (O); 225 patients, into super-obese (SO); and 109 patients, into super-super-obese (SSO) cohort. There were no significant differences regarding patient characteristics including quantity of comorbidities and perioperative outcome. BMI was significantly lower in patients with complications, compared to patients without complications (p < 0.05), whereas patients' age was significantly higher (p < 0.05) in complication cohort. One SSO patient died of a septic multiorgan failure. Thus, the 30-day overall mortality was 0.14%. The BMI showed an inverse correlation to the patients' age at surgery (p < 0.05). CONCLUSION: Super-super-obesity should not be considered as a limiting factor for bariatric surgery outcome; however, the patients' age, surgeries prior to the bariatric procedure, and comorbidities must be considered prior to bariatric surgical treatment.

Upper Gastrointestinal Endoscopy prior to Bariatric Surgery-Mandatory or Expendable? An Analysis of 801 Cases.

BACKGROUND: Upper gastrointestinal pathologies are common in bariatric patients. Preoperative esophagogastroduodenal endoscopy (EGD) should detect and treat pathologies that might alter the type of bariatric surgery. However, clinical consequences of these findings are often insignificant. The aim of this study was to assess the influence of preoperative endoscopy in our cohort and its clinical consequences. METHODS: We conducted a retrospective analysis of endoscopic findings in patients under evaluation for bariatric surgery. Endoscopic findings were compared to preoperative risk factors as well as postoperative complications, and its clinical consequences were analyzed. RESULTS: Data was available for 801 patients. Abnormal endoscopic findings were found in 65.7% of all patients. The most common conditions were gastritis (32.1%) and gastroesophageal reflux (24.8%). Malignancies were observed in 0.5% of all patients. We observed early-stage adenocarcinoma of the esophagus in two patients through our routine preoperative evaluation. Helicobacter pylori infections were detected in preoperative biopsies in only 3.7% of all patients. Patients who reported reflux symptoms had a higher rate of pathological EGDs (74.2 vs. 64.9%, p .019). We did not find any other risk factors for a pathological endoscopy. The postoperative complication rate was 11.2%. Leakage rate was 1.1%. Mortality rate was 0.4%. We did not find any correlation between the incidence of postoperative complications and preoperative endoscopic findings. CONCLUSIONS: Relevant findings in routine preoperative endoscopy are rare but have significant influence on decision-making in bariatric patients and should be assessed as a necessary diagnostic tool.

A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease.

Intestinal inflammation can impair mucosal healing, thereby establishing a vicious cycle leading to chronic inflammatory bowel disease (IBD). However, the signaling networks driving chronic inflammation remain unclear. Here we report that CD4+ T cells isolated from patients with IBD produce high levels of interleukin-22 binding protein (IL-22BP), the endogenous inhibitor of the tissue-protective cytokine IL-22. Using mouse models, we demonstrate that IBD development requires T cell-derived IL-22BP. Lastly, intestinal CD4+ T cells isolated from IBD patients responsive to treatment with antibodies against tumor necrosis factor-α (anti-TNF-α), the most effective known IBD therapy, exhibited reduced amounts of IL-22BP expression but still expressed IL-22. Our findings suggest that anti-TNF-α therapy may act at least in part by suppressing IL-22BP and point toward a more specific potential therapy for IBD.

Autoimmune Renal Disease Is Exacerbated by S1P-Receptor-1-Dependent Intestinal Th17 Cell Migration to the Kidney.

Th17 cells are most abundant in the gut, where their presence depends on the intestinal microbiota. Here, we examined whether intestinal Th17 cells contribute to extra-intestinal Th17 responses in autoimmune kidney disease. We found high frequencies of Th17 cells in the kidneys of patients with antineutrophil cytoplasmatic antibody (ANCA)-associated glomerulonephritis. We utilized photoconversion of intestinal cells in Kaede mice to track intestinal T cell mobilization upon glomerulonephritis induction, and we found that Th17 cells egress from the gut in a S1P-receptor-1-dependent fashion and subsequently migrate to the kidney via the CCL20/CCR6 axis. Depletion of intestinal Th17 cells in germ-free and antibiotic-treated mice ameliorated renal disease, whereas expansion of these cells upon Citrobacter rodentium infection exacerbated pathology. Thus, in some autoimmune settings, intestinal Th17 cells migrate into target organs, where they contribute to pathology. Targeting the intestinal Th17 cell "reservoir" may present a therapeutic strategy for these autoimmune disorders.

Attachment, Viability and Adipodifferentiation of Pre-adipose Cells on Silk Scaffolds with and Without Co-expressed FGF-2 and VEGF.

BACKGROUND/AIM: For application of stem cells and progenitor cells in regenerative medicine, scaffolds for carrying the cells play a key role. One promising biomaterial for scaffold generation is silk because of its mechanical strength, good cytocompatibility and low immunogenicity. Furthermore, bioengineering of silk proteins enable co-expression of various growth, differentiation and angiogenic factors on silk fibers, which may promote cell growth, differentiation and angiogenesis. This study aimed to test cytocompatibility and growth/differentiation of pre-adipose cells on scaffolds with and without expressed growth factors fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Disk-form scaffolds of 15×3 mm (diameter × thickness) were manufactured in two different densities using silk with and without expressed growth factors FGF-2 or VEGF. Pre-adipose cells were prepared from fatty tissues of patients undergoing operation. Cells (1.6×10(6)) were seeded onto each of the silk-scaffold disks, that were placed into wells of 12-well culturing plates. Adipose-differentiation was induced using differentiation medium containing DMEM/F-12, insulin, pantothenate, biotin, triiodothyronine (T3), transferrin, dexamethasone, isobuthylmethylxanthine and rosiglitazone. Cells on the scaffolds were visualized using a confocal microscope. Viability and adiponectin were measured on days 0, 7 and 14. Expression of adipose-differentiation markers was assessed by means of real-time polymerase chain reaction (RT-PCR). RESULTS: Pre-adipose cells attached well onto the silk fibers. The highest initial viability was measured on the low-density scaffolds with expressed VEGF. Adipose-differentiation was evident in visible oil droplets and significantly increased adiponectin protein levels were seen in ELISA. Furthermore, increased expression of adipose-differentiation genes were measured in RT-PCR. Adipose-differentiation was more profound in cells on high-density scaffolds. In concordance, viability of cells on high-density scaffolds did not increase, while that of cells on low-density scaffolds doubled over the 14-day experimental period. Slightly enhanced adipose-differentiation was observed in cells on scaffolds with expressed FGF-2 or VEGF. CONCLUSION: Silk scaffolds exhibit excellent cytocompatibility for human pre-adipose cells and have application potential in tissue engineering and regenerative medicine. VEGF and FGF-2 expressed on silk fibers could have a potential positive effect on pre-adipose cells, while the effect of VEGF should be further addressed in vivo.

Duodenal Electric Stimulation: Results of a First-in-Man Study.

BACKGROUND: The aim of this study was to demonstrate feasibility and safety of a new electric duodenal stimulation system (EDS, BALANCE) in humans. Secondary objectives were to evaluate the effect on glycemic control and weight loss in patients with obesity and type 2 diabetes mellitus (T2DM). METHODS: In an open-labeled, prospective, single-arm, non-randomized multicenter study, 12 obese T2DM patients with a mean HbA1c of 8.0% received laparoscopic implantation of the BALANCE duodenal stimulating device. Adverse events, changes in glycemic control, cardiovascular parameters, and weight were collected. The follow-up period after implantation was 12 months. RESULTS: Device related severe adverse events did not occur. Mean HbA1c decreased by 0.8% (p = 0.02) and mean fasting blood glucose level (FBG) was reduced by 19% (p = 0.038) after the 12 months. Mean HDL level increased from 44 to 48 mg/dl (p = 0.033). CONCLUSIONS: EDS is a feasible and safe procedure. Positive effects on T2DM and some cardiovascular parameters (HDL, weight) were seen. However, further prospective randomized blinded studies are needed in order to evaluate the potential of this new minimally invasive method.

Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion.

Recent studies indicate that murine Tregs highly express the ENTDP1, as well as the 5'-NT and thereby, suppress Teff function by extracellular adenosine production. Furthermore, CD73 seems to play a role as costimulatory molecule for T cell differentiation. In this study, we analyzed the expression of CD73 on peripheral and lymph nodal Teffs and Tregs in a cohort of 95 HIV patients at different stages of disease, including LTNP and ECs. In contrast to murine Tregs, CD73 was only expressed on a small minority (∼10%) of peripheral Tregs. In contrast, we see high expression of CD73 on peripheral CD8(+) T cells. In HIV infection, CD73 is markedly reduced on all Teffs and Tregs, regardless of the memory subtype. On CD8(+) T cells, a positive correlation between CD73 expression and CD4 counts (P=0.0003) was detected. CD73 expression on CD8(+) T cells negatively correlated with HLA-DR (<0.0001) and PD1 (P=0.0457) expression. The lower CD73 expression on CD8(+) T cells was partially reversible after initiation of ART (P=0.0016). Functionally, we observed that CD8(+)CD73(+) T cells produce more IL-2 upon HIV-specific and unspecific stimulation than their CD73(-) counterparts and show a higher proliferative capacity. These data indicate that down-regulation of CD73 on CD8(+) T cells correlates with immune activation and leads to functional deficits in HIV infection.

Heme oxygenase-1 germ line GTn promoter polymorphism is an independent prognosticator of tumor recurrence and survival in pancreatic cancer.

BACKGROUND: Heme oxygenase-1 (HO-1) correlates with aggressive tumor behavior and chemotherapy resistance in pancreatic cancer (PC). We evaluated the prognostic value of the basal transcription controlling germ line GTn repeat polymorphism (GTn) in the promoter region of the HO-1 gene in PC. PATIENTS AND METHODS: We determined the GTn in 100 controls and 150 PC patients. DNA was extracted from blood leukocytes and GTn determined by PCR, electrophoresis, and sequencing. Clinicopathological parameters, disease-free, and overall survival (DFS, OS) were correlated with GTn. RESULTS: Three genotypes were defined based on short (S) <25 and long (L) ≥25 GTn repeat alleles. In PC patients, a steadily increasing risk was evident between LL, SL, and SS genotype patients for larger tumor size, presence of lymph node metastasis, poor tumor differentiation and higher recurrence rate (P < 0.001 each). The SS genotype displayed the most aggressive tumor biology. The LL genotype had the best and the SS genotype the worst DFS and OS (P < 0.001 each). The GTn genotype was the strongest prognostic factor for recurrence and survival (P < 0.001 each). CONCLUSION: The GTn repeat polymorphism is a strong prognostic marker for recurrence and survival in PC patients.

Treatment with sibutramine prior to Roux-en-Y gastric bypass leads to an improvement of metabolic parameters and to a reduction of liver size and operative time.

BACKGROUND: Previous studies have shown that a preoperative weight loss is associated with better long-term outcome, fewer complications, and less time in the operating room in bariatric patients. However, preoperative weight loss is hard to achieve in many patients. METHODS: We, therefore, conducted a study in which 20 bariatric patients received 15 mg of the weight loss medication sibutramine prior to laparoscopic Roux-en-Y gastric bypass (RYGBP) while patients in the control group did not. It was our interest to find out if these patients had a benefit compared to a control group who did not receive medication. RESULTS: Whereas patients in the sibutramine group lost 4.8 kg within 6 weeks, patients in the control group gained 7.0 kg. Along with the change in weight, the size of the left liver lobe decreased in the sibutramine-treated patients and increased in the control group. Glutamic pyruvic transaminase as a parameter of liver function improved with reduction of liver size. Finally, time in the operating room was shorter for patients with preoperative weight loss due to sibutramine intake. CONCLUSIONS: Medical therapy with sibutramine in preparation for bariatric surgery can improve the health status of patients and lead to a reduction of liver size and operating time. It should be considered as an alternative or addition to dietary therapy or gastric balloon treatment in the preparation of patients expecting a RYGBP.

Genetic variation may influence obesity only under conditions of diet: analysis of three candidate genes.

Under the hypothesis of obesity as a polygenetic disease numerous genes have been associated with an obese phenotype and metabolic co-morbidities. The cannabinoid receptor 1 (CB 1) is part of an underinvestigated system that participates in appetite control. Previous publications suggest that the endocannabinoid systems interact with the better understood leptin-melanocortin axis. Neuropeptide Y (NPY) is a player in the latter. Finally resistin has been shown to influence NPY expression in the brain. In a cohort of 1721 caucasion men and women with a BMI of 25kg/m(2) or more we therefore investigated three candidate polymorphisms at baseline and following 3 months low fat caloric restriction diet by polymerase chain reaction and restriction digestion: the 1359 G/A variant of the cannabinoid receptor 1 (CB1), the L7P variation in neuropeptide Y (NPY) and the -420C>G polymorphism in resistin. Comparing groups according to genotype for each gene separately revealed significant results at baseline only for the CB1 gene. However, upon dieting significant data was found for all 3 genes. Carriers of at least one A allele in CB1 lost more weight and reduced LDL cholesterol more than wildtype patients. LL homocygotes in NPY had a greater reduction in glucose, triglycerides, and LDL cholesterol whereas in resistin carriers of the G allele had a greater reduction in weight and triglycerides. Creating two groups defined by NPY and resistin genotype, respectively, with similar BMI values resulted in significant differences concerning weight loss and metabolic improvement. In conclusion, genetic polymorphisms associated with obesity may become relevant only under the condition of a low calory diet. The presence of a certain genotype may then be beneficial for obesity treatment.

Resection vs drainage in treatment of chronic pancreatitis: long-term results of a randomized trial.

BACKGROUND & AIMS: Tailored organ-sparing procedures have been shown to alleviate pain and are potentially superior in terms of preservation of endocrine and exocrine function as compared with standard resection (Whipple) for chronic pancreatitis with inflammatory pancreatic head tumor. Long-term results comparing these 2 procedures have not been published so far. The aim of this study was to report on long-term results of a randomized trial comparing a classical resective procedure (pylorus-preserving Whipple) with an extended drainage procedure (Frey) for chronic pancreatitis. METHODS: All patients who participated in a previously published randomized trial on the perioperative course comparing both procedures were contacted with a standardized, validated, quality of life and pain questionnaire. Additionally, patients were seen in the outpatient clinic to assess endocrine and exocrine pancreatic function by an oral glucose tolerance test and fecal chymotrypsin test. RESULTS: There were no differences between both groups regarding quality of life, pain control, or other somatic parameters after a median of 7 years postoperatively. Correlations among continuous alcohol consumption, endocrine or exocrine pancreatic function, and pain were not found. CONCLUSIONS: Both procedures provide adequate pain relief and quality of life after long-term follow-up with no differences regarding exocrine and endocrine function. However, short-term results favor the organ-sparing procedure.