Prognostic value of Mandard score and nodal status for recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma.

BACKGROUND: This study evaluated the association of pathological tumour response (tumour regression grade, TRG) and a novel scoring system, combining both TRG and nodal status (TRG-ypN score; TRG1-ypN0, TRG>1-ypN0, TRG1-ypN+ and TRG>1-ypN+), with recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma. METHODS: This Dutch nationwide cohort study included patients treated with neoadjuvant chemoradiotherapy followed by oesophagectomy for distal oesophageal or gastro-oesophageal junctional adenocarcinoma between 2007 and 2016. The primary endpoint was the association of Mandard score and TRG-ypN score with recurrence patterns (rate, location, and time to recurrence). The secondary endpoint was overall survival. RESULTS: Among 2746 inclusions, recurrence rates increased with higher Mandard scores (TRG1 30.6%, TRG2 44.9%, TRG3 52.9%, TRG4 61.4%, TRG5 58.2%; P < 0.001). Among patients with recurrent disease, the distribution (locoregional versus distant) was the same for the different TRG groups. Patients with TRG1 developed more brain recurrences (17.7 versus 9.8%; P = 0.001) and had a longer mean overall survival (44 versus 35 months; P < 0.001) than those with TRG>1. The TRG>1-ypN+ group had the highest recurrence rate (64.9%) and worst overall survival (mean 27 months). Compared with the TRG>1-ypN0 group, patients with TRG1-ypN+ had a higher risk of recurrence (51.9 versus 39.6%; P < 0.001) and worse mean overall survival (33 versus 41 months; P < 0.001). CONCLUSION: Improved tumour response to neoadjuvant therapy was associated with lower recurrence rates and higher overall survival rates. Among patients with recurrent disease, TRG1 was associated with a higher incidence of brain recurrence than TRG>1. Residual nodal disease influenced prognosis more negatively than residual disease at the primary tumour site.

TSH suppression aggravates arterial inflammation - an 18F-FDG PET study in thyroid carcinoma patients.

PURPOSE: We aimed to investigate the influence of both hypothyroidism and thyroid-stimulating hormone (TSH) suppression on vascular inflammation, as assessed with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT). METHODS: Ten thyroid carcinoma patients underwent an 18F-FDG PET/CT during post-thyroidectomy hypothyroidism and during thyrotropin (TSH) suppression after 131I (radioiodine) ablation therapy. We analysed the 18F-FDG uptake in the carotids, aortic arch, ascending, descending, and abdominal aorta to investigate the effects of thyroid hormone status on arterial inflammation. Target-to-background ratios (TBRs) corrected for blood pool activity were established for all arterial territories. Results were further compared to euthyroid historic control subjects. RESULTS: In general, there was a trend towards higher vascular TBRs during TSH suppression than during hypothyroidism (TBRmax all vessels = 1.6 and 1.8, respectively, p = 0.058), suggesting a higher degree of arterial inflammation. In concurrence with this, we found increased C-reactive protein (CRP) levels after levothyroxine treatment (CRP = 2.9 mg/l and 4.8 mg/l, p = 0.005). An exploratory comparison with euthyroid controls showed significant higher TBRs during TSH suppression for the carotids, aortic arch, thoracic descending aorta, and when all vascular territories were combined (TBRmaxp = 0.013, p = 0.016, p = 0.030 and p = 0.018 respectively). CONCLUSIONS: Arterial inflammation is increased during TSH suppression. This finding sheds new light on the underlying mechanism of the suspected increased risk of cardiovascular disease in patients with TSH suppression.

[Iatrogenic cecal perforation two days after a caesarian section]. / Een vrouw met buikpijn en braken na een sectio.

A 32-year-old healthy woman was seen two days after a complicated c-section with abdominal pain and vomiting. Inflammatory parameters were high and imaging showed a dilatated colon with intestinal pneumatosis. Surgical exploration showed an iatrogenic perforation of the coecum. Therefore, an ileocecal resection with primary anastomosis was performed. Full recovery occurred two weeks later.

[A man with a bloated abdomen]. / Een man met een bolle buik.

A 61-year-old intellectually disabled, otherwise healthy man presented himself at the emergency department with a painful, abdominal distension and constipation. Abdominal computed tomography showed an impressive, acute urinary retention with a volume of 8.5 liter, without signs of renal dysfunction. Drainage with a urinary catheter provided immediate relief of symptoms.

Iatrogenic caecal perforation two days after a caesarean section, a case report.

INTRODUCTION: and importance: The caesarean section is a widely spread procedure and 29.7 million times performed every year inn 169 countries in the world. Overall, complications are seen in 6% for elective caesarean to 15% for emergency caesarean. CASE PRESENTATION: We here report a case which was initially diagnosed as a postoperative paralytic ileus. After a complicated caesarean section caused by bleeding and problems with haemostasis, a healthy child was born with full mother recovery for the first 24 hours after surgery. Unfortunately, her condition deteriorated between 24 and 48 hours and she reported progressive nausea and painful bloating. Laboratory tests and CT imaging showed progressive signs of inflammation and distention of the caecum and colon. A second CT scan the next day revealed signs of perforation. An ileocecal resection was performed with a primary anastomosis. Full recovery occurred two weeks later. CLINICAL DISCUSSION: With an estimated incidence of only 0,08%, bowel perforations due to caesarean section, are rare. Moreover, is the clinical presentation diverse and computed topography is essential during the diagnostic process. To avoid potential morbidity and mortality, the surgeon must consider performing a laparotomy in case of a deteriorating patient in non-invasive treatment fails. CONCLUSION: Caecal perforation must be considered as complication after a caesarean section. An ileocecal resection is necessary in this situation. This case report shows that a primary anastomosis is a possible option in a healthy patient that is hemodynamically stable during the operation. In case of an unhealthy or hemodynamic unstable patient, the safest option is a temporary ileostomy.

First Inventory of Access and Quality of Metabolic Surgery Across Europe.

INTRODUCTION: Europe consists of 51 independent countries. Variation in healthcare regulations results in differing challenges faced by patients and professionals. This study aimed to gain more insight into the accessibility, patient pathway and quality indicators of metabolic and body contouring surgery. METHODS AND MATERIALS: Expert representatives in the metabolic field from all 51 countries were sent an electronic self-administered online questionnaire on their data and experiences from the previous year exploring accessibility to and quality indicators for metabolic surgery and plastic surgery after weight loss. RESULTS: Forty-five responses were collected. Sixty-eight percent of countries had eligibility criteria for metabolic surgery; 59% adhered to the guidelines. Forty-six percent had reimbursement criteria for metabolic surgery. Forty-one percent had eligibility criteria for plastic surgery and 31% reimbursement criteria. Average tariffs for a metabolic procedure varied € 800 to 16,000. MDTs were mandated in 78%, with team members varying significantly. Referral practices differed. In 45%, metabolic surgery is performed by pure metabolic surgeons, whilst re-operations were performed by a metabolic surgeon in 28%. A metabolic training programme was available in 23%. Access to metabolic surgery was rated poor to very poor in 33%. Thirty-five percent had a bariatric registry. Procedure numbers and numbers of hospitals performing metabolic surgery varied significantly. Twenty-four percent of countries required a minimum procedure number for metabolic centres, which varied from 25 to 200 procedures. CONCLUSION: There are myriad differences between European countries in terms of accessibility to and quality indicators of metabolic surgery. Lack of funding, education and structure fuels this disparity. Criteria should be standardised across Europe with clear guidelines.

[A man with fever following laparotomy]. / Een man met koorts na een laparotomie.

An 80-year-old man had peritoneal metastases of a resected rectal carcinoma. Cytoreductive surgery was performed, with a wedge resection of the sigmoid colon. Postoperatively he developed subcutaneous emphysema of the neck. A CT scan showed a pneumoperitoneum with air in the mediastinum, due to leakage of the sigmoid colon.

Short-term discontinuation of vagal nerve stimulation alters 18F-FDG blood pool activity: an exploratory interventional study in epilepsy patients.

BACKGROUND: Vagus nerve activation impacts inflammation. Therefore, we hypothesized that vagal nerve stimulation (VNS) influenced arterial wall inflammation as measured by 18F-FDG uptake. RESULTS: Ten patients with left-sided VNS for refractory epilepsy were studied during stimulation (VNS-on) and in the hours after stimulation was switched off (VNS-off). In nine patients, 18F-FDG uptake was measured in the right carotid artery, aorta, bone marrow, spleen, and adipose tissue. Target-to-background ratios (TBRs) were calculated to normalize the respective standardized uptake values (SUVs) for venous blood pool activity. Median values are shown with interquartile range and compared using the Wilcoxon signed-rank test. Arterial SUVs tended to be higher during VNS-off than VNS-on [SUVmax all vessels 1.8 (1.5-2.2) vs. 1.7 (1.2-2.0), p = 0.051]. However, a larger difference was found for the venous blood pool at this time point, reaching statistical significance in the vena cava superior [meanSUVmean 1.3 (1.1-1.4) vs. 1.0 (0.8-1.1); p = 0.011], resulting in non-significant lower arterial TBRs during VNS-off than VNS-on. Differences in the remaining tissues were not significant. Insulin levels increased after VNS was switched off [55.0 pmol/L (45.9-96.8) vs. 48.1 pmol/L (36.9-61.8); p = 0.047]. The concurrent increase in glucose levels was not statistically significant [4.8 mmol/L (4.7-5.3) vs. 4.6 mmol/L (4.5-5.2); p = 0.075]. CONCLUSIONS: Short-term discontinuation of VNS did not show a consistent change in arterial wall 18F-FDG-uptake. However, VNS did alter insulin and 18F-FDG blood levels, possibly as a result of sympathetic activation.

Discrepancies Between BMI and Classic Cardiovascular Risk Factors.

BACKGROUND: Obesity is related to increased cardiovascular risk. It is unknown whether increasing levels of obesity also increase levels of cardiovascular risk factors and systemic inflammation. This study describes the relationship between classic cardiovascular risk factors and inflammatory markers with BMI in a group of obese and non-obese subjects. MATERIALS AND METHODS: Obese subjects (BMI ≥ 30 kg/m2; n = 576; mean ± SD BMI 43.8 ± 7.58 kg/m2) scheduled for bariatric surgery were included. The reference population consisted of non-obese volunteers (BMI < 30 kg/m2; n = 377, BMI 25.0 ± 2.81 kg/m2). The relationship between BMI quintiles and the levels of cardiovascular risk factors was analyzed. Adipose tissue volumetry was performed in 42 obese subjects using abdominal CT scans. RESULTS: The obese group included more women and subjects with type 2 diabetes mellitus, hypertension, and current smoking behavior. In obese subjects, HDL-C and triglycerides decreased with increasing BMI. Systolic and diastolic blood pressure, total cholesterol, LDL-C, and apoB were not related to BMI in the obese group, in contrast to the non-obese group. Inflammatory markers CRP, leukocyte count, and serum complement C3 increased with increasing BMI in the obese group, while these relations were less clear in the non-obese group. The subcutaneous adipose tissue surface was positively correlated to BMI, while no correlation was observed between BMI and visceral adipose tissue. CONCLUSIONS: Markers of inflammation are strongest related to BMI in obese subjects, most likely due to increased adipose tissue mass, while cardiovascular risk factors do not seem to deteriorate above a certain BMI level. Limited expansion capacity of visceral adipose tissue may explain these findings.

Correction: Thyroid Hormone Activates Brown Adipose Tissue and Increases Non-Shivering Thermogenesis-A Cohort Study in a Group of Thyroid Carcinoma Patients.

[This corrects the article DOI: 10.1371/journal.pone.0145049.].

Quality of Life 1 Year After Laparoscopic Sleeve Gastrectomy Versus Laparoscopic Roux-en-Y Gastric Bypass: a Randomized Controlled Trial Focusing on Gastroesophageal Reflux Disease.

INTRODUCTION: Bariatric surgery is the only treatment option that achieves sustained weight loss in obese patients and that also has positive effects on obesity-related comorbidities. Laparoscopic sleeve gastrectomy (LSG) seems to achieve equal weight loss as laparoscopic Roux-en-Y gastric bypass (LRYGB), but there is still much debate about the quality of life (QOL) after LSG, mainly concerning the association with gastroesophageal reflux. Our hypothesis is that QOL after LSG is comparable with QOL after LRYGB. MATERIALS AND METHODS: Between February 2013 and February 2014, 150 patients were randomized to undergo either LSG or LRYGB in our clinic. Differences in QOL were compared between groups by using multiple QOL questionnaires at follow-up moments preoperatively and 2 and 12 months after surgery. RESULTS: After 12 months of follow-up, 128 patients had returned the questionnaires. Most QOL questionnaires showed significant improvement in scores between the preoperative moment and after 12 months of follow-up. The Gastroesophageal Reflux Disease Questionnaire (GerdQ) score deteriorated in the LSG group after 2 months, but recovered again after 12 months. After 2 months of follow-up, the mean GerdQ score was 6.95 ± 2.14 in the LSG group versus 5.50 ± 1.49 in the LRYGB group (p < 0.001). After 1 year, the mean GerdQ score was 6.63 ± 2.26 in the LSG group and 5.60 ± 1.07 in the LRYGB group (p = 0.001). CONCLUSION: This randomized controlled trial shows that patients who underwent LSG have significantly higher GerdQ scores at both 2 and 12 months postoperatively than patients who underwent LRYGB, whereas overall QOL did not differ significantly.

Thyroid Hormone Activates Brown Adipose Tissue and Increases Non-Shivering Thermogenesis--A Cohort Study in a Group of Thyroid Carcinoma Patients.

BACKGROUND/OBJECTIVES: Thyroid hormone receptors are present on brown adipose tissue (BAT), indicating a role for thyroid hormone in the regulation of BAT activation. The objective of this study was to examine the effect of thyroid hormone withdrawal followed by thyroid hormone in TSH-suppressive dosages, on energy expenditure and brown adipose tissue activity. SUBJECTS/METHODS: This study was a longitudinal study in an academic center, with a follow-up period of 6 months. Ten patients with well-differentiated thyroid carcinoma eligible for surgical treatment and subsequent radioactive iodine ablation therapy were studied in a hypothyroid state after thyroidectomy and in a subclinical hyperthyroid state (TSH-suppression according to treatment protocol). Paired two-tailed t-tests and linear regression analyses were used. RESULTS: Basal metabolic rate (BMR) was significantly higher after treatment with synthetic thyroid hormone (levothyroxine) than in the hypothyroid state (BMR 3.8 ± 0.5 kJ/min versus 4.4 ± 0.6 kJ/min, P = 0.012), and non-shivering thermogenesis (NST) significantly increased from 15 ± 10% to 25 ± 6% (P = 0.009). Mean BAT activity was significantly higher in the subclinical hyperthyroid state than in the hypothyroid state (BAT standard uptake value (SUVMean) 4.0 ± 2.9 versus 2.4 ± 1.8, P = 0.039). CONCLUSIONS: Our study shows that higher levels of thyroid hormone are associated with a higher level of cold-activated BAT. TRIAL REGISTRATION: ClinicalTrials.gov NCT02499471.

Impact of bariatric surgery on carotid artery inflammation and the metabolic activity in different adipose tissues.

In this study, we unravel a molecular imaging marker correlated with the known reduction of cardiovascular events (most commonly related to vulnerable plaques) in morbidly obese patients after bariatric surgery (BaS).We prospectively imaged 10 morbidly obese subjects with F-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography before and 1 year after BaS. F-FDG uptake-which is enhanced in inflamed, atherosclerotic vessels and in metabolically active adipose tissues-was quantified in the carotids, pericardial adipose tissue (PAT), visceral adipose tissue (VAT), as well as brown adipose tissue (BAT). The degree of carotid inflammation was compared to lean and overweight controls.Carotid inflammation significantly declined leading to an F-FDG uptake comparable to the 2 control groups. Metabolic activity significantly decreased in PAT and VAT and increased in BAT.BaS leads to a normalization of carotid artery inflammation and a beneficial impact on the metabolic activity in PAT, VAT, and BAT that is related to the metabolic syndrome observed in this patient group.

Frequent extreme cold exposure and brown fat and cold-induced thermogenesis: a study in a monozygotic twin.

INTRODUCTION: Mild cold acclimation is known to increase brown adipose tissue (BAT) activity and cold-induced thermogenesis (CIT) in humans. We here tested the effect of a lifestyle with frequent exposure to extreme cold on BAT and CIT in a Dutch man known as 'the Iceman', who has multiple world records in withstanding extreme cold challenges. Furthermore, his monozygotic twin brother who has a 'normal' sedentary lifestyle without extreme cold exposures was measured. METHODS: The Iceman (subject A) and his brother (subject B) were studied during mild cold (13°C) and thermoneutral conditions (31°C). Measurements included BAT activity and respiratory muscle activity by [18F]FDG-PET/CT imaging and energy expenditure through indirect calorimetry. In addition, body temperatures, cardiovascular parameters, skin perfusion, and thermal sensation and comfort were measured. Finally, we determined polymorphisms for uncoupling protein-1 and ß3-adrenergic receptor. RESULTS: Subjects had comparable BAT activity (A: 1144 SUVtotal and B: 1325 SUVtotal), within the range previously observed in young adult men. They were genotyped with the polymorphism for uncoupling protein-1 (G/G). CIT was relatively high (A: 40.1% and B: 41.9%), but unlike during our previous cold exposure tests in young adult men, here both subjects practiced a g-Tummo like breathing technique, which involves vigorous respiratory muscle activity. This was confirmed by high [18F]FDG-uptake in respiratory muscle. CONCLUSION: No significant differences were found between the two subjects, indicating that a lifestyle with frequent exposures to extreme cold does not seem to affect BAT activity and CIT. In both subjects, BAT was not higher compared to earlier observations, whereas CIT was very high, suggesting that g-Tummo like breathing during cold exposure may cause additional heat production by vigorous isometric respiratory muscle contraction. The results must be interpreted with caution given the low subject number and the fact that both participants practised the g-Tummo like breathing technique.

Increased oxygen consumption in human adipose tissue from the "brown adipose tissue" region.

CONTEXT: Since the discovery of functional brown adipose tissue (BAT) in adult humans, there has been a renewed interest in the physiology of human BAT. Imaging studies from our laboratory and others have shown increased glucose uptake in adipose tissue regions assumed to be BAT in humans. We have also shown that human BAT from the supraclavicular (SCV) region is positive for uncoupling protein-1. To date, however, the oxidative capacity of this adipose tissue (AT) depot has not been characterized in humans. OBJECTIVE: We hypothesize that oxidative capacity is increased in the AT of the SCV region known to contain human BAT. DESIGN: This was an observational prospective cohort study. SETTING: The study was conducted at a referral center. PATIENTS: Participants were 13 patients for whom thyroid gland surgery was indicated. MAIN OUTCOME MEASURE: Basal cellular oxygen consumption in human AT biopsy samples from the SCV region, known to be [¹8F]fluorodeoxyglucose positron emission tomography-computed tomography-positive, was compared with the cellular oxygen consumption in subcutaneous white adipose tissue (WAT) from the same region of the same subject. RESULTS: We show for the first time that AT from the human BAT region displays increased oxygen consumption (P < .05), on average 300% higher, than subcutaneous WAT of the same individual. The contribution of the proton leak to maximal respiration increased with age in the WAT but not in the AT from the BAT region. CONCLUSIONS: These results suggest that human adipose tissue from the BAT region can be distinguished from subcutaneous WAT by a higher basal oxidative capacity. Additional studies are warranted to further elucidate the metabolic and bioenergetic characteristics of this AT depot in humans.

Impaired skeletal muscle mitochondrial function in morbidly obese patients is normalized one year after bariatric surgery.

BACKGROUND: Obesity and type 2 diabetes are associated with impaired skeletal muscle mitochondrial metabolism. As an intrinsic characteristic of an individual, skeletal muscle mitochondrial dysfunction could be a risk factor for weight gain and obesity-associated co-morbidities, such as type 2 diabetes. On the other hand, impaired skeletal muscle metabolism could be a consequence of obesity. We hypothesize that marked weight loss after bariatric surgery recovers skeletal muscle mitochondrial function. METHODS: Skeletal muscle mitochondrial function as assessed by high-resolution respirometry was measured in 8 morbidly obese patients (body mass index [BMI], 41.3±4.7 kg/m(2); body fat, 48.3%±5.2%) before and 1 year after bariatric surgery (mean weight loss: 35.0±8.6 kg). The results were compared with a lean (BMI 22.8±1.1 kg/m(2); body fat, 15.6%±4.7%) and obese (BMI 33.5±4.2 kg/m(2); body fat, 34.1%±6.3%) control group. RESULTS: Before surgery, adenosine diphosphate (ADP)-stimulated (state 3) respiration on glutamate/succinate was decreased compared with lean patients (9.5±2.4 versus 15.6±4.4 O2 flux/mtDNA; P<.05). One year after surgery, mitochondrial function was comparable to that of lean controls (after weight loss, 12.3±5.5; lean, 15.6±4.4 O2 flux/mtDNA). In addition, we observed an increased state 3 respiration on a lipid substrate after weight loss (10.0±3.2 versus 14.0±6.6 O2 flux/mtDNA; P< .05). CONCLUSION: We conclude that impaired skeletal muscle mitochondrial function is a consequence of obesity that recovers after marked weight loss.

Vagus nerve stimulation increases energy expenditure: relation to brown adipose tissue activity.

BACKGROUND: Human brown adipose tissue (BAT) activity is inversely related to obesity and positively related to energy expenditure. BAT is highly innervated and it is suggested the vagus nerve mediates peripheral signals to the central nervous system, there connecting to sympathetic nerves that innervate BAT. Vagus nerve stimulation (VNS) is used for refractory epilepsy, but is also reported to generate weight loss. We hypothesize VNS increases energy expenditure by activating BAT. METHODS AND FINDINGS: Fifteen patients with stable vns therapy (age: 45 ± 10 yrs; body mass index; 25.2 ± 3.5 kg/m(2)) were included between January 2011 and June 2012. Ten subjects were measured twice, once with active and once with inactivated VNS. Five other subjects were measured twice, once with active VNS at room temperature and once with active VNS under cold exposure in order to determine maximal cold-induced BAT activity. BAT activity was assessed by 18-Fluoro-Deoxy-Glucose-Positron-Emission-Tomography-and-Computed-Tomography. Basal metabolic rate (BMR) was significantly higher when VNS was turned on (mean change; +2.2%). Mean BAT activity was not significantly different between active VNS and inactive VNS (BAT SUV(Mean); 0.55 ± 0.25 versus 0.67 ± 0.46, P = 0.619). However, the change in energy expenditure upon VNS intervention (On-Off) was significantly correlated to the change in BAT activity (r = 0.935, P<0.001). CONCLUSIONS: VNS significantly increases energy expenditure. The observed change in energy expenditure was significantly related to the change in BAT activity. This suggests a role for BAT in the VNS increase in energy expenditure. Chronic VNS may have a beneficial effect on the human energy balance that has potential application for weight management therapy. TRIAL REGISTRATION: The study was registered in the Clinical Trial Register under the ClinicalTrials.gov Identifier NCT01491282.

Cold acclimation recruits human brown fat and increases nonshivering thermogenesis.

In recent years, it has been shown that humans have active brown adipose tissue (BAT) depots, raising the question of whether activation and recruitment of BAT can be a target to counterbalance the current obesity pandemic. Here, we show that a 10-day cold acclimation protocol in humans increases BAT activity in parallel with an increase in nonshivering thermogenesis (NST). No sex differences in BAT presence and activity were found either before or after cold acclimation. Respiration measurements in permeabilized fibers and isolated mitochondria revealed no significant contribution of skeletal muscle mitochondrial uncoupling to the increased NST. Based on cell-specific markers and on uncoupling protein-1 (characteristic of both BAT and beige/brite cells), this study did not show "browning" of abdominal subcutaneous white adipose tissue upon cold acclimation. The observed physiological acclimation is in line with the subjective changes in temperature sensation; upon cold acclimation, the subjects judged the environment warmer, felt more comfortable in the cold, and reported less shivering. The combined results suggest that a variable indoor environment with frequent cold exposures might be an acceptable and economic manner to increase energy expenditure and may contribute to counteracting the current obesity epidemic.