Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer.

Tissue-resident memory T (TRM ) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty-three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in-vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin-expressing TRM cells. Surprisingly, programmed cell death 1 (PD-1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin-15 and T cell receptor stimulation, perforin and T-bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

Is it possible to predict treatment response to a proton pump inhibitor in functional dyspepsia?

BACKGROUND: The efficacy of proton pump inhibitors in functional dyspepsia is modest and the prognostic factors are almost unknown. METHODS: Data were pooled on patients (n = 826) with a diagnosis of functional dyspepsia from two placebo-controlled trials who were treated with omeprazole, 10 or 20 mg once daily, for 4 weeks. Self-administered questionnaires for the assessment of symptoms and health-related quality of life were completed before entry, and epigastric pain/discomfort was recorded on diary cards. Treatment success was defined as the complete absence of epigastric pain/discomfort on each of the last 3 days of week 4. Prognostic factors were identified by multiple logistic regression analysis. RESULTS: The most discriminating predictor of treatment success (P < 0.0001) was the number of days with epigastric pain/discomfort during the first week of treatment. Fewer days with symptoms during the first week led to higher response rates at 4 weeks. In addition, age > 40 years, bothersome heartburn, low scores for bloating, epigastric pain and diarrhoea, history of symptoms for < 3 months and low impairment of vitality at baseline were identified as positive predictors of outcome. CONCLUSIONS: Early response to treatment with a proton pump inhibitor, during the first week, seems to predict the outcome after 4 weeks in patients with functional dyspepsia.

The role of the gut flora in health and disease, and its modification as therapy.

The gut flora is a vast interior ecosystem whose nature is only beginning to be unravelled, due to the emergence of sophisticated molecular tools. Techniques such as 16S ribosomal RNA analysis, polymerase chain reaction amplification and the use of DNA microarrays now facilitate rapid identification and characterization of species resistant to conventional culture and possibly unknown species. Life-long cross-talk between the host and the gut flora determines whether health is maintained or disease intervenes. An understanding of these bacteria-bacteria and bacteria-host immune and epithelial cell interactions is likely to lead to a greater insight into disease pathogenesis. Studies of single organism-epithelial interactions have revealed the large range of metabolic processes that gut bacteria may influence. In inflammatory bowel diseases, bacteria drive the inflammatory process, and genetic predisposition to disease identified to date, such as the recently described NOD2/CARD15 gene variants, may relate to altered bacterial recognition. Extra-intestinal disorders, such as atopy and arthritis, may also have an altered gut milieu as their basis. Clinical evidence is emerging that the modification of this internal environment, using either antibiotics or probiotic bacteria, is beneficial in preventing and treating disease. This natural and apparently safe approach holds great appeal.

Self-administered symptom questionnaires in patients with dyspepsia and their yield in discriminating between endoscopic diagnoses.

BACKGROUND/AIMS: Symptoms are generally considered to be poor predictors of organic findings in patients with dyspepsia. We aimed at evaluating whether specific gastrointestinal symptoms, identified by self-administered questionnaires, correlate with specific endoscopic diagnoses and discriminate organic from functional dyspepsia. METHODS: Adult patients with pain or discomfort centred in the upper abdominal region were consecutively enrolled. Patients with heartburn, acid regurgitation, or defaecation and bowel habit problems as their predominant symptoms were excluded. Three self-administered questionnaires were applied before an oesophagogastroduodenoscopy was performed. RESULTS: Among the 799 patients, 50.6% had a normal endoscopy. Endoscopic diagnoses comprised: non-erosive oesophagitis (7.5%), erosive oesophagitis (11.1%), Barrett's oesophagus (1.1%), gastritis/duodenitis (8.4%), gastric ulcer (4.5%), duodenal ulcer (8.3%), and cancer (1.3%). Non-dominant heartburn and acid regurgitation were significantly more common in patients with organic dyspepsia, whereas hunger pains and rumbling occurred more often in those with functional dyspepsia. Multivariate analyses demonstrated that younger age, female gender, high scores for hunger pain, rumbling, hard stools, low scores for heartburn, and acid regurgitation predicted functional dyspepsia. CONCLUSIONS: Self-administered questionnaires revealed differences in the symptom patterns between patients with functional and organic dyspepsia. Furthermore, the health-related well-being in patients with functional and organic dyspepsia centred was impaired to the same extent.

Effect of profound acid suppression in functional dyspepsia: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Functional dyspepsia (FD) is defined as persistent or recurrent pain/discomfort centred in the upper abdomen, where no structural explanation for the symptoms is found. The role of drug treatment remains controversial. The aim in this study was to evaluate the effect of omeprazole 20 mg twice daily (b.i.d) and to test methods for symptom assessment. METHODS: 197 patients fulfilling the criteria for FD were randomly allocated to double-blind treatment with omeprazole 20 mg b.i.d (n = 100) or placebo (n = 97) for 14 days. Patients with a known gastrointestinal disorder or with main symptoms indicating gastro-oesophageal reflux disease or irritable bowel syndrome were excluded. Helicobacter pylori testing and 24-h intra-oesophageal 24-h pH-metry were performed before randomization. The patients recorded dyspeptic symptoms on diary cards. RESULTS: A stringent endpoint, 'complete symptom relief on the last day of treatment', was the primary efficacy variable. For the APT cohort, this was achieved in 29.0% and 17.7% on omeprazole and placebo, respectively (95% CI of difference (11.3%): -0.4%-23.0%, P = 0.057). Similar figures in the PP cohort were 31.0% and 15.5%, respectively (95% Cl of difference (15.5%): 3.2%-27.7%, P = 0.018). The benefit of omeprazole in the PP cohort was confirmed by secondary endpoints such as, no dyspeptic symptoms on the last 2 days of treatment and overall treatment response. H. pylori status and the level of oesophageal acid exposure did not significantly influence the response to therapy. CONCLUSION: A subset of patients with FD will respond to therapy with omeprazole.

Laparoscopic mesh versus open preperitoneal mesh versus conventional technique for inguinal hernia repair: a randomized multicenter trial (SCUR Hernia Repair Study).

OBJECTIVE: To evaluate the influence of the laparoscopic technique in hernia repair regarding time to full recovery and return to work, complications, recurrence rate, and economic aspects. SUMMARY BACKGROUND DATA: Several studies have shown advantages in terms of less pain and faster recovery after laparoscopic hernia repair, whereas others have not, and the cost-effectiveness has been questioned. The laparoscopic technique must be thoroughly compared with the open procedures before its true place in hernia surgery can be defined. METHODS: Six hundred thirteen male patients aged 40 to 75 years were randomized to the conventional procedure, preperitoneal mesh placed by the open technique, or laparoscopic preperitoneal mesh (TAPP). Follow-up was after 7 days, 8 weeks, and 1 year. RESULTS: Of 613 patients undergoing surgery, 604 (98.5%) were followed for 1 year. Patients who underwent TAPP gained full recovery after 18.4 days, compared with 24.2 days for open mesh (p < 0.001) and 26.4 days for the conventional procedure (p < 0.001). Patients who underwent TAPP returned to work after 14.7 days, compared with 17.7 days for open mesh (p = 0.05) and 17.9 days for the conventional procedure (p = 0.04). They also had significantly less restriction in physical activities after 7 days. The TAPP procedure was more expensive, mainly as a result of longer surgical time and equipment costs, even after compensation for earlier return to work. Complications were more common in the TAPP group, with a varying pattern between the groups. Four recurrences in the conventional, 11 in the open mesh, and 4 in the TAPP group were recorded after 1 year (p = n.s.). CONCLUSION: The laparoscopic technique results in both shorter time to full recovery and shorter time to return to work, at the price of substantially increased costs.

Quality of life in patients with heartburn but without esophagitis: effects of treatment with omeprazole.

OBJECTIVE: Because improvement in quality of life (QoL) is an important therapeutic goal in patients with heartburn but without esophagitis, the aim of the present study was to compare the impact of omeprazole 20 mg or 10 mg daily with that of placebo on QoL in patients with heartburn as the predominant symptom. METHODS: QoL was measured at baseline and after 4 wk using two validated questionnaires, the Psychological General Well-Being (PGWB) index and the Gastrointestinal Symptom Rating Scale. RESULTS: The two questionnaires were completed by 163 patients in the omeprazole 20 mg group, 163 in the omeprazole 10 mg group, and 82 in the placebo group. The reflux dimension of the Gastrointestinal Symptom Rating Scale showed a significant improvement in terms of reflux symptoms on omeprazole 20 mg versus omeprazole 10 mg and placebo, and on omeprazole 10 mg compared with placebo. The total score of the PGWB index improved significantly more on both doses of omeprazole than on placebo. The mean scores rose from 96.8 to 103.9 on omeprazole 20 mg, from 98.4 to 106.0 on omeprazole 10 mg, and from 98.0 to 100.6 on placebo. All dimensions of the PGWB index improved on treatment with omeprazole, but the improvements were most pronounced in the dimensions depicting anxiety, depressed mood, and self-control. CONCLUSIONS: It is concluded that treatment with omeprazole 20 mg and omeprazole 10 mg restores QoL to a level comparable with that observed in a healthy population.

On demand therapy with omeprazole for the long-term management of patients with heartburn without oesophagitis--a placebo-controlled randomized trial.

AIM: To observe the natural course of gastro-oesophageal reflux disease (GERD) in patients without oesophagitis following effective symptom relief, and to determine the place of acid pump inhibitor therapy in the long-term management of these patients. METHODS: We investigated the efficacy of on-demand therapy with omeprazole 20 mg or 10 mg, or placebo in a double-blind, randomized multicentre trial. It involved 424 patients with troublesome heartburn without endoscopic evidence of oesophagitis in whom heartburn had been resolved with short-term treatment. Patients were told to take study medication on demand once daily on recurrence of symptoms until symptoms resolved over a 6-month period. They also had access to antacids. The primary efficacy variable was time to discontinuation of treatment, due to unwillingness to continue. RESULTS: According to life-table analysis, after 6 months the remission rates were 83% (95% CI: 77-89%) with omeprazole 20 mg, 69% (61-77%) with omeprazole 10 mg, and 56% (46-64%) with placebo (P < 0.01 for all intergroup differences). The mean (s.d.) number of study medications used per day in these groups was 0.43 (0.27), 0.41 (0.27) and 0.47 (0.27), respectively. The use of antacids was highest in the placebo group and lowest in the omeprazole 20 mg group. Treatment failure was associated with more than a doubling of antacid use, and a deterioration in patient quality of life. CONCLUSIONS: Approximately 50% of patients with heartburn who do not have oesophagitis need acid inhibitory therapy in addition to antacid medication to maintain a normal quality of life. On-demand therapy with omeprazole 20 mg, is an effective treatment strategy in these patients.

Complications following Swedish adjustable gastric banding: a long-term follow-up.

BACKGROUND: The Swedish adjustable gastric band (SAGB) has been in use since 1985. The aim of this study was to analyze short and long-term complications linked to the SAGB. MATERIALS AND METHODS: Between August 1990 and December 1996, we operated on a series of 326 patients (78 men and 248 women) at the Huddinge University Hospital and the Norra Alvsborg County Hospital. The mean age of patients at surgery was 40 years (range 19-62). The mean preoperative weight was 125 kg (range 81-181). The mean excess weight was 80%. RESULTS: The mean time of follow-up was 28 months (range 6-76). Complications requiring reoperation included two (0.6%) band dislocations, six (1.8%) band leakages, and 16 (4.6%) band migrations-erosions. The most common reason for abdominal reoperation, band migration, was attributed to overfilling of the band system. In the patients in whom migration occurred, the bands had been filled with a mean volume of 12.6 ml fluid. In the remaining patients, the mean volume was 8.7 ml. The most common complication not requiring reoperation was reflux disease (4.7%). In cases with a small pouch, this complication did not seem to be a serious problem. The mean excess weight loss in the 296 patients without complications was 68%. CONCLUSION: The overall long-term complication rate following SAGB is reasonable. With improved operating technique and closer follow-up, it should be possible to reduce the complication rate further. Reoperation because of band migration appears to be related to overfilling of the system and should therefore be avoidable in most cases.

Does endoscopy have a positive impact on quality of life in dyspepsia?

BACKGROUND: It is unclear whether normal endoscopy results in patients investigated for dyspepsia has therapeutic value. Therefore the aim of this study was to evaluate the effect of the endoscopy on quality of life and dyspeptic symptoms. METHODS: One hundred ninety-six symptomatic patients (85 men and 111 women, mean age 42.9 years), who were receiving no treatment, were investigated before and 1 week after endoscopy with the use of a battery of validated questionnaires. RESULTS: Before endoscopy the health-related quality of life was compromised in comparison with a normal population, but 1 week after a negative endoscopy it is increased to a level which was close to the normal range despite no major change in symptoms. Physical activity and sleep scores improved significantly after endoscopy. CONCLUSION: The present results suggest that a negative endoscopy improves quality of life in the short-term in patients with dyspepsia, even though symptoms may persist.

Gastro-oesophageal reflux symptoms--clinical findings and effect of ranitidine treatment.

BACKGROUND: This study was performed to study the demography, effect of treatment with ranitidine and relapse pattern in patients with reflux symptoms. METHODS: Patients with reflux symptoms were examined by endoscopy and included in a double-blind, comparative trial of placebo and ranitidine 150 mg b.i.d. for two weeks. At two weeks satisfied patients continued the same treatment. Non-satisfied patients were randomised to ranitidine 150 mg b.i.d. or q.i.d for another two weeks. After four weeks medication was stopped and satisfied patients were followed for 24 weeks. No further endoscopy was performed. RESULTS: Four hundred and twenty-seven patients were randomised. At two weeks there was no significant difference between placebo and ranitidine, regarding the proportion of patients with complete relief from symptoms or satisfied with treatment. Ranitidine was superior to placebo in improving symptoms at two weeks. Ranitidine, 150 mg q.i.d. offered no additional advantage in weeks three to four over prolonging treatment with 150 mg b.i.d. after the first two weeks. Patients with oesophagitis at inclusion relapsed more than those with symptoms only, 67% compared with 52%, (p = 0.013). CONCLUSIONS: The effect of ranitidine was marginal compared to placebo. The relapse rate was high after treatment stopped.

Burden of illness in functional gastrointestinal disorder--the consequences for the individual and society.

OBJECTIVE: To review the consequences of functional gastrointestinal disorders (FGD), i.e. heartburn without esophagitis, dyspepsia and IBS for the individual and society. RESULTS: Current publications indicate that functional gastrointestinal disorders are more prevalent than organic gastrointestinal disorders in the population. Symptoms, not the organic finding per se, are most important to the individual. Functional disorders are furthermore linked to somatic symptoms, from other parts of the body, as well as to mental health. Together they constitute a large medical burden on society in terms of consultations, drug consumption and surgery. Social costs are further increased by problems at work and a considerable increase in absenteeism. CONCLUSIONS: Functional gastrointestinal disorders should be taken more seriously by the medical community and society, since the burden of illness seems much larger than earlier anticipated.

Quality of life in different gastrointestinal conditions.

In recent years, there has been increasing interest in how gastrointestinal symptoms relate to and impact on patients' health-related quality of life. This is particularly the case for functional gastrointestinal disorders that are characterized by a lack of biological markers for disease activity. There is only a slight variation in the type of gastrointestinal symptoms reported with different gastrointestinal disorders, and patients with dyspepsia or irritable bowel syndrome, for example, often describe a variety of gastrointestinal symptoms with considerable overlap between them. The same pattern has been observed in patients with gastroesophageal reflux disease, even though heartburn and acid regurgitation are easier to distinguish from other gastrointestinal symptoms, particularly in patients in whom objective reflux is verified. Most aspects of health-related quality of life in patients with gastrointestinal disorders are compromised, irrespective of diagnosis. Patients with functional disorders seem, if anything, to display more emotional distress than those with organic disorders. Given the considerable overlap between different gastrointestinal symptom clusters, it is not surprising that these conditions have a similar impact in terms of perceived health status and quality of life. The key factors associated with the degree of perceived distress and dysfunction relate to disease severity and the presence of abdominal pain symptoms.

Laparoscopic surgery for morbid obesity.

Morbid obesity, defined as a body mass index (BMI), i.e. weight (kg)/height (m2) over 36 for males and 38 for females, is a common condition and a threat for health, life and individual well being. Hitherto, surgery is the only effective treatment for weight reduction. Surgical methods can be malabsorptive, reducing the patients ability to absorb nutrients, or restrictive, reducing the capacity of food intake. Exclusively malabsorptive methods have been abandoned due to severe side effects. Restrictive methods, gastroplasties, reduces the compliance capacity of the stomach. Two types are performed laparoscopically, the vertical banded gastroplasty and the adjustable gastric banding. The proximal gastric by pass is also performed laparoscopically and is a combination of a restrictive proximal gastroplasty and a malabsorptive Roux-en-Y gastro-jejunal anastomosis. With laparoscopic adjustable gastric banding mean BMI was reduced from 41 kg/m2 to 33 kg/m2 (n = 43) after one year. Two years after surgery mean BMI was 30 kg/m2 (n = 16). The different operative techniques are further discussed in this paper.

Heartburn without oesophagitis: efficacy of omeprazole therapy and features determining therapeutic response.

BACKGROUND: Data are limited on the value of effective antisecretory therapy in the relief of heartburn in patients without oesophagitis. METHODS: Patients with heartburn, without endoscopic signs of oesophagitis, were randomized to double-blind treatment with omeprazole, 20 or 10 mg once daily, or placebo, for 4 weeks (n = 509). Pre-treatment oesophageal acid exposure was assessed using 24-h intra-oesophageal pH monitoring. Heartburn was assessed at 2 and 4 weeks. RESULTS: At 4 weeks the proportion of patients with complete absence of heartburn was 46% (95% confidence interval, 39-53%) with 20 mg omeprazole, 31% (25-38%) with 10 mg omeprazole, and 13% (7-20%) with placebo. Satisfaction with therapy was reported by 66%, 57%, and 31% of the patients, respectively. CONCLUSION: Omeprazole, 20 and 10 mg once daily, provides rapid relief of heartburn in patients without endoscopic oesophagitis.

Preoperative local infiltration with ropivacaine for postoperative pain relief after inguinal hernia repair. A randomised controlled trial.

OBJECTIVE: To assess the effect of preoperative local anaesthesia with ropivacaine and find out if there was a dose-response relationship with postoperative pain after inguinal hernia repair. DESIGN: Randomised, double-blind, placebo-controlled trial. SETTING: Two Swedish and two Norwegian hospitals. SUBJECTS: 131 Male patients undergoing elective inguinal hernia repair. INTERVENTION: Infiltration of the inguinal field before operation with 0.5% ropivacaine 40 ml (200 mg), 0.25% ropivacaine 40 ml (100 mg) or saline 40 ml. MAIN OUTCOME MEASURES: Wound pain at rest and during mobilisation, pressure exerted to reach pain threshold and maximum pain tolerance after 3, 6, 10, and 24 hours, and after 7 days; consumption of analgesics; and Quality of Life assessed by two independent questionnaires before and after operation. RESULTS: Pain scores after 3 hours were significantly lower in the ropivacaine groups compared with the saline group for all variables (p < 0.05). At 6 hours pain scores were significantly lower for ropivacaine 0.5% compared with saline for wound pain during mobilisation and pressure exerted to reach maximum pain tolerance. Patients given saline made their first request for analgesics significantly sooner than in the other two groups (p < 0.05), and a significantly larger percentage of them requested analgesics during the first 24 hours (p < 0.05). Evaluation of the Quality of Life questionnaires showed no significant differences between the groups. CONCLUSION: Ropivacaine has a significant, dose-related pain-reducing effect in the immediate postoperative period but we could find no support for the theory that preoperative infiltration analgesia reduces long term pain.

Laparoscopic suture closure of perforated peptic ulcer. A nonrandomized comparison with open surgery.

BACKGROUND: Laparoscopic vs open suture in the surgical treatment of perforated peptic ulcer were compared in a retrospective study. METHODS: The outcome of 10 patients having the laparoscopic procedure was compared with the outcome of 17 patients treated with suture via laparotomy during the same time period. RESULTS: The mortality rate and the complication rate were comparable. The laparoscopic procedure was more time consuming; hospital stay did not differ. CONCLUSIONS: The results indicate that surgery for perforated peptic ulcer can be performed with the laparoscopic technique with an outcome comparable to open surgery. No obvious advantages to the patient were noted with the laparoscopic method.

Pathophysiology in gastroesophageal reflux disease: the surgeon's view.

Symptoms of gastroesophageal reflux are common in the general population. Pathophysiological factors of importance include esophageal and gastric motility, hiatal hernia, acid secretion as well as anatomical and hormonal factors. In the eye of the surgeon several of the most important factors for severe reflux can be corrected surgically. These include lower esophageal sphincter pressure, esophageal intra-abdominal length and hiatal hernia. The result of surgery is dependent on whether the patient has symptoms related to gastroesophageal reflux or not. It is important that disease history symptoms and pathophysiological findings at investigations match. We have found that not all physiological investigations have to be pathological. Symptomatic response to profound acid inhibition is essential, however, and patients not responding to a high dosage of proton-pump inhibitors should be reconsidered.