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The Bergen Research Group for UltraSound in GastroEnterology (BRUSE)
Research projects

CURRENT PROJECTS

Ongoing research in the Bergen Research Group for UltraSound in GastroEnterology (BRUSE) includes:

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Helmsley USE-IT Project: Development of an intestinal ultrasound score to evaluate inflammation and treatment response in Crohn's disease.

A prospective multicenter study initiated by International Bowel Ultrasound (IBUS) group. This project will occur in 4 parts over 3 years in close collaboration with Alimentiv Inc. (formerly Robarts) who bring methodologic and design expertise in addition to their immense experience with central reading (for endoscopy and MRI).
There will be 16 international sites included in this audacious project, across Europe, Canada/ USA and Australia. 
Part I: RAND/ consensus regarding IUS case acquisition (completed), in addition to activity parameters, response and healing (completed)
Part II: Reliability study – 4 expert centers (Norway, Germany, Italy and Denmark) (now recruiting)
Part III and IV: Validation, responsiveness and patient experience, including 16 centers.

Contact: Kim Nylund

SonoDOCc: Utilizing ultrasound contrast agents in Crohn's disease

In recent times, ultrasound has been recognised as an essential part in the follow-up and diagnosis of patients with Crohn's, and the medical department at HUH, in collaboration with NCUG, has extensive expertise in this area. However, there are limitations associated with the current survey method. The project therefore aims to develop a new method with ultrasound to better visualize disease changes in the terminal ileum

Contact: Kim Nylund

Pancreatic focal lesions: Differentiation of benign and malignant lesions using advanced endoscopic ultrasound and proteomics

The aim of Prof. Havre’s team is to find better diagnostic methods for diagnosing cancer and other diseases of the pancreas.

Research focus
The team has focused on the diagnosis of pancreatic cysts with EUS imaging with colour Doppler, contrast-enhanced EUS and EUS guided biopsy with a microbiopsi forceps. The study has included patients continuously 2016-2020.

Projects and important results
The results show a diagnostic benefit in 23/29 patients (79%), with microbiopses of pancreatic cysts against only 5/29 (17%) based on cytology of cyst fluid from the same patients. In December 2020, 49 patients were included, of whom cyst biopsy was performed in 41. The most common complication after cyst biopsy is pancreatitis. In the material up to patient 29, there were five such complications. The pancreatitis has most often been mild to moderate, and has receded with conservative treatment with painkillers, fluids and antibiotics. Bleeding in the cyst after a biopsy has been registered in a few cases, this has been self-limiting and has not required measures beyond observation. In 2018, the team introduced enhanced prophylaxis with intravenous fluids and prolonged antibiotic prophylaxis as well as NSAIDs rectally. This protocol change has led to a slightly stricter inclusion, some smaller cysts (<2 cm) are not included. The team has not experienced cases of pancreatitis post- procedures in 2020. Inclusion ended on 31.12.2020. Patients are followed up with imaging and a one-year follow-up of the patients with EUS or MRI control is planned.

Contact: Roald Flesland Havre

EUS-Guided gastroenterostomy vs Enteral stenting for malignant gastric outlet obstruction - a randomised clinical trial

The aim of Prof. Havre’s team is to compare two procedures, luminal stent or gastroenterostomy, for alleviating symptoms in patients where cancerous tissue obstructs gastric outlet.

Research focus
The project compares endoscopic treatment for patients with a cancer in which tumour tissue reduces the passage from the stomach to the duodenum to such an extent that it affects the patient's nutrition and quality of life and causes symptoms. Patients with this condition often have a very reduced quality of life and a short life perspective. The methods to be compared are

  1. Gastroenterestomy: Placing an open or partially covered metal stent in the lumen of the stomach / duodenum through the tumour stenosis to keep it open (established procedure)
  2. Luminal stent: Inserting a stent from the stomach into a suitable small bowel sling guided by ultrasound. This will make an artificial connection that avoids the tumour area all together and at the same time holds the two hollow organs together (new procedure)

The study aims to record the patients' ability to resume oral food, record symptoms such as nausea, vomiting and pain, weight development, quality of life, longevity and place of death.

Contact: Roald Flesland Havre
 

Gastric dysmotility and visceral hypersensitivity - an ultrasound approach to functional GI disorders

The aim of Dr. Steinsvik’s team is to explore commonalities between chronic fatigue syndrome (ME / CFS) and functional gastrointestinal disorders such as functional dyspepsia (FD) and irritable bowel syndrome (IBS). This is done mainly by examining the stomach in connection with a soup meal using an ultrasound function examination (Ultrasound Meal Accommodation test or ULFU).

Research focus
Ultrasound function examination (ULFU) is a clinical examination in which several factors are studied at once in a non-invasive, harmless and affordable procedure. Recording the amount of symptoms the patient experience by drinking 500 ml of broth, provides information about the degree of visceral hypersensitivity. In addition, the patient completes a survey of which meal-related symptoms are most prominent. By using the broth as a contrast fluid in the stomach, the team can then study the stomach's ability to expand in response to the meal ("accommodation capacity"), the distribution of fluid between the upper and lower part of the stomach, in addition, an indication of the stomach’s ability to empty. An important sub-project has been to collect normal material for ULFU to create reference values for the test. This is useful for all subprojects in the study.

Projects and important results
This project studies how different patient groups respond to this ultrasound examination, but has also compared ultrasound function examination with scintigraphy, the gold standard method of gastric emptying. The team has found that ULFU provides valuable information about both symptoms and dysmotility in more patient groups than have previously been mapped. Furthermore, that enlarged antrum in the fasting state, and dilation of the proximal stomach 20 minutes after consuming low-calorie soup is associated with delayed gastric emptying measured by conventional methods. The team conclude that this ultrasound method contributes to increased knowledge about the individual patient that can improve treatment and guide further investigation, and thus facilitate personalized treatment for these complex disorders.

Contact: Elisabeth Kjelsvik Steinsvik
 

Validation and interobserver variation of an ultrasound-based scoring tool to assess disease activity in patients with Crohn's disease

The aim of Dr. Nylund’s team is to validate their ultrasound scoring tool developed for Crohn’s disease, in a new patient population, further investigating if ultrasound can replace colonoscopy in disease monitoring. 

Research focus
Crohn's disease is an inflammatory disease of the intestine, which often debuts in adolescents. In addition to significant ailments, patients can get serious complications. The disease is characterized by periods of healing and flare-up, and it is therefore important to assess disease activity. The best option today is to perform a colonoscopy, but the method causes great discomfort to the patient, requires extensive resources and the procedure is limited in considering inflammation deep in the intestinal wall. Ultrasound (US) has the potential to assess disease activity, but to date there are no validated scoring tools in clinical practice. The team recently made a simple US score that correlated well with colonoscopy, and Dr. Nylund and associates want to validate this score in a new patient population. If the US score correlates well with colonoscopy, US may prove to be the preferred method of choice, reducing the need for endoscopic examinations. The team will also investigate if US can predict treatment effect after initiating pharmaceutical treatment. This is a multi-centre, prospective, observational study with 12 months follow-up.

Contact: Kim Nylund

Relapse of Ulcerative colitis diagnosed by ultrasonography

The aim of Dr. Nylund’s team is to investigate whether ultrasound measurements can predict endoscopic recurrence in patients with ulcerative colitis.

Research focus
Ulcerative colitis is an inflammatory disease of the intestine with a variable course. It is important to be able to diagnose a relapse early to adjust the medical treatment. Currently, ileocolonoscopy is the best tool, but the examination is invasive and should be replaced by a method that is more agreeable to patients. Ultrasound of the bowel can be such a method. The PRELAPSE study should include ulcerative colitis patients who have been treated with an anti-TNF drug for a year or longer and who have been disease-free for the past 3 months. The same patients are already being recruited in another study (BIOSTOP). The aim of the study is to investigate whether ultrasound measurements can predict endoscopic recurrence in patients in persistent clinical and endoscopic remission. It is a longitudinal, exploratory, observational study.

Contact: Kim Nylund

Sonorescue: selecting patients with severe ulcerative colitis for rescue therapy using ultrasonography

The aim of Dr. Nylund’s team is to identify patients with acute severe ulcerative colitis in need of “rescue” therapy by repeated ultrasound examinations during hospitalization. 

Research focus
Acute severe ulcerative colitis (ASUC) is a medical emergency that requires hospitalization and prompt treatment with intravenous corticosteroids. Unfortunately, 1/3 of the patients do not respond to this treatment and need so-called "rescue" treatment. This is a clinical decision, but repeated ultrasound examinations of the bowel can be used to distinguish responders from non-responders. The primary endpoint of this prospective, longitudinal observational study of 90 patients with ASUC is "rescue" treatment due to insufficient efficacy of iv corticosteroids. The study involves repeated examinations of the patient, but three of these can be performed during hospitalization. A faster and better selection of patients for "rescue" treatment can improve the outcome of the treatment, but also reduce costs.

Contact: Kim Nylund
 

Sonoporation-enhanced treatment of inoperable pancreatic cancer

Our team, led by Prof. Dimcevski, aims to study the safety and efficacy of sonoporation combined with chemotherapy for patients with inoperable pancreatic cancer.  We hypothesize that the combined treatment will result in improved survival without increasing systemic toxicity.

Pancreatic cancer is the seventh most common cause of cancer death in both men and women worldwide, with more than 450,000 new cases in 2018. With a mortality-to-incidence ratio of 0.94 and five-year survival rates at around 8.5% (1, 2), pancreatic cancer is a diagnosis dreaded by both clinicians and patients, and advances in treatment options are warranted. When treating pancreatic ductal adenocarcinoma (PDAC), the tumour’s response to chemotherapy is notoriously very low. This is caused by a dense desmoplastic stroma and poor blood supply in and around the tumour (3, 4) albeit, perfusion is sufficient to observe substantial signals in contrast-enhanced ultrasound (5). Regardless of the curative intent of treatment for patients who present with surgically amenable PDAC and undergo resection followed by adjuvant chemotherapy, their median overall survival is still only 15 months (6, 7).

Sonoporation is a novel technique that uses ultrasound and ultrasound contrast agents (microbubbles) to enhance the therapeutic efficacy of a given drug at a localised area. When ultrasound waves reach the microbubbles, they oscillate, and through a range of mechanisms, sonoporation allow for increased drug delivery and tissue sensitisation in the targeted area, i.e., the tumour. Taking into account that a major drawback to traditional chemotherapy is the systemic toxic side effects, especially when used in high therapeutic concentrations, sonoporation may provide an effective solution.

In this open, randomized, single-center clinical trial, we will study the safety and efficacy of sonoporation combined with standard of care chemotherapeutic regimens (Gemcitabine and Nab-Paclitaxel, or FOLFIRINOX). All patients will receive standard of care chemotherapy, and through randomization, patients will be allocated to either sonoporation or control. Patients in the sonoporation groups will undergo 30 minutes of treatment with microbubbles (SonoVue) and targeted ultrasound in addition to the chemotherapy. We hypothesize that the sonoporation group will have increased median survival, be able to undergo more treatment cycles and maintain a high quality of life - without increased side effects. The techniques being developed through the study may have major consequences both for this patient group, but also for patients with other solid cancers where the treatment may prove relevant.

References
1. Bray F et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2018). 2. Reichman M et al. SEER Cancer Statistics Review, 1975-2005. SEER Cancer Statistics Review (2008). 3. Provenzano PP et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell (2012). 4. Tod J et al. Tumor-stromal interactions in pancreatic cancer. Pancreatology (2013). 5. Kotopoulis S et al. Treatment of human pancreatic cancer using combined ultrasound, microbubbles, and gemcitabine: a clinical case study. Med Phys (2013). 6. Riall TS et al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma--part 3: update on 5-year survival. J Gastrointest Surg (2005). 7. Chen EL et al. Long-term survival after pancreatic cancer treatment. Am J Surg (2007)
 

Contact: Georg Dimcevski and Ingrid Kvåle Nordaas 

Optimizing Ultrasound Enhanced Delivery of Therapeutics: A Randomized Clinical Trial in Patients With Inoperable Pancreatic Cancer

In this multicenter clinical trial, we aim to study the safety and efficacy of sonoporation combined with chemotherapy for patients with inoperable pancreatic cancer.  We hypothesize that the combined treatment will result in improved survival without increasing systemic toxicity.

Pancreatic cancer is the seventh most common cause of cancer death in both men and women worldwide, with more than 450,000 new cases in 2018. With a mortality-to-incidence ratio of 0.94 and five-year survival rates at around 8.5% (1, 2), pancreatic cancer is a diagnosis dreaded by both clinicians and patients, and advances in treatment options are warranted. When treating pancreatic ductal adenocarcinoma (PDAC), the tumour’s response to chemotherapy is notoriously very low. This is caused by a dense desmoplastic stroma and poor blood supply in and around the tumour (3, 4) albeit, perfusion is sufficient to observe substantial signals in contrast-enhanced ultrasound (5). Regardless of the curative intent of treatment for patients who present with surgically amenable PDAC and undergo resection followed by adjuvant chemotherapy, their median overall survival is still only 15 months (6, 7).

Sonoporation is a novel technique that uses ultrasound and ultrasound contrast agents (microbubbles) to enhance the therapeutic efficacy of a given drug at a localised area. When ultrasound waves reach the microbubbles, they oscillate, and through a range of mechanisms, sonoporation allow for increased drug delivery and tissue sensitisation in the targeted area, i.e., the tumour. Taking into account that a major drawback to traditional chemotherapy is the systemic toxic side effects, especially when used in high therapeutic concentrations, sonoporation may provide an effective solution.

In this open, randomized, multicenter clinical trial, we will study the safety and efficacy of sonoporation combined with standard of care chemotherapeutic regimens (Gemcitabine and Nab-Paclitaxel, or FOLFIRINOX). All patients will receive standard of care chemotherapy, and through randomization, patients will be allocated to either sonoporation or control. Patients in the sonoporation groups will undergo 20 minutes of treatment with microbubbles (Sonazoid) and targeted ultrasound in addition to the chemotherapy. We hypothesize that the sonoporation group will have increased median survival, be able to undergo more treatment cycles and maintain a high quality of life - without increased side effects. The techniques being developed through the study may have major consequences both for this patient group, but also for patients with other solid cancers where the treatment may prove relevant.

References
1. Bray F et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin (2018). 2. Reichman M et al. SEER Cancer Statistics Review, 1975-2005. SEER Cancer Statistics Review (2008). 3. Provenzano PP et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell (2012). 4. Tod J et al. Tumor-stromal interactions in pancreatic cancer. Pancreatology (2013). 5. Kotopoulis S et al. Treatment of human pancreatic cancer using combined ultrasound, microbubbles, and gemcitabine: a clinical case study. Med Phys (2013). 6. Riall TS et al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma--part 3: update on 5-year survival. J Gastrointest Surg (2005). 7. Chen EL et al. Long-term survival after pancreatic cancer treatment. Am J Surg (2007)
 

Contact: Georg Dimcevski, Odd Helge Gilja and Ingrid Kvåle Nordaas

New diagnostics and treatment of diabetic gastroparesis

Contact: Dag André Sangnes

The PanGut study, work package: gastrointestinal hormonal responses and gall bladder emptying

Contact: Eirik Søfteland

Intestinal fluid balance and inflammation in experimental ETEC infection

Contact: Hilde Løland von Volkmann

Minimal invasive endoscopic procedures for diagnosis and treatment of esophageal motility disorders

Contact: Khanh Do-Cong Pham

Ultrasound-enhanced delivery of chemotherapeutic drugs to cancer patients

Contact: Spiros Kotopoulis

The effect of nutrients on GI physiology

Contact: Trygve Hausken

Scandinavian Baltic database for chronic pancreatitis

Contact: Friedemann Georg Erchinger

Improving diagnostics and building a new scoring system for chronic pancreatitis based on Bergen multimodal pancreas database. 

Contact: Trond Engjom