Practice patterns in diagnostics, staging, and management strategies of gallbladder cancer among Nordic tertiary centers.

BACKGROUND AND OBJECTIVE: Gallbladder cancer (GBC) is a rare malignancy in the Nordic countries and no common Nordic treatment guidelines exist. This study aimed to characterize the current diagnostic and treatment strategies in the Nordic countries and disclose differences in these strategies. METHODS: This was a survey study with a cross-sectional questionnaire of all 19 university hospitals providing curative-intent surgery for GBC in Sweden, Norway, Denmark, and Finland. RESULTS: In all Nordic countries except Sweden, neoadjuvant/downstaging chemotherapy was used in GBC patients. In T1b and T2, majority of the centers (15-18/19) performed extended cholecystectomy. In T3, majority of the centers (13/19) performed cholecystectomy with resection of segments 4b and 5. In T4, majority of the centers (12-14/19) chose palliative/oncological care. The centers in Sweden extended lymphadenectomy beyond the hepatoduodenal ligament, whereas all other Nordic centers usually limited lymphadenectomy to the hepatoduodenal ligament. All Nordic centers except those in Norway used adjuvant chemotherapy routinely for GBC. There were no major differences between the Nordic centers in diagnostics and follow-up. CONCLUSIONS: The surgical and oncological treatment strategies of GBC vary considerably between the Nordic centers and countries.

Preoperative Inflammatory Markers in Liver Resection for Colorectal Liver Metastases: A National Registry-Based Study.

BACKGROUND: Preoperative inflammatory markers were shown to be associated with prognosis following surgery for hepato-pancreato-biliary cancer. Yet little evidence exists about their role in patients with colorectal liver metastases (CRLM). This study aimed to examine the association between selected preoperative inflammatory markers and outcomes of liver resection for CRLM. METHODS: Data from the Norwegian National Registry for Gastrointestinal Surgery (NORGAST) was used to capture all liver resections performed in Norway within the study period (November 2015-April 2021). Preoperative inflammatory markers were Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS) and C-reactive protein to albumin ratio (CAR). The impact of these on postoperative outcomes, as well as on survival were studied. RESULTS: Liver resections for CRLM were performed in 1442 patients. Preoperative GPS ≥ 1 and mGPS ≥ 1 were present in 170 (11.8%) and 147 (10.2%) patients, respectively. Both were associated with severe complications but became non-significant in the multivariable model. GPS, mGPS, CAR were significant predictors for overall survival in the univariable analysis, but only CAR remained such in the multivariable model. When stratified by the type of surgical approach, CAR was a significant predictor for survival after open but not laparoscopic liver resections. CONCLUSIONS: GPS, mGPS and CAR have no impact on severe complications after liver resection for CRLM. CAR outperforms GPS and mGPS in predicting overall survival in these patients, especially following open resections. The prognostic significance of CAR in CRLM should be tested against other clinical and pathology parameters relevant for prognosis.

The overriding role of surgery and tumor grade for long-term survival in patients with gastroenteropancreatic neuroendocrine neoplasms: A population-based cohort study.

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) comprise a heterogeneous disease group. Factors that affect long-term survival remain uncertain. Complete population-representative cohorts with long-term follow-up are scarce. AIM: To evaluate factors of importance for the long-term survival. METHODS AND RESULTS: An Observational population-based study on consecutive GEP-NEN patients diagnosed from 2003 to 2013, managed according to national guidelines. Univariable and multivariable survival analyses were performed to evaluate overall survival (OS) and to identify independent prognostic factors. One hundred ninety eligible patients (males, 58.9%) (median age, 60.0 years; range, 10.0-94.2 years) were included. The small bowel, appendix, and pancreas were the most common tumor locations. The World Health Organization (WHO) tumor grade 1-3 distributions varied according to the primary location and disease stage. Primary surgery with curative intent was performed in 66% of the patients. The median OS of the study population was 183 months with 5- and 10-year OS rates of 66% and 57%, respectively. Only age, WHO tumor grade, and primary surgical treatment were independent prognostic factors for OS. CONCLUSION: The outcomes of GEP-NEN patients are related to several factors including age and primary surgical treatment. WHO tumor grading, based on the established criteria, should be routine in clinical practice. This may improve clinical decision-making and allow the comparison of outcomes among different centers.

Aspirin as secondary prevention in colorectal cancer liver metastasis (ASAC trial): study protocol for a multicentre randomized placebo-controlled trial.

BACKGROUND: Colorectal cancer is one the most common cancers in the western world with increasing incidence. Approximately 50% of the patients develop liver metastases. Resection of liver metastases is the treatment of choice although almost half of the resected patients get recurrence in the liver. METHODS: The ASAC trial is a Scandinavian, multicentre, double-blinded, randomized, placebo-controlled study to determine whether adjuvant treatment with low-dose aspirin (acetylsalicylic acid (ASA)) can improve disease-free survival in patients treated for colorectal cancer liver metastases (CRCLM). Up to 800 patients operated for CRCLM will be randomized to Arm#1 ASA 160 mg once daily or Arm#2 Placebo, for a period of 3 years or until disease recurrence. The patients will be recruited at all major hepatobiliary surgical units in Norway, Sweden and Denmark and have follow-up according to standard of care and the National Guidelines. DISCUSSION: The ASAC trial will be the first clinical interventional trial to assess the potential beneficial role of ASA in recurrence of CRCLM and survival. ASA is an inexpensive, well-tolerated and easily accessible drug that will be highly potential as adjuvant drug in secondary prevention of CRCLM if the study shows a beneficial effect. We will also determine the effect of ASA as adjuvant treatment on Health-Related Quality of Life and the cost-effectiveness. TRIAL REGISTRATION: ClinicalTrials.gov NCT03326791 . Registered on 31 October 2017.

Improving pancreas surgery over time: Performance factors related to transition of care and patient volume.

BACKGROUND: Pancreas surgery has evolved with better diagnostic imaging, changing indications, and improved patient selection. Outside high-volume tertiary centers, the documented effect of evolution in care and volumes are limited. Thus, we aimed to review indications and outcomes in pancreas surgery during the transition from community-based hospital to a university hospital. METHODS: All pancreatic surgeries performed between 1986 and 2012 within a well-defined Norwegian population were identified from the hospital's database. Indications and postoperative outcomes, including mortality, were investigated. RESULTS: Of the 219 included patients (54% males; median age, 64 years), 150 (69%) underwent pancreatoduodenectomy; 55 (25%), distal resection; and 5 (2%), enucleation. The annual number of operations increased during the study period (from <10/yr to >20/yr). Most patients (169; 77%) underwent surgery for suspected malignancy. The 30-day mortality decreased significantly over time among patients treated for pancreatic cancer (from 16.1% to 3.5%; p = 0.012). Over time, significant reductions in median hospitalization time (19 versus 12 days; p < 0.001), re-operation rate (37.1% versus 8.4%; p < 0.001), and median ICU stay (3 versus 0 days; p < 0.001) were observed. CONCLUSION: The transition to university hospital and increase in volume has led to significant improvements in several performance metrics and reduced postoperative mortality. We believe improved perioperative management and focused, multidisciplinary care-bundles to be of importance.

Global epidemiology of gastrointestinal stromal tumours (GIST): A systematic review of population-based cohort studies.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are rare, yet the most common mesenchymal tumour within the digestive tract. Lack of diagnostic criteria and no specific code in the ICD system has prevented epidemiological evaluation except from overt malignant cases in the past. A global estimate of incidence and disease patterns has thus not been available. METHODS: A systematic literature search of all available population-based studies on GIST published between January 2000 and December 2014 were reviewed. Descriptive epidemiological data are presented. RESULTS: The search found 29 studies of more than 13,550 patients from 19 countries that reported sufficient data for regional or national population-based statistics. Age at diagnosis ranged from 10 to 100 years, with median age being mid 60s across most studies. Gender distribution was equal across studies. On average, 18% of patients had an incidental diagnosis (range from 5% to 40%). Anatomical location of primary tumour in 9747 GISTs demonstrated gastric location as the most frequent (55.6%) followed by small bowel (31.8%), colorectal (6.0%), other/various location (5.5%) and oesophagus (0.7%). Most studies reported incidence at 10-15 per million per year. Notably, lowest incidence was in China (Shanxi province) with 4.3 per million per year. Highest incidence rates were reported also from China (Hong Kong and Shanghai areas), and in Taiwan and Norway (Northern part), with up to 19-22 per million per year. CONCLUSIONS: Epidemiology of GIST demonstrates some consistent features across geographical regions. Whether the reported extreme differences in incidence reflect real variation in population risk warrants further investigation.

Surgery for gastrointestinal stromal tumors (GISTs) of the stomach and small bowel: short- and long-term outcomes over three decades.

BACKGROUND: Many studies on gastrointestinal stromal tumors (GISTs) derive from tertiary referral centers, but few examine strictly population-based cohorts. Thus, we evaluated the clinical features, surgical treatments, clinical outcomes, and factors predicting the survival of patients with GISTs in a population-based series. METHODS: Patients with GISTs diagnosed at Stavanger University Hospital over three decades (1980-2012) were analyzed. Data were retrieved from hospital records. Descriptive statistics and survival analyses (Kaplan-Meier) are presented. A limited number of colorectal GISTs (n = 6) restricted most analyses to those with a gastric or small bowel location. RESULTS: Among 66 patients surgically treated for GISTs, 60 patients (91 %) had either a gastric or a small bowel localization. Females comprised 61 %. The median age at diagnosis was 63 (range, 15-88) years. Clinical symptoms were recorded in 43 patients (65 %). Complete tumor resection was achieved in 85 % of the patients. During follow-up, 6 patients were surgically treated for local recurrence or metastatic disease. The median follow-up time was 6.1 years. At last follow-up, 30 patients (46 %) were deceased, 10 of whom died from GISTs. The median overall survival was 10.4 years. For GISTs with a gastric or small bowel location, a 1- and 5-year disease-specific survival of 100 and 96 %, and a relapse-free survival of 96 and 78 % were observed. Male gender, incidental diagnosis, smaller tumor size, a low mitotic rate, an intact pseudocapsule, low-risk categorization, and an early stage were significantly associated with improved outcomes. CONCLUSION: Surgery in a low-volume, population-based setting yields enhanced long-term disease and recurrence-free survival for patients with GISTs of the stomach or small bowel. Incidental diagnosis, complete tumor resection, and low-risk categorization are good predictors of long-term prognosis.

Tyrosine-kinase mutations in c-KIT and PDGFR-alpha genes of imatinib naïve adult patients with gastrointestinal stromal tumours (GISTs) of the stomach and small intestine: relation to tumour-biological risk-profile and long-term outcome.

BACKGROUND: The identification of activating mutations in either c-KIT cell surface growth factor receptor or platelet-derived growth factor receptor alpha (PDGFRA) has lead the way for the development of novel agents that selectively inhibit key molecular events in gastrointestinal stromal tumour (GIST) pathogenesis. The aim of this study was to investigate the role of c-KIT and PDGFRA gene mutations in primary resectable, imatinib naïve GISTs located in the stomach and small intestine. METHODS: All adult patients with GIST located in either stomach or small intestine who underwent surgical resection without prior imatinib (Glivec) treatment were included. DNA extraction and mutational analysis were performed. Mutational analyses were performed for c-KIT (exons 9, 11, 13, and 17) and the PDGFRA genes (exons 12, 14 and 18). Clinical and pathological parameters were analyzed in relation to the mutations in c-KIT and PDGFRA. RESULTS: A total of 38 patients who underwent surgery for GIST located in either the stomach (n = 24) or in the small intestines (n = 14) were included. Mutations were found in 31 of 38 (81.6 %) patients, with 24 (63.2 %) located in c-KIT and 7 (18.4 %) in the PDGRFA exons, respectively. Seven patients (18.4 %) were wildtype (WT). The most common mutation was in c-KIT exon 11. Incidentally found GISTs were significantly smaller (size >5 cm in 15 % for incidental vs. 71 % for symptomatic; OR of 13.4, 95 % CI 2.3-76.5; P = 0.001) and had lower mitotic rate (0 % for incidental vs. 44 % of the symptomatic; OR 0.52, 95 % CI 0.36-0.75; P = 0.005). Accordingly, the Fletcher grade was significantly better for incidental cases, with most having very low or low risk (85 %) in contrast to 19 of 25 (76 %) symptomatic cases showing moderate to high-risk features (OR 17.4, 95 % CI 2.98-101.7; P < 0.001). However, the distribution of c-KIT, PDGFRA and WT was not differently distributed between incidental and symptomatic GISTs. Long-term survival up to 25 years (median: 8 years) was best determined by Fletcher risk-score in the multivariate model (HR 14.1, 95 % CI 1.7-114.5; p = 0.013). CONCLUSIONS: Long-term survival in resected GISTs of the stomach and small intestine is best determined by Fletcher risk-score. Mitotic activity appears related to tumour size and young age at onset. Mutational status did not influence the clinical or tumour-specific features in this cohort.

Esophageal perforation: clinical patterns and outcomes from a patient cohort of Western Norway.

BACKGROUND: Esophageal perforation is a rare, often life-threatening condition, and management remains challenging. METHODS: Retrospective review of consecutive patients with esophageal perforation treated at two university hospitals between 2000 and 2010. Pertinent data from hospital records were retrieved for statistical calculations and evaluation of perforation score. RESULTS: Forty-seven patients [47% female, median age 62 years (range 15-88)] were included. The annual incidence was 4.7/1,000,000. Perforations were spontaneous in 14 patients (30%), iatrogenic in 25 (53%), and caused by trauma and foreign body impaction in 8 patients (17%). ASA score (p = 0.004), perforation localization (p = 0.001), diagnostic delay (p = 0.002), and perforation score (p < 0.001) differed significantly between patient groups with different etiology, but not between groups with different outcomes. Early diagnosis (≤24 h) was significantly associated with a low perforation score (p = 0.033). A non-operative approach was employed in 26 patients (55%) - more commonly for proximally localized perforations (p = 0.045). The non-operative group showed lower severe complication rates (p = 0.033), shorter ICU stays (p < 0.001) and durations of mechanical ventilation (p = 0.022). The overall 30-day mortality was 23.4%. CONCLUSION: Careful clinical evaluation and appropriate, individualized treatment are important. The high mortality may be partly explained by the underlying disease and the complexity of the clinical condition in many patients.

Epidemiology of gastrointestinal stromal tumours: single-institution experience and clinical presentation over three decades.

BACKGROUND: Epidemiology of gastrointestinal stromal tumour (GIST) is sparsely described. We report a population-based consecutive case series of GIST over three decades from south-western Norway. METHODS: All mesenchymal tumours registered at Stavanger University Hospital between 1980 and 2009 were reviewed and those of the gastrointestinal tract were reclassified with regard to histomorphology and/or immunohistochemistry profiles consistent with GIST. Reported are patients' characteristics and GIST incidence and prevalence estimated using population statistics. RESULTS: Fifty-two cases were identified; 62% of the patients were women. Median age at diagnosis was 67 years. Fifty-eight percent of the tumours were located in the stomach, 38% in the small bowel and one each in colon and rectum. One third were considered to be high risk according to the NIH consensus criteria. The crude incidence rate of GIST was 1.8 per million in the study population per year in the 5-year period 1980-1984, and increased to around 6 in the following years with a peak at 12.5 per million in 2000-2004. The over all crude incidence rate for 1980-2009 was 6.5 per million (95% CI 4.8-8.3 per mill.). Standardized age- and gender adjusted incidence for Norway was 7.4 per million (95% CI 5.4-9.4). The number of patients alive with GIST increased over the study period, with a peak in 2000-2004 at 92.1 per million (95% CI 60.7-134.0 per mill.). One in five had an additional gastrointestinal cancer, located in the colon (n=6), rectum (n=2), stomach (n=3) or, pancreas (n=1). CONCLUSION: Incidence of GIST in the south-western part of Norway is relatively stable and towards the lower end of the range reported in the worldwide literature. An increasing prevalence likely reflects therapy effects. Synchronous gastrointestinal cancers are relatively common in patients with GIST.

DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset.

The incidence of colorectal cancer (CRC) increases with age and early onset indicates an increased likelihood for genetic predisposition for this disease. The somatic genetics of tumor development in relation to patient age remains mostly unknown. We have examined the mutation status of five known cancer critical genes in relation to age at diagnosis, and compared the genomic complexity of tumors from young patients without known CRC syndromes with those from elderly patients. Among 181 CRC patients, stratified by microsatellite instability status, DNA sequence changes were identified in KRAS (32%), BRAF (16%), PIK3CA (4%), PTEN (14%) and TP53 (51%). In patients younger than 50 years (n = 45), PIK3CA mutations were not observed and TP53 mutations were more frequent than in the older age groups. The total gene mutation index was lowest in tumors from the youngest patients. In contrast, the genome complexity, assessed as copy number aberrations, was highest in tumors from the youngest patients. A comparable number of tumors from young (<50 years) and old patients (>70 years) was quadruple negative for the four predictive gene markers (KRAS-BRAF-PIK3CA-PTEN); however, 16% of young versus only 1% of the old patients had tumor mutations in PTEN/PIK3CA exclusively. This implies that mutation testing for prediction of EGFR treatment response may be restricted to KRAS and BRAF in elderly (>70 years) patients. Distinct genetic differences found in tumors from young and elderly patients, whom are comparable for known clinical and pathological variables, indicate that young patients have a different genetic risk profile for CRC development than older patients.

[Surgical treatment of liver metastases from colorectal cancer]. / Kirurgisk behandling av levermetastaser fra kolorektal kreft.

BACKGROUND: The liver is the most common location for metastases from colorectal cancer. Current treatment options (i.e. neo-adjuvant chemotherapy, pre-operative portal vein embolization), IMPROVED OPERATIVE TECHNIQUES: and combinations of modalities and have rendered more patients eligible for liver surgery. MATERIAL AND METHODS: Literature from 1996 to July 2007 was retrieved from Pubmed using the search terms "liver metastases", "liver resection", "colorectal cancer", "randomized controlled trial", "systematic review" and "meta-analysis". RESULTS: No randomized controlled trials were identified that compared liver resection with non-surgical treatment of these patients. Except for a few systematic review articles, the scientific basis for resection of liver metastases from colorectal cancer consists mainly of retrospective studies from single institutions. Median survival for patients with colorectal liver metastases is about 20 months; a five-year survival of 30-50% is reported in resected patients. Patients with non-resectable disease rarely survive for five years. 30-40% of the resected patients have post-operative complications (mostly minor) and postoperative mortality is 3-5%. INTERPRETATION: Surgical treatment of liver metastases is established practice. Patients with colorectal liver metastases should be referred to a multidisciplinary team for appropriate evaluation. Neoadjuvant treatment and multimodal approaches may increase the proportion of patients with resectable liver metastases, and better preoperative imaging may help to more carefully select patients who can benefit from this treatment.