Kjetil Søreide

Microsatellite instability in colorectal cancer

Microsatellite instability (MSI) causes hereditary non‐polyposis colorectal cancer (HNPCC), and occurs in about 15 per cent of sporadic colorectal cancers. Although the basic mechanisms are not clear, there is increased understanding of the clinicopathological consequences of MSI.

The global burden of injury: incidence, mortality, disability-adjusted life years and time trends from the Global Burden of Disease study 2013

Background The Global Burden of Diseases (GBD), Injuries, and Risk Factors study used the disability-adjusted life year (DALY) to quantify the burden of diseases, injuries, and risk factors. This paper provides an overview of injury estimates from the 2013 update of GBD, with detailed information on incidence, mortality, DALYs and rates of change from 1990 to 2013 for 26 causes of injury, globally, by region and by country. Methods Injury mortality was estimated using the extensive GBD mortality database, corrections for ill-defined cause of death and the cause of death ensemble modelling tool. Morbidity estimation was based on inpatient and outpatient data sets, 26 cause-of-injury and 47 nature-of-injury categories, and seven follow-up studies with patient-reported long-term outcome measures. Results In 2013, 973 million (uncertainty interval (UI) 942 to 993) people sustained injuries that warranted some type of healthcare and 4.8 million (UI 4.5 to 5.1) people died from injuries. Between 1990 and 2013 the global age-standardised injury DALY rate decreased by 31% (UI 26% to 35%). The rate of decline in DALY rates was significant for 22 cause-of-injury categories, including all the major injuries. Conclusions Injuries continue to be an important cause of morbidity and mortality in the developed and developing world. The decline in rates for almost all injuries is so prominent that it warrants a general statement that the world is becoming a safer place to live in. However, the patterns vary widely by cause, age, sex, region and time and there are still large improvements that need to be made.

Receiver-operating characteristic curve analysis in diagnostic, prognostic and predictive biomarker research.

#### Take-home messages From a clinical perspective, biomarkers may have a variety of functions, which correspond to different stages (table 1) in disease development, such as in the progression in cancer or cardiovascular disease.1 2 Biomarkers can assist in the care of patients who are asymptomatic (screening biomarkers), those who are suspected to have the disease (diagnostic biomarkers) and those with overt disease (prognostic biomarkers) for whom therapy may or may not have been initiated. Biomarkers can also be used for treatment response (predictive biomarkers) or surveillance after therapy (monitoring biomarkers). Fundamental for the use of biomarkers in all situations is biomarker accuracy—the ability to correctly classify one condition and/or outcome from another (eg, healthy versus diseased). View this table: Table 1 Clinical use of biomarkers: rationale and objectives for use of cancer biomarkers For the clinician, diagnostic testing plays a fundamental role in clinical practice. For instance, daily surgical decision making is based on the correct classification by pathology, radiology and/or clinical chemistry reports involving tissue and/or image evaluation and interpretation of disease conditions—in many decisions the interpretation is based on results in the “grey-area” although requiring “black-and-white” answers for choice of treatment (fig 1). Further, predictive modelling to estimate expected outcomes such as mortality or adverse events based on patient risk characteristics is common in any type of clinical research. Receiver-operating characteristic (ROC) …

Epidemiology and Contemporary Patterns of Trauma Deaths: Changing Place, Similar Pace, Older Face

AbstractBackgroundThe epidemiology of trauma deaths in Europe is less than well investigated. Thus, our goal was to study the contemporary patterns of trauma deaths within a defined population with an exceptionally high trauma autopsy rate.MethodsThis was a retrospective evaluation of 260 consecutive trauma autopsies for which we collected demographic, pre-hospital and in-hospital data. Patients were analyzed for injury severity by standard scoring systems (Abbreviated Injury Scale [AIS], Revised Trauma Score [RTS], and Injury Severity Score [ISS]), and the Trauma and Injury Severity Scale [TRISS] methodology.ResultsThe fatal trauma incidence was 10.0 per 100,000 inhabitants (17.4 per 100,000 age-adjusted ≥ 55 years). Blunt mechanism (87%), male gender (75%), and pre-hospital deaths (52%) predominated. Median ISS was 38 (range: 4–75). Younger patients (<55 years) who died in the hospital were more often hypotensive (SBP < 90 mmHg; p = 0.001), in respiratory distress (RR < 10/min, or > 29/min; p < 0.0001), and had deranged neurology on admission (Glasgow Coma Score [GCS] ≤ 8; p < 0.0001), compared to those ≥ 55 years. Causes of death were central nervous system (CNS) injuries (67%), exsanguination (25%), and multiorgan failure (8%). The temporal death distribution is model-dependent and can be visualized in unimodal, bimodal, or trimodal patterns. Age increased (r = 0.43) and ISS decreased (r = –0.52) with longer time from injury to death (p < 0.001). Mean age of the trauma patients who died increased by almost a decade during the study period (from mean 41.7 ± 24.2 years to mean 50.5 ± 25.4 years; p = 0.04). The pre-hospital:in-hospital death ratio shifted from 1.5 to 0.75 (p < 0.007).ConclusionsWhile pre-hospital and early deaths still predominate, an increasing proportion succumb after arrival in hospital. Focus on injury prevention is imperative, particularly for brain injuries. Although hemorrhage and multiorgan failure deaths have decreased, they do still occur. Redirected attention and focus on the geriatric trauma population is mandated.

Bile duct cysts in adults

Bile duct cysts are rare and of uncertain origin. Most have been reported in young females of Asian descent, but an increasing number have occurred in Western adults.

Epidemiology of major trauma

Major injury is a leading cause of death and disability around the world. For both sexes, one in every ten deaths is the result of injury. Globally, unintentional injuries are ranked as the sixth leading cause of death and the fifth leading cause of moderate and severe disability1. Road traffic accidents alone cause 1·3 million deaths annually – a sobering 148 deaths every hour. For those under 35 years of age, injury is the leading cause of death2, and males aged 15–24 years are responsible for the greatest share of the burden of injury2,3. Furthermore, 45 million people each year – more than 2000 per hour – suffer moderate to severe disability following unintentional injuries1. While those who live in lowincome regions are associated with over 80 per cent of this global injury total, 3·9 million people in highincome countries are also disabled from injuries every year. Those in the latter group tend to be affected at a young age and, as a consequence, many years of productivity are lost at both an individual and a societal level. The ‘disability-adjusted lifeyear’ (DALY) is a time-based measure that combines years of life lost owing to premature death and years of life lost due to time lived in states of less than full health. In 2004, the World Health Organization (WHO) ranked road traffic accidents as the ninth leading cause of DALYs. By 2030, such accidents are projected by the WHO to rank third1. Regrettably, trauma is a worldwide problem that has a particular impact on mortality and life expectancy among young people. ‘Major trauma’ is a generic term and different regions have different dominating injuries. Outside of war zones and areas of armed conflict, penetrating trauma from firearms makes up a relatively small share, typically less than 15 per cent. However, urban epidemics of civilian penetrating injuries are seen in the USA (20–45 per cent) and South Africa (as high as 60 per cent). Interestingly, the easy availability of handguns has a dramatic impact on homicide and suicide statistics, with more than 50 per cent of all suicides in the USA being related to handguns4, and several thousands of murders each year. Knife violence is proportionately similar in the UK and USA5. For Europe in general, it is highest in Spain and Portugal, and lowest in Scandinavia and Greece. Where there is a high prevalence of penetrating injury, major trauma tends to be associated with socioeconomic deprivation, high alcohol consumption, drug abuse and, in some regions, a higher prevalence of bloodborne viral diseases. Most injuries in Europe are blunt trauma, commonly from falls or motor vehicle collisions. Spinal cord and brain injuries are responsible for the greatest injury burden due to permanent disability3. Differences exist between countries. In the Netherlands and the UK, the injury burden and related costs per capita are relatively low, whereas the opposite is true for Austria, Denmark, Norway and Ireland3. For all countries, costs per capita increase greatly for those over 65 years old, but costs are high at both extremes of age. The injury pattern in blunt trauma is a preponderance of serious head, thoracic and limb injuries. Severe thoracic and/or abdominal injuries affect less than 20 per cent of all blunt trauma victims; about a third are abdominal injuries and about a fifth include both body cavities. In the abdomen, solid organ damage occurs most often to the liver (36 per cent), followed by the spleen (32 per cent) and kidney (24 per cent)6. Surgery is required for less than 5 per cent of thoracic injuries, and for less than

Acute appendicitis: modern understanding of pathogenesis, diagnosis, and management

Acute appendicitis is one of the most common abdominal emergencies worldwide. The cause remains poorly understood, with few advances in the past few decades. To obtain a confident preoperative diagnosis is still a challenge, since the possibility of appendicitis must be entertained in any patient presenting with an acute abdomen. Although biomarkers and imaging are valuable adjuncts to history and examination, their limitations mean that clinical assessment is still the mainstay of diagnosis. A clinical classification is used to stratify management based on simple (non-perforated) and complex (gangrenous or perforated) inflammation, although many patients remain with an equivocal diagnosis, which is one of the most challenging dilemmas. An observed divide in disease course suggests that some cases of simple appendicitis might be self-limiting or respond to antibiotics alone, whereas another type often seems to perforate before the patient reaches hospital. Although the mortality rate is low, postoperative complications are common in complex disease. We discuss existing knowledge in pathogenesis, modern diagnosis, and evolving strategies in management that are leading to stratified care for patients.

Epidemiology of perforated peptic ulcer: Age- and gender-adjusted analysis of incidence and mortality

AIM To investigate the epidemiological trends in incidence and mortality of perforated peptic ulcer (PPU) in a well-defined Norwegian population. METHODS A retrospective, population-based, single-center, consecutive cohort study of all patients diagnosed with benign perforated peptic ulcer. Included were both gastric and duodenal ulcer patients admitted to Stavanger University Hospital between January 2001 and December 2010. Ulcers with a malignant neoplasia diagnosis, verified by histology after biopsy or resection, were excluded. Patients were identified from the hospitals administrative electronic database using pertinent ICD-9 and ICD-10 codes (K25.1, K25.2, K25.5, K25.6, K26.1, K26.2, K26.5, K26.6). Additional searches using appropriate codes for relevant laparoscopic and open surgical procedures (e.g., JDA 60, JDA 61, JDH 70 and JDH 71) were performed to enable a complete identification of all patients. Patient demographics, presentation patterns and clinical data were retrieved from hospital records and surgical notes. Crude and adjusted incidence and mortality rates were estimated by using national population demographics data. RESULTS In the study period, a total of 172 patients with PPU were identified. The adjusted incidence rate for the overall 10-year period was 6.5 per 100 000 per year (95%CI: 5.6-7.6) and the adjusted mortality rate for the overall 10-year period was 1.1 per 100 000 per year (95%CI: 0.7-1.6). A non-significant decline in adjusted incidence rate from 9.7 to 5.6 occurred during the decade. The standardized mortality ratio for the whole study period was 5.7 (95%CI: 3.9-8.2), while the total 30-d mortality was 16.3%. No difference in incidence or mortality was found between genders. However, for patients ≥ 60 years, the incidence increased over 10-fold, and mortality more than 50-fold, compared to younger ages. The admission rates outside office hours were high with almost two out of three (63%) admissions seen at evening/night time shifts and/or during weekends. The observed seasonal variations in admissions were not statistically significant. CONCLUSION The adjusted incidence rate, seasonal distribution and mortality rate was stable. PPU frequently presents outside regular work-hours. Increase in incidence and mortality occurs with older age.

Trypsin in colorectal cancer: molecular biological mechanisms of proliferation, invasion, and metastasis.

Trypsin is involved in colorectal carcinogenesis and promotes proliferation, invasion, and metastasis. Although a well‐known pancreatic digestive enzyme, trypsin has also been found in other tissues and various cancers, most importantly of the colorectum. Moreover, colorectal cancers with trypsin expression have a poor prognosis and shorter disease‐free survival. Biological understanding of how trypsin causes cancer progression is emerging. It seems to act both directly and indirectly through a ‘proteinase–antiproteinase‐system’, and by activation of other proteinase cascades. Invasion of the basal membrane by cancer cells may be promoted directly by trypsin digestion of type I collagen. Trypsin activates, and is co‐expressed with matrix metalloproteinases (MMPs), which are known to facilitate invasion and metastasis. MMP‐2, MMP‐7, and MMP‐9 are co‐expressed together with trypsin and seem to be of particular importance in proliferation, progression, and invasion. MMPs may play a role in both conversion from adenoma to carcinoma, and in the initiation of invasion and metastasis. Co‐segregation of trypsin and MMPs within the tumour environment is important for the activation of MMPs, and may explain the deleterious effect of trypsin on prognosis in colorectal cancer. Trypsin and proteinase‐activated receptor 2 (PAR‐2) act together in an autocrine loop that promotes proliferation, invasion, and metastasis through various mechanisms, of which prostaglandin synthesis is important. Stimulated by trypsin, both MMP and PAR‐2 may activate the mitogenic MAPK–ERK pathway through activation of the epidermal growth factor receptor. Experimental trypsin inhibition is feasible but not very effective, and trypsin as a target for clinical therapy is unlikely to be successful owing to its universal distribution. However, as the pathways of trypsin and co‐activated protein cascades emerge, biological understanding of colorectal carcinogenesis will be further illuminated and may pave the way for prognosticators, predictors, and novel targets of therapy. Copyright

Evolving molecular classification by genomic and proteomic biomarkers in colorectal cancer: Potential implications for the surgical oncologist

Colorectal cancer (CRC) is one of the most frequent cancers in the Western world and represents a major health burden. CRC development is a multi-step process that spans 10-15years, thereby providing an opportunity for early detection and even prevention. As almost half of all patients undergoing surgery develop recurrent disease, surveillance is advocated, albeit with various means and intervals. Current screening and surveillance efforts have so far only had limited impact due to suboptimal compliance. Currently, CEA is the only biomarker in clinical use for CRC, but has suboptimal sensitivity and specificity. New and better biomarkers are therefore strongly needed. Non-invasive biomarkers may develop through the understanding of colorectal carcinogenesis. Three main pathways occur in CRC, including chromosomal instability (CIN), microsatellite instability (MSI) and epigenetic silencing through the CpG Island Methylator Phenotype (CIMP). These pathways have distinct clinical, pathological, and genetic characteristics, which can be used for molecular classification and comprehensive tumour profiling for improved diagnostics, prognosis and treatment in CRC. Molecular-biological research has advanced with the sequencing of the human genome and the availability of genomic and proteomic high-throughput technologies using different chip platforms, such as tissue microarrays, DNA microarrays, and mass spectrometry. This review aims to give an overview of the evolving biomarker concepts in CRC, with concerns on methods, and potential for clinical implications for the surgical oncologist.