Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study.

BACKGROUND: As studies on gastrointestinal neuroendocrine carcinoma (WHO G3) (GI-NEC) are limited, we reviewed clinical data to identify predictive and prognostic markers for advanced GI-NEC patients. PATIENTS AND METHODS: Data from advanced GI-NEC patients diagnosed 2000-2009 were retrospectively registered at 12 Nordic hospitals. RESULTS: The median survival was 11 months in 252 patients given palliative chemotherapy and 1 month in 53 patients receiving best supportive care (BSC) only. The response rate to first-line chemotherapy was 31% and 33% had stable disease. Ki-67<55% was by receiver operating characteristic analysis the best cut-off value concerning correlation to the response rate. Patients with Ki-67<55% had a lower response rate (15% versus 42%, P<0.001), but better survival than patients with Ki-67≥55% (14 versus 10 months, P<0.001). Platinum schedule did not affect the response rate or survival. The most important negative prognostic factors for survival were poor performance status (PS), primary colorectal tumors and elevated platelets or lactate dehydrogenase (LDH) levels. CONCLUSIONS: Advanced GI-NEC patients should be considered for chemotherapy treatment without delay.PS, colorectal primary and elevated platelets and LDH levels were prognostic factors for survival. Patients with Ki-67<55% were less responsive to platinum-based chemotherapy, but had a longer survival. Our data indicate that it may not be correct to consider all GI-NEC as one single disease entity.

CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer.

Colorectal cancer (CRC) incidence increases with age, and early onset of the disease is an indication of genetic predisposition, estimated to cause up to 30% of all cases. To identify genes associated with early-onset CRC, we investigated gene expression levels within a series of young patients with CRCs who are not known to carry any hereditary syndromes (n=24; mean 43 years at diagnosis), and compared this with a series of CRCs from patients diagnosed at an older age (n=17; mean 79 years). Two individual genes were found to be differentially expressed between the two groups, with statistical significance; CLC was higher and IFNAR1 was less expressed in early-onset CRCs. Furthermore, genes located at chromosome band 19q13 were found to be enriched significantly among the genes with higher expression in the early-onset samples, including CLC. An elevated immune content within the early-onset group was observed from the differentially expressed genes. By application of outlier statistics, H3F3A was identified as a top candidate gene for a subset of the early-onset CRCs. In conclusion, CLC and IFNAR1 were identified to be overall differentially expressed between early- and late-onset CRC, and are important in the development of early-onset CRC.

SPG20, a novel biomarker for early detection of colorectal cancer, encodes a regulator of cytokinesis.

Colorectal cancer is a common disease with high mortality. Suitable biomarkers for detection of tumors at an early curable stage would significantly improve patient survival. Here, we show that the SPG20 (spastic paraplegia-20) promoter, encoding the multifunctional Spartin protein, is hypermethylated in 89% of colorectal carcinomas, 78% of adenomas and only 1% of normal mucosa samples. SPG20 methylation was also present in a pilot series of stool samples and corresponding tumors from colorectal cancer patients. SPG20 promoter hypermethylation resulted in loss of mRNA expression in various cancer types and subsequent depletion of Spartin. We further showed that Spartin downregulation in cancer cells resulted in cytokinesis arrest, which was reversed when SPG20 methylation was inhibited. The present study identifies SPG20 promoter hypermethylation as a biomarker suitable for non-invasive detection of colorectal cancer, and a possible mechanism for cytokinesis arrest in colorectal tumorigenesis.

Carbon dioxide insufflation in colonoscopy: safe and effective in sedated patients.

BACKGROUND AND STUDY AIMS: Several studies have shown that insufflation of carbon dioxide (CO2) instead of air during colonoscopy can reduce postprocedural pain. However, CO2 insufflation might also lead to CO2 retention in the human body. It was recently shown that this side effect does not occur in unsedated patients, but that sedation leads to impaired respiration. Sedated patients may therefore be more prone to CO2 retention. This randomized, double-blinded study was designed to investigate whether CO2 insufflation leads to CO2 retention in sedated patients. PATIENTS AND METHODS: A total of 103 consecutive patients undergoing colonoscopy were randomly assigned to the use of either CO2 or air insufflation. End-tidal carbon dioxide (ETCO2), a noninvasive parameter for arterial P CO2, was recorded before the examination, twice during it, and 10 min after it. Midazolam or pethidine, or both, were used for sedation. The patient's pain during the examination and 1, 3, 6, and 24 h afterwards was registered using a questionnaire. RESULTS: CO2 was used in 52 patients and air insufflation in 51. A total of 52 patients (51 %) received sedation. There were no differences in ETCO2 between the CO2 and air group. A slight increase in ETCO2 was observed in sedated patients, while there was no increase in unsedated patients. CO2 insufflation significantly reduced pain after the procedure at all time points. CONCLUSIONS: This study indicates that CO2 insufflation reduces pain and is safe to use in colonoscopy for sedated patients.

Testing for faecal calprotectin (PhiCal) in the Norwegian Colorectal Cancer Prevention trial on flexible sigmoidoscopy screening: comparison with an immunochemical test for occult blood (FlexSure OBT).

BACKGROUND: Screening for colorectal cancer (CRC) using guaiac based faecal occult blood tests (FOBT) has an estimated programme sensitivity of >60% but <30% for strictly asymptomatic CRC in a single screening round. In search for improved non-invasive tests for screening, we compared a test for faecal calprotectin (PhiCal) with a human haemoglobin immunochemical FOBT (FlexSure OBT). METHODS: In the Norwegian Colorectal Cancer Prevention (NORCCAP) trial, screenees in one screening arm were offered screening with combined flexible sigmoidoscopy (FS) and FlexSure OBT. They were also requested to bring a fresh frozen sample of stool for the PhiCal test which was performed on samples from screenees with CRC (n = 16), high risk adenoma (n = 195), low risk adenoma (n = 592), and no adenoma (n = 1518) (2321 screenees in total). A positive PhiCal test was defined by a calprotectin level > or =50 microg/g. RESULTS: The PhiCal test was positive in 24-27% of screenees whether they had no adenoma, low risk adenoma, or high risk adenoma. Ten (63%) of 16 CRCs gave a positive PhiCal test. The total positivity rate in this population was 25% for the PhiCal test compared with 12% for FlexSure OBT, with a sensitivity for advanced neoplasia of 27% and 35%, respectively. Specificity for "any neoplasia" was 76% for the PhiCal test and 90% for FlexSure OBT. CONCLUSIONS: In colorectal screening, the performance of the PhiCal test on a single spot from one stool sample was poorer than a single screening round with FlexSure OBT and cannot be recommended for population screening purposes. The findings indicate a place for FlexSure OBT in FOBT screening.

Inter-endoscopist variation in polyp and neoplasia pick-up rates in flexible sigmoidoscopy screening for colorectal cancer.

BACKGROUND: The Norwegian Colorectal Cancer Prevention study is an ongoing flexible sigmoidoscopy (FS) screening trial for colorectal cancer. Twenty-one thousand average-risk individuals, aged 50-64 years, living in two separate areas in Norway were randomly drawn from the Population Registry and invited to once-only screening flexible sigmoidoscopy. Examinations were performed over 3 years, at 2 centres, by 8 different endoscopists, using the same type of equipment. The aim of the present study was to investigate possible differences between endoscopists in detecting individuals with polyps, adenomas and advanced lesions (adenomas with severe dysplasia and/or villous components and/or size larger than 9 mm and carcinoma) in flexible sigmoidoscopy screening. METHODS: The present trial comprises data from 8822 individuals, aged 55-64 years, who have undergone a flexible sigmoidoscopy. In the study period, all lesions detected by the different endoscopists were registered. Tissue samples were taken from all lesions detected. RESULTS: Detection rates varied significantly between endoscopists, ranging from 36.4% to 65.5% for individuals with any polyp, from 12.7% to 21.2% for any adenoma and from 2.9% to 5.0% for advanced lesions. In a multiple logistic regression model, the performing endoscopist was a strong independent predictor for detection of individuals with polyps (P < 0.001 ), adenomas (P < 0.001) and advanced lesions (P = 0.01). CONCLUSION: Detection rates for colorectal lesions vary significantly between endoscopists in colorectal cancer screening. Establishing systems for monitoring performance in screening programmes is important. Supervised training and re-certification for endoscopists with poor performance should be considered.

Carbon dioxide insufflation reduces discomfort due to flexible sigmoidoscopy in colorectal cancer screening.

BACKGROUND: Flexible sigmoidoscopy is currently recommended as a screening modality for colorectal cancer. However, a substantial number of patients experience discomfort because of the procedure. possibly limiting compliance and thus screening success. During endoscopy, air is commonly used to insufflate the bowel. Carbon dioxide rather than air insufflation has been shown to reduce procedure-related pain and discomfort in colonoscopy. The aim of the present study was to evaluate whether carbon dioxide insufflation reduces discomfort during and after flexible sigmoidoscopy for colorectal cancer screening. METHODS: In a randomized, double-blinded design, 230 consecutive participants in a population-based flexible sigmoidoscopy colorectal cancer screening trial were assigned to have their examination performed with either carbon dioxide or air insufflation. Patients were asked to grade discomfort experienced both during and in the hours after the procedure on a visual analogue scale. RESULTS: Carbon dioxide insufflation significantly reduced the amount of discomfort at 1, 3 and 6 h after the sigmoidoscopy. One hour after the examination. 84% of patients in the CO2 group reported no discomfort, compared to 64% in the air group (P = 0.006). No differences between the groups were observed during the examination. CONCLUSIONS: Carbon dioxide insufflation significantly reduced post-examination discomfort. The use of carbon dioxide rather than air insufflation may contribute to better public acceptance for flexible sigmoidoscopy screening.

Use of a disposable sheath system for flexible sigmoidoscopy in decentralized colorectal cancer screening.

BACKGROUND AND STUDY AIMS: To prevent transmission of infectious agents and to reduce instrument reprocessing time, the use of disposable sheath systems instead of conventionally reprocessed endoscopes has been promoted for flexible sigmoidoscopy. This trial primarily investigated the feasibility of a disposable sheath system for flexible sigmoidoscopy in decentralized colorectal cancer screening. PATIENTS AND METHODS: In an ongoing colorectal cancer screening trial, 226 consecutive participants were randomly allocated to have their flexible sigmoidoscopy performed with either a fiberoptic sigmoidoscope covered with a disposable sheath ("EndoSheath group") or a conventional video colonoscope ("standard colonoscope group"). All examinations were performed at a temporary screening center. The patients' experience was documented using a questionnaire. The feasibility of running temporary screening units was evaluated. RESULTS: Examinations beyond the 60-cm level were excluded. Thus, 113 patients (examined with the disposable instrument) and 87 (standard instrument) were eligible for analysis. When the sheathed system was used, all the devices needed could be satisfactorily transported. A screening center could be set up within a few hours. No differences were observed in patient discomfort. Fewer patients with polyps were observed in the EndoSheath group (48 [42%]), compared with 55 (63%) in the standard colonoscope group; P = 0.005). No significant differences were observed for polyps larger than 5 mm (14 [12%] in the EndoSheath group, 13 [15%] in the standard colonoscope group; P = 0.6). CONCLUSIONS: Using the disposable system, decentralized colorectal cancer screening was easily established. However, fewer polyps were found, possibly due to the fiberoptic nature of the instrument. Sheathed video instruments are desirable and may increase the diagnostic yield.

NORCCAP (Norwegian colorectal cancer prevention): a randomised trial to assess the safety and efficacy of carbon dioxide versus air insufflation in colonoscopy.

BACKGROUND: To eliminate the risk of combustion during electrosurgical procedures and to reduce patient discomfort, carbon dioxide (CO2) insufflation has been recommended during colonoscopy. However, air insufflation is still the standard method, perhaps due to the lack of suitable equipment and shortage of randomised studies. AIMS: This randomised controlled trial was conducted to assess patient tolerance and safety when using CO2 insufflation during colonoscopy. PATIENTS: Over an eight month period a successive series of patients referred for a baseline colonoscopy due to findings in a flexible sigmoidoscopy screening trial were randomly assigned to the use of either air or CO2 insufflation during colonoscopy. METHODS: End tidal CO2 (ETCO2), a non-invasive parameter of arterial pCO2, was registered before and repeatedly during and after the examination. The patient's experience of pain during and after the examination was registered using a visual analogue scale (VAS). Sedation was not used routinely. RESULTS: CO2 insufflation was used in 121 patients (51%) and air in 119 patients (49%). The groups were similar in age, sex, and caecal intubation rate. No rise in ETCO2 was registered. There were statistically significant differences in VAS scores between the groups with less pain reported when using CO2. CONCLUSIONS: This randomised study of unsedated patients shows that CO2 insufflation is safe during colonoscopy with no rise in ETCO2 level. CO2 was found to be superior to air in terms of pain experienced after the examination.

The effect of attending a flexible sigmoidoscopic screening program on the prevalence of colorectal adenomas at 13-year follow-up.

OBJECTIVES: Understanding the epidemiology of colorectal adenomas is a prerequisite for designing follow-up programs after polypectomy. The aim of the study was to investigate the effect of polypectomy on the long-term prevalence of adenomas. METHODS: In 1983, a total of 799 men and women aged 50-59 yr were drawn from the general population register. Of these, 400 comprised a screening group and 399 a matched control group. The screenees were invited to undergo a once-only flexible sigmoidoscopy. Persons with polyps had a baseline colonoscopy with follow-ups in 1985 and 1989. In 1996, both the screenees and the controls were invited to a colonoscopic examination. RESULTS: In 1996, a total of 451 (71%) individuals attended. Adenomas were found in 78 (37%) individuals in the screening group and 103 (43%) in the control group, relative risk (95% confidence interval): 0.9 (0.7-1.1), p = 0.3, and high-risk adenomas (severe dysplasia, adenomas > or = 10 mm, villous components) were found in 16 (8%) and 32 (13%), respectively; relative risk (95% confidence interval): 0.6 (0.3-1.0), p = 0.07. CONCLUSIONS: There was no significant difference in adenoma prevalence between the group after the screening program and the controls after the usual care. There was a trend toward more high-risk adenomas in the control group. This suggests a very limited effect of one-time screening sigmoidoscopy with surveillance colonoscopy on the prevalence of adenomas, but a preventive effect on the development of high-risk adenomas consistent with the reported effect on cancer prevention.

Do undesirable effects of screening affect all-cause mortality in flexible sigmoidoscopy programmes? Experience from the Telemark Polyp Study 1983-1996.

There is substantial evidence for the beneficial effect of screening programmes aimed at reducing mortality from colorectal cancer (CRC). The effect on all-cause mortality, however, may not necessarily be beneficial. In the present study we used the follow-up results 13 years after a flexible sigmoidoscopy screening to evaluate the long-term effects of informing participants about findings at flexible sigmoidoscopy (FS) screening. There were no severe complications and there was no long-term difference in deaths related to whether there had been any mucosal rupture (biopsy or snare resection) or not. As a group, those who attended in 1983 and were informed that they had polyps tended to improve their smoking habits more than those informed that they had no polyps. Similarly, and in spite of more people giving up smoking, the group with polyps had a trend towards a smaller increase in BMI (+0.7 (95% CI 0.2-1.1)) than the polyp-free group (+1.2 (95% CI 0.9-1.6)) (P = 0.07). The observations suggest that flexible sigmoidoscopy screening may face an educational challenge to avoid unfavourable changes in the lifestyle of screenees, an effect that may more than outweigh the beneficial effect of screening.

Patient tolerance of colonoscopy without sedation during screening examination for colorectal polyps.

BACKGROUND: The administration of sedative drugs at colonoscopy has its drawbacks such as increases in the rate of complications and cost. Our aim was to study how individuals, drawn from a population registry and invited to undergo screening colonoscopy for colorectal polyps, experienced the procedure without conscious sedation. METHODS: Four hundred fifty-one individuals underwent the screening examination (median age 67 years, range 63 to 72). The cecum was intubated in 369 (82%). Fourteen days after the examination, 429 of the attendees received a questionnaire designed to evaluate their tolerance of the procedure. RESULTS: Four hundred nine participants (95%) replied.Twenty-one (5%) of these individuals found the examination very uncomfortable, 184 (45%) found it moderately uncomfortable, and 204 (50%) did not find it uncomfortable. A larger proportion of women than men, 110 (63%) versus 79 (41%), found the procedure very or moderately uncomfortable (p<0.001). Three hundred sixty-eight (90%) individuals stated that they would undergo repeat colonoscopy in 5 years. CONCLUSION: In this screening setting, routine use of conscious sedation did not seem to be necessary, as most participants found the examination to be only moderately uncomfortable or not at all uncomfortable. Colonoscopy without conscious sedation may, however, reduce the rate of intubation of the cecum and increase the risk of missing adenomas and cancers.

Flexible sigmoidoscopy or colonoscopy as a screening modality for colorectal adenomas in older age groups? Findings in a cohort of the normal population aged 63-72 years.

BACKGROUND: Most cases of colorectal cancer originate from adenomas. Removing adenomas has been shown to reduce the incidence of colorectal cancer. The design of cost effective endoscopic screening programmes requires a knowledge of the distribution of adenomas in different age groups. AIM: To investigate the distribution of colorectal adenomas in older age groups in the normal population. METHOD: A total of 356 men and women selected randomly from the population register were offered a colonoscopic screening examination to detect and remove polyps. RESULTS: In all, 241(68%) subjects, mean age 67.4 years (range 62-73), attended. The caecum was intubated in 193 (80%), and in this group 32 (38%) women and 51 (47%) men had adenomas. One hundred and ten (54%) of the adenomas and 11 (39%) of the "high risk adenomas" (adenomas larger than 10 mm in diameter, adenomas containing villous components, and adenomas with severe dysplasia) were found proximal to the sigmoid colon. In 36 (43%) of the subjects with adenomas, the adenomas were only found proximal to the sigmoid colon. Twenty two (11%) subjects had more than two adenomas. Of 203 adenomas discovered, 189 (93%) were less than 10 mm in diameter. CONCLUSION: More than half of the adenomas were localised proximal to the sigmoid colon, and, in nearly half of the adenoma bearing subjects examined, the adenoma was proximal to the descending colon. This indicates that a sigmoidoscopic screening examination in this age group would miss a substantial number of adenomas, but this may be acceptable as the vast majority of proximal adenomas do not progress to clinical cancer within the life expectancy of this age group.

Population-based surveillance by colonoscopy: effect on the incidence of colorectal cancer. Telemark Polyp Study I.

BACKGROUND: Most cases of colorectal cancer (CRC) develop from adenomas. Polypectomy is believed to reduce the incidence of CRC, but this effect has never been explored in prospective controlled studies. The aim of the present study was to evaluate the effect of polypectomy on colorectal cancer incidence in a population-based screening program. METHODS: In 1983, 400 men and women aged 50-59 years were randomly drawn from the population registry of Telemark, Norway. They were offered a flexible sigmoidoscopy and, if polyps were found, a full colonoscopy with polypectomy and follow-up colonoscopies in 1985 and 1989. A control group of 399 individuals was drawn from the same registry. In 1996 both groups (age, 63-72 years) were invited to have a colonoscopic examination. Hospital files and the files of The Norwegian Cancer Registry were searched to register any cases of CRC in the period 1983-96. RESULTS: At screening endoscopy 324 (81%) individuals attended in 1983 and 451 (71%) in 1996. From 1983 to 1996, altogether 10 individuals in the control group and 2 in the screening group were registered to have developed CRC (relative risk, 0.2; 95% confidence interval (CI), 0.03-0.95; P = 0.02). A higher overall mortality was observed in the screening group, with 55 (14%) deaths, compared with 35 (9%) in the control group (relative risk, 1.57; 95% CI, 1.03-2.4; P = 0.03). CONCLUSION: Endoscopic screening examination with polypectomy and follow-up was shown to reduce the incidence of CRC in a Norwegian normal population. The possible effect of screening on overall mortality should be addressed in larger studies.

The psychologic effect of attending a screening program for colorectal polyps.

BACKGROUND: Participation in screening programs for malignant disease may have negative psychologic health effects that could outweigh the beneficial effects of the screening itself. The present study was designed to investigate the psychologic effect of attending a screening program for detection and removal of colorectal adenomas, which are precursors to colorectal cancer. METHOD: In 1983 a prospective. controlled screening study using flexible sigmoidoscopy to detect adenomas was started in Telemark County, Norway. Four hundred individuals were enrolled as a screening group and 399 as a control group. In 1996 survivors in both groups were invited to have a colonoscopic screening examination for detection and removal of polyps. Four hundred and fifty-one individuals (71%) attended; their mean age was 67.2 years (range, 63-72 years), and 48% were women. Fourteen days and 3 and 17 months after the examination the attendees received by mail a questionnaire composed of Goldberg's General Health Questionnaire (GHQ-28) and the Hospital Anxiety and Depression Scale (HADS). The questionnaire was also mailed to an age- and sex-matched group not enrolled in the endoscopic screening study. Four hundred and nine (95%), 395 (92%), and 389 (91%), respectively, returned the questionnaire. Of the controls 314 (70%) returned filled-in questionnaires. RESULTS: The scores for both GHQ-28 and HADS were lower, indicating a lower level of psychiatric morbidity among those attending the examination in 1996 than among the controls. There was a trend towards higher scores with increasing time after the examination in the screened group. CONCLUSION: During the first 17 months after screening the attendees, as a group, did not appear to have developed untoward psychologic effects as judged by HADS and GHQ questionnaires.

[Long-term result of a life style intervention group program]. / Langtidsresultat ved livsstilsintervensjon i grupper.

156 former participants in a lifestyle modification programme for persons with coronary heart disease, or at high risk of developing this disease, were invited to a follow-up examination. The aim was to evaluate the long-term effect of a lifestyle intervention programme. Median time since completion of the programme was 3 years. The participants' serum cholesterol level at the time of the control examination was lower than before they attended the programme, but slightly higher than at the end of it. The body weight was similar at the control and before participation. The self-reported amount of physical activity of persons with established coronary heart disease was higher at the control examination than before the programme. For persons with no established coronary heart disease, the self-reported level of physical activity was the same before and after attending the programme. The most pronounced effect as regards a reduction of the risk factor profile was seen among the participants with established coronary heart disease. The number of smokers was reduced, but not significantly.

[Integration of preventive medicine in an emergency department. A pedagogic model for improvement of communication]. / Integrering av forebyggende medisin i en akuttmedisinsk avdeling. En pedagogisk modell for utvikling av kommunikasjon.

At the Medical Department, Telemark Central Hospital, a project has been going on for five years now to evaluate consultations in lifestyle groups in preference to individual consultations for persons with dyslipidemia. 363 persons were recruited to participate in a series of 5 group consultations at intervals of 3 months, each session to last for 2 hours. Altogether 1469 consultations were of this type. After the first session 79% said they preferred lifestyle group consultations, rather than spending their share of the allotted time on personal consultations, and after the fifth session 81%. The concept has been extended to include patients with chronic disease (asthma and chronic inflammatory bowel disease), with the principal aim of improving the patients' understanding of their disease, and showing them how to control it themselves. The project has attracted much attention, and a consultant in preventive medicine has recently been appointed to the staff. We think it important in terms of impact that the initiative to establish local expertise in preventive medicine emerged from a department that deals with emergency admissions due to lifestyle-related diseases.

Polypectomy of adenomas in the prevention of colorectal cancer: 10 years' follow-up of the Telemark Polyp Study I. A prospective, controlled population study.

BACKGROUND: The efficacy of polypectomy in preventing colorectal cancer (CRC) has never been demonstrated in a controlled, prospective study. This must be done by randomization within a population with a high prevalence of colorectal polyps, and the feasibility and safety of endoscopic screening examination is a prerequisite for this type of study. METHODS: The present study is a randomized, controlled study of the feasibility and safety of flexible sigmoidoscopic screening of a normal population sample of 799 men and women aged 50-59 years, findings at 2 and 6 years' colonoscopic follow-up, and the appearance of clinical colorectal cancer (CRC) after 10 years. RESULTS: The attendance rate was high, and there were no complications. After 10 years 1 of 400 in the screening group had developed CRC (in the group of 76 (19%) not attending for screening examination). Four of 399 controls developed CRC. CONCLUSIONS: Poor yield of polyps at follow-up, slow growth of in situ polyps, and no clinical CRC among screenees after 10 years provides support to infrequent or no colonoscopic follow-up after initial polypectomy in individuals with otherwise average risk of CRC.