Eva Skovlund

Morphologic reappraisal of serrated colorectal polyps.

The “hyperplastic polyp” is considered a benign lesion with no malignant potential, whereas “serrated adenoma” is a precursor of adenocarcinoma. The morphologic complexity of the serrated adenoma varies from being clearly adenomatous to being difficult to distinguish from hyperplastic polyp, which creates a need for more detailed morphologic analysis of all serrated polyps. We evaluated 24 morphologic variables in 289 serrated polyps from the colon and rectum. Cluster analysis and discriminant analysis were performed. A subset of polyps was immunostained for hMLH1 and hMSH2. Major differences were found between right-sided and left-sided polyps. A distinct group of serrated polyps with abnormal proliferation was identified throughout the colon and rectum. These polyps demonstrated decreased expression of hMHL1 and hMSH2 compared with polyps with normal proliferation. Left-sided serrated polyps with normal proliferation further clustered into three groups: vesicular cell-type, goblet cell-type, and mucin-poor-type. We recommend evaluation of the localization, size, and morphologic features when serrated polyps are included in colorectal carcinogenesis research. Polyps with abnormal proliferation are similar to the polyps in “hyperplastic polyposis” and, because of their decreased expression of hMLH1 and hMSH2, may be the subset of polyps associated with the development of colorectal carcinoma via the microsatellite instability pathway.

A comparison of pain rating scales by sampling from clinical trial data.

OBJECTIVE The goals of this study were to examine agreement and estimate differences in sensitivity between pain assessment scales. DESIGN Multiple simultaneous pain assessments by patients in acute pain after oral surgery were used to compare a four-category verbal rating scale (VRS-4) and an 11-point numeric rating scale (NRS-11) with a 100-mm visual analog scale (VAS). The sensitivity of the scales (i.e., their ability [power] to detect differences between treatments) was compared in a simulation model by sampling from true pairs of observations using varying treatment differences of predetermined size. RESULTS There was considerable variability in VAS scores within each VRS-4 or NRS-11 category both between patients and for repeated measures from the same patient. Simulation experiments showed that the VAS was systematically more powerful than the VRS-4 in all simulations performed. The sensitivity of the VAS and NRS-11 was approximately equal. CONCLUSIONS In this acute pain model, the VRS-4 was less sensitive than the VAS. The simulation results demonstrated similar sensitivity of the NRS-11 and VAS when comparing acute postoperative pain intensity. The choice between the VAS and NRS-11 can thus be based on subjective preferences.

Phase III Trial of Cetuximab With Continuous or Intermittent Fluorouracil, Leucovorin, and Oxaliplatin (Nordic FLOX) Versus FLOX Alone in First-Line Treatment of Metastatic Colorectal Cancer: The NORDIC-VII Study

PURPOSE The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated. PATIENTS AND METHODS Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points. RESULTS Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated. CONCLUSION Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.

Risk of colorectal cancer seven years after flexible sigmoidoscopy screening: randomised controlled trial

Objective To determine the risk of colorectal cancer after screening with flexible sigmoidoscopy. Design Randomised controlled trial. Setting Population based screening in two areas in Norway—city of Oslo and Telemark county (urban and mixed urban and rural populations). Participants 55 736 men and women aged 55-64 years. Intervention Once only flexible sigmoidoscopy screening with or without a single round of faecal occult blood testing (n=13 823) compared with no screening (n=41 913). Main outcome measures Planned end points were cumulative incidence and mortality of colorectal cancer after 5, 10, and 15 years. This first report from the study presents cumulative incidence after 7 years of follow-up and hazard ratio for mortality after 6 years. Results No difference was found in the 7 year cumulative incidence of colorectal cancer between the screening and control groups (134.5 v 131.9 cases per 100 000 person years). In intention to screen analysis, a trend towards reduced colorectal cancer mortality was found (hazard ratio 0.73, 95% confidence interval 0.47 to 1.13, P=0.16). For attenders compared with controls, a statistically significant reduction in mortality was apparent for both total colorectal cancer (hazard ratio 0.41, 0.21 to 0.82, P=0.011) and rectosigmoidal cancer (0.24, 0.08 to 0.76, P=0.016). Conclusions A reduction in incidence of colorectal cancer with flexible sigmoidoscopy screening could not be shown after 7 years’ follow-up. Mortality from colorectal cancer was not significantly reduced in the screening group but seemed to be lower for attenders, with a reduction of 59% for any location of colorectal cancer and 76% for rectosigmoidal cancer in per protocol analysis, an analysis prone to selection bias. Trial registration Clinical trials NCT00119912.

Comprehensive geriatric assessment can predict complications in elderly patients after elective surgery for colorectal cancer: A prospective observational cohort study

OBJECTIVE To examine the association between the outcomes of a pre-operative comprehensive geriatric assessment (CGA) and the risk of severe post-operative complications in elderly patients electively operated for colorectal cancer. METHODS One hundred seventy-eight consecutive patients ≥ 70 years electively operated for all stages of colorectal cancer were prospectively examined. A pre-operative CGA was performed, and patients were categorized as fit, intermediate, or frail. The main outcome measure was severe complications within 30 days of surgery. RESULTS Twenty-one patients (12%) were categorized as fit, 81 (46%) as intermediate, and 76 (43%) as frail. Eighty-three patients experienced severe complications, including three deaths; 7/21 (33%) of fit patients, 29/81 (36%) of intermediate patients and 47/76 (62%) of frail patients (p=0.002). Increasing age and ASA classification were not associated with complications in this series. CONCLUSION CGA can identify frail patients who have a significantly increased risk of severe complications after elective surgery for colorectal cancer.

Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response

A recent nonrandomized pilot trial showed that hepatitis C virus (HCV) patients with genotype 2/3 and rapid virological response (RVR) had a 90% sustained virological response (SVR) rate after 14 weeks of treatment. We aimed to assess this concept in a randomized controlled trial. In the trial, 428 treatment‐naïve HCV RNA–positive patients with genotype 2 or 3 were enrolled. Patients with RVR were randomized to 14 (group A) or 24 (group B) weeks of treatment. Patients were treated with pegylated interferon α‐2b (1.5 μg/kg) subcutaneously weekly and ribavirin (800‐1400 mg) orally daily. The noninferiority margin was set to be 10% between the two groups with a one‐sided 2.5% significance level. RVR was obtained in 302 of 428 (71%), and 298 of these were randomized to group A (n = 148) or group B (n = 150). In the intention‐to‐treat analysis, SVR rates were 120 of 148 (81.1%) in group A and 136 of 150 (90.7%) in group B (difference, 9.6%; 95% confidence interval, 1.7‐17.7). Among patients with an HCV RNA test 24 weeks after the end of treatment, 120 of 139 (86.3%) patients in group A achieved SVR compared with 136 of 146 (93.2%) in group B (difference, 6.9%; 95% confidence interval, −0.1 to +13.9). Conclusion: We cannot formally claim that 14 weeks of treatment is noninferior to 24 weeks of treatment. However, the SVR rate after 14 weeks of treatment is high, and although longer treatment may give slightly better SVR, we believe economical savings and fewer side effects make it rational to treat patients with genotype 2 or 3 and RVR for only 14 weeks. (HEPATOLOGY 2007.)

EGFR family expression in breast carcinomas. c-erbB-2 and c-erbB-4 receptors have different effects on survival

One hundred patients with breast carcinoma followed for 7–11 years were included in the present study of EGFR family members, using immunohistochemistry and RT‐PCR. By immunohistochemistry, 36%, 27%, 26%, and 82% of the tumours were positive for EGFR, c‐erbB‐2, c‐erbB‐3, and c‐erbB‐4. All the immunoreactive tumours were confirmed positive by RT‐PCR. Tumour size, histological grade, lymph node status, S‐phase fraction, and stage were confirmed to be significantly associated with both disease‐free and cancer‐specific survival in the present study. Methods of treatment, histological type, and ploidy had no significant effect on survival. Statistical analysis of EGFR family members in these tumours showed a significant association between c‐erbB‐2 expression and reduced disease‐free and cancer‐specific survival. c‐erbB‐4 expression was associated with a more favourable outcome. Co‐expression of c‐erbB‐2 and EGFR was associated with a worse prognosis. c‐erbB‐4 expression, however, showed an antagonistic effect on the clinical influence of c‐erbB‐2 expression. In conclusion, c‐erbB‐2 expression in breast carcinomas is associated with an unfavourable clinical course and EGFR expression has a synergistic effect. However, c‐erbB‐4 antagonizes the c‐erbB‐2 effect on clinical course in breast carcinomas. To achieve best results with immunotherapy against the c‐erbB‐2 receptor, clarifying the status of c‐erbB‐4 expression may be of significance. Copyright

Effect of Flexible Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality A Randomized Clinical Trial

IMPORTANCE Colorectal cancer is a major health burden. Screening is recommended in many countries. OBJECTIVE To estimate the effectiveness of flexible sigmoidoscopy screening on colorectal cancer incidence and mortality in a population-based trial. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 100,210 individuals aged 50 to 64 years, identified from the population of Oslo city and Telemark County, Norway. Screening was performed in 1999-2000 (55-64-year age group) and in 2001 (50-54-year age group), with follow-up ending December 31, 2011. Of those selected, 1415 were excluded due to prior colorectal cancer, emigration, or death, and 3 could not be traced in the population registry. INTERVENTIONS Participants randomized to the screening group were invited to undergo screening. Within the screening group, participants were randomized 1:1 to receive once-only flexible sigmoidoscopy or combination of once-only flexible sigmoidoscopy and fecal occult blood testing (FOBT). Participants with positive screening test results (cancer, adenoma, polyp ≥10 mm, or positive FOBT) were offered colonoscopy. The control group received no intervention. MAIN OUTCOMES AND MEASURES Colorectal cancer incidence and mortality. RESULTS A total of 98,792 participants were included in the intention-to-screen analyses, of whom 78,220 comprised the control group and 20,572 comprised the screening group (10,283 randomized to receive a flexible sigmoidoscopy and 10,289 to receive flexible sigmoidoscopy and FOBT). Adherence with screening was 63%. After a median of 10.9 years, 71 participants died of colorectal cancer in the screening group vs 330 in the control group (31.4 vs 43.1 deaths per 100,000 person-years; absolute rate difference, 11.7 [95% CI, 3.0-20.4]; hazard ratio [HR], 0.73 [95% CI, 0.56-0.94]). Colorectal cancer was diagnosed in 253 participants in the screening group vs 1086 in the control group (112.6 vs 141.0 cases per 100,000 person-years; absolute rate difference, 28.4 [95% CI, 12.1-44.7]; HR, 0.80 [95% CI, 0.70-0.92]). Colorectal cancer incidence was reduced in both the 50- to 54-year age group (HR, 0.68; 95% CI, 0.49-0.94) and the 55- to 64-year age group (HR, 0.83; 95% CI, 0.71-0.96). There was no difference between the flexible sigmoidoscopy only vs the flexible sigmoidoscopy and FOBT screening groups. CONCLUSIONS AND RELEVANCE In Norway, once-only flexible sigmoidoscopy screening or flexible sigmoidoscopy and FOBT reduced colorectal cancer incidence and mortality on a population level compared with no screening. Screening was effective both in the 50- to 54-year and the 55- to 64-year age groups. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00119912.

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 patients 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.

Significance of Candida recovered from intraoperative specimens in patients with intra-abdominal perforations.

OBJECTIVE Determine the significance of recovering yeasts from intraoperative specimens from the abdominal cavity and to evaluate the effect of a single intraoperative dose of fluconazole on clinical outcome in patients with intra-abdominal perforations. DESIGN Prospective, randomized, double-blind study. SETTING Multicenter study from 13 hospitals in Norway. PATIENTS One hundred nine patients with intra-abdominal perforations. INTERVENTIONS Patients were randomized to receive either a single 400-mg fluconazole dose or placebo during the operation. MEASUREMENTS AND MAIN RESULTS An intra-abdominal specimen for microbiological culture was obtained at the time of the operation. The primary response variable in the study was death. Secondary response variables were three parameters indicating a complicated postoperative period: mechanical ventilation for > or = 5 days, intensive care treatment for > or = 10 days, and use of a central venous catheter for > or = 10 days. Yeasts were recovered from a intraoperative intra-abdominal specimen from only 1 (3.5%) of 28 patients with perforated appendicitis and from 32 (39.5%) of 81 nonappendicitis patients. Excluding the appendicitis patients, the yeast recovery rate was high both for patients hospitalized at the time of the perforation (45%) and for nonhospitalized patients (32%). The overall mortality was 11% (12 patients). Single-dose intraoperative fluconazole prophylaxis did not reach a statistically significant effect on mortality (4 of 53 patients in the fluconazole group and 8 of 56 patients in the placebo group died [p = .059]). The only two explanatory variables significantly related to death were a intraoperative finding of yeast from an intra-abdominal specimen and the occurrence of a spontaneous perforation in a patient already hospitalized for nonsurgical cancer treatment. Detection of yeast was also a significant explanatory variable for a prolonged period of mechanical ventilation, intensive care treatment, and prolonged use of a central venous catheter. CONCLUSIONS Single-dose intraoperative fluconazole prophylaxis did not have a statistically significant effect on overall mortality (odds ratio = 0.21; 95% confidence interval, 0.04-1.06; p = .059) in patients with intra-abdominal perforation. The recovery rate of yeast from intraoperative specimens from the abdominal cavity was high (>30%) and was associated with death and a complicated postoperative course.