A systematic review of population-based studies on metachronous metastases of colorectal cancer.

BACKGROUND: The occurrence of metachronous metastases (MM) of colorectal (CRC), colon (CC), and rectal (RC) cancer of population-based studies has not been compiled in a systematic review previously. METHODS: MEDLINE, Embase, and Cochrane Library were searched for primary studies of any design from inception until January 2021 and updated in August 2023 (CRD42021261648). The PRISMA guidelines were adopted, and the Newcastle-Ottawa Quality Assessment Scale used for risk of bias assessment. Outcomes on overall and organ-specific MM were extracted. A narrative analysis followed. RESULTS: Out of 2143 unique hits, 162 publications were read in full-text and 37 population-based cohort studies published in 1981-2022 were included. Ten studies adopted time-dependent analyses; eight were registry-based and seven had a low risk of bias. Three studies reported 5-year recurrence rate of MM overall of stages I-III; for CRC, it was 20.5%, for CC, it was 18% and 25.6%, and for RC, it was 23%. Four studies reported 5-year recurrence rate of organ-specific MM of stages I-III-for CRC, it was 2.2% and 5.5% for peritoneal metastases and 5.8% for lung metastases and for CC 4.5% for peritoneal metastases. Twenty-seven studies reported proportions of patients diagnosed with MM, but data on the length of follow-up was incomplete and varied widely. Proportions of patients with CRC stages I-III that developed MM overall was 14.4%-26.1% in 10 studies. In relation to the enrollment period, a downward trend may be discernible. CONCLUSION: Studies adopting a more appropriate analysis were highly heterogeneous, whereas uncertain data of partly inadequate studies may indicate that MM are overall declining.

A population-based study on time trends of hemoglobin in primary care comparing prediagnostic colorectal cancer patients vs age- and sex-matched controls.

BACKGROUND: Some 40% of colorectal cancer (CRC) patients present with anemia. Temporal trends of gradually decreasing Hb are suggested as a supplementary diagnostic tool for CRC. We set out to explore this concept in a strictly defined population. METHODS: A laboratory database identified patients ≥40 years that had ≥1 Hb test reported from primary care, Örebro county in 2000-17. Linkage to the Swedish Colorectal Cancer Registry identified patients diagnosed with CRC. Other primary care patients served as controls (1:10), matched by age and sex. Prediagnostic Hb in cases and controls were compared and temporal trajectories of Hb modelled using a nonlinear three-parameter logistic function. RESULTS: 1,534 CRC patients and 15,333 controls were identified. The average number of reported Hb tests in primary care per year increased successively, and diagnostic delay from detection of anemia to diagnosis of CRC decreased; in 2015-17 it was median 4 (IQR 2-6) months. No association was found between last Hb and stage of right-/left-sided colon, or rectal cancer.A statistically significantly lower Hb in CRC patients was discernable 609 days (20 months) prior to diagnosis for men and 905 days (30 months) for women, both in the range of normal Hb. The frequency of Hb testing in the general population via primary care was surprisingly low, and was ≥50% annually only in octogenarians. CONCLUSION: The findings indicate a potential for Hb trends to inform the diagnostic process of CRC but whether it will translate into any clinical advantage is yet uncertain.

War termination and women's political rights.

Does the manner in which a civil war is terminated affect women's political rights developments? In this article, we develop an analytical framework showing how the context of war termination type affects both the opportunity and willingness of warring parties and their openness towards the influence of international actors, thereby making it possible to translate social ruptures and pressures from women's groups into post-war improvements in women's political rights. Studying 205 civil war terminations in 69 countries since 1989, we find support for our claim that a conflict terminated through the negotiation and implementation of a comprehensive peace agreement significantly improved women's political rights in the post-war period when compared to other types of conflict termination. This finding holds after controlling for the women's rights provisions negotiated in the agreement. Our results carry substantial policy relevance by underlining the significance of women's inclusion in peace processes.

Diagnostic accuracy of a quantitative faecal immunochemical test vs. symptoms suspected for colorectal cancer in patients referred for colonoscopy.

Objective: Determine diagnostic accuracy of a quantitative faecal immunochemical haemoglobin test (QuikRead go® FIT, Orion Diagnostica Oy) in symptomatic patients referred for colonoscopy, at various cut-offs and for one or two tests.Methods: Patients referred to four endoscopy units in mid-Sweden between 2013 and 2017 provided information on lower abdominal symptoms and faecal samples from two separate days prior to colonoscopy.Results: In all, 5.4% (13/242) patients had colorectal cancer (CRC). For one FIT at cut-off 10 µg Hb/g faeces, sensitivity for CRC was 92% (95% CI 78-100%) and specificity 77% (95% CI 72-83%); equal to 74%; 95% CI 68-80 (178/242) colonoscopies potentially avoidable and one CRC missed. Based on the maximal outcome of two FITs, sensitivity was 100%, specificity 71% (66-77%) and 68%; 95% CI 62-74 (160/237) colonoscopies potentially avoidable. Among 17% (42/242) patients with one FIT of >200 µg Hb/g faeces, 85% (11/13) had CRC. Positive predictive values of FIT varied 16.9-26.2% depending on cut-off and one or two FITs, whereas NPVs were 99% and above in all scenarios.In 60 patients reporting rectal bleeding, one FIT at cut-off 10 µg Hb/g discriminated well between CRC and other conditions (p = .001). In regression models, FIT was more important than age, sex and all symptoms.Conclusion: One or two FITs in symptomatic patients referred for colonoscopy imply powerful risk stratification abilities for CRC, even among patients reporting rectal bleeding. Larger studies in various settings will clarify how to make the best use of this opportunity. Trial registration: Clinicaltrails.gov NCT02491593.

Immune checkpoint inhibitors of the PD-1/PD-L1-axis in non-small cell lung cancer: promise, controversies and ambiguities in the novel treatment paradigm.

Immune checkpoint inhibitors (ICIs) have received much attention not least for melanoma since the award of the Nobel prize in 2018. Here, we review the current state of knowledge about the use of these monoclonal antibodies (mAbs) in non-small cell lung cancer (NSCLC). These drugs have generally been conditionally approved on limited early data and there are few long-term follow-up data from randomized clinical trials. The effect observed for NSCLC thus far is, on average, moderately better than that obtained with chemotherapy. Severe side-effects are more common than might have been expected. The drugs themselves are expensive and are associated with time-consuming histopathologic testing even though the predictive value of these tests can be discussed. In addition, monitoring for side-effects involves increased workload and budgetary expense for clinical chemistry laboratories. Here, we review and summarize the current knowledge, controversies and ambiguities of ICIs for the treatment of NSCLC.

First-degree relatives of cancer patients: a target group for primary prevention? A cross-sectional study.

BACKGROUND: Persons with a first-degree relative (FDR) with cancer are at increased cancer risk. We investigated preventive behaviour, cancer risk perception and readiness to change an unhealthy lifestyle in persons with and without an FDR with cancer. METHODS: Using an online questionnaire, we conducted a cross-sectional study in Germany including persons (≥35 years) with an FDR with colorectal, lung, prostate, breast, stomach or cervical/uterine cancer (n = 621) and persons without cancer in FDRs (n = 303). Quota sampling ensured similar age and sex distributions in both groups. RESULTS: Unfavourable lifestyle factors were equally common in both groups. The proportion perceiving an increased cancer risk significantly differed (p < 0.0001) with 4% among respondents without cancer in FDRs and 18% (colorectal cancer) to 30% (stomach cancer) among cancer patients' relatives. The proportion of smokers ready to quit smoking was significantly higher among those perceiving an increased vs. a lower cancer risk (64 vs. 46%, p = 0.04). There was a similar association for readiness to increase physical activity and consumption of fruits/vegetables and to reduce alcohol consumption. CONCLUSIONS: Given the increased risk perception and motivation to change an unhealthy lifestyle, our study provides a strong rationale for research on the effectiveness of lifestyle interventions in cancer patients' relatives.

The effect of soot on ammonium nitrate species and NO2 selective catalytic reduction over Cu-zeolite catalyst-coated particulate filter.

A selective catalytic reduction (SCR)-coated particulate filter was evaluated by means of dynamic tests performed using NH3, NO2, O2 and H2O. The reactions were examined both prior to and after soot removal in order to study the effect of soot on ammonium nitrate formation and decomposition, ammonia storage and NO2 SCR. A slightly larger ammonia storage capacity was observed when soot was present in the sample, which indicated that small amounts of ammonia can adsorb on the soot. Feeding of NO2 and NH3 in the presence of O2 and H2O at low temperature (150, 175 and 200°C) leads to a large formation of ammonium nitrate species and during the subsequent temperature ramp using H2O and argon, a production of nitrous oxides was observed. The N2O formation is often related to ammonium nitrate decomposition, and our results showed that the N2O formation was clearly decreased by the presence of soot. We therefore propose that in the presence of soot, there are fewer ammonium nitrate species on the surface due to the interactions with the soot. Indeed, we do observe CO2 production during the reaction conditions also at 150°C, which shows that there is a reaction with these species and soot. In addition, the conversion of NOx due to NO2 SCR was significantly enhanced in the presence of soot; we attribute this to the smaller amount of ammonium nitrate species present in the experiments where soot is available since it is well known that ammonium nitrate formation is a major problem at low temperature due to the blocking of the catalytic sites. Further, a scanning electron microscopy analysis of the soot particles shows that they are about 30-40 nm and are therefore too large to enter the pores of the zeolites. There are likely CuxOy or other copper species available on the outside of the zeolite crystallites, which could have been enhanced due to the hydrothermal treatment at 850°C of the SCR-coated filter prior to the soot loading. We therefore propose that soot is interacting with the ammonium nitrate species on the CuxOy or other copper species on the surface of the zeolite particles, which reduces the ammonium nitrate blocking of the catalyst and thereby results in higher NO2 SCR activity.

Interpretation of H2-TPR from Cu-CHA Using First-Principles Calculations.

Temperature-programmed reduction and oxidation are used to obtain information on the presence and abundance of different species in complex catalytic materials. The interpretation of the temperature-programmed reaction profiles is, however, often challenging. One example is H2 temperature-programmed reduction (H2-TPR) of Cu-chabazite (Cu-CHA), which is a material used for ammonia assisted selective catalytic reduction of NOx (NH3-SCR). The TPR profiles of Cu-CHA consist generally of three main peaks. A peak at 220 °C is commonly assigned to ZCuOH, whereas peaks at 360 and 500 °C generally are assigned to Z2Cu, where Z represents an Al site. Here, we analyze H2-TPR over Cu-CHA by density functional theory calculations, microkinetic modeling, and TPR measurements of samples pretreated to have a dominant Cu species. We find that H2 can react with Cu ions in oxidation state +2, whereas adsorption on Cu ions in +1 is endothermic. Kinetic modeling of the TPR profiles suggests that the 220 °C peak can be assigned to Z2CuOCu and ZCuOH, whereas the peaks at higher temperatures can be assigned to paired Z2Cu and Z2CuHOOHCu species (360 °C) or paired Z2Cu and Z2CuOOCu (500 °C). The results are in good agreement with the experiments and facilitate the interpretation of future TPR experiments.

[Conflicts of interest are ever present in medical research]. / Intressekonflikter påverkar den medicinska forskningen i alla led.

Considerable efforts have been undertaken to optimize the disclosures of authors but transparency alone will not solve the problem. Financial conflicts of interest in clinical trials are known to affect the research question, study design, and results as well as the conclusions. Non-financial conflicts of interest are less well studied. As a non-negligible proportion of studies are associated with conflicts of interest, more research in this field is warranted, in particular on the management and consequences of such conflicts.

Accuracy of a faecal immunochemical test in patients under colonoscopy surveillance of colorectal adenoma and cancer.

Background: Surveillance of colorectal neoplasia place great strain on colonoscopy resources, and faecal immunochemical tests (FIT) are under-investigated for this purpose. The aim of this study was to report the outcome of FIT among patients scheduled for post-polypectomy and post-resection colorectal cancer (CRC) surveillance. Methods: Patients scheduled for colonoscopy surveillance at five endoscopy units in mid-Sweden in 2016-2020 were eligible. They provided a faecal sample from 2 separate days, which were analysed by iFOBT QuikRead go® (Aidian Oy). Both the colonoscopies, and the FIT analyses were conducted by staff blinded to the other. Results: Out of 216 included patients, 157 (73%) underwent both a complete colonoscopy and had at least one FIT analysed prior to the examination. The indication for surveillance was previous adenoma in 69 (44%) and post-resection CRC in 88 (56%) patients. Two (1%) in the CRC surveillance group were diagnosed with a metachronous CRC, whereas 49 (56%) patients in the CRC surveillance, and 17 (25%) in the adenoma group had no pathology identified at colonscopy (P < 0.001). The proportion of patients diagnosed with adenomas requiring surveillance according to European Society of Gastrointestinal Society (ESGE) guidelines 2020 was 6 (7%) in the post-CRC resection versus 7 (10%) in the adenoma surveillance group (P = 0.4). Based on one FIT and at cut-off 10 µg Hb/g, sensitivity for CRC was 100%, specificity 83% (95% confidence interval [CI]: 77-89), Positive Predictive Value (PPV) 7% (-2 to 16) and Negative Predictive Value (NPV) 100%. All patients with an adenoma requiring surveillance had a FIT below this cut-off. Adding a second FIT decreased the specificity. Conclusion: Larger studies to evaluate the accuracy and consequences of using FIT for surveillance of colorectal neoplasia are needed. FIT may be more interesting for post-resection CRC surveillance than follow-up of adenoma.

Conflict of interest and risk of bias in systematic reviews on methylphenidate for attention-deficit hyperactivity disorder: a cross-sectional study.

BACKGROUND: Systematic reviews (SRs) are pivotal to evidence-based medicine, yet there is limited research on conflicts of interest in SRs. Our aim was to investigate financial conflicts of interest and risk of bias (RoB) in SRs of a well-defined clinical topic. METHODS: A librarian searched Medline, Cochrane Library, Embase, and PsycINFO for SRs investigating the effect of methylphenidate on ADHD in December 2020. The selection process adhered to the PRISMA guidelines. Two blinded reviewers independently searched open websites, including other publications, for information on financial conflicts of interest of all authors of the included SRs. A time limit of 3 years before or after the index SR was adopted. Declarations on conflict of interest were extracted from the included SRs for comparison. ROBIS was used for RoB assessment. RESULTS: Out of 44 SRs included, 15 (34%) declared conflict of interest, 27 (61%) did not, and a declaration of conflict of interest was missing for 2 (5%). On open websites, conflict of interest was found for at least one author of 23 (52%) SRs: disclosed in 15 (34%) and not disclosed in 8 (18%) SRs. Seven (16%) SRs had low, 36 (82%) had high, and 1 (2%) had unclear RoB. Among SRs with financial conflict of interest found in open sources, 6/22 (27%) had low RoB compared to 1/21 (5%) if no such conflict of interest was identified. Among SRs with financial conflict of interest identified, 1/6 (17%) at low RoB did not disclose their conflict of interest, whereas the corresponding proportion among SRs at high RoB was 7/16 (44%). Eight (18%) SRs presented conflict of interest disclosed in the included primary studies. Four of them (50%) had low RoB, compared to 3/36 (8%) for SRs not reporting on this aspect. CONCLUSION: Financial conflict of interest was underreported in 18% of the SRs using our reference standard, and overall it was present for every second SR. This group embraced both SRs at low RoB disclosing conflict of interest and SRs at high RoB not disclosing their conflict of interest. Further studies to explore this heterogeneity are warranted.

Diagnostic accuracy for colorectal cancer of a quantitative faecal immunochemical test in symptomatic primary care patients: a study protocol.

BACKGROUND: There is increasing evidence supporting the use of faecal immunochemical tests (FIT) in patients reporting symptoms associated with colorectal cancer (CRC), but most studies until now have focused on selected subjects already referred for investigation. We therefore set out to determine the accuracy and predictive values of FIT in a primary care population. METHOD: A prospective, multicentre, single-gated comparative diagnostic study on quantitative FIT in patients aged 40 years and above presenting in primary care with symptoms associated with CRC will be conducted. Patients representing the whole spectrum of severity of such symptoms met with in primary care will be eligible and identified by GPs. Participants will answer a short form on symptoms during the last month. They will provide two faecal samples from two separate days. Analyses will be performed within 5 days (QuikRead go®, Aidian Oy). The analytical working range is 10-200 µg Hb/g faeces. Reference test will be linked to the Swedish Colorectal Cancer Registry up to 2 years after inclusion. Accuracy, area under ROC curves, and predictive values will be calculated for one FIT compared to the highest value of two FIT and at cutoff < 10, 10-14.9, 15-19.9 and ≥ 20 µg Hb/g faeces. Subgroup analyses will be conducted for patients with anaemia and those reporting rectal bleeding. A model-based cost-effectiveness analysis based on the clinical accuracy study will be performed. Based on previous literature, we hypothesized that the sensitivity of the highest value of two FIT at cutoff 10 µg Hb/g faeces will be 95% (95% CI + / - 15%). The prevalence of CRC in the study population was estimated to be 2%, and the rate of non-responders to be 1/6. In all, 3000 patients will be invited at 30 primary care centres. DISCUSSION: This study will generate important clinical real-life structured data on accuracy and predictive values of FIT in the most critical population for work-up of CRC, i.e. patients presenting with at times ambiguous symptoms in primary care. It will help establish the role of FIT in this large group. TRIAL REGISTRATION: NCT05156307 . Registered on 14 December 2021-retrospectively registered.

The glimmering embers: experiences of hope among cancer patients in palliative home care.

OBJECTIVE: The experience of hope among cancer patients in palliative care is important information for healthcare providers, but research on the subject is sparse. The aim of this article was to explore how cancer patients admitted to palliative home care experienced the significance of hope and used hope during 6 weeks throughout the last phase of their life, and to assess their symptoms and hope status during 6 weeks throughout the last phase of their lives. METHOD: Eleven adult patients with cancer participated in 20 interviews and completed seven diaries. The participants were recruited from two palliative care units in the southeast of Sweden. The method used was Grounded Theory (GT), and analysis was based on the constant comparative method. RESULTS: The core category, glimmering embers, was generated from four processes: (1) The creation of "convinced" hope, with a focus on positive events, formed in order to have something to look forward to; (2) The creation of "simulated hope," including awareness of the lack of realism, but including attempts to believe in unrealistic reasons for hope; (3) The collection of and maintaining of moments of hope, expressing a wish to "seize the day" and hold on to moments of joy and pleasure; and (4) "Gradually extinct" hope, characterized by a lack of energy and a sense of time running out. SIGNIFICANCE OF RESULTS: The different processes of hope helped the patients to continue to live when they were close to death. Hope should be respected and understood by the professionals giving them support.

A Nationwide Cohort Study of Outcome after Pediatric Appendicitis.

INTRODUCTION: Children with appendicitis often present with complicated disease. The aim of this study was to describe the clinical management of pediatric appendicitis, and to report how disease severity and operative modality are associated with short- and long-term risks of adverse outcome. MATERIALS AND METHODS: A nationwide retrospective cohort study of all Swedish children (<18 years) diagnosed with appendicitis, 2001 to 2014 (n = 38,939). Primary and secondary outcomes were length of stay, surgical site infections, readmissions, 30-day mortality, and long-term risk of surgery for small bowel obstruction (SBO). Implications of complicated disease and operative modality were assessed with adjustment for age, gender, and trends over time. RESULTS: Complicated appendicitis was associated with longer hospital stay (4 vs. 2 days, p < 0.001), increased risk of surgical site infection (5.9 vs. 2.3%, adjusted odds ratio [aOR]: 2.64 [95% confidence interval, CI: 2.18-3.18], p < 0.001), readmission (5.5 vs. 1.2, aOR: 4.74 [95% CI: 4.08-5.53], p < 0.001), as well as long-term risk of surgery for SBO (0.7 vs. 0.2%, adjusted hazard ratio [aHR]: 3.89 [95% CI: 2.61-5.78], p < 0.001). Intended laparoscopic approach was associated with reduced risk of surgical site infections (2.3 vs. 3.1%, aOR: 0.74 [95% CI: 0.62-0.89], p = 0.001), but no overall reduction in risk for SBO; however, successful laparoscopic appendectomy was associated with less SBO during follow-up compared with open appendectomy (aHR: 0.27 [95% CI: 0.11-0.63], p = 0.002). CONCLUSION: Children treated for complicated appendicitis are at risk of substantial short- and long-term morbidities. Fewer surgical site infections were seen after intended laparoscopic appendectomy, compared with open appendectomy, also when converted procedures were accounted for.

Maintaining hope when close to death: insight from cancer patients in palliative home care.

PURPOSE: This article reports the social and psychological processes that 11 cancer patients receiving palliative home care used to keep their hope alive. METHOD: The patients described their ways of dealing with hope in interviews and diaries, and it was from these accounts that the processes were extracted, using a grounded theory methodology. RESULTS: Two main processes emerged: maintaining life and preparing for death. When the patients focused on maintaining life, they tried to preserve its meaning and to communicate with others about life and death. They found it helpful to shift their focus and to involve fellow 'travellers' in their journey. To prepare for death was to take responsibility for the future and to see possibilities of living on even after death. CONCLUSION: This paper revealed two parallel and interdependent processes used by patients in the palliative care phase to maintain hope and respond to living close to death.

Prognostic Potential of Circulating Tumor DNA Measurement in Postoperative Surveillance of Nonmetastatic Colorectal Cancer.

IMPORTANCE: For patients with resected, nonmetastatic colorectal cancer (CRC), the optimal surveillance protocol remains unclear. OBJECTIVE: To evaluate whether serial circulating tumor DNA (ctDNA) levels detected disease recurrence earlier, compared with conventional postoperative surveillance, in patients with resected CRC. DESIGN, SETTING, AND PARTICIPANTS: This study included patients (n = 58) with stage I, II, or III CRC who underwent radical surgical resection at 4 Swedish hospitals from February 2, 2007, to May 8, 2013. Eighteen patients received adjuvant chemotherapy at the discretion of their clinicians, who were blinded to the ctDNA results. Blood samples were collected at 1 month after the surgical procedure and every 3 to 6 months thereafter for ctDNA analysis. Patients were followed up until metachronous metastases were detected, or for a median of 49 months. Data analysis was performed from March 1, 2009, to June 23, 2018. MAIN OUTCOMES AND MEASURES: Sensitivity and timing of ctDNA positivity were compared with those of conventional surveillance modalities (computed tomographic scans and serum carcinoembryonic antigen tests) for the detection of disease recurrence. RESULTS: This study included 319 blood samples from 58 patients, with a median (range) age of 69 (47-83) years and 34 males (59%). The recurrence rate among patients with positive ctDNA levels was 77% (10 of 13 patients). Positive ctDNA preceded radiologic and clinical evidence of recurrence by a median of 3 months. Of the 45 patients with negative ctDNA throughout follow-up, none (0%; 95% CI, 0%-7.9%) experienced a relapse, with a median follow-up of 49 months. However, 3 (6%; 95% CI, 1.3%-17%) of the 48 patients without relapse had a positive ctDNA result, which subsequently fell to undetectable levels during follow-up. CONCLUSION AND RELEVANCE: Although these findings need to be validated in a larger, prospective trial, they suggest that ctDNA analysis could complement conventional surveillance strategies as a triage test to stratify patients with resected CRC on the basis of risk of disease recurrence.

Lack of an association between the TGFBR1*6A variant and colorectal cancer risk.

PURPOSE: Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies. EXPERIMENTAL DESIGN: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted. RESULTS: We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A. CONCLUSION: Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer.

Detection of APC mutations in fecal DNA from patients with colorectal tumors.

BACKGROUND: Noninvasive methods for detecting colorectal tumors have the potential to reduce morbidity and mortality from this disease. The mutations in the adenomatous polyposis coli (APC) gene that initiate colorectal tumors theoretically provide an optimal marker for detecting colorectal tumors. The purpose of our study was to determine the feasibility of detecting APC mutations in fecal DNA with the use of newly developed methods. METHODS: We purified DNA from routinely collected stool samples and screened for APC mutations with the use of a novel approach called digital protein truncation. Many different mutations could potentially be identified in a sensitive and specific manner with this technique. RESULTS: Stool samples from 28 patients with nonmetastatic colorectal cancers, 18 patients with adenomas that were at least 1 cm in diameter, and 28 control patients without neoplastic disease were studied. APC mutations were identified in 26 of the 46 patients with neoplasia (57 percent; 95 percent confidence interval, 41 to 71 percent) and in none of the 28 control patients (0 percent; 95 percent confidence interval, 0 to 12 percent; P<0.001). In the patients with positive tests, mutant APC genes made up 0.4 to 14.1 percent of all APC genes in the stool. CONCLUSIONS: APC mutations can be detected in fecal DNA from patients with relatively early colorectal tumors. This feasibility study suggests a new approach for the early detection of colorectal neoplasms.

The CHEK2 1100delC variant in Swedish colorectal cancer.

BACKGROUND: The cell cycle checkpoint kinase 2 (CHEK2) 1100delC variant has recently been identified at high frequency in families with both breast and colorectal cancer, suggesting the possible role of this variant in colorectal cancer predisposition. PATIENTS AND METHODS: To evaluate the role of CHEK2 ll00delC among Swedish colorectal cancer patients, the variant frequency was determined in 174 selected familial cases, 644 unselected cases and 760 controls, as well as in l8 families used in the genome-wide linkage analysis, where weak linkage was seen for the region harboring the CHEK2 gene. RESULTS: CHEK2 l100delC was found in 1.15% of familial and in 0.93% of unselected cases, compared to 0.66% of controls, showing no significant difference between groups. One out of 45 familial cases with a family history of breast cancer was shown to be a carrier. The variant was not identified in the 18 families included in the linkage analysis. CONCLUSION: The CHEK2 1100delC was not significantly increased in Swedish colorectal cancer patients, however, in order to determine the role of the variant in colorectal cancer families with the history of breast cancer a larger sample size is needed.

Family history of colorectal cancer in a Sweden county.

Hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatosis polyposis (FAP) are well-known high-risk cancer syndromes. Hereditary colorectal cancer (HCRC) with at least three relatives with colorectal cancer and a dominant pattern of inheritance but with no specifications for age at onset and two close relatives with colorectal cancer (TCR) are other forms of familial clustering known to carry an increased risk of the disease. The frequency of the total burden of familial colorectal cancer is not well known. We therefore investigated the family history of 400/411 (97%) eligible patients with recently diagnosed colorectal cancer in Västmanland county, Sweden, during a 3-year period. Records or death certificates confirmed the diagnoses of relatives. Five patients (1.2%, 95% CI 0.15-2.2) were diagnosed as having HNPCC, eight (1.9%, 95% CI 0.6-3.2) as having HCRC and thirty-four (8.3%, 95% CI 5.6-11.0) were identified as having TCR. In total, 47 patients (11.4%, 95% CI 8.3-14.5) were found to have a contributing familial background. The implication is thus that every ninth patient with colorectal cancer represents a highly or intermediately increased risk of the disease among relatives. We conclude that the low frequency of individuals identified by family history alone makes the establishment of surveillance programs feasible.