Therapy with pembrolizumab in treatment-naïve patients with nonmetastatic, mismatch repair deficient colorectal cancer.

Therapy with immune checkpoint inhibitors (ICI) is effective in patients with metastatic mismatch-repair deficient (dMMR) colorectal cancer (CRC); however, data on treatment with neoadjuvant ICI in patients with locally advanced CRC are limited. From March 2019 to June 2020, five Danish oncological centers treated 10 patients with a treatment-naïve dMMR CRC with preoperative pembrolizumab, 9 with a nonmetastatic, unresectable colon cancer and 1 with a locally advanced rectum cancer. All 10 patients were evaluated regularly at a multidisciplinary team (MDT) meeting, and they all had a radical resection after a median of 8 cycles (range 2-13) of pembrolizumab. A microscopic evaluation of the resected tumors revealed no remaining tumor cells in five patients, while five still had tumor cells present. The patients were given no additional therapy. No recurrences were reported after a median follow-up of 26 months (range 23-38.5 months). Biopsies from Danish patients with CRC are routinely screened for dMMR proteins. In 2017, data from the Danish Colorectal Cancer Group showed that 19% (565/3000) of the patients with colon cancer and 1.5% (19/1279) of those with rectum cancer had an dMMR tumor. Among the patients with MMR determination, 26% (99/384) patients had a T4 dMMR colon cancer; thus, the 10 patients treated with neoadjuvant pembrolizumab comprised about 9% of the patients with a T4 dMMR colon cancer (9/99) and 5% of patients with dMMR rectal cancer (1/19). Therapy with pembrolizumab was feasible and effective. Larger prospective trials are needed to confirm our findings.

Association between plane of mesocolic dissection and recurrence after complete mesocolic excision for right-sided colon cancer: a cohort study.

AIM: Dissection in the mesocolic plane is considered by some medical professionals to be crucial in complete mesocolic excision. We aimed to assess whether intramesocolic plane dissection is associated with a risk of recurrence after complete mesocolic excision for right-sided colon cancer. METHOD: This is a single-centre study based on prospectively registered data on patients undergoing resection for Union for International Cancer Control Stage I-III right-sided colon adenocarcinoma during the period 2010-2017. Patients were stratified in an intramesocolic plane group or a mesocolic plane group based on a prospective assessment of fresh specimens by a pathologist. Primary outcome was the 4.2 year risk of recurrence after inverse probability treatment weighting and competing risk analyses. RESULTS: Of 383 patients, 4 (1%) were excluded as the specimen was assessed as muscularis propria plane, 347 (91.6%) specimens were deemed as mesocolic and 32 (8.4%) as intramesocolic. The 4.2 year cumulative incidence of recurrence after inverse probability treatment weighting was 9.1% (95% CI 6.0%-12.1%) in the mesocolic group compared with 14.0% (3.6%-24.5%) in the intramesocolic group with an absolute risk difference in favour of mesocolic plane dissection of 4.9% (-5.7 to 15.6, p = 0.37). No difference was observed in the risk of local recurrence, death before recurrence or overall survival after 4.2 years between the two groups. CONCLUSION: Mesocolic plane dissection can be achieved in more than 90% of patients. The classification seems to be a guide for good surgical practice and not to be used for research purposes.

Validation of the German classification system for quality assessment of right-sided colon cancer specimens.

AIM: The German classification system of the completeness of mesocolic excision aims to assess the quality of right-sided colonic cancer surgery by review of photographs. We aimed to validate the reliability of the classification in a clinical context. METHOD: The study was based on a cohort of patients undergoing resection for right-sided colon cancer in two university hospitals served by the same group of pathologists. Prospectively collected photographs of the specimens were assessed twice by six colorectal surgeons to determine the intra-rater and inter-rater accuracy of the German classification and a modification assessing extended right-sided resections. RESULTS: Specimens from 613 resections for right-sided colon cancer were reviewed. Twenty-one specimens were found to be non-assessable, leaving 436 right hemicolectomies, 139 extended right hemicolectomies and 17 right-sided subtotal colectomies. Intra-rater reliability was 0.57-0.74 and weighted kappa coefficients 0.58-0.74, without differences between subgroups. The percentage of agreement between all six participants was 20.3% for all specimens, 21.1% for right hemicolectomy specimens and 18.1% for extended hemicolectomy and right-sided subtotal colectomy specimens. For the right hemicolectomy specimens, the model-based kappa coefficient for agreement was 0.27 (95% CI 0.24-0.30) and for association 0.45 (95% CI 0.41-0.49). CONCLUSION: The German classification of right hemicolectomy specimens showed low intra-rater reliability and inter-rater agreement and association. The use of this classification for scientific purposes appeared not to be reliable.

Early detection of colorectal neoplasia: application of a blood-based serological protein test on subjects undergoing population-based screening.

BACKGROUND: Blood-based biomarkers used for colorectal cancer screening need to be developed and validated in appropriate screening populations. We aimed to develop a cancer-associated protein biomarker test for the detection of colorectal cancer in a screening population. METHODS: Participants from the Danish Colorectal Cancer Screening Program were recruited. Blood samples were collected prior to colonoscopy. The cohort was divided into training and validation sets. We present the results of model development using the training set. Age, sex, and the serological proteins CEA, hsCRP, TIMP-1, Pepsinogen-2, HE4, CyFra21-1, Galectin-3, ferritin and B2M were used to develop a signature test to discriminate between participants with colorectal cancer versus all other findings at colonoscopy. RESULTS: The training set included 4048 FIT-positive participants of whom 242 had a colorectal cancer. The final model for discriminating colorectal cancer versus all other findings at colonoscopy had an AUC of 0.70 (95% CI: 0.66-0.74) and included age, sex, CEA, hsCRP, HE4 and ferritin. CONCLUSION: The performance of the biomarker signature in this FIT-positive screening population did not reflect the positive performance of biomarker signatures seen in symptomatic populations. Additional biomarkers are needed if the serological biomarkers are to be used as a frontline screening test.

Nonmicroradical Resection Margin as a Predictor of Recurrence in Patients With Stage III Colon Cancer Undergoing Complete Mesocolic Excision: A Prospective Cohort Study.

BACKGROUND: The prognostic value of the present definition of microradicality in colon cancer is poorly understood, especially considering the vast influence it has in rectal cancer prognosis. OBJECTIVE: This study aimed to investigate whether the risk of recurrence after complete mesocolic excision for stage III colon cancer is associated with the distance from tumor tissue to resection margin and whether the location of the involved margin is of any significance. DESIGN: A prospective cohort of patients was stratified into 2 groups to distinguish between direct margin invasion (0-mm resection margin) and a ≤1-mm resection margin without direct invasion or 3 groups to distinguish between the location of margin involvement (lateral tumor resection margin, central vascular ligation margin, and nonperitonealized mesocolic resection margin). Patients with microradical resections were used as a control group. SETTINGS: We included all patients undergoing elective complete mesocolic excision for International Union Against Cancer stage III colon cancer at Nordsjællands Hospital between January 1, 2008, and December 31, 2016. PATIENTS: A total of 276 patients met all inclusion criteria and none of the exclusion criteria. MAIN OUTCOME MEASURES: Primary outcome was risk of recurrence after 3.2 years. RESULTS: A total of 41 patients (15%) had a nonmicroradical resection. The 3.2-year cumulative incidence of recurrence for a 0-mm margin was 43% and 24% for a ≤1-mm margin without direct invasion, corresponding with an HR of 4.3 (p = 0.0146) and 1.3 (p = 0.474). The location of the involved margin showed no significant differences. LIMITATIONS: This was a single-center study containing a limited number of patients with a nonmicroradical resection with a risk of type II error. CONCLUSIONS: We found no increased risk of recurrence for a ≤1-mm margin without direct invasion, indicating that the present classification of microradicality might not be justified if an intact posterior mesocolic fascia without invasion of tumor tissue is present. See Video Abstract at http://links.lww.com/DCR/B625. MARGEN DE RESECCIN NO MICRORRADICAL COMO PREDICTOR DE RECURRENCIA EN PACIENTES CON CNCER DE COLON EN ESTADIO III SOMETIDOS A ESCISIN MESOCLICA COMPLETA UN ESTUDIO DE COHORTE PROSPECTIVO: ANTECEDENTES:El valor pronóstico de la definición actual de microrradicalidad en el cáncer de colon es poco conocido, especialmente considerando la gran influencia que tiene en el pronóstico del cáncer de recto.OBJETIVO:Este estudio tiene como objetivo investigar si el riesgo de recurrencia después de la escisión mesocólica completa (CME) para el cáncer de colon en estadio III está asociado con la distancia desde el tejido tumoral hasta el margen de resección y si la localización del margen afectado tiene alguna importancia.DISEÑO:Una cohorte prospectiva de pacientes se estratificó en dos grupos para distinguir entre la invasión del margen directo (margen de resección de 0 mm) y un margen de resección ≤1 mm sin invasión directa, o tres grupos para distinguir entre la localización de la afectación del margen (resección lateral del margen del tumor, margen de ligadura vascular central y margen de resección mesocólica no peritonizada). Los pacientes con resecciones microrradicales se utilizaron como grupo control.ENTORNO CLÍNICO:Incluimos a todos los pacientes sometidos a CME electiva por cáncer de colon en estadio III de la UICC en el Hospital Nordsjællands, Dinamarca, entre el 1 de enero de 2008 y el 31 de diciembre de 2016.PACIENTES:Un total de 276 pacientes cumplieron todos los criterios de inclusión y ninguno de los criterios de exclusión.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue el riesgo de recurrencia después de 3 · 2 años.RESULTADOS:Un total de 41 (15%) pacientes tuvieron una resección no microrradical. La incidencia acumulada de recurrencia a los 3,2 años para un margen de 0 mm fue del 43% y del 24% para un margen ≤1 mm sin invasión directa, lo que corresponde a un cociente de riesgo de 4,3 (p = 0,0146) y 1,3 (p = 0,474) respectivamente. La localización del margen afectado no mostró diferencias significativas.LIMITACIONES:Estudio unicéntrico con un número limitado de pacientes con resección no microrradical con riesgo de error tipo II.CONCLUSIONES:No encontramos un mayor riesgo de recurrencia para un margen ≤1 mm sin invasión directa, lo que indica que la clasificación actual de microrradicalidad podría no estar justificada si está presente una fascia mesocólica posterior intacta sin invasión del tejido tumoral. Consulte Video Resumen en http://links.lww.com/DCR/B625. (Traducción-Dr Yazmin Berrones-Medina).

Plane of mesocolic dissection as predictor of recurrence after complete mesocolic excision for sigmoid colon cancer: A cohort study.

AIM: To investigate whether intramesocolic plane dissection assessed on fresh specimens by the pathologist is a risk factor for recurrence after complete mesocolic excision for sigmoid cancer when compared with mesocolic plane dissection. METHOD: Single-centre study based on prospectively registered data on patients undergoing resection for UICC stage I-III sigmoid colon adenocarcinoma during the period 2010-2017. The patients were stratified into either an intramesocolic plane group or a mesocolic plane group. Primary outcome was risk of recurrence after 4.2 years using inverse probability treatment weighting and competing risk analyses. RESULTS: Of a total of 332 patients, two were excluded as the specimen was assessed as muscularis propria plane, 237 (72%) specimens were deemed as mesocolic and 93 (28%) as intramesocolic. The 4.2-year cumulative incidence of recurrence after inverse probability treatment weighting was 14.9% (10.4-19.3) in the mesocolic group compared with 9.4% (3.7-15.0) in the intramesocolic group, thus the absolute risk difference between the mesocolic plane and intramesocolic plane was 5.5% (-12.5-1.6; p = 0.13) in favour of the intramesocolic group. CONCLUSION: Intramesocolic plane dissection was not a risk factor for recurrence after complete mesocolic excision for sigmoid cancer when compared with mesocolic plane dissection. No difference in risk of local recurrence, death before recurrence, and in overall survival after 4.2 years was observed between the two groups. With less than 1% of the specimens deemed as muscularis propria plane dissection, the classification appears unusable for the risk prediction of sigmoid colon cancer.

Agreement between the Danish Cancer Registry and the Danish Colorectal Cancer Group Database.

Background: The Danish Cancer Registry (DCR) and the Danish Colorectal Cancer Group (DCCG) database are population-based registries collecting information on Danish patients with colorectal cancer (CRC). DCR registers all patients with incident CRC whereas DCCG records patients with first time CRC. The registries use different inclusion criteria. The consequencenses of this are unknown and not previously evaluated. The aim of this study was to examine the agreement between patients registered in DCR and DCCG and to evaluate its influence on estimated survival and mortality.Material and methods: Patients registered in DCR and DCCG with CRC in 2014-2015 were included. Because of different inclusion criteria, DCCG's inclusion criteria were applied to DCR. Descriptive statistics were used for comparisons. One-year relative survival (1-year RS) was calculated, and the Cox proportional hazard model used for calculating 1-year mortality rate ratios (1-year MRR).Results: In 2014-2015, DCR registered 9678 Danish residents with CRC that fulfilled DCCG's inclusion criteria, while DCCG registered 10,312 Danish residents with CRC. Allowing ±180 days between dates of diagnosis, 10,688 patients were registered with CRC in the merger of the two registries. Of these, 86% were included in both registers, 4% only in DCR, and 10% only in DCCG. No difference was found in 1-year RS between patients in DCR 86% (95% CI: 85-87) and DCCG 85% (95% CI: 84-86). However, patients registered in DCCG had a 1-year MRR of 1.09 (95% CI: 1.01-1.17) compared to DCR.Conclusion: An agreement of 86% of patients was found between the two registries. The discrepancy did not influence 1-year RS. DCCG registered more patients than DCR, and 1-year MRR of patients in DCCG was increased compared to patients in DCR. Regular linkage of the registries is recommended to improve data quality of both registries.

5-year outcome after complete mesocolic excision for right-sided colon cancer: a population-based cohort study.

BACKGROUND: The benefits of extensive lymph node dissection as performed in complete mesocolic excision are still debated, although recent studies have shown an association with improved long-term outcomes. However, none of these studies had an intention-to-treat design or aimed to show a causal effect; therefore in this study, we aimed to estimate the causal oncological treatment effects of complete mesocolic excision on right-sided colon cancer. METHODS: We did a population-based cohort study involving prospective data collected from four hospitals in Denmark. We compared the oncological outcome data of patients at one centre performing central lymph node dissection and vascular division after almost complete exposure of the proximal part of the superior mesenteric vein (ie, the complete mesocolic excision group) with three other centres performing conventional resections with unstandardised and limited lymph node dissection (ie, non-complete mesocolic excision; control group). We included data for all patients in the Capital Region of Denmark undergoing elective curative-intent right-sided colon resections for stages I-III colon cancer, as categorised by the Union for International Cancer Control (UICC; 5th edition), from June 1, 2008, to Dec 31, 2013. Patients were followed-up for 5·2 years after surgery. The primary outcome was the cumulative incidence of recurrence after 5·2 years of surgery. Inverse probability of treatment weighting and competing risk analyses were used to estimate the possible causal effects of complete mesocolic excision. This study is registered with ClinicalTrials.gov, number NCT03754075. FINDINGS: 1069 patients (813 in the control group and 256 in the complete mesocolic excision group) underwent curative-intent elective surgery for right-sided colon cancer during the study period. None of the patients were lost to follow-up regarding survival or recurrence status, and consequently no patient was censored in the analyses. The 5·2-year cumulative incidence of recurrence was 9·7% (95% CI 6·3-13·1) in the complete mesocolic excision group compared with 17·9% (15·3-20·5) in the control group, and the absolute risk reduction of complete mesocolic excision after 5·2 years was 8·2% (95% CI 4·0-12·4; p=0·00015). In the control group, 145 (18%) of 813 patients were diagnosed with a recurrence and 281 (35%) died during follow-up, whereas in the complete mesocolic excision group 25 (10%) of 256 patients were diagnosed with a recurrence and 75 (29%) died during follow-up. INTERPRETATION: This study shows a causal treatment effect of central mesocolic lymph node excision on risk of recurrence after resection for right-sided colon adenocarcinoma. Complete mesocolic excision has the potential to reduce the risk of recurrence and improve long-term outcome after resection for all UICC stages I-III of right-sided colon adenocarcinomas. FUNDING: The Tvergaard Fund, Helen Rude Fund, Krista and Viggo Petersen Fund, Olga Bryde Nielsen Fund, and Else and Mogens Wedell-Wedellsborg Fund.

Effectiveness of Colorectal Cancer Screening in Detecting Earlier-Stage Disease-A Nationwide Cohort Study in Denmark.

BACKGROUND & AIMS: Most studies of the effectiveness of screening for colorectal cancer (CRC) using the fecal occult blood test tested the guaiac fecal occult blood test. However, the fecal immunochemical test (FIT) is now commonly used in screening. We aimed to evaluate the effectiveness of FIT-based screening for CRC on the number of incident CRC diagnoses and stage at diagnosis for individuals in Denmark who were invited for screening vs not yet invited. METHODS: We collected data for this register-based retrospective cohort study during the first 16 months of the prevalence round of a FIT-based CRC screening program (March 1, 2014 through June 30, 2015). A total of 402,826 residents of Denmark (50-72 years old) were randomly invited to undergo CRC screening within the study period, and 956,514 were invited thereafter. We obtained information on CRC diagnosis, date, and stage at diagnosis from the Danish Colorectal Cancer Group database. Cancer incidence per 100,000 invited/not yet invited individuals was calculated, along with the relative risk (RR) of CRC among invited compared with not yet invited individuals. RESULTS: CRC incidence during the study period was 339.4/100,000 invited individuals and 169.6/100,000 not yet invited individuals. CRC incidence increased with age among invited and not yet invited individuals. For invited women compared with not yet invited women, the RR of being diagnosed with stage I CRC was 3.39 (95% CI, 2.61-4.39), with stage II CRC was 2.16 (95% CI, 1.71-2.72), with stage III CRC was 1.37 (95% CI, 1.08-1.75), and with stage IV CRC was 0.92 (95% CI, 0.68-1.23). For invited men compared with not yet invited men, the RR of being diagnosed with stage I CRC was 3.71 (95% CI, 2.97-4.64); with stage II CRC was 2.26 (95% CI, 1.84-2.77), with stage III CRC was 1.88 (95% CI, 1.53-2.30), and with stage IV CRC was 1.20 (95% CI, 0.95-1.52). CONCLUSIONS: In analyzing data from a register-based cohort study in Denmark, we found that inviting individuals to undergo FIT-based CRC screening led to detection of almost 2-fold more cases of CRC than not inviting participants. The significant increase of CRC incidence among those invited for screening indicates a need for awareness of treatment capacity in countries introducing FIT-based CRC screening.

Potential for prevention: a cohort study of colonoscopies and removal of adenomas in a FIT-based colorectal cancer screening programme.

Introduction: Evidence suggests that colorectal cancer (CRC) screening using guaiac faecal occult blood tests (gFOBT) reduces the CRC burden by facilitating timely removal of adenomas. Yet, the faecal immunochemical test (FIT) is being implemented in many countries. The aim of this study was to analyse the risk of having adenomas detected when invited for FIT-based screening as compared to those not yet invited. Material and Methods: The study was designed as a register-based retrospective cohort study. The potential for prevention was estimated as number of individuals who had no adenomas, non-advanced adenomas, and advanced adenomas detected per 1000 invited/not yet invited individuals and the relative risk (RR) of each of the three outcomes. Results: A total of 1,359,340 individuals were included, 29.6% of whom had been invited and 70.4% had not yet been invited to participate in CRC screening. Compared with the not yet invited population, the invited group had a RR of no adenomas of 2.28 (2.22-2.34) and a RR of advanced adenomas of 7.41 (6.93-7.91). The RR of colonoscopy was 2.93 (2.87-2.99) for the invited population compared with the not yet invited population. Conclusion: The RR of having a colonoscopy was three times higher among those invited compared to those not yet invited for CRC screening and twice as often those who had been invited compared to those not yet invited had no adenomas detected. Still, the risk of advanced adenomas was more than seven times higher among the invited population, indicating that the screening programme holds great potential for reducing the CRC burden. Abbreviations: CI: Confidence interval; CRC: Colorectal cancer; FIT: Faecal immunochemical test; ICD: International Classification of Disease; RR: Relative risk.

Improved survival of colorectal cancer in Denmark during 2001-2012 - The efforts of several national initiatives.

Background The Danish Colorectal Cancer Group (DCCG) established a national clinical database in 2001 with the aim to monitor and improve outcome of colorectal cancer patients. Since 2000 several national initiatives have been taken to improve cancer outcome. In the present study we used DCCG data to evaluate mortality and survival of CRC patients with focus on comorbidity, stage, and perioperative treatment. Material and methods Patients notified to the DCCG database from 2001 to 2012 were included. Patients with primary cancer of the colon and rectum were analyzed separately. Analyses were stratified according to gender, comorbidity, Union for International Cancer Control (UICC) stage, and operative priority (elective/emergency/no surgery). Data were stratified into three time periods (2001-2004, 2005-2008, 2009-2012). Mortality and survival were age adjusted. Results In total 29 385 patients with colon cancer and 15 213 patients with rectal cancer were included. The stage distribution was almost stable over time. The mortality rate per 100 patient year within one year decreased from 32 to 26 in colon cancer and from 26 to 19 in rectal cancer with associated improvements in absolute survival from 73% to 78% in colon cancer and from 78% to 83% in rectal cancer. The five-year relative survival of colon cancer improved from 58% to 63% and in rectal cancer from 59% to 65%. Comorbidity had major negative impact on outcome. Irrespective of tumor location, outcome improved relatively more in patients with stage III and IV disease. The proportion of patients who were spared surgery increased from 8% to 15% in colon cancer and from 13% to 19% in rectal cancer, and these changes were associated with improved outcome for rectal cancer patients, whereas outcome worsened for colon cancer patients. Conclusion The Danish efforts to improve outcome of cancer have succeeded with improved outcomes in patients with colorectal cancer.

Disease-free survival after complete mesocolic excision compared with conventional colon cancer surgery: a retrospective, population-based study.

BACKGROUND: Application of the principles of total mesorectal excision to colon cancer by undertaking complete mesocolic excision (CME) has been proposed to improve oncological outcomes. We aimed to investigate whether implementation of CME improved disease-free survival compared with conventional colon resection. METHODS: Data for all patients who underwent elective resection for Union for International Cancer Control (UICC) stage I-III colon adenocarcinomas in the Capital Region of Denmark between June 1, 2008, and Dec 31, 2011, were retrieved for this population-based study. The CME group consisted of patients who underwent CME surgery in a centre validated to perform such surgery; the control group consisted of patients undergoing conventional colon resection in three other hospitals. Data were collected from the Danish Colorectal Cancer Group (DCCG) database and medical charts. Patients were excluded if they had stage IV disease, metachronous colorectal cancer, rectal cancer (≤ 15 cm from anal verge) in the absence of synchronous colon adenocarcinoma, tumour of the appendix, or R2 resections. Survival data were collected on Nov 13, 2014, from the DCCG database, which is continuously updated by the National Central Office of Civil Registration. FINDINGS: The CME group consisted of 364 patients and the non-CME group consisted of 1031 patients. For all patients, 4-year disease-free survival was 85.8% (95% CI 81.4-90.1) after CME and 75.9% (72.2-79.7) after non-CME surgery (log-rank p=0.0010). 4-year disease-free survival for patients with UICC stage I disease in the CME group was 100% compared with 89.8% (83.1-96.6) in the non-CME group (log-rank p=0.046). For patients with UICC stage II disease, 4-year disease-free survival was 91.9% (95% CI 87.2-96.6) in the CME group compared with 77.9% (71.6-84.1) in the non-CME group (log-rank p=0.0033), and for patients with UICC stage III disease, it was 73.5% (63.6-83.5) in the CME group compared with 67.5% (61.8-73.2) in the non-CME group (log-rank p=0.13). Multivariable Cox regression showed that CME surgery was a significant, independent predictive factor for higher disease-free survival for all patients (hazard ratio 0.59, 95% CI 0.42-0.83), and also for patients with UICC stage II (0.44, 0.23-0.86) and stage III disease (0.64, 0.42-1.00). After propensity score matching, disease-free survival was significantly higher after CME, irrespective of UICC stage, with 4-year disease-free survival of 85.8% (95% CI 81.4-90.1) after CME and 73.4% (66.2-80.6) after non-CME (log-rank p=0·0014). INTERPRETATION: Our data indicate that CME surgery is associated with better disease-free survival than is conventional colon cancer resection for patients with stage I-III colon adenocarcinoma. Implementation of CME surgery might improve outcomes for patients with colon cancer. FUNDING: Tvergaards Fund and Edgar and Hustru Gilberte Schnohrs Fund.

Major reduction in 30-day mortality after elective colorectal cancer surgery: a nationwide population-based study in Denmark 2001-2011.

BACKGROUND: For years, the outcome of colorectal cancer (CRC) surgery has been inferior in Denmark compared to its neighbouring countries. Several strategies have been initiated in Denmark to improve CRC prognosis. We studied whether there has been any effect on postoperative mortality based on the information from a national database. METHODS: Patients who underwent elective major surgery for CRC in the period 2001-2011 were identified in the national Danish Colorectal Cancer Group database. Thirty-day mortality rates were calculated and factors with impact on mortality were identified using logistic regression analysis. RESULTS: In total, 27,563 patients underwent elective major surgery and their 30-day mortality rate decreased significantly from 7.3 % in 2001-2002 to 2.8 % in 2011 (P < 0.001). Aside from the year of surgery, independent risk factors of mortality were male gender, age ≥ 61 years, American Society of Anesthesiologists score ≥ II, tumor located in the colon, palliative intent, outcome of surgery "not cured," and open surgical approach. Additionally, 3-month mortality of all 37,022 CRC patients, irrespective of surgical treatment, decreased significantly from 15.8 to 11.3 % during the study period. CONCLUSION: The 30-day mortality rate after elective major surgery for CRC has decreased significantly in Denmark in the past decade. Laparoscopic surgical approach was associated with a reduction in mortality in colon cancer.

Lymph node metastases in the gastrocolic ligament in patients with colon cancer.

BACKGROUND: Long-term survival after colorectal cancer may be improved by more extensive resection of the primary tumor and lymph nodes. Resection of the gastroepiploic and infrapyloric lymph nodes in the gastrocolic ligament has been proposed as a standard procedure when resecting tumors located in the proximity of the flexures or in the transverse colon. OBJECTIVE: The purpose of this work was to present our findings of metastases in the gastrocolic ligament in a consecutive series of patients. DESIGN: This was a single-center retrospective study. SETTINGS: The study was conducted in a colorectal cancer center. PATIENTS: All of the colon adenocarcinoma resections with relevant tumor location from June 1, 2008, to December 31, 2012 were included in this study. MAIN OUTCOME MEASURES: The presence of lymph node metastases in the gastrocolic ligament in colon adenocarcinomas located in the proximity of the flexures or in the transverse colon was measured. RESULTS: Gastrocolic resection was performed in 130 patients. Thirty-two patients were excluded because of a lack of information about gastrocolic lymph node status in the pathology reports. Median age of the remaining 98 patients was 70 years (range, 30-90 years), and 57% were men. Gastrocolic lymph nodes were found in 86 specimens (88%) with a median number of 4 lymph nodes (range, 0-16 lymph nodes). Thirty-four patients (35%) had mesocolic lymph node metastases. Gastrocolic lymph node metastases were found in 4 (12%) of these 34 patients and in 4% of all 98 included patients. Gastrocolic lymph node metastases were related to perineural invasion (p > 0.001). LIMITATIONS: Limitations of this study include the retrospective design, size of material, and lack of gastrocolic ligament lymph node status in the pathology report in some patients. CONCLUSIONS: Metastases in the gastroepiploic or infrapyloric lymph nodes can be found in patients with tumors located in the proximity of the flexures or in the transverse colon. Further studies are needed to reveal the clinical relevance of this finding, with special focus on recurrence risk and long-term survival.

Upstaging of early colorectal cancers following improved lymph node yield after methylene blue injection.

AIMS: To evaluate whether the use of intra-arterial methylene blue injection improves lymph node yield, and to determine whether a higher lymph node count results in upstaging in colorectal cancer. METHOD AND RESULTS: We performed a retrospective study of colorectal cancer specimens (n = 234) 1 year after implementation of the method. All colorectal cancer specimens from the previous year served as our control group. Data concerning tumour characteristics, lymph node count, number of positive lymph nodes and success of methylene injection had been prospectively collected in accordance with the department's ongoing registration. The method was easy to implement and perform with a high rate of success (86%). The number of identified lymph nodes was highly significantly improved in the study group (P < 0.0001). In resections with pT1/T2 tumours, we demonstrated a significant increase in the number of resection specimens containing positive lymph nodes, with an increase in pN1 resections from 9.4% in the control group to 26.7% in the study group (P = 0.04). CONCLUSIONS: THE methylene blue technique significantly improves lymph node identification in colorectal cancer specimens, and the improved lymph node identification leads to upstaging of International Union Against Cancer (UICC) pT1/pT2 cancers.

The relative effectiveness of fecal immunochemical test-based colorectal cancer screening to detect adenomas and cancer in different demographic and socioeconomic groups. A nationwide cohort study.

INTRODUCTION: This study aimed at analyzing the relative effectiveness in removal of adenomas and detection of cancer of implementing colorectal cancer (CRC) screening in different demographic and socioeconomic groups. METHODS: This register-based retrospective cohort study included residents aged 50-72 years. Those randomly selected to be invited for CRC screening from 1 March 2014 to 30 June 2015 were classified as invited; those invited from 1 January 2016 to 31 December 2017 were classified as not yet invited. Strata-specific relative risks (RRs) of having adenomas removed and CRC detected were estimated. RESULTS: A total of 1 343 090 individuals were included. The RR of having adenomas removed were higher among men compared with women [RR women = 6.41 (95% confidence interval [CI]: 5.08-8.09), RR men = 7.74 (95% CI: 6.16-9.73), P < 0.01] and among Danes compared with immigrants [RR Danes = 4.71 (95% CI: 3.73-5.93), RR Western = 4.76 (95% CI: 3.39-6.69), RR non-Western = 3.35 (95% CI: 2.39-4.69), P = 0.03]. Regarding detection of CRC, the effectiveness increased with increasing age ranging from RR = 1.53 (95% CI: 0.93- 2.51) to RR = 1.97 (95% CI: 1.22-3.17) ( P = 0.04) and was higher among men compared with women (RR women = 1.75 (95% CI: 1.10-2.76), RR men = 2.07 (95% CI: 1.32-3.26), P = 0.02. CONCLUSION: Attention must be paid to the potential differences in screening effectiveness among diverse subpopulations; first, by securing equal opportunities for participation across subpopulations and second, by considering sex and age-specific screening programs.

Improving the quality of colon cancer surgery through a surgical education program.

PURPOSE: Recent evidence has demonstrated the importance of dissection in the correct tissue plane for the resection of colon cancer. We have previously shown that meticulous mesocolic plane surgery yields better outcomes and that the addition of central vascular ligation produces an oncologically superior specimen compared with standard techniques. We aimed to assess the effect of surgical education on the oncological quality of the resection specimen produced. METHODS: We received clinicopathological data and specimen photographs from 263 resections for primary colon cancer from 6 hospitals in the Capital and Zealand regions of Denmark before a national training program. Ninety-three cases were from Hillerød Hospital, where surgeons had previously implemented a surgical educational training program in complete mesocolic excision with central vascular ligation and adopted the procedure as standard practice. The specimen photographs were assessed for the plane of surgery and tissue morphometry was performed. RESULTS: Hillerød specimens had a higher rate of mesocolic plane surgery (75% vs 48%; P < .0001) compared with the other hospitals. The surgeons at Hillerød Hospital also removed a greater length of colon in both fresh (median, 315 vs 247 mm; P < .0001) and fixed (269 vs 207 mm; P < .0001) specimens with a greater distance between the tumor and the closest vascular tie in both fresh (105 vs 84 mm; P = .006) and fixed (82 vs 67 mm; P = .002) specimens. This resulted in the removal of more mesentery in both fresh (14,466 vs 8706 mm; P < .0001) and fixed (9418 vs 6789 mm; P < .0001) specimens and a greater median lymph node yield (28 vs 18; P < .0001). CONCLUSIONS: We have shown that adoption of complete mesocolic excision with central vascular ligation results in a change to the production of an oncologically superior specimen compared with standard techniques. This should improve outcomes toward those reported by centers that have long practiced meticulous colon cancer surgery.

Danish Colorectal Cancer Group Database.

AIM OF DATABASE: The aim of the database, which has existed for registration of all patients with colorectal cancer in Denmark since 2001, is to improve the prognosis for this patient group. STUDY POPULATION: All Danish patients with newly diagnosed colorectal cancer who are either diagnosed or treated in a surgical department of a public Danish hospital. MAIN VARIABLES: The database comprises an array of surgical, radiological, oncological, and pathological variables. The surgeons record data such as diagnostics performed, including type and results of radiological examinations, lifestyle factors, comorbidity and performance, treatment including the surgical procedure, urgency of surgery, and intra- and postoperative complications within 30 days after surgery. The pathologists record data such as tumor type, number of lymph nodes and metastatic lymph nodes, surgical margin status, and other pathological risk factors. DESCRIPTIVE DATA: The database has had >95% completeness in including patients with colorectal adenocarcinoma with >54,000 patients registered so far with approximately one-third rectal cancers and two-third colon cancers and an overrepresentation of men among rectal cancer patients. The stage distribution has been more or less constant until 2014 with a tendency toward a lower rate of stage IV and higher rate of stage I after introduction of the national screening program in 2014. The 30-day mortality rate after elective surgery has been reduced from >7% in 2001-2003 to <2% since 2013. CONCLUSION: The database is a national population-based clinical database with high patient and data completeness for the perioperative period. The resolution of data is high for description of the patient at the time of diagnosis, including comorbidities, and for characterizing diagnosis, surgical interventions, and short-term outcomes. The database does not have high-resolution oncological data and does not register recurrences after primary surgery. The Danish Colorectal Cancer Group provides high-quality data and has been documenting an increase in short- and long-term survivals since it started in 2001 for both patients with colon and rectal cancers.

The pathological phenotype of colon cancer with microsatellite instability.

INTRODUCTION: Colorectal cancer is a common malignant disease, caused by different aetiologies and molecular pathways. Heterogeneous results have been published regarding the association of microsatellite instability and clinicopathological features. The aim of this study was to compare clinicopathological features of microsatellite unstable tumours with stable ones. METHODS: Data were collected retrospectively, but the pathological analyses were all made prospectively. The study included a total of 833 patients undergoing resection of their colon tumour at Nordsjællands Hospital - Hillerød, with mismatch repair analysis from 1 January 2007 to 30 November 2012. The study was performed in a setting with complete mesocolic excision surgery and post-operative expert pathological examination of the tumours. Mismatch repair analysis was done by immuno-histochemical staining for the mismatch repair proteins: pMLH1, pMSH2, pMSH6 and pPMS2 for the determination of microsatellite instability. Microsatellite instability was defined as deficient expression of one or more of these proteins. RESULTS: Of the 833 patients, 177 had microsatellite instable tumours (21%). Using multivariable logistic regression analysis, we demonstrated that microsatellite unstable cancers were significantly associated with a lower degree of lymph node metastases (odds ratio (OR) = 0.92), distant metastases (OR = 0.33) and tumour budding (OR = 0.41). CONCLUSIONS: We found that microsatellite unstable tumours show a pathological profile that appears less aggressive than the pathological profile of stable tumours. FUNDING: none. TRIAL REGISTRATION: not relevant.

Esthesioneuroblastoma: a Danish clinicopathological study of 40 consecutive cases.

Aims. To review all cases of esthesioneuroblastoma in Denmark from 1978 to 2000 with respect to staging, grading, histopathological and immunohistochemical evaluation, and prognostication. Methods and results. Possible cases of esthesioneuroblastoma were retrieved from Danish oncology departments. Patients were included on the basis of review of their files or pathology reports, and/or on the basis of histopathological and immunohistochemical examination. Forty-nine possible cases were retrieved. Nine cases were excluded. Esthesioneuroblastoma is a malignant neuroendocrine tumour originating in the olfactory mucosa. It is a small blue cell neoplasm with a characteristic lobular architecture. It has a neuroendocrine immunophenotype and a sustentacular S-100 staining pattern. The tumours were staged according to Kadish and graded according to Hyams. Kaplan-Meier survival analysis was used to identify prognostic factors. Conclusion. The Kadish staging system was able to group the patients into prognostically relevant groups. Intracranial involvement and metastases at the time of diagnosis were found to be poor prognostic factors. Hyams grading system is difficult to work with and it was not possible to divide patients into prognostically relevant groups. Presence of necrosis, a diffuse growth pattern and a high proliferation index proved to be equally poor prognostic factors.