Association of Clinicopathological Factors With MMP13 (rs2252070) Gene Polymorphism in Swedish Patients With Colorectal Cancer.

BACKGROUND/AIM: Matrix metalloproteinase 13 (MMP13) has been reported to be involved in tumor development and progression, including of colorectal cancer (CRC). This study aimed at evaluating whether the MMP13 rs2252070 gene polymorphism is associated with clinicopathological factors and its influence on long-term survival in Swedish patients with CRC. PATIENTS AND METHODS: A total of 723 patients with CRC were genotyped using TaqMan single nucleotide polymorphism assays based on polymerase chain reaction. RESULTS: Assessing clinicopathological factors, we demonstrated that having the G/G genotype for MMP13 rs2252070 was significantly associated with poor differentiation, higher serum level of carcinoembryonic antigen and higher lymph node status. Moreover, the presence of a G allele was significantly related to larger tumor size in rectal cancer but had a significantly protective role against mucinous cancer, perineural invasion and lymphovascular invasion. Kaplan-Meier analysis showed no difference between genotypes regarding cancer-specific survival. CONCLUSION: Our findings highlight the potential of MMP13 rs2252070 polymorphism as a useful predictor of poor differentiation, serum level of carcinoembryonic antigen, lymph node status, tumor size, mucinous cancer, perineural invasion and lymphovascular invasion in patients with CRC.

Assessment by a multidisciplinary team conference affects treatment strategy and overall survival in patients with synchronous colorectal liver metastases.

BACKGROUND: The aim of this retrospective observational study was to investigate the geographical or sex differences in patients with synchronous colorectal liver metastases (sCRLM) in terms of assessment by a multidisciplinary team conference (MDT), curative treatment, and overall survival. METHOD: All sCRLM patients in the South-East Health Care Region of Sweden from 2009 to 2015 were included (n = 615). Data were derived from the Swedish Colorectal Cancer Registry, Swedish Registry of Liver and Bile Surgery and medical records. RESULTS: Patients who had a hepatobiliary unit (HBU) at the nearest hospital were more likely to undergo liver surgery (HBU+, 37% (n = 106), compared to HBU-, 22% (n = 60); p = 0.001) and had a better median survival (p < 0.001). No sex differences were observed. In multivariate Cox regression analyses of overall survival, assessment by an MDT that included a liver surgeon was independently linked to better survival (HR 0.574, 0.433-0.760). CONCLUSION: There were no sex differences in access to liver surgery or overall survival, however, there were geographical inequalities, where residency near a hospital with HBU was associated with increased overall survival and the possibility to receive liver surgery. Assessment at MDT with liver surgeon present was associated with greater survival, indicating its important role for treatment.

Validation of the Appendicitis Inflammatory Response (AIR) score during pregnancy: A nested case-control study.

OBJECTIVES: Appendicitis poses diagnostic challenges. A correct diagnosis is important during pregnancy to avoid unnecessary surgery on the one hand and delayed surgery on the other hand, as both may negatively affect pregnancy outcomes. Clinical scores for risk-stratified management of suspected appendicitis are well established in adults but have not been validated during pregnancy. This nested case-control study evaluated the diagnostic accuracy of the Appendicitis Inflammatory Response (AIR) score and imaging during pregnancy. METHODS: By cross-linking national Swedish health registries from a defined geographical area, we identified a cohort of 154 women who underwent appendectomy for suspected appendicitis during pregnancy and a matched cohort of 232 pregnant women admitted for acute abdominal pain and suspected appendicitis but with a discharge diagnosis of nonspecific abdominal pain (NSAP). All variables were extracted from medical records. The diagnostic value of AIR score and imaging was estimated for patients with a final diagnosis of appendicitis compared with patients with negative appendectomy and NSAP patients. RESULTS: The final diagnoses for the operated patients were uncomplicated and complicated appendicitis in 49.4% and 26.6%, respectively, and negative appendectomy in 24.0%. Nearly half of all the patients underwent diagnostic imaging (41%), mainly by ultrasonography. The sensitivity and specificity of diagnostic imaging were 44.9% (95% CI 32.9%-57.4%) and 42.2% (95% CI 31.9%-53.1%), respectively. The area under the receiver operating characteristic curve of AIR score was 0.88 (95% CI 0.84-0.92) for all appendicitis and 0.90 (95% CI 0.84-0.95) for complicated appendicitis. The sensitivity for complicated appendicitis was 100% at a score of ≥4. The specificity for all appendicitis was 97% at a score of ≥9. CONCLUSIONS: The results of this study suggest that the AIR score may be a suitable diagnostic tool for risk stratification of pregnant women with abdominal pain and suspected appendicitis but further validation among pregnant women is needed.

Emerging role and clinical implication of mRNA scavenger decapping enzyme in colorectal cancer.

BACKGROUND: Turnover of RNA is a regulated process that in part controls gene expression. This process is partly controlled by the scavenger decapping enzyme (DcpS). This study aimed to investigate the expression of DcpS in colorectal cancer (CRC) tissue, to evaluate its prognostic significance in patients with CRC and to investigate potentially targeted genes by DcpS. METHODS: Immunohistochemical analysis was used to determine localization of DcpS in normal and CRC tissue, western blot analysis for quantification of protein expression and qPCR for mRNA expression in normal and CRC tissue and expression in cell lines after silencing using siRNA. Gene array analysis was used to study regulation of genes after silencing of DcpS. Proliferation was studied using BRDU. RESULTS: DcpS expression was localized to the epithelial cells of both control and cancer tissue. Tumor and paired control tissue samples from 100 patients who underwent surgical resection for primary colorectal adenocarcinomas were utilized. mRNA and protein of DcpS was significantly up-regulated in the patients with CRC and the mRNA level was higher in rectal cancer tissue compared to colon cancer tissue (p < 0.05). Lowest tertile levels of DcpS mRNA in cancer tissue was associated with a decreased cancer-specific survival rate with a hazard ratio (HR) of 4.7 (95% CI=1.02-12.3), independent of disease stage. The low level of DcpS mRNA was a predictor of poorer survival in patients with rectal and disseminated cancer and in patients receiving adjuvant treatment (p < 0.05). After silencing DcpS in Caco-2 cancer cells, altered expression of several genes associated with RNA, cell cycle regulation, alternative splicing and microRNA was observed and resulted in 23% increase in proliferation. CONCLUSIONS: These results indicate that DcpS has potential as a prognostic factor for CRC but further studies in a broader cohort are warranted to evaluate the significance of the findings in the clinic.

Female and Male Fertility after Colectomy and Reconstructive Surgery in Inflammatory Bowel Diesase: A National Cohort Study from Sweden.

BACKGROUND AND AIMS: Colectomy and reconstruction in patients with inflammatory bowel disease [IBD] may adversely affect fertility, but few population-based studies on this subject are available. METHODS: Fertility was assessed in 2989 women and 3771 men with IBD and prior colectomy during 1964-2014, identified from the Swedish National Patient Register, and in 35 092 matched individuals. RESULTS: Reconstruction with ileoanal pouch anastomosis [IPAA] was as common as ileorectal anastomosis [IRA] in ulcerative colitis [UC] and IBD-unclassified [IBD-U] but rare in Crohn's disease [CD]. Compared with the matched reference cohort, women with IBD had lower fertility overall after colectomy (hazard ratio [HR] 0.65, confidence interval [CI] 0.61-0.69), with least impact with leaving the rectum intact [HR 0.79, CI 0.70-0.90]. Compared with colectomy only, fertility in female patients remained unaffected after IRA [HR 0.86, CI 0.63-1.17 for UC, 0.86, CI 0.68-1.08 for IBD-U and 1.07, CI 0.70-1.63 for CD], but was impaired after IPAA, especially in UC [HR 0.67, CI 0.50-0.88], and after completion proctectomy [HR 0.65, CI 0.49-0.85 for UC, 0.68, CI 0.55-0.85 for IBD-U and 0.61, CI 0.38-0.96 for CD]. In men, fertility was marginally reduced following colectomy [HR 0.89, CI 0.85-0.94], regardless of reconstruction. CONCLUSIONS: Fertility was reduced in women after colectomy for IBD. The least impact was seen when a deviated rectum was left intact. IRA was associated with no further reduction in fertility, whereas proctectomy and IPAA were associated with the strongest impairment. IRA therefore seems to be the preferred reconstruction to preserve fertility in selected female patients. Fertility in men was only moderately reduced after colectomy.

Clinicopathological and prognostic value of CD44 gene polymorphism (rs187115) in Swedish patients with colorectal cancer.

Cluster of differentiation (CD) 44 plays a crucial role in apoptosis, cell-cell interactions, angiogenesis, metastasis and proliferation. The aim of the present study was to examine the influence of CD44 gene polymorphism rs187115 on colorectal cancer (CRC) susceptibility and the association with various clinical features including long-term survival in Swedish patients with CRC. Genotypes were screened, using TaqMan single nucleotide polymorphism (SNP) assays based on polymerase chain reaction, in 612 CRC patients and 575 healthy controls.The carriers of G allele, genotypes (AG + GG), were found to be associated with an increased risk of CRC with an odds ratio (OR) of 1.35 (95% confidence interval (CI) = 1.01-1.81; p = 0.039) and found to be more common in patients with mucinous cancer compared with non-mucinous cancer, OR = 1.69 (95% CI = 1.02-2.80; p = 0.011). By using Kaplan-Meier analysis, the patients with genotype GG showed shorter cancer-specific and recurrence free survival with a hazard ratio (HR) of 1.25 (95% CI = 1.02-1.54; p = 0.036) and 1.52 (95% CI = 1.12-2.06; p = 0.007), respectively, in comparison with the carriers of A allele (AG + AA). The present findings demonstrated that the variant G allele of CD44 gene polymorphism rs187115 was related to risk for CRC and associated to mucinous cancer and predict worse prognosis in Swedish patients with CRC.

Autoimmune and Metabolic Diseases and the Risk of Early-Onset Colorectal Cancer, a Nationwide Nested Case-Control Study.

Incidence of early-onset (<50 years) colorectal cancer (EOCRC) is increasing in developed countries. The aim was to investigate autoimmune and metabolic conditions as risk factors for EOCRC. In a nationwide nested case-control study, we included all EOCRC cases in Sweden diagnosed during 2007-2016, together with controls, matched for birth year, sex, and county. Information on exposure of autoimmune or metabolic disease was collected from the National Patient Register and Prescribed Drugs Registry. Hazard ratios (HR) as measures of the association between EOCRC and the exposures were estimated using conditional logistic regression. In total, 2626 EOCRC patients and 15,756 controls were included. A history of metabolic disease nearly doubled the incidence hazard of EOCRC (HR 1.82, 95% CI 1.66-1.99). A sixfold increased incidence hazard of EOCRC (HR 5.98, 95% CI 4.78-7.48) was seen in those with inflammatory bowel disease (IBD), but the risk increment decreased in presence of concomitant metabolic disease (HR 3.65, 95% CI 2.57-5.19). Non-IBD autoimmune disease was not statistically significantly associated with EOCRC. IBD and metabolic disease are risk factors for EOCRC and should be considered in screening guidelines.

Treatment efficacy in a metastatic small intestinal neuroendocrine tumour grade 2 cohort.

Small intestinal neuroendocrine tumours (Si-NET) are often studied as a uniform group. Proliferation index Ki-67 influences prognosis and determines tumour grade. We hypothesized that Si-NET grade 2 (G2) tumours, which have a higher Ki-67 than G1 tumours, might benefit less from established treatments for metastatic disease. We conducted a retrospective cohort study of 212 patients with metastatic Si-NET G2 treated in two Swedish hospitals during 20 years (2000-2019). Median cancer-specific survival on first-line somatostatin analogues (SSA) was 77 months. Median progression-free survival (PFS) was 12.4 months when SSA was given as monotherapy and 19 months for all patients receiving first-line SSA. PFS after SSA dose escalation was 6 months in patients with radiological progression. Treatment efficacies of SSA and peptide receptor radionuclide treatment (PRRT) were studied separately in patients with Ki-67 of 3-5%, 5-10% and 10-20%. For SSA, PFS was significantly shorter at higher Ki-67 levels (31, 18 and 10 months, respectively), while there was only a minor difference in PFS for PRRT (29, 25 and 25 months). Median PFS for sequential treatment with interferon-alpha (IFNα), everolimus and chemotherapy was 6, 5 and 9 months. IFNα seemed to be effective in tumours with low somatostatin-receptor expression. In conclusion, established treatments appeared effective in Si-NET G2, despite their higher proliferation index compared to G1 tumours. However, efficacy of SSA but not PRRT was reduced at higher Ki-67 levels. SSA dose escalation provided limited disease stabilization.

Reoperations and Long-term Survival of Kock's Continent Ileostomy in Patients With IBD: A Population-Based National Cohort Study From Sweden.

BACKGROUND: Kock's continent ileostomy is an option after proctocolectomy for patients not suitable for IPAA or ileorectal anastomosis. Ulcerative colitis is the most common indication for continent ileostomy. OBJECTIVE: The aim of this study was to evaluate the long-term outcome of continent ileostomy. DESIGN: Retrospective cohort register study. SETTINGS: Data were obtained from the Swedish National Patient Registry. PATIENTS: All patients with IBD and a continent ileostomy were identified. Data on demographics, diagnosis, reoperations, and excisions of the continent ileostomy were obtained. Patients with inconsistent diagnostic coding were classified as IBD-unclassified. MAIN OUTCOME MEASURES: The main outcome measures were number of reoperations, time to reoperations, and time to excision of continent ileostomy. RESULTS: We identified 727 patients, 428 (59%) with ulcerative colitis, 45 (6%) with Crohn's disease, and 254 (35%) with IBD-unclassified. After a median follow-up time of 27 (interquartile range, 21-31) years, 191 patients (26%) never had revision surgery. Some 1484 reoperations were performed on 536 patients (74%), and the median number of reoperations was 1 (interquartile range, 0-3) per patient. The continent ileostomy was excised in 77 patients (11%). Reoperation within the first year after reconstruction was associated with a higher rate of revisions (incidence rate ratio, 2.90; p < 0.001) and shorter time to excision (HR 2.38; p < 0.001). Constructing the continent ileostomy after year 2000 was associated with increased revision and excision rates (incidence rate ratio, 2.7; p < 0.001 and HR 2.74; p = 0.013). IBD-unclassified was associated with increased revisions (incidence rate ratio, 1.3; p < 0.001)' and the proportion of IBD-unclassified patients almost doubled from the 1980s (32%) to after 2000 (50%). LIMITATIONS: Retrospective design, data from a register, and no data on quality of life were available were the limitations of this study. CONCLUSION: Continent ileostomy is associated with substantial need for revision surgery, but most patients keep their reconstruction for a long time. See Video Abstract at http://links.lww.com/DCR/C122 . REOPERACIONES Y SUPERVIVENCIA A LARGO PLAZO DE LA ILEOSTOMA CONTINENTE DE KOCK EN PACIENTES CON ENFERMEDAD INFLAMATORIA INTESTINAL UN ESTUDIO DE COHORTE NACIONAL BASADO EN LA POBLACIN DE SUECIA: ANTECEDENTES:La ileostomía continente de Kock es una opción después de la proctocolectomía para los pacientes que no son aptos para la anastomosis ileoanal con reservorio o la anastomosis ileorrectal. La colitis ulcerativa es la indicación más común para la ileostomía continente.OBJETIVO:El objetivo de este estudio fue evaluar el resultado a largo plazo de la ileostomía continente.DISEÑO:Estudio de registro de cohorte retrospectivo.AJUSTES:Los datos se obtuvieron del Registro Nacional de Pacientes de Suecia.PACIENTES:Se identificaron todos los pacientes con enfermedad inflamatoria intestinal e ileostomía continente. Se obtuvieron datos demograficos, diagnóstico, reoperaciones y extirpaciones de la ileostomía continente. Los pacientes con codificación diagnóstica inconsistente se clasificaron como no clasificados con EII.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas de resultado fueron el número de reoperaciones, el tiempo hasta las reoperaciones y el tiempo hasta la escisión de la ileostomía continente.RESULTADOS:Identificamos 727 pacientes, 428 (59%) con colitis ulcerativa, 45 (6%) con enfermedad de Crohn y 254 (35%) con EII no clasificada. Después de una mediana de tiempo de seguimiento de 27 (IQR 21-31) años, 191 (26%) pacientes nunca se habían sometido a una cirugía de revisión. Se realizaron 1.484 reintervenciones en 536 (74%) pacientes, la mediana de reintervenciones fue de 1 (RIC 0-3) por paciente. La ileostomía continente se extirpó en 77 (11%) pacientes. La reoperación dentro del primer año después de la reconstrucción se asoció con una mayor tasa de revisiones (IRR 2,90 p < 0,001) y un tiempo más corto hasta la escisión (HR 2,38 p < 0,001). La construcción de la ileostomía continente después del año 2000 se asoció con mayores tasas de revisión y escisión (IRR 2,7 p < 0,001 y HR 2,74 p = 0,013). La EII no clasificada se asoció con un aumento de las revisiones (IRR 1,3 p < 0,001) y la proporción de pacientes con EII no clasificada casi se duplicó desde la década de 1980 (32%) hasta después de 2000 (50%).LIMITACIONES:Diseño retrospectivo, datos de registro. No hay datos disponibles sobre la calidad de vida.CONCLUSIÓN:La ileostomía continente se asocia con una necesidad sustancial de cirugía de revisión, pero la mayoría de los pacientes logran mantener su reconstrucción durante mucho tiempo. Consulte Video Resumen en http://links.lww.com/DCR/C122 . (Traducción-Dr. Yolanda Colorado ).

Hartmann's Reversal: Controversies of a Challenging Operation.

Purpose: Hartmann's reversal is a complex operation with a high morbidity rate. Minimally invasive surgery has been used to reduce the impact of surgery on fragile patients. The aim of this comparative study is to look at the results of Hartmann's reversal procedures with different approaches. Methods: All the patients who underwent Hartmann's reversal were collected retrospectively (124 cases). Sixty-four patients (50.4%) had an open operation, 6 cases (5%) were treated with a conventional laparoscopic approach, 34 patients (28.1%) underwent single incision laparoscopic surgery (SILS), and 20 (16.5%) required other additional trocars. Results: SILS operations were slightly longer than the open procedures (175 min vs 150 min), with the same rate of postoperative complications and reoperations (p = 0.83 and p = 0.42), but with a shorter hospital stay (5 days p = 0.007). Age (p = 0.03), long operative time (p = 0.01), and ASA score (p = 0.05) were identified as independent factors affecting postoperative morbidity. The grade of adhesions caused a longer operative time (p = 0.001) and a higher risk of conversion (p < 0.001), and short rectal stump increased the risk of protective loop ileostomy (p = 0.008). Patients with grade 2-3 of adhesions had a longer length of stay (p = 0.05). Conclusions: Minimally invasive procedures had a shorter hospital stay and did not show any increase in morbidity rate when compared with open cases. Age, longer operative time, and ASA score increased the risk of postoperative complications. Furthermore, patients with a short rectal stump had a higher chance of having a defunctioning ileostomy.

Effects of diabetes type 2 and metformin treatment in Swedish patients with colorectal cancer.

The association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) has been thoroughly investigated and reports have demonstrated that the risk of CRC is increased in DM patients. The association between DM and the survival of patients with CRC is controversial. Evidence suggests that metformin with its anti-inflammatory effects is a protective factor against the development of CRC among DM patients and that metformin therapy is associated with a better prognosis in patients with DM. In our cohort, we did not find any associations between the presence of DM or metformin and cancer specific survival or any relation to plasma levels of a panel of 40 inflammatory factors and irisin. On the other hand, we identified that the insulin-like growth factor binding protein 7 single nucleotide polymorphism rs2041437 was associated with DM in CRC patients. The dominance of the T bearing genotypes in patients with DM was statistically significant (P = 0.038), with an odds ratio of 1.66 (95% confidence interval: 1.03-2.69).

Minor impact on fertility in men with inflammatory bowel disease: A National Cohort Study from Sweden.

BACKGROUND AND AIMS: Onset of inflammatory bowel disease (IBD) in men is most common during childbearing age, but little is known about the impact on fertility. Previous studies of fertility in men were small, which justifies this large nation-based registry study. METHODS: Fertility was assessed in a national cohort of men with IBD aged 15-44 years in 1964-2014, identified from the Swedish National Patient Register, and in a reference cohort matched for age and place of residence (ratio 1:5). Information about childbirths was found in the Swedish Multi-Generation Register. Patients with indeterminate colitis or inconsistent IBD coding were classified as IBD-unclassified (IBD-U). RESULTS: The cohorts included 29,104 men with IBD and 140,901 matched individuals. IBD patients had a lower fertility rate (number of births per 1000 person years) compared with the matched individuals; 1.28 (SD 1.27) versus 1.35 (SD 1.31; p < 0.001). Fertility was somewhat impaired in all IBD subtypes compared with the matched cohort; ulcerative colitis (UC) (hazard ratio [HR] 0.93, 95% CI 0.91-0.96), Crohn's disease (CD) (HR 0.95, 95% CI 0.92-0.98) and IBD-U 0.92, 95% CI 0.89-0.95. The cumulated total parity and the parity progression were also decreased for all IBD subtypes. Within the IBD cohort disease severity, intensity of medical treatment (CD) and bowel surgery (IBD-U) were further associated with impaired fertility. CONCLUSIONS: This nationwide cohort study shows only slightly impaired fertility in men with IBD.

Hereditary evaluation and genetic counselling in young individuals with colorectal cancer in a population-based cohort.

AIM: Early-onset colorectal cancer should raise suspicions of a hereditary colorectal cancer (CRC) syndrome, including Lynch syndrome (LS) and Familial Adenomatous Polyposis (FAP). Collection of family history and genetic counselling (GC) is mandatory but previous studies have revealed low awareness of hereditary CRC among clinicians why there has been an incentive to implement universal LS screening. In this population-based cohort study, we aimed to observe the uptake of GC in the Swedish South-Eastern medical care region for young CRC patients and to investigate the frequency of patients diagnosed with LS. METHODS: Patients below 50 years of age diagnosed with CRC between 2008 and 2017 were identified from the national Swedish Colorectal Cancer Registry. Medical records were reviewed regarding family history, co-morbidity and referral for GC, with a follow-up time of at least three years. RESULTS: The analysis included 278 patients with 287 tumours, 108 (38%) located in rectum and 179 (62%) in colon. One hundred sixteen (42%) individuals were referred to the Regional Clinical Genetics service, whereof 74 (27%) underwent complete investigation. Thirteen (18%) patients were identified with a mutation, eleven (15%) had LS and two (3%) FAP. The remaining 61 (82%), without proven mutation, were considered as familial CRC. Younger age correlated with a higher chance of referral for GC. CONCLUSION: The study found that only a minority of young CRC patients underwent genetic counselling, contrary to clinical guidelines. Hereditary CRC is therefore probably underdiagnosed even among young individuals.

Association of gene and protein expression and genetic polymorphism of CC chemokine ligand 4 in colorectal cancer.

BACKGROUND: Leukocytes, such as T cells and macrophages, play an important role in tumorigenesis. CC chemokine ligand (CCL) 4, which is produced by lymphocytes and macrophages, has been found to be expressed in the mucosa of the gastrointestinal tract and is a potent chemoattractant for various leukocytes. AIM: To examine CCL4 expression and its genetic polymorphism rs10491121 in patients with colorectal cancer (CRC) and evaluate their prognostic significance. METHODS: Luminex technology was used to determine CCL4 Levels in CRC tissue (n = 98), compared with paired normal tissue, and in plasma from patients with CRC (n = 103), compared with healthy controls (n = 97). Included patients had undergone surgical resection for primary colorectal adenocarcinomas between 1996 and 2019 at the Department of Surgery, Ryhov County Hospital, Jönköping, Sweden. Reverse transcription quantitative PCR was used to investigate the CCL4 gene expression in CRC tissue (n = 101). Paired normal tissue and TaqMan single nucleotide polymorphism assays were used for the CCL4 rs10491121 polymorphism in 610 CRC patients and 409 healthy controls. RESULTS: The CCL4 protein and messenger RNA expression levels were higher in CRC tissue than in normal paired tissue (90%, P < 0.001 and 45%, P < 0.05, respectively). CRC tissue from patients with localized disease had 2.8-fold higher protein expression levels than that from patients with disseminated disease. Low CCL4 protein expression levels in CRC tissue were associated with a 30% lower cancer-specific survival rate in patients (P < 0.01). The level of plasma CCL4 was 11% higher in CRC patients than in healthy controls (P < 0.05) and was positively correlated (r = 0.56, P < 0.01) with the CCL4 protein level in CRC tissue. The analysis of CCL4 gene polymorphism rs10491121 showed a difference (P < 0.05) between localized disease and disseminated disease in the right colon, with a dominance of allele A in localized disease. Moreover, the rate of the A allele was higher among CRC patients with mucinous cancer than among those with non-mucinous cancer. CONCLUSION: The present study indicates that the CRC tissue levels of CCL4 and CCL4 gene polymorphism rs10491121, particularly in the right colon, are associated with clinical outcome in CRC patients.

Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) Gene Polymorphism (rs3087243) Is Related to Risk and Survival in Patients With Colorectal Cancer.

BACKGROUND/AIM: Cytotoxic T-lymphocyte antigen-4 (CTLA-4), transiently expressed on T cells, plays a pivotal role in the negative feedback regulation of T-cell activation and proliferation. The aim of the present study was to examine the influence of CTLA-4 gene polymorphism rs3087243 on CRC susceptibility and long-term survival in Swedish patients with CRC. PATIENTS AND METHODS: Genotypes of 491 patients and 433 healthy controls were determined, using TaqMan single nucleotide polymorphism (SNP) assays based on polymerase chain reaction. RESULTS: Patients carrying allele A were found to be at a higher risk of CRC and this allele was found to be more common in patients with disseminated disease compared to localized disease in the right colon. Kaplan-Meier analysis of cancer-specific survival showed that carriers of allele A had the highest risk of CRC-related death. CONCLUSION: The SNP rs3087243 of the CTLA-4 gene was associated with CRC risk and, therefore, it could be a prognostic marker for Swedish patients with CRC.

A Plasma Protein Biomarker Strategy for Detection of Small Intestinal Neuroendocrine Tumors.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. METHODS: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. RESULTS: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. CONCLUSION: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.

Impaired Fertility in Women With Inflammatory Bowel Disease: A National Cohort Study From Sweden.

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] has been associated with reduced female fertility. We analyse fertility in a national cohort of women with IBD. METHODS: Fertility was assessed in women with IBD aged 15-44 years in 1964-2014, identified from the Swedish National Patient Register and a matched cohort [ratio 1:5]. Patients with indeterminate colitis or inconsistent IBD coding were classified as IBD-unclassified [IBD-U]. RESULTS: The cohorts included 27 331 women with IBD and 131 892 matched individuals. The fertility rate in IBD was 1.52 (standard deviation [SD] 1.22) births per 1000 person-years and 1.62 [SD 1.28] [p <0.001] in matched individuals. Fertility was impaired in all IBD subtypes compared with the matched cohort (hazard ratio Crohn's disease [CD] 0.88, 95% confidence interval [CI] 0.85-0.91; IBD-U 0.86, 95% CI 0.83-0.89; and ulcerative colitis [UC] 0.96, 95% CI 0.93-0.98). Fertility improved during the study period for the IBD cohort except for CD. Parity progression ratio, the proportion of IBD women progressing from one parity to the next compared with the matched cohort, was decreased at all parity levels for CD and IBD-U, but only for multiparous women in UC. Contraceptive usage was higher in IBD, both before and after the diagnosis. Disease severity, bowel resections, and perianal disease in CD affected fertility negatively. CONCLUSIONS: Fertility was impaired mainly in women with CD and IBD-U, and less so in UC. During the study period, fertility improved in women with UC or IBD-U. Some results suggest a role of voluntarily reduced fertility.

Assessment of hormonal levels as prognostic markers and of their optimal cut-offs in small intestinal neuroendocrine tumours grade 2.

PURPOSE: Small intestinal neuroendocrine tumours (siNETs) with a Ki-67 proliferation index between 3 and 20% belong to WHO grade 2. Response to treatment may be monitored by blood chromogranin A (CgA) and urine 5-hydroxyindoleacetic acid (5HIAA). The aim of this retrospective study was to investigate the prognostic value of baseline CgA and 5HIAA and of the early biochemical response to treatment, and to compare different cut-off values used in the literature. METHODS: A retrospective cohort study of 184 patients with siNET Grade 2 treated with somatostatin analogues (SSA), interferon-alpha (IFN) or peptide receptor radionuclide therapy (PRRT). RESULTS: Baseline CgA was a statistically significant prognostic marker for both cancer-specific survival (CSS) and progression-free survival (PFS). A cut-off of 5 × ULN (upper limit of normal) was best discriminative in most cases, but 2 × ULN discriminated better for SSA. Baseline 5HIAA was a prognostic marker for CSS in treatment with IFN and PRRT, but not for single SSA. Early changes of CgA and 5HIAA correlated well with CSS (HR 3.18, 95% CI 1.82-5.56 and HR 1.47, 95% CI 1.16-1.86) and PFS (HR 3.08, 95% CI 1.86-5.10 and HR 1.37, 95% CI 1.11-1.68) for SSA, but not for PRRT. CONCLUSIONS: Baseline CgA and to a lesser extent 5HIAA are associated with CSS irrespective of treatment used, and with PFS after PRRT, and 5 × ULN provides best discrimination in many, but not all, cases. Early reductions of CgA and 5HIAA are prognostic for treatment with SSA, but not PRRT.

Incidence of Appendiceal Malignancies in Sweden Between 1970 and 2012.

BACKGROUND: There is limited knowledge about the epidemiology of the major histological subtypes of appendiceal malignancy: adenocarcinoma and neuroendocrine neoplasm of the appendix (A-NEN). The aims of this national cohort study were to assess the prevalence, incidence and trends of appendiceal malignancies in Sweden. METHOD: All individuals who underwent appendicectomy and all diagnosed with appendiceal malignancy from 1970 to 2012 were identified from the National Patient Register and the Swedish Cancer Registry. Demographic data of the background population were obtained from Statistics Sweden. The incidence rate (IR) and the prevalence of appendiceal malignancy per performed appendicectomy were calculated. RESULTS: We identified 3774 patients with appendiceal malignancy. IR of A-NEN was 5.8/106 person-years with a peak of 8.4/106 at age 20-30 years, whereafter it plateaued at a somewhat lower level. IR for adenocarcinoma was 3.7/106 person-years, starting at a very low level among the youngest and increasing to 15.4/106 at age 80-89 years. The IR of adenocarcinoma increased from 2.6/106 in 1970-1979 to 5.4/106 in 2010-2012. The IR of A-NEN was stable during the study period. The prevalence per appendicectomy was low for both types of malignancies among the young but increased with age, most dramatically for adenocarcinoma. There was a trend during the study period towards more extensive surgery. CONCLUSION: Adenocarcinoma is most common and increasing in the elderly, whereas A-NEN affects all ages with a peak in young age. This peak probably reflects removal of occult A-NEN due to the higher appendicectomy frequency in the young.

Anorectal Function After Ileo-Rectal Anastomosis Is Better than Pelvic Pouch in Selected Ulcerative Colitis Patients.

BACKGROUND: With a lifelong perspective, 12% of ulcerative colitis patients will need a colectomy. Further reconstruction via ileo-rectal anastomosis or pouch can be affected by patients' perspective of their quality of life after surgery. AIM: To assess the function and quality of life after restorative procedures with either ileo-rectal anastomosis or ileal pouch-anal anastomosis in relation to the inflammatory activity on endoscopy and in biopsies. METHOD: A total of 143 UC patients operated with subtotal colectomy and ileo-rectal anastomosis or pouches between 1992 and 2006 at Linköping University Hospital were invited to participate. Those who completed the validated questionnaires (Öresland score, SF-36, Short Health Scale) were offered an endoscopic evaluation including multiple biopsies. Associations between anorectal function and quality of life with type of restorative procedure and severity of endoscopic and histopathologic grading of inflammation were evaluated. RESULTS: Some 77 (53.9%) eligible patients completed questionnaires, of these 68 (88.3%) underwent endoscopic evaluation after a median follow-up of 12.5 (range 3.5-19.4) years after restorative procedure. Patients with ileo-rectal anastomosis reported better overall Öresland score: median = 3 (IQR 2-5) for ileo-rectal anastomosis (n = 38) and 10 (IQR 5-15) for pouch patients (n = 39) (p < 0.001). Anorectal function (Öresland score) and endoscopic findings (Baron-Ginsberg score) were positively correlated in pouch patients (tau: 0.28, p = 0.006). CONCLUSION: Patients operated with ileo-rectal anastomosis reported better continence compared to pouches. Minor differences were noted regarding the quality of life. Ileo-rectal anastomosis is a valid option for properly selected ulcerative colitis patients if strict postoperative endoscopic surveillance is carried out.