Clinical and immunohistochemical studies of small bowel carcinoid tumours

Small bowel carcinoid tumours arising from enterochromaffin cells in the jejunum and ileum are neuroendocrine tumours (NETs) characterized by secretion of serotonin, tachykinins and other bioactive substances. These substances may lead to the typical carcinoid syndrome as well as pronounced fibrosis locally and in the heart. Although the most frequent histological subtype of malignancy in the small bowel, small bowel carcinoids are rare and therefore difficult to study. We found that previous studies either described selected patients at referral centres, or were based on limited data from large registries. The main objective of this thesis was to investigate small bowel carcinoid patients from a geographically defined cohort with no selection bias. PAPERS I AND II The aims of papers I and II were to investigate the incidence, histopathological characteristics, stage atdiagnosis, symptomatology, surgical treatment, prognostic factors and survival of small bowel carcinoid.All patients resident in Jönköping County when diagnosed with small bowel carcinoid between 1960 and2005 were eligible for inclusion. After thorough review of medical records and reexamination of availabletumour specimens, 145 patients were included. A higher incidence of small bowel carcinoid than previously described was found: 1.12 per 100,000 persons and year. The incidence increased during the study period. Symptoms were most often uncharacteristic: the carcinoid syndrome was seen in only 13% of symptomatic patients. Many small bowel carcinoid tumours presented as surgical emergencies without preceding symptoms, often as intestinal obstruction (35%) caused by mesenteric fibrosis. The majority of small bowel carcinoid tumours had metastasized to the mesentery or the liver at diagnosis. Disease-specific survival after 5 years was 75.0% and after 10 years 63.5%. Independent prognostic factors for worse disease-specific survival were higher age at diagnosis, more advanced disease stage at diagnosis and incomplete tumour resection. Completeness of resection was of particular importance in patients with regional metastases. PAPER III There are previous case reports describing small bowel carcinoid in two first-degree relatives, but it is unknown whether this represents hereditary disease forms or chance. Paper III was the first article to describe metastasizing ileal carcinoid tumours in three consecutive generations − strongly suggestive of a hereditary disease form. PAPER IV We recently demonstrated expression of cocaine- and amphetamine-regulated transcript (CART) in several types of NETs, including small bowel carcinoid. The aim of paper IV was to investigate whether content of CART in small bowel carcinoid tumours is associated with tumour characteristics, symptoms and survival. CART expression was examined in all available tumour specimens from the patients in Papers I and II − 97 patients were included. Presence of CART IR tumour cells was associated with histological grade, but not with stage or age. CART expression in small bowel carcinoid tumours was not associated with clinical symptoms. Increasing levels of CART IR in small bowel carcinoid tumour cells was associated with worse disease-specific survival. CART was also found to increase cell viability in an enteroendocrine cell line in vitro. The results suggest that CART could be used as a prognostic biomarker and that CART is a potential anti-tumour treatment target

Time trends in incidence and survival of small intestinal cancer in Sweden

Background: Small intestinal cancer is less common than some other gastrointestinal malignancies. Tumours of different histological types and anatomical sites of origin have therefore often been described together. The aim of this study was to investigate the epidemiology for each of the four main subtypes: duodenal adenocarcinoma (D-AC), duodenal neuroendocrine tumour (D-NET), jejunoileal adenocarcinoma (J/I-AC), and jejunoileal neuroendocrine tumour (J/I-NET). Methods: All patients with small intestinal cancer diagnosed between 1960 and 2015 were identified from the Swedish Cancer Register. The age-adjusted incidence rate with incidence rate ratios, as well as overall (OS) and net (NS) survival, were determined and temporal trends were analysed. Results: The incidence rate was highest for J/I-NET, with 9.98 clinical diagnoses per million in 2010-2015. Clinical diagnosis of D-AC increased more than 10-fold and surpassed J/I-AC as the second most common subtype. D-NET was by far the least common subtype. Diagnosis at autopsy became less common over time, whereas clinical diagnoses increased significantly for all four subtypes. All subtypes except J/I-AC affected men more often than women. The age distribution was similar between subtypes, although patients with adenocarcinomas were slightly older. Survival was generally much better for patients with NET than for those with adenocarcinoma. Both OS and NS showed a negative association with advancing age. Survival improved only for J/I-NET from a 5-year NS of 0.69 in the 1960s to 0.81 in 2010-2015. Conclusion: The incidence of small intestinal cancer is increasing, particularly for D-AC and in the elderly. Survival of patients with small intestinal cancer has improved only for J/I-NET over the last decades.Funding Agencies|Futurum; Academy for Health and Care, Region Jonkoping County</p

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)

Survival of ileal pouch anal anastomosis constructed after colectomy or secondary to a previous ileorectal anastomosis in ulcerative colitis patients: a population-based cohort study

Objectives: Ileorectal anastomosis (IRA) affects bowel function, sexual function and reproduction less negatively than ileal pouch anal anastomosis (IPAA), the standard reconstruction after colectomy for ulcerative colitis (UC). In younger UC patients, IRA may have a role postponing pelvic surgery and IPAA. The aim of the present study was to investigate the survival of IPAA secondary to IRA compared to IPAA as primary reconstruction, as this has not previously been studied in UC. Patients and methods: All patients with UC diagnosis between 1960 and 2010 in Sweden were identified from the National Patient Registry. From this cohort, colectomized patients reconstructed with primary IPAA and patients reconstructed with IPAA secondary to IRA were identified. The survival of the IPAA was followed up until pouch failure, defined as pouchectomy and ileostomy or a diverting ileostomy alone. Results: Out of 63,796 patients, 1796 were reconstructed with IPAA, either primarily (n=1720) or secondary to a previous IRA (n=76). There were no demographic differences between the groups, including length of follow-up (median 12.6 (IQR 6.7-16.6) years and 10.0 (IQR 3.5-15.9) years, respectively). Failure of the IPAA occurred in 103 (6.0%) patients with primary and in 6 (8%) patients after secondary IPAA (P=0.38 log-rank). The 10-year pouch survival was 94% (95% CI 93-96) for primary IPAA and 92% (81-97) for secondary. Conclusions: Patients choosing IRA as primary reconstruction do not have an increased risk of failure of a later secondary IPAA in comparison with patients with primary IPAA.Funding Agencies|Bengt Ihres Fund; Medical Research Council of Southeast Sweden; Futurum - Academy for Health and Care; Region Jonkoping County, Sweden</p

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 &lt; 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

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 are available. METHODS: Fertility was assessed in 2,989 women and 3,771 men with IBD and prior colectomy 1964-2014, identified from the Swedish National Patient Register, and 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) while rare in Crohn's disease (CD). Compared with the matched reference cohort, women with IBD had lower fertility overall after colectomy (HR 0.65, CI 0.61-0.69), with least impact 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 0.67CI 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 post 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.Funding agencies: FORSS—Medical Research Council of Southeast Sweden [Grant number: FORSS-570791], Futurum—Academy for Health and Care, Region Jönköping County, Sweden [Grant number: FUTURUM-962541]</p

Immunomodulators: Friends or Enemies in Surgery for Crohns Disease?

Crohns disease may severely impact the quality of life and being a chronic disease it requires both medical and surgical treatment aimed at induction and maintenance of remission to prevent relapsing symptoms and the need for further surgery. Surgery in Crohns disease often has to be performed in patients with well-known risk factors of post-operative complications, particularly intra-abdominal septic complications. This review will look at the current knowledge of immunomodulating therapies in the peri-operative phase of Crohns disease. The influence of immunomodulators on postoperative complications is evaluated by reviewing available clinical reports and data from animal studies. Furthermore, the effect of immunomodulators on preventing or deferring primary as well as repeat surgery in Crohns disease is reviewed with particular consideration given to high-risk cohorts and timing of prophylaxis

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 &lt; 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 &lt; 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

Risk of Rectal Cancer After Colectomy for Patients With Ulcerative Colitis: A National Cohort Study

BACKGROUND amp; AIMS: Patients with ulcerative colitis (UC) have an increased risk of rectal cancer, therefore reconstruction with an ileal pouch-anal anastomosis (IPAA) generally is preferred to an ileorectal anastomosis (IRA) after subtotal colectomy. Similarly, completion proctectomy is recommended for patients with ileostomy and a diverted rectum, although this approach has been questioned because anti-inflammatory agents might reduce cancer risk. We performed a national cohort study in Sweden to assess the risk of rectal cancer in patients with UC who have an IRA, IPAA, or diverted rectum after subtotal colectomy. METHODS: We collected data from the Swedish National Patient Register for a cohort of 5886 patients with UC who underwent subtotal colectomy with an IRA, IPAA, or diverted rectum from 1964 through 2010. Patients who developed rectal cancer were identified from the Swedish National Cancer Register. The risk of rectal cancer was compared between this cohort and the general population by standardized incidence ratio analysis. RESULTS: Rectal cancer occurred in 20 of 1112 patients (1.8%) who received IRA, 1 of 1796 patients (0.06%) who received an IPAA, and 25 of 4358 patients (0.6%) with a diverted rectum. Standardized incidence ratios for rectal cancer were 8.7 in patients with an IRA, 0.4 in patients with an IPAA, and 3.8 in patients with a diverted rectum. Risk factors for rectal cancer were primary sclerosing cholangitis in patients with an IRA (hazard ratio, 6.12), and colonic severe dysplasia or cancer before subtotal colectomy in patients with a diverted rectum (hazard ratio, 3.67). CONCLUSIONS: In an analysis of the Swedish National Patient Register, we found that the risk for rectal cancer after colectomy in patients with UC is low, in relative and absolute terms, after reconstruction with an IPAA. An IRA and diverted rectum are associated with an increased risk of rectal cancer, compared with the general population, but the absolute risk is low. Patients and their health care providers should consider these findings in making decisions to leave the rectum intact, perform completion proctectomy, or reconstruct the colon with an IRA or IPAA.Funding Agencies|Medical Research Council of Southeast Sweden; Futurum Academy for Health and Care (Region Jonkoping County, Sweden)</p

Cocaine- and Amphetamine-Regulated Transcript in Neuroendocrine Tumors

Background/Aims: Cocaine-and amphetamine-regulated transcript (CART) is an anorexigenic regulatory peptide highly expressed in the brain's appetite control centers, but also in peripheral neurons and in endocrine cells in the adrenal medulla, thyroid, pancreatic islets, and in the gastrointestinal tract. Plasma levels of CART were recently shown to be elevated in patients with neuroendocrine tumors (NETs), but the cellular sources of CART in NETs have remained unknown. The aim of the study was to establish whether CART is expressed in various types of NETs and, if so, to examine the frequency, distribution and phenotype of CART-expressing cells. Methods: Tumor specimens from 133 NETs originating in the stomach, ileum, rectum, pancreas and thyroid were examined with immunohistochemistry and in situ hybridization. The expression of CART was quantified and the CART-expressing cells were phenotyped by double staining for established markers and hormones. Results: CART-expressing tumor cells were found in the majority of the examined NETs. The expression pattern of CART was highly heterogeneous not only between tumors, but also within individual tumors. In 14% of the NETs, CART was found in a major population of the tumor cells. Conclusion: CART is produced in the majority of NETs, regardless of tumor origin. This likely explains the elevated levels of circulating CART in certain NETs patients, as recently described. CART could therefore prove to be a useful tool in the diagnostics of NETs not only in blood samples, but also in histopathological specimens. Copyright (C) 2011 S. Karger AG, Base