| 1. |
- Abdalla, Maie
(författare)
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Cancer and reconstructive surgery in Inflammatory bowel disease
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ulcerative colitis (UC) is a chronic inflammatory disease that affects the colon. According to the literature, some thirty percent of UC patients may require a subtotal colectomy and ileostomy due to failure of medical treatment, acute toxic colitis or dysplasia/cancer diagnosis. Some patients choose to get continence restored with either an ileorectal anastomosis (IRA) or an ileal pouch-anal anastomosis (IPAA). Worldwide most surgeons prefer an IPAA to an IRA, despite reports of pouchitis, impaired fertility and fecundity. Fear of recurring proctitis and fear of rectal cancer in the remaining rectum is contributing to the choice of an IPAA. Little is known regarding the outcomes of IRA compared with IPAA in UC patients. We aimed to investigate the anorectal function, quality of life (QoL), risk of failure and rectal cancer in patients with UC restored with IRA and IPAA respectively. Methods: Data about all Inflammatory bowel disease (IBD) patients was obtained from the Swedish National Patient Register (NPR) between 1964-2014 and in one study from the Linköping University Hospital medical records 2006-2012. Patients who developed cancer were identified from the Swedish National Cancer Register. We investigated the risk of cancer and inflammation, functional outcome and failure as well as the quality of life for IRA and IPAA patients. Investigation of risk for cancer in IRA and IPAA compared with the background population was performed using survival analytic techniques: uni-and multivariate regression, Kaplan Meier curves and standardized incidence ratio. Results: Twelve percent (7,889 /63,795) of UC patients required colectomy according to the NPR. The relative risk for rectal cancer among patients with an IRA was increased (SIR 8.7). However, the absolute risk was 1.8% after a mean follow up of 8.6 years and the cumulative risk 10- and 20-years after IRA was 1.6% and 5.6%, respectively. Risk factors for rectal cancer were primary sclerosing cholangitis in patients with an IRA (hazard ratio 6.12), and severe dysplasia or cancer of the colon prior to subtotal colectomy in patients with a diverted rectum in place (hazard ratio 3.67). Regarding IPAA, the relative risk to develop rectal cancer was (SIR 0.4) compared with the background population and the absolute risk was only 0.06% after a mean of 12.2 years of follow up. Among patients operated at the Linköping University Hospital: IRA patients reported better overall continence according to the Öresland score with in median3 (IQR 2–5) for IRA (n=38) and 10 (IQR 5–15) for IPAA (n=39, p<0.001). There were no major differences regarding the QoL. According to the NPR, after a median follow up of 12.4 years failure occurred in 265(32%) out of 1112 patients, of which 76 were secondarily reconstructed with an IPAA. Failure of the IPAA occurred in 103 (6%) patients with primary and in 6 (8%) patients after secondary IPAA (log-rank p=0.38). Conclusion: IRA is a safe restorative procedure for selected UC patients. Patients should be aware of the annual postoperative endoscopic evaluation with biopsies as well as the need to the use of local anti-inflammatory preparations. However, IRA should not be offered for UC patients with an associated primary sclerosing cholangitis diagnosis due to the increased risk to develop rectal cancer in their rectal mucosa. In such case, IPAA is probably the treatment of choice.
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| 2. |
- Druvefors, Emma, 1985-
(författare)
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Fertility in Inflammatory Bowel Disease
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inflammatory bowel diseases (IBD) often present in adolescence or early adulthood and is thus frequently diagnosed in men and women in their reproductive age. Previous population-based studies of fertility in patients with IBD are scarce.From the Swedish National Patient Register (NPR) all patients diagnosed with IBD of fertile age between 1964–2014 were identified. Statistics Sweden identified a matched reference cohort (ratio 1:5) from the general population matched for sex, age and place of birth. Children born were identified through the Medical Birth Register and the Swedish Multigeneration Register. For subgroup analyses information about medication was collected through Medical Drug Register and information about socioeconomic status from Longitudinal Integrated Database for Health Insurance and Labour Market Studies. From the SWedish Inflammatory Bowel disease quality REGister (SWIBREG) a cohort of women with UC who underwent colectomy 2000–2020 was identified. Demographic data from SWIBREG and information from a study specific questionnaire regarding reproductive history and voluntary childlessness were analysed.From the NPR 27,331 women and 29,104 men with IBD were identified, corresponding to 272,793 matched individuals.The fertility rate in women with IBD was 1.52 (standard deviation [SD] 1.22) births per 1000 person-years, compared with 1.62 (SD 1.28) (p <0.001) in the matched reference cohort. Fertility was negatively affected mainly in women with Crohn's disease (CD) and IBD-unclassified (IBD-U) and to a lesser extent in ulcerative colitis (UC). Disease activity, bowel resections and, in the case of CD, also perianal disease further adversely affected fertility. For women with UC and IBD-U, but not for women with CD, fertility improved throughout the study period. Contraceptive use was higher in female IBD patients, both before and after the diagnosis.In total 2,989 women underwent colectomy during the study period. Reconstruction with ileal pouch anal anastomosis (IPAA) and ileorectal anastomosis (IRA) was used to about the same extent in UC and IBD-U, although this was rare in 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 for operations that left the rectum intact (HR 0.79, CI 0.70–0.90). When the comparison was made within the group of patients undergoing colectomy, fertility in female patients remained nearly unaffected after IRA in all subtypes of IBD, but was impaired after IPAA, especially in UC (HR 0.67 CI 0.50–0.88), and after completion proctectomy in all subtypes of IBD (CD 0.61 CI 0.38–0.96), UC HR 0.65, CI 0.49–0.85 and IBD-U0.68, 0.55–0.85).The survey regarding reproductive behavior after colectomy was completed by 214 (73%) out of 294 eligible women identified in SWIBREG. The desire to have children was negatively affected by disease onset in 59% of the women, colectomy in 44% and by reconstruction in 37%. Altogether, 39% women with UC estimated that they chose to have fewer children in the end because of the disease, but only 10% expressed that the disease made them completely restrain from having children. On the contrary 37% of the women reported that they had experienced difficulties to conceive and 19% expressed that they could not conceive at all. Of the women undergoing reconstruction post colectomy, 37% reported that the choice of reconstruction method was influenced by their desire to have children. Difficulty conceiving was more commonly reported after reconstruction with IPAA (odds ratio [OR] 5.54) than IRA (OR 2.57).Men with IBD also had lower fertility rate compared with the matched reference population, although the impact on parity was limited; 1.28 (SD 1.27) versus 1.35 (SD 1.31) (p < 0.001). Fertility in men was nevertheless impaired in all IBD subtypes. The disease severity measured as order of hospital admissions (UC and IBD-U), intensity of medical treatment (CD), and bowel surgery (IBD-U) were further associated with impaired fertility in men. In the 3,771 men undergoing colectomy during the study period, fertility was only marginally (HR 0.89, CI 0.85–0.94) impaired, regardless of reconstruction.In conclusion, women with IBD have only slightly reduced fertility rates compared with the matched reference population with some exceptions. In non-surgically treated patients, the impact was most pronounced in female patients with CD. Women post colectomy have a particularly marked impact on fertility independent of IBD subtype. Bowel reconstruction with IPAA and proctectomy had a pronounced negative impact on fertility, while fertility was not further affected after IRA. More than half of the women with UC post colectomy reported that developing UC has affected their desire to have children, but difficulty to conceiving is also commonly reported. The impact of IBD in men was only minor.
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| 3. |
- Landerholm, Kalle, 1976-
(författare)
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Clinical and immunohistochemical studies of small bowel carcinoid tumours
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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 IIThe 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 IIIThere 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 IVWe 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.
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| 4. |
- Shamoun, Levar, 1979-
(författare)
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Investigation of immune cell-derived factors as potential biomarkers in patients with colorectal cancer
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer related death. It is a heterogeneous disease involving multiple molecular pathways that result in differing phenotypes. Individual variability in CRC susceptibility is influenced by genetic variation, such as single nucleotide polymorphisms (SNPs). Changes in genetics and epigenetics can disrupt intact signalling pathways involved in metabolism, proliferation, differentiation, and apoptosis. Inflammatory factors such as cytokines and chemokines, as well as their receptors, play important roles in immune regulation.In Papers I, II and III, selected SNPs in the genes of interleukin (IL)-4, IL-13, IL-2 or chemokine C-C motif ligand (CCL) 4 in patients with CRC were investigated to determine their prognostic significance by identifying associations with various clinicopathological parameters and long-term survival. The investigated IL-13 and IL-4 SNPs were found to be risk factors for CRC and could be useful potential prognostic markers in CRC patient follow-up and clinical management. The investigated IL-2 SNPs were significantly associated with an increased risk of CRC and worse cancer-specific survival in patients with stage II or stage III CRC.In Paper III, levels of CCL4 protein were measured in CRC patients to investigate their prognostic significance for CRC. The data showed that CRC tissue had a higher protein expression than normal paired tissue, and plasma CCL4 levels were higher in patients than in controls, being positively correlated with CRC tissue levels. Further, higher levels of tissue CCL4 protein were linked to a lower disease stage and a better prognosis.Paper IV was an investigation of the expression of zinc finger MYND-type containing 15 (zmynd15) and its roles in CRC. In CRC tissue, protein expression was found primarily in cluster of differentiation (CD) 68 positive cells. Zmynd15 messenger ribonucleic acid expression was lower in CRC tissue than in non-cancerous tissue. When zmynd15 was silenced in CRC cell lines, it caused alteration in genes known to be important in CRC, indicating that zmynd15-regulated genes are involved in CRC. Furthermore, tumour development in the colon was higher in zmynd15 knockout mice than in wild-type mice.In conclusion, the work presented in this thesis contributes to an understanding of the association of inflammatory markers in CRC with risk and survival, and their potential use as tools for monitoring CRC patients. In addition, it showed that zmynd15, a transcriptional suppressor, plays an important role in the development of CRC.
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