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- Gadan, Soran, 1976-
(författare)
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Long term aspects of defunctioning stoma following low anterior resection for rectal cancer
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Sweden, more than 2 000 individuals are diagnosed with rectal cancer each year. Surgery is the main curative treatment, and involves removal of the tumor with the surrounding mesorectum in adefined anatomical plane. Intestinal continuity is restored by anastomosing the colon to the rectalstump at the pelvic floor. Leakage of the anastomosis is a potentially life-threatening complication, and is most common in low anastomoses located at the pelvic floor. A temporary defunctioning loop stoma (DS) reduces both the rate of leakage and the severity when leakage occurs despite DS. The use of DS has increased substantially in Sweden over the last 15 years, especially in low anastomoses at the level of the pelvic floor. The purpose of this thesis was to increase the understanding of different aspects of DS and its impact on anorectal function, long-term survival, cancer recurrence, timing of stoma reversal, and the risk of having a permanent stoma.In Paper I, the LARS score questionnaire was used to assess anorectal function among patients who had participated in a Swedish nationwide randomized trial. Those who had a DS (n=116) were compared to those without DS (n=118). After a median follow-up time of 12 years, patients with DS had a poorer bowel function than those without DS in terms of incontinence for gas and loose stools. No differences were found with regard to fecal incontinence, defragmentation, and urgency. Women and patients who had received preoperative radiotherapy had poorer anorectal function. Impaired anorectal function was associated with lower self-perceived health.In Paper II, a cohort of 110 patients from Örebro Region, Sweden, was investigated with regard to whether or not the DS was reversed within a 4-month period. Only 25% had their stoma reversed within this timeframe. Moreover, a third of the patients had a delayed stoma closure without any identifiable medical reason. This was an improvement compared to a previous study from the same region, which found that 58% of patients operated between 1995 and 2007 had a delayed stoma reversal without any identifiable medical reason. The most common cause for delayed DS reversal in our study was adjuvant chemotherapy (38%).In Paper III, the impact of DS on long-term survival and local and distant cancer recurrence was investigated in a nationwide population-based study cohort operated with low anterior resection (LAR) between 1995 and 2010 (n=4130), retrieved from the Swedish Colorectal Cancer Registry. Patients with a DS at LAR (n=2163) had an increased survival rate during the first 3 years afterindex surgery in comparison with those without a DS. Beyond 3 years of follow-up, no difference was noted between the two groups. There were no differences regarding either local cancer recurrence or distant metastases between patients with and without DS.In Paper IV, the risk of having a permanent stoma beyond 5 years after rectal cancer surgery was evaluated in 232 patients (excluding mortality within 90 days; n=2) previously randomized to DS or no DS. After a median follow-up of 15 years, 25% (57/232) had a permanent stoma. Of these, 23% (13/57) had their permanent stoma constructed at median 10 years after the index surgery. The incidence of permanent stoma was numerically lower in the group originally randomized to DS, but this difference was not statistically significant. Anastomotic leakage was the most common riskfactor for ending up with a permanent stoma.
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| 2. |
- Boström, Petrus, 1981-
(författare)
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Rectal cancer : the influence of surgical technique on morbidity, mortality and survival
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Surgery is still the most common treatment for rectal cancer, being the most effective and cost-efficient modality. However, it is not without risk, nor without controversies. This dissertation is an evaluation of the pros and cons of high versus low ligation, whether anastomotic leakage is still prevalent after surgery and associated with increased mortality, and if the risk of leakage could be predicted by early postoperative pain.Study I relied upon case records and registry data to evaluate the causal effect of high ligation on the risk of anastomotic leakage after anterior resection in 722 patients with increased cardiovascular risk. When controlling for confounders, no association was found overall. However, an increased risk for leakage after high ligation was noted for the few patients who suffered from both manifest cardiovascular disease and ASA III–IV (OR 3.66, 95% CI 1.04–12.85) and when performed in a low volume hospital (OR 3.89, 95% 1.58– 9.59). Study II estimated the risk of anastomotic leakage and death after anterior resection today. Among the 6,948 patients, 10.0% suffered from leakage, in whom mortality was 3.9% versus 1.5% for patients without a leak. However, this increased mortality was driven entirely by patients in need of reintervention, who exhibited a 7.5% 90-day mortality, resulting in a significantly increased risk (OR 5.57, 95% CI 3.29–9.44), when controlling for confounders, while conservatively treated leakage was not associated with mortality. Age acted as an effect modifier, as postoperative mortality after leakage was increased in the elderly.Study III returned to high versus low ligation as exposure, to evaluate the long-term oncological benefits of either ligation level, with cancer-specific survival as primary outcome. The final cohort of 8,287 patients who underwent abdominal surgery for rectal cancer, with curative intent, was followed for a minimum of 3.5 years. After propensity score matching, no significant differences were found between high and low ligation for any survival or recurrence analysis, nor in the unmatched cohort, when controlling for confounders. A statistically significant difference was found for lymph node harvest, which was slightly greater in high ligation (17.7 vs 16.7 lymph nodes). Finally, study IV estimated the independent predictive ability of postoperative pain, measured on the numerical rating scale (NRS), on the risk for anastomotic leakage after colorectal cancer surgery. It seems as if increased early pain is an independent predictor for leakage (OR 1.73, 95% CI 1.22– 2.46 for NRS 4–10), with increasing risk of leakage with increasing pain (OR 2.42 for NRS 8–10). In addition, increased pain was more strongly associated with more severe leakage.In summary, the level of ligation seems to be of importance only in a select group of high-risk patients, but offers no obvious oncological advantages. The high incidence and serious sequelae of anastomotic leakage makes it one of the most important clinical challenges in colorectal surgery, with especially detrimental effects in the elderly. A better understanding of the causal pathways behind leakage, and the overall harm and benefit of ligation level and diverting stomas, might allow a better selection of treatment for future patients.
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| 3. |
- Grahn, Oskar, 1985-
(författare)
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Modulating the inflammatory response after colorectal cancer surgery : friend or foe?
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer was the second most deadly and third most common cancer globally in 2020. In Sweden, more than 5,000 new colonic cancer cases and more than 2,000 rectalcancer cases were reported in 2021, making colorectal cancer the third most common in Sweden (excluding skin malignancies).Anastomotic leakage after colorectal cancer surgery is a feared complication that confers substantial morbidity, including a higher risk of permanent stoma and cardiovascular morbidity, but can also impart an increased risk of recurrence and mortality; the reason why leakage might cause this is not established. Perioperative inflammation including upregulation of cyclooxygenase-enzymes, which is further increased by anastomotic leakage, can possibly modulate both anastomotic healing as well as impact minimal residual disease. Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibiting COX-enzymes and can be part of a postoperative multimodal analgesia protocol. However, their postoperative use has been debated, with fears of NSAIDs possibly increasing anastomotic leakage rates.Study I was a retrospective cohort study on 1,341 patients who had undergone anterior resection for rectal cancer. Exposure was at least two days with NSAIDs during the first postoperative week, and the primary outcome was recurrence-free survival. A Cox regression model could not demonstrate a significant association with a hazard ratio (HR) of 1.02 (95% confidence interval (CI): 0.79–1.33) and neither did a propensity score-matched analysis. An instrumental variable analysis displayed a tentative improvement in recurrence-free survival in the NSAID-exposed (HR 0.61; 95% CI 0.38–0.99), but the core assumptions to perform such an analysis were not fully satisfied.Study II was a protocol-based retrospective cohort study with a total of 6,945 patients resected for colorectal cancer with a primary anastomosis formed. NSAID-exposure was determined by each individual hospital’s postoperative analgesia protocol, while patient data and outcomes were retrieved from the Swedish colorectal cancer registry. Some 3,996 (58%) patients were treated at a hospital with NSAIDs included in their postoperative analgesia protocol. No significant association with recurrence-free survival was seen (HR 0.97, 95% CI0.87–1.09). However, a reduction in cancer recurrence was demonstrated (HR 0.83, 95% CI0.72‒0.95), with an increased risk reduction for locoregional (HR 0.68, 95% CI 0.48–0.97) in comparison to distant recurrence (HR 0.85, 95% CI 0.74–0.98). Anastomotic leakage was less frequent as well, mainly because of a reduction in the group with colorectal or ileorectal anastomoses (HR 0.47, 95% CI 0.33–0.68).In Study III, the aim was to explore proteomic and biological pathway alterations in patients with peritoneal infection. This was a 1:1 matched cohort study on patients resected for colorectal cancer with a primary anastomosis formed, including 32 cases who suffered a postoperative peritoneal infection matched with 32 controls with a complication-free postoperative stay. Serum samples were retrieved from their first postoperative visit and at one year postoperatively. Out of a total of 270 proteins tested, 77 were differentially expressed at the first postoperative visit at a median sampling time of 41 days after surgery. Many of the top hub proteins are known actors in colorectal cancer progression, including survival and invasiveness, potentially enhancing minimal residual disease. Over-represented pathways were related to cardiomyopathy, cell-adhesion, extracellular matrix, phosphatidylinositol-3-kinase/Akt (PI3K-Akt) and transforming growth factor beta (TGF-Beta) signalling.In Study IV, the aim was to evaluate the frequency of a known polymorphism of the COX-2 gene promotor -765G>C in a Swedish cohort of colorectal cancer patients, and whether a previously reported association between this gene variant with an increase in anastomotic leakage could be reproduced. This was a 1:1 matched case-control study on a total of 94 patients who were resected for colorectal cancer with a subsequent primary anastomosis, with cases suffering a peritoneal infection. Preoperative blood and serum samples were genotyped and analysed using pre-defined protein panels. Of the 94 patients in total, one in each group were homozygous for the minor allele C/C, and ten cases and 14 controls were heterozygous with G/C and the rest were homozygous for the major allele. Thus, there were fewer individuals with the minor allele in the case group, with a non-significant odds ratio of 0.71(p=0.413), ultimately not replicating the finding of the previous study. The protein quantitative trait loci analysis rendered no associations of interest.In conclusion, no statistically significant effects on recurrence-free survival from postoperative NSAIDs in patients resected for colorectal cancer could be demonstrated in study I, whereas significant associations between NSAID use and reduction in frequency of anastomotic leaks as well as cancer recurrence could be shown in study II. In study III, numerous proteins were differentially expressed in patients suffering a postoperative peritoneal infection, even after more than a month’s duration, potentially stimulating minimal residual disease. The over-representation analysis found pathways related to cardiomyopathy, which could help explain the increase in cardiovascular morbidity in patients suffering anastomotic leakage. Study IV could not reproduce the potentially marked increase in anastomotic leak frequency in carriers of the COX-2 gene promotor -765G>C polymorphism in a Swedish sample. Whether to include NSAIDs or not in postoperative multimodal analgesia is a question still not answered, and it may depend on the genotype, the patient’s preoperative inflammatory state, tumour location, the specific NSAID used, and whether a leak has already occurred. NSAIDs might have effects on both morbidity including cardiovascular and anastomotic leakage as well as minimal residual disease including recurrence and mortality. This thesis suggests potential protective effects regarding both anastomotic leakage as well as cancer recurrence, but it seems to depend on at least some of the aforementioned factors. The proteomic landscape regarding postoperative peritoneal infection has been investigated, and where it has also been demonstrated that the duration of said alterations can be greater than was earlier suspected. Finally, even if a replication attempt was not successful considering the relation between a COX-2 gene promotor polymorphism and anastomotic leakage, it could be worthwhile to attempt further replication studies.
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| 4. |
- Baban, Bayar, 1973-
(författare)
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Colorectal cancer and surgery : Insights into insulin resistance and inflammatory markers
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The art of surgery has progressively extended from the realm of anatomy to encompass physiology and beyond, in search of further refinement and optimal recovery. Integral to this is a deeper understanding of the body’s essential metabolic and inflammatory responses to surgical trauma.This thesis aims to provide insights into the intricate interplay between insulin resistance, inflammation and surgical interventions in colorectal cancer patients, as each has an influence on postoperative recovery. Particular emphasis is placed on the role of inflammasomes – central mediators of the innate immune response, adept at detecting and responding to a diverse range of triggers, yet insufficiently explored in these specific contexts.Study I is a comparative analysis of the hyperinsulinemic–euglycaemic clamp and homeostatic model assessment (HOMA) in determining postoperative insulin resistance in 113 patients undergoing various elective surgeries. The findings establish the clamp as the accurate method, detecting key physiological distinctions missed by HOMA.Study II, an exploratory case–control study, assesses insulin sensitivity and inflammatory markers in 20 colorectal cancer patients compared to 10 matched healthy controls. Results indicate insulin resistance, reduced inflammasome activity in circulating immune cells and elevated systemic IL-1β and IL-6 levels in patients.Study III, a pilot exploratory study of 17 patients from Study II, assesses the impact of surgical technique, open versus minimally invasive surgery, on postoperative insulin resistance and inflammation in colorectal cancer resections. It indicates a differential inflammatory response with higher levels in open surgeries, yet a consistent degree of insulin resistance across both surgical techniques.Study IV explores the perioperative temporal sequencing of inflammation and inflammasome action in 18 patients from Study II undergoing elective colorectal cancer resections. It points to a more immediate and pronounced inflammatory response in open surgery compared to minimally invasive surgery, though both techniques show reduced intraoperative caspase-1 activity.In conclusion, the hyperinsulinemic euglycaemic clamp is the accurate method in determinations of postoperative insulin resistance. Patients with colorectal cancer, in comparison to matched healthy controls, exhibit insulin resistance and higher levels of inflammation, but decreased inflammasome (caspase-1) activity in circulating immune cells. Finally, colorectal cancer resections induce both insulin resistance and inflammation; however, the surgical technique utilized only significantly affects the latter, with generally higher inflammatory / inflammasome responses in open surgery.
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| 5. |
- Dehlaghi Jadid, Kaveh, 1985-
(författare)
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Long-term outcome, socioeconomic aspects and postoperative inflammatory response in minimally invasive rectal cancer surgery
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In Sweden, more than 2,200 individuals are diagnosed with rectal cancer each year and surgical resection is the cornerstone of treatment. Minimally invasive surgery (MIS) was introduced for abdominal rectal cancer resection in the 1990s. Proven advantages of MIS in the short term include less intraoperative bleeding, less postoperative pain, faster postoperative mobilization, and shorter hospital stay. Large randomized studies have also shown that MIS is not inferior to OPEN with regard to the oncological short-term or long-term outcome.The aim of this thesis was to increase the knowledge of MIS from a Swedish perspective regarding long-term oncological outcome, socioeconomic aspects, and the postoperative inflammatory response in curative abdominal rectal cancer surgery.Study I included all patients who were diagnosed with clinical stage I-III rectal cancer during 2010-2016. More than 8,300 patients were identified via the Swedish Colorectal Cancer Registry (SCRCR). The study had a so-called non-inferiority design and investigated overall 5-year survival. The results showed that survival was not worse in patients who underwent minimally invasive surgery in comparison to patients who underwent open surgery.Study II included all patients who were diagnosed with pathological stage I-III cancer of the colon 2010-2016. More than 11,000 patients were identified via the SCRCR. The study was designed in the same way as Study I. The results demonstrated that minimally invasive surgery was not inferior to open surgery.Study III analysed the potential impact of socioeconomic status, measured as level of education and household income, regarding the likelihood of receiving minimally invasive surgery. All patients who underwent curative abdominal rectal resection surgery during 2010-2016 were included. More than 8,000 patients were identified. The results showed that patients with the highest level of education and those in the highest income quartile were more likely to be operated on with minimally invasive technique.Study IV analysed the inflammatory response, measured as serum C-reactive protein during postoperative days 1-5, in all 520 patients undergoing abdominal rectal resection in Örebro between 2011 and 2021. Following exclusions based on postoperative adverse events, 382 patients remained for final analysis. The study demonstrated a trend for a less pronounced inflammatory response in patients operated with robot-assisted laparoscopy compared with conventional laparoscopy.
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