digitalisering@umu

digitalisering@umu.se

<p>2022-03-23</p>

Background: Minor procedures in surgery and urology such as groin hernia and hydrocele repair, as well as prostate biopsies are very frequently done in routine practice. Complications and insufficient outcomes thus affecting many patients and the cumulative effect of this are of major importance in a population perspective. Aim: To explore complications and outcomes of surgical or diagnostic procedures and possible risk factors or predictors for adverse effects. Methods: By using both national quality and administrative registers, and by complementing registers with patient reported outcome measures, examine outcomes such as complications, persistent pain and recurrences. Also, in the case of hydro and spermatoceles, report incidence numbers. Further, by using a randomized trial, explore minimally invasive procedure such as sclerotheraphy compared to conventional surgery in respect to cure and adverse events. Results: When comparing with the open anterior mesh repair, endoscopic technique is advantageous in respect to the patient reported outcome of persistent pain. The drawback was an increased risk of postoperative complications and reoperation for recurrence. Incidence numbers for hydro and spematocele were 100/100000 men. Aspiration (± sclerotherapy) had a significantly lower rate of complications as compared to conventional surgery. In the interim analysis of the randomized trial, comparing sclerotherapy to Lord´s procedure for hydroceles, the cure rate was similar between treatments. Definite conclusions cannot be made due to the risk of type 2 errors, and the study will thus continue. In the case of trans-rectal prostate biopsy, the rates increased every year during the study time frame, up to an approximate risk of two per cent in 2012 for hospital readmission within 30 days, without an increased mortality within 30 days. Conclusions: The open anterior mesh procedure is still the preferred method for groin hernia repair in routine surgical practice. Hydro and spermatocele surgery is associated with high rates of complications, and the indication for repair should be scrutinized. The rates of infection after prostate biopsy is increasing and methods to reduce unnecessary biopsies as well as improved prophylaxis should be investigated.

Colorectal cancer (CRC) is defined as a cancer appearing in the colon or in the rectum. In Sweden, ~ 6300 individuals were diagnosed with the disease in 2014 and ~ 2550 individuals diagnosed with CRC die each year due to their cancer. Surgery is the main treatment option of CRC and a survival rate of ~ 10 % is estimated if distant metastases have developed. It is therefore of importance to find factors that may be useful together with tumour, node, metastasis (TNM) stage to establish early CRC diagnosis, prognosis and follow-up of CRC patients. The aim of this thesis was to study the possible association of CD93, PLA2G4C, PDGF-D and inflammatory cytokines with CRC disease progression. In a prospective study approach CD93 and PLA2G4C single nucleotide polymorphisms (SNPs) were of potential importance in CRC prognosis. The T/T genotype of CD93 was associated with an increased CD93 expression in CRC tissue. Further, CRC patients carrying this genotype were associated with disseminated CRC at diagnosis and a lower recurrence-free survival after surgery. The A allele of a SNP of PLA2G4C was a stronger predictor for CRC-specific mortality than the conventional risk factors used in the clinic for selection of TNM stage II patients for adjuvant treatment. This indicates that the T/T genotype of CD93 and the A allele of PLA2G4C may be potential genetic factors related to disease severity and spread. Furthermore, they distinguish CRC patients that may benefit from a more comprehensive follow-up and adjuvant treatment. To study the putative involvement of PDGF-D in CRC the effects of PDGF-D signalling was studied in vitro. PDGF-D signalling altered the expression of genes of importance in CRC carcinogenesis and proliferation which was blocked by imatinib, a tyrosine kinase inhibitor. This indicates that PDGF-D signalling may be an important pathway in CRC progression and a potential target in CRC treatment. The analysis of various inflammatory cytokines in plasma at diagnosis showed an association between high levels and increased total- or CRC-specific mortality two years after surgery. High levels of CCL1 and CCL24 was the only cytokines strongly correlated with a worse CRC prognosis after statistical adjustments and may be of interest for further evaluation. In conclusion, this thesis presents circulating and genetic factors such as CD93, PLA2G4C, PDGF-D, CCL1 and CCL24 that may be of importance in CRC progression and may be of clinical value together with TNM stage in establishing prognosis. / Kolorektal cancer är en tumör i kolon eller rektum. I Sverige diagnosticerades år 2014 ca6300 individer med denna cancertyp och ca 2550 personer dör årligen till följd av kolorektalcancer. Operation är det huvudsakliga behandlingsalternativet för kolorektal cancer och vidfjärrmetastaser är överlevnaden &lt; 10 %. Det är därför viktigt att hitta markörer somtillsammans med TNM-stadium kan ge tidig information om sjukdomens prognos och lämpliguppföljning av patienter. Utveckling av kolorektal cancer sker genom ackumulering av genetiska mutationer ochepigenetisk nedreglering av tumörsuppressorgener. Därutöver spelar interaktionen mellantumören och dess närmaste omgivning, innehållande tillväxt- och inflammatoriska faktorer,en viktig roll i tumörens utveckling och metastasering. Syftet med avhandlingen var att studera associationen mellan CD93, PLA2G4C, PDGF-D samtinflammatoriska cytokiner och kolorektal cancer progression. En prospektiv studie visade att CD93 och PLA2G4C SNP var potentiellt viktiga förbedömningav kolorektal cancer prognos. T/T genotypen av SNP rs2749817 i CD93 var associerad medhögre uttryck av CD93 i kolorektal cancer vävnad, främst bland patienter i stadium IV.Därutöver observerades fler återfall efter operation hos patienter med T/T genotypen. Aallelen hos PLA2G4C SNP rs1549637 är en möjligtvis bättre markör för cancerspecifiköverlevnad vid stadium II än faktorer som idag används för att selektera patienter tilladjuvant behandling. Sammantaget antyder detta att T/T genotypen av CD93 och A allelenav PLA2G4C kan vara genetiska markörer relaterade till allvarlig tumörsjukdom ochspridning. Därutöver kan de eventuellt selektera patienter som kräver tätare uppföljning ochadjuvant behandling. För att studera den förmodade inblandningen av PDGF-D i kolorektal cancer undersöktesdess effekt på PDGF-D signalering in vitro. PDGF-D signaleringen förändradegenexpressionen av gener involverade i tumörutveckling och spridning, vilken kundeblockeras av tyrosinkinashämmaren imatinib. Det antyder att PDGF-D signalering kan vara enviktig faktor vid kolorektal cancer progression och ett potentiellt mål för behandling. Analysen av ett flertal inflammatoriska cytokiner visade en korrelation mellan högacytokinnivåer och ökad cancerspecifik och total dödlighet två år efter operation. Höga CCL1och CCL24 nivåer var de enda faktorerna som förblev signifikant associerade medcancerspecifik mortalitet vid fördjupad statistisk analys och bör studeras vidare. Sammanfattningsvis presenterar denna avhandling cirkulerande och genetiska faktorersåsom CD93, PLA2G4C, PDGF-D, CCL1 and CCL24 som eventuellt är viktiga vid bedömning avkolorektal cancer progression tillsammans med TNM stadium.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a group of vasculitides characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of ANCA in the circulation. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. NETs were first described to be involved in capture and elimination of pathogens but dysregulated production and/or clearance of NETs are thought to contribute to vessel inflammation in AAV; directly by damaging endothelial cells and indirectly by acting as a link between the innate and adaptive immune system through the generation of pathogenic PR3-ANCA and MPO-ANCA that can activate neutrophils. ANCA can, however, be found in all individuals and are therefore suggested to belong to the repertoire of natural antibodies produced by innate-like B cells, implying that not all ANCA are pathogenic.  In paper I, we found neutrophils in patients to be more prone to undergo NETosis/necrosis spontaneously compared with neutrophils in healthy controls (HC), as well as that active patients possessed elevated levels of NETs in the circulation. Our results also suggest that ANCA during remission could contribute to the clearance of NETs as we observed an inverse relation between ANCA and NETs. In paper II, we observed neutrophils in patients to be more easily activated upon ANCA stimulation as they produced more ROS than neutrophils in HC. In paper III, we showed for the first time that cells of adaptive immunity (B and T cells) in addition to cells of innate immunity can release ET-like structures, in this case consisting of mitochondrial (mt) DNA. mtDNA can act as a damage-associated pattern molecule (DAMP) and promote inflammation, and increased levels of mtDNA has been observed in AAV. Our finding broadens our perspective of the possible roles of T and B cells in immunological responses, and should be further investigated in AAV. In paper IV, we observed reduced frequencies of MZ-like B cells, considered to be innate-like B cells that produce natural antibodies, and of the proposed regulatory B (Breg) cell populations CD24highCD27+ and CD25+CD27+ B cells in patients, particularly in those with active disease. We also observed the phenotypes of these different Breg cell populations to be different from the corresponding cells in HC. We hypothesize that the increased activation potential by neutrophils in AAV to produce ROS and undergo NETosis/necrosis contribute to the excessive inflammation as well as an increased antigen load of PR3 and MPO, and that this in combination with dysregulation of innate-like B cells and Breg cells could lead to break of tolerance to these antigens and production of pathogenic autoantibodies. ANCA can in turn activate neutrophils to release NETs, suggesting a vicious circle in disease development.

Bladder dysfunction is seen as a public health problem with a strongly increasing incidence in older men. Despite this, the man's experience of bladder dysfunction is a topic that has not been researched in the empirical field as much as women’s experiences. Not highlighting the man's experience leads to suffering and constitutes an obstacle to equal care. The aim of this study was to illustrate the man's experience of living with bladder dysfunction. This study is intended to illustrate experiences, therefore it was well suited to make an integrative compilation of qualitative research – inspired by meta-synthesis. Nine qualitative articles that described the man's experiences were analysed schematically and resulted in three themes and six sub-themes. Experiences that were noticed in the man were the impact of the environment in bladder dysfunction which included environmental and health care responses. Emotional impact in bladder dysfunction, which highlighted the experiences that arose in connection with bladder dysfunction. The life adaptations in bladder dysfunction was an experience which described the changes the man made to achieve a normality in everyday life as well as changes to hide the condition. The man used a range of strategies to maintain normality in life and to keep his condition a secret from those around him. This is seen because of the stigmatization that emerged through this study. Healthcare failed to care for the man with bladder dysfunction and was seen as partially responsible for the stigmatization the man experienced.

Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data. Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome. Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases. Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.

Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT. Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer. Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer. Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour. Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.

This thesis focused on the acute management of patients with ST-segment elevation myocardial infarction (STEMI) in an effort to provide information that may improve outcome. The aim was to evaluate the efficacy and safety of bivalirudin versus unfractionated heparin (UFH) in STEMI patients during primary PCI. Furthermore, to provide pharmacodynamic data of novel ways of ticagrelor administration compared to standard tivcagrelor. Additionally, to identify subgroups of patients, such as women who may derive greater benefit from specific antithrombotic strategies due to their risk/benefit profile. Finally, to evaluate current formulas for estimation of renal function in the acute phase of STEMI. In Paper I, all STEMI patients in Sweden between 2008 and 2014, treated with primary PCI and UFH or bivalirudin were included in our analysis. Of the total population of 23 800 patients, 8 783 (36.9%) were included in the UFH group and 15 017 (63.1%) in the bivalirudin group. Concomitant GPI administration was 68.5% in the UFH arm compared to 3.5% in the bivalirudin arm (p&lt;0.01).The adjusted incidence of 30-day mortality was not significant different between the two groups (UFH vs bivalirudin, adjusted HR 0.94; 95% CI 0.82 -1.07). The adjusted risk for 1-year mortality, 30-day and 1-year stent thrombosis and re-infarction did not differ significantly between the two groups. In contrast, patients treated with UFH had a significantly higher incidence of major in-hospital bleeding (adjusted OR 1.62; 95%CI 1.30 -2.03). In Paper II pharmacodynamic data of chewed or crushed ticagrelor compared to standard ticagrelor loading dose (LD) was assessed in 99 patients with stable angina. Platelet reactivity (PR) was assessed with VerifyNow before, 20 and 60 minutes after LD. High Residual platelet reactivity (HRPR) was defined as &gt; 208 P2Y12 reaction units (PRU). Chewed ticagrelor tablets resulted in significantly lower PRU values compared to crushed or integral tablets at 20 and 60 minutes. Crushed ticagrelor LD resulted in significantly lower PRU values compared to integral tablets at 20 minutes whereas no difference was observed at 60 minutes. At 20 minutes, no patients had HRPR with chewed ticagrelor compared to 68% with integral and 30% with crushed ticagrelor LD (p&lt;0.01). In Paper III we presented a pre-specified gender analysis of the ATLANTIC trial including 1 862 STEMI patients that were randomly assigned to pre-hospital versus in-hospital administration of 180mg ticagrelor. Women were older and had higher TIMI risk score. Women had a 3-fold higher risk for all-cause mortality compared to men (5.7% vs 1.9%, HR 3.13, 95% CI 1.78 – 5.51). However, after adjustment for baseline characteristics, the difference was lesser and no longer significant (HR 1.98, 95% CI 0.97 – 4.04). Female gender was not an independent predictor of risk for bleeding after multivariable adjustments (BARC type 3-5 HR 1.52, 95% CI 0.74-3.09). There was no interaction between gender and efficacy or safety of randomised treatment. In Paper IV, forty patients with PCI- treated STEMI were included between November 2011 and February 2013. We validated the performance of the Cockcroft-Gault (CG), the Modification of Diet in Renal Disease (MDRD-IDMS), the Chronic Kidney Disease Epidemiology (CKD-EPI) and the Grubb relative cystatin C (rGCystC) equations for estimation of GFR against measured GFR (mGFR) during the index hospitalisation for STEMI. MDRD-IDMS and CKD-EPI demonstrated a good performance to estimate GFR with accuracy within 30% (P30) 82.5% vs 82.5%, respectively. CKD was best classified by CKD-EPI (Kappa 0.83). CG showed the worst performance with the lowest P30. The rG-CystC equation had a marked bias of -17.8% and significantly underestimated mGFR (p=0.03). Conclusions – In STEMI patients treated with primary PCI, bivalirudin should be preferred in patient at high risk for bleeding. With crushed or chewed ticagrelor tablets a more rapid platelet inhibition may be achieved, compared with standard integral tablets. In STEMI patients, fast and potent platelet inhibition with chewed ticagrelor may reduce the risk of early stent thrombosis and patients treated with a less aggressive antithrombotic strategy, such as UFH or bivalirudin monotherapy, may derive a greater benefit. Although gender differences in adverse outcomes could mainly be explained by older age and clustering of comorbidities in women, a bleedreduction strategy in women with high risk characteristics is warranted in order to improve their outcome. Regardless the choice of antithrombotic strategy, dose adjustment of drugs cleared by kidneys based on GFR estimation is of crucial importance. MDRD and CKD-EPI should be the formulas used for estimation of GFR in STEMI patients