<p>The laparoscopic way of performing general surgical procedures was introduced all over the Western world in a few years around 1990. No previous scientific studies of the safety of this new way of performing general surgery had been undertaken.</p><p>In an animal study, it was shown that carbon dioxide pneumoperitoneum (CO₂PP) causes an increase in inferior caval vein (ICV) pressure, although there were no effects on the ICV blood flow. There were gradual increases in systemic, pulmonary and ICV vascular resistance, which remained after exsufflation. These effects on vascular resistance could not be reproduced in a second animal study, presumably due to a different form of anesthesia. In this study, there was only indirect evidence of CO₂ PP decreasing urine output. No increase in vasopressin, which is commonly seen during CO₂ PP, was found, indicating that vasopressin may play a role in the decreased urine output during CO₂ PP but that there must be other contributing factors as well. Only brief effects on the renal arterial blood flow were seen.Renal venous pressure increased to that of the ICV.</p><p>A literature review indicated that thromboembolic complications do occur after laparoscopic cholecystectomy (LC). The relative frequencies indicated an underreporting of deep vein thrombosis (DVT) in relation to pulmonary embolism (PE).</p><p>In a clinical study, activation of the coagulation after LC was demonstrated. There were differences between the groups receiving dextran and low molecular weight heparin as prophylaxis. A further clinical study showed the incidence of DVT, as demonstrated by phlebography, to be 2.0 % (95 % confidence interval 0-6.0 %) 7-11 days after LC, even though thromboembolism prophylaxis was given in shorter courses than those scientifically proven to be effective against DVT. D-dimer values increased at the first postoperative day and even further at the time of phlebography, suggesting that the effects of LC on coagulation and/or fibrinolysis may be of longer duration than previously known.</p>

<p>During a three-year period (1989-91), all patients living in the county of Uppsala, Sweden, with a radiographically verified fracture of the clavicle were prospectively, consecutively followed (n=245). </p><p>The epidemiological study (I) was restricted to the two first years with 187 fractures in185 patients. The short term study (II) with 6 months follow-up included 222 patients. The long term study (III) with 10 years follow-up included 208 patients. The malunion study (IV) included eight patients and the nonunion study (V) 24 patients all of whom were consecutively operated between 1988-2000.</p><p>Displacement, especially with no bony contact in the initial radiographs, was a statistically significant risk factor for sequelae.</p><p>Comminute fractures, especially if including transversally placed fragments, were associated with a significantly increased risk of remaining symptoms. An increasing number of fragments was also associated with an increased risk of sequelae.</p><p>Patients with remainig symptoms after 6 months were on average older at the time of injury as compared to patients without remaining symptoms. Advancing age was also a significant risk factor for sequelae – specifically pain at rest – still after 10 years.</p><p>There was no difference between gender with respect to the risk of sequelae, except for nonunion.</p><p>Fracture location did not predict outcome, except for more cosmetic defects (middle part).</p><p>Shortening defined as overlapping at the fracture site was a significant risk factor for cosmetic defects after 10 years.</p><p>Patients who experience pain at rest and/or cosmetic defects more than twelve weeks after the fracture have a higher risk for sequelae.</p><p>The radiographic examination should always consist of two projections: the AP (0°) view and the 45° tilted view. Transversally placed fragments are not seen in the 0° view.</p><p>Removal of excessive callus in patients with persistent symptoms even several years after the fracture showed a good outcome. One does not have to stabilize the clavicle when excising the hypertrophic callus.</p><p>Symptomatic clavicular nonunions should be treated with surgery. Reconstruction plate combined with cancellous bone gives a faster and more reliable healing rate than external fixation.</p>

<p>Correa, P. 2002. Vitamin D and its receptor in parathyroid tumors. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1186. 49 pp. Uppsala. ISBN 91-554-541-0 </p><p>Hyperparathyroidism (HPT) is characterized by tumor development in the parathyroid glands and excessive production of parathyroid hormone. Parathyroidectomy is the only considered therapy for the majority of patients. </p><p>LOH (loss of heterozygosity) analysis revealed putative tumor suppressor genes on chromosome regions 1p and 11q in tumors from patients with truly mild hypercalcemia.</p><p>Active vitamin D [1,25(OH)2D3] and its receptors, the vitamin D receptor (VDR), are essential regulators of the calcium homeostasis and are involved in HPT development. The VDR-FokI polymorphism, coupled to bone mineral density, was found not to be associated to development of primary HPT (pHPT). The total VDR mRNA levels is reduced in adenomas of pHPT as well as in hyperplastic glands of secondary HPT (sHPT). The VDR exon 1f transcripts were exclusively downregulated in the adenomas of pHPT, suggesting default regulation of the tissue-specially expressed VDR 1f promoter. The cytochrome P450 enzymes responsible for synthesis and degradation of 1,25(OH)2D3, namely vitamin D3 25-hydroxylase (25-hydroxylase), 25-hydroxyvitamin D3 1a-hydroxylase (1a-hydroxylase) and 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) were found to be expressed in normal and pathological parathyroid glands. Tumors of pHPT and sHPT demonstrated increased 1a-hydroxylase and reduced 24- and 25-hydroxylase expression, suggesting an augmented local production of active vitamin D. In contrast, parathyroid carcinomas displayed reduced expression of all three hydroxylases. The gained knowledge of vitamin D metabolism and catabolism in parathyroid tumors may indicate possibilities for novel treatment of sHPT and perhaps pHPT.</p>

<p>One main hurdle to xenotransplantation, i.e. transplantation between different species, is the immunological barrier that the organ meets in the recipient. The aim of this thesis was to characterise xenogeneic rejection mechanisms by using the concordant mouse-to-rat heart transplantation model.</p><p>Graft-infiltrating immune cells could be isolated from both rejecting and non-rejecting grafts using ex vivo propagation, a technique based on incubation of graft biopsies in culture medium for 48 hours. The numbers of recovered T lymphocytes were considerably higher in grafts undergoing cell-mediated rejection than in grafts undergoing acute vascular rejection (AVR) or in non-rejecting transplants. Thus, ex vivo propagation should be a valuable tool for further studies of cell-mediated rejection.</p><p>Cytokine patterns in the grafts, as measured by a quantitative real-time RT-PCR method, showed that AVR and cell-mediated rejection are associated with an increase of both pro-inflammatory cytokines (IL-1β and TNF-α) and more specific cytokines (IL-2, IL-10, IL-12p40 and IFN-γ). These data differed considerably from the patterns seen in the spleens of the recipients. Cell-mediated xenograft rejection was also found to be associated with a local accumulation of hyaluronan.</p><p>Oral administration of xenogeneic cells stimulated a production of antibodies that could induce hyperacute rejection of cardiac xenografts when passively transferred to graft recipients. This is in contrast to several models for autoimmune diseases and allogeneic transplantation where oral administration of antigens is an effective way to induce unresponsiveness. Hence, future attempts to induce oral tolerance in xenotransplantation should be done with caution.</p>

<p>Xenotransplantation, i.e. transplantation between different species, could be a possible solution to the present shortage of organ donors. The immunological response to a xenograft is strong and difficult to suppress. It is driven both by the humoral and cellular part of the immune system. The aim of this thesis was to characterise and modulate this response in a concordant mouse-to-rat model, using both vascularised and non-vascularised grafts.</p><p>Exposure of mouse cells or tissue to the circulation of a rat, either through transplantation or transfusions, easily evoked an immune response, consisting of IgM antibodies. A response that was aimed both at antigens present on mouse mononuclear cells and on erythrocytes. A non-immunosuppressed rat rejected a mouse heart graft within three days. The combined use of cyclosporine A (CyA) and deoxyspergualin (DSG) as immunosuppression prevented the rejection of vascularised heart transplants as well as of non-vascularised pancreatic islet grafts. This acceptance was sustained for the heart transplant also after the termination of DSG treatment, but not for the pancreatic islet graft. Furthermore, a second heart graft was accepted when transplanted under monotherapy with CyA 56-154 days after the first transplantation. This finding was interpreted as a humoral unresponsiveness, which could not be reproduced when the primary heart was substituted with a cellular graft, consisting of pancreatic islets or heart cells, or by blood transfusions. However, the rejection of a mouse heart after blood transfusions occurred in the absence of antibodies directed against mouse erythrocytes, in contrast to the observations in non-transfused animals. This indicates that a partial humoral tolerance restricted to the response against erythrocytes can be induced. This mechanism may offer a possibility to induce total humoral tolerance against a xenograft if the appropriate antigens are administered in conjunction with CyA and DSG.</p>

<p>Angiogenesis is necessary for the growth and spread of solid tumors. In these studies angiogenesis was measured in childhood malignancies in general and in Wilms’ tumor in particular, and cutting needle biopsy (CNB) specimens were evaluated for diagnosis in childhood renal tumors. </p><p>In 33 patients with Wilms’ tumor, tumor capillaries were quantified, expression of angiogenic growth factors in tumor tissue investigated, and concentrations of angiogenic growth factors in serum measured. Reference values for angiogenic growth factors were obtained in 80 healthy adults (fibroblast growth factor 2 [FGF-2], vascular endothelial growth factor A [VEGF-A]) and 94 healthy children (angiogenin [ANG], epidermal growth factor [EGF], FGF-2, hepatocyte growth factor [HGF], tumor necrosis factor alpha [TNFA] and VEGF-A) aged 0.5-18 years. These reference values were compared with values in sera taken at diagnosis in 268 children with tumors and leukemias. CNB specimens were evaluated in 25 children with renal tumors.</p><p>A large number of capillaries was an independent prognostic factor for a poor outcome in Wilms’ tumor. Angiogenic growth factors were expressed in Wilms’ tumor tissue, and elevated concentrations of HGF and VEGF-A were found in both benign and malignant tumors. HGF was increased in leukemia, and TNFA was increased in leukemia, lymphoma and neuroblastoma. CNB, which proved to be a safe procedure, had a sensitivity of 76%. </p><p>These studies have demonstrated that quantification of capillaries is a prognostic factor in Wilms’ tumor and that HGF, TNFA and VEGF-A are frequently elevated in sera from children with cancer. Quantification of capillaries in tumor tissue and of circulating angiogenic growth factors would therefore seem to be of clinical relevance in managing children with cancer.</p>

<p>The two purposes of this thesis were to evaluate new diagnostic techniques of lymphnode staging in invasive bladder cancer and to evaluate the results of neoadjuvant chemotherapy in invasive bladder cancer.</p><p>Sentinel node detection was performed in 13 patients in preparation for radical cystectomy. The method showed to be feasible, and the results displayed the occurrence of metastatic nodes outside the traditional area of diagnostic dissection in a majority of patients. Four patients were metastasized, each one with one metastatic node detected with the help of the sentinel node procedure.</p><p>Four randomly selected sentinel nodes from four different unmetastasized patients were compared to the four metastatic sentinel nodes from the first series. After microdissection, p53 genomic structure, immunohistochemical expression and MVD (microvessel density) were assessed in the primary tumors and corresponding sentinel nodes. The results suggested that invasive bladder cancer mainly involved monoclonal proliferation with predominantly homogenous biomarker profile, but there were also signs of clonal evolution.</p><p>The Nordic Cystectomy Trial 2 (NCT2), is a randomized prospective trial investigating the possible benefit of neoadjuvant chemotherapy versus cystectomy only, in 311 eligible patients with urinary bladder cancer T2-T4aNXM0.Evaluation of overall survival did not show any statistically significant benefit in the experimental arm. This probably due to lack of statistical power.</p><p>To increase the statistical power we performed a combined analysis of randomized patients from both the Nordic Cystectomy Trial 1 (NCT1) and NCT2, n = 620. Eligible patients from NCT1 had T1G3, T2-T4a NXM0 urinary bladder cancer. Standard meta-analysis methods were used. The only end-point analysed was overall survival. Neoadjuvant platinum based combination therapy was associated with a 20 % reduction in the relative hazard in probability of death.</p>

<p>In the healing of cutaneous wounds, paracrine communication between keratinocytes and fibroblasts regulates cell differentiation, proliferation and synthesis of extracellular matrix. Deficient epidermal coverage, as seen in burn-wounds, frequently results in hypertrophic scars. Previous studies suggest that keratinocytes downregulate the production of collagen and profibrotic factors in fibroblasts. We hypothesized that keratinocytes downregulate the expression of the profibrotic factor connective tissue growth factor (CTGF) in fibroblasts, and regulate fibroblast expression of genes important to wound healing. In keratinocyte-fibroblast cocultures, keratinocytes downregulated CTGF mRNA and protein in fibroblasts, through the secretion of interleukin-1 (IL-1) α. Using Affymetrix DNA microarrays, it was demonstrated that factors from keratinocytes regulate the expression of 69 genes important to wound healing. The regulation of 16 of these genes was confirmed by Northern blotting, and IL-1α from keratinocytes regulated all the 16 genes examined. IL-1-mediated CTGF gene regulation was further investigated. Both IL-1 isoforms, α and β, suppressed CTGF expression through an inhibition of CTGF promoter activity. Interestingly, transforming growth factor-β-stimulated Smad phosphorylation was not affected by IL-1. Finally, we hypothesized that CTGF is downregulated in burn wound by split-thickness skin grafting and that the expression of CTGF is suppressed during reepithelialization. The expression of CTGF protein was decreased in successfully skin-grafted wound areas, and increased in open, granulating burn wounds. Moreover, CTGF protein expression was absent beneath the migrating edge of reepithelialization <i>ex vivo</i>. In conclusion, we demonstrate that, in <i>in vitro</i> models, keratinocyte-derived IL-1α regulates the expression of CTGF and other genes with importance to wound healing. Furthermore, it is shown that CTGF expression is suppressed by epidermal wound coverage i burn wounds. These findings may have implications for the understanding of keratinocyte-fibroblast interplay during wound healing and in hypertrophic scar pathogenesis.</p>

<p>Treatment for varicose veins (VV) is insufficiently evidence based and recurrence rates are high. The aim of this thesis was to study the long-term results after VV surgery, risk factors for recurrences and the effect of preoperative duplex scanning on recurrence rate, quality of life (QoL) and costs.</p><p>In a follow-up study 89 patients with 100 legs operated on for VV 6–10 years earlier were re-examined with duplex, in 13 cases also with varicography. 57% had incompetent vessels in the groin visible with duplex, equally well defined by varicography. Residual branches could not be differentiated from new vessel formation. The recurrence rate did not correlate to the surgeon’s level of experience or perioperative difficulties at primary surgery. </p><p>In a prospective randomized study 293 patients (343 legs) were operated on for primary VV with or without preoperative duplex. Duplex was done postoperatively, at 2 months and 2 years. QoL was measured with SF-36 preoperatively, at 1 month, 1 year and 2 years. </p><p>After 2 years the number of reoperations were 2 in the group with preoperative duplex and 14 in the group without (p=0.002). Incompetent veins were seen in the saphenofemoral or saphenopopliteal junction in 19 and 53 legs respectively (p<0.001).</p><p>Preoperative QoL was worse in the VV patients compared to a reference population, and was normalised 2 years postoperatively. The improved surgical result in the duplex group was not reflected in a significantly higher QoL. </p><p>The lower costs for redo surgery in the duplex group did not offset the costs for duplex, partly due to more extensive primary surgery. </p><p>A significant proportion of recurrences after 2 years was new vessel formation and progression of disease. Preoperative perforating vein incompetence did not influence recurrence rate, and was abolished without specific interruption in 60% at 2 years postoperatively.</p>

<p>One hundred haemorrhoid patients were compared with 300 matched control persons. Haemorrhoid symptoms and bowel symptoms were studied. Most common symptom of the patients was bleeding (44%), followed by prolapse (24%), hygiene problem (14%), pain (12%) and itching (5%). Bowel symptoms, as bloating and evacuation difficulties, possibly related to IBS, were frequent among the patients.</p><p>556 patients were operated upon with Milligan-Morgan haemorrhoidectomy. 418 (81%) answered a questionnaire on results, and on disturbances in anal continence. Totally140 (33%) reported recurrence, and 139 (33%) patients reported anal incontinence. Forty of the 139 patients associated this to the surgical procedure. Female gender was associated to increased risk of incontinence.</p><p>The 40 patients who reported incontinence, were invited to undergo ano-rectal manometry, saline infusion test, endo-anal ultrasound, proctoscopy and clinical examination. Altogether 19 patients approved to participate. Matched control subjects and 15 persons previously operated for haemorrhoids, but without symptoms of incontinence, served as two reference groups. Incontinence score and saline infusion test showed significantly poorer continence in the patient group. Endo-anal ultrasound showed injury to the external sphincter in 20% of the patients. Anal pressure was slightly lower in the patient group, but the difference was not significant. </p><p>Totally 225 patients were randomised to Milligan-Morgan or Ferguson haemorrhoidectomy. Primary aim was to study changes in anal continence. Other aims were to study postoperative pain, wound healing, complications, patient satisfaction and recurrence and changes in bowel function. Patients in the Ferguson group reported, slightly quicker wound healing (P=0.06). Postoperative pain was equal, as was rate of complications. After one year the Ferguson group reported lower incontinence score, and more satisfied patients. Recurrence rate was equal, 15-17%. Most bowel symptoms were reduced one year after surgery.</p><p>In conclusion, functional bowel symptoms are common in haemorrhoid patients. Haemorrhoidectomy is associated with risk for incontinence in 5-10% of patients and females are at greater risk. A proportion of the patients who claim postoperative incontinence have physiological signs of sphincter incompetence, and external sphincter injuries are observed in those patients. Ferguson haemorrhoidectomy results in better anal continence and more satisfied patients. </p>