The treatment of rectal cancer is complex and comprises: diagnostic measures; different preoperative treatments; a multitude of surgical and technical choices; possibilities of postoperative treatments and postoperative care and follow up. In this thesis, some aspects of this complex paradigm have been further investigated. One of the most feared complications after rectal cancer surgery is anastomotic leakage. The risk of anastomotic leakage is affected by non-influenceable factors related to the tumour and the patient. In the first paper, the risk of anastomotic leakage in relation to a surgical instrument, the circular stapler, was investigated. The risk of leakage was 7% or 11%, depending on the choice of instrument. In the second paper, a long-term evaluation of survival and local recurrence rates in the Swedish Rectal Cancer Trial was made. Randomisation was to either preoperative radiotherapy followed by surgery or surgery alone. After 13 years median follow-up, survival was 38% in the radiotherapy group and 30% in the surgery alone group. Differences in local recurrence rates were seen in all stages. Most rectal cancer operations carry a high risk of morbidity and mortality. For early stage cancers, a local procedure may be sufficient and in the third paper, population-based results of local excision of rectal cancer were explored. In stage I, cancer specific survival was the same after local excision as after major resection, but the relative survival was lower. The risk of local recurrence was higher after local excision than after resections. In the fourth paper, differences in survival rates in the Nordic countries and Scotland were investigated. The relative excess risk of death was highest in Denmark, but only in the first 90 postoperative days. Through applying already existing knowledge and successively introducing new treatments, the results for rectal cancer treatment will be further improved.

The most important prognostic factor in breast cancer is the axillary lymph node status. The sentinel node biopsy (SNB) is reported to stage the axilla with an accuracy > 95 % in early breast cancer. Tumour-related perturbation of T-cell function has been observed in patients with malignancies, including breast cancer. The down-regulation of the important T-cell activation molecules CD3-ζ and CD28 may cause T-cell dysfunction, anergy, tolerance and deletion. The expression of CD3-ζ and CD28 was evaluated in 25 sentinel node biopsies. The most pronounced down-regulation was seen in the paracortical area, where the best agreement between both parameters was observed. CD28 expression was significantly more suppressed in CD4+ than in CD8+ T-cells. From the Swedish sentinel node database, 109 patients with breast cancer > 3 cm planned for both SNB and a subsequent axillary dissection were identified. The false negative rate (FNR) was 12.5%. Thirteen cases of tumour multifocality were detected on postoperative pathology. The FNR in this subgroup was higher (30.8%) than in patients with unifocal disease (7.8%; P = 0.012). From the Swedish SNB multicentre cohort trial, 2246 sentinel node-negative patients who had not undergone further axillary surgery were selected for analysis. After a median follow-up time of 37 months (range 0-75), 13 isolated axillary recurrences (13/2246; 0.6%) were found. In another 14 cases, local or distant failure preceded or coincided with axillary relapse (27/2246; 1.2%). In conclusion, the immunological analysis of the sentinel node might provide valuable prognostic information and aid selection of patients for immunotherapy. SNB is encouraged in breast cancer larger than 3 cm, if no multifocal growth pattern is present. The axillary recurrence rate after a negative SNB in Sweden is in accordance with international figures. However, a longer follow-up is mandatory before the true failure rate of the SNB can be determined.

Even if popliteal artery aneurysm (PAA) is the most common peripheral aneurysm, no single surgeon or institution has enough patients to study this disease with appropriate scientific methods, and no population-based investigation exists. PAA epidemiology, treatment, management, and outcome were studied in a population-based study of 571 patients (717 legs) primarily operated on for PAAs and 100 episodes of preoperative thrombolysis in Sweden between 1987 and 2002. Patients were identified in the Swedish Vascular Registry and case-records were reviewed. Information on amputation and survival was obtained for all patients, and 190 patients were re-examined with ultrasound, after mean 7.2 years (range 2-18) Median age was 71 years; 5.8% were women. Patients with unilateral PAA had AAA in 28%, increasing to 38% when PAAs were bilateral. Crude survival was 91.4% at one and 70% at five years, significantly lower than among age and sex matched controls. The cumulative incidence for operation of PAA in Sweden was estimated to 8.3/million person year. One-year amputation-rate was 8.8 %, increasing to 11% after follow-up (7.2 years). Independent risk factors for amputation within one year were poor run-off, age, emergency procedure, and prosthetic graft. Run-off was improved by preoperative thrombolysis among 87% of legs, when acute ischemia. After surgical repair with a medial approach the risk of late expansion of the aneurysm was 33%, with a posterior approach 8% , p=0.014. Among 190 re-examined patients, 108 (57%) had at least one additional aneurysm at index-operation, increasing to 131 (68%) at re-examination, the total number of aneurysms increasing by 42% (from 244 to 346). Conclusions: Multiple aneurysms are common among patients operated on for PAA. Preoperative thrombolysis improves run-off and decreases the amputation-rate in PAAs with acute ischemia. Vein grafts do better than prosthetic grafts, especially when a long bypass is needed. Posterior approach, when possible, reduces the risk of late expansion. A complete examination of the aorto-iliac and femoro-popliteal arteries is warranted at the time of surgery. All patients should be kept under life-long surveillance in order to detect and treat newly developed aneurysms timely. Normal arterial segments should be re-examined after three years.

Primary hyperparathyroidism (pHPT) due to parathyroid tumours with hypersecretion of parathyroid hormone and hypercalcaemia is a common disease with incompletely understood etiology affecting more than 1 % of the population, primarily postmenopausal women. In secondary hyperparathyroidism (sHPT), parathyroid tumours develop in response to calcium and vitamin D deficiency generally in patients with uraemia. HPT is usually treated by surgical removal of enlarged parathyroid glands. The aim of this thesis was to examine the Wnt/β-catenin signalling pathway in parathyroid tumours. Aberrantly accumulated β-catenin was found in all analysed pHPT and sHPT tumours, with a stabilising homozygous mutation (Ser37Ala) in 7.3% of the pHPT tumours. Truncation of the APC protein was not found. MYC, a β-catenin target gene was overexpressed in a substantial fraction of pHPT and sHPT parathyroid tumours. A parathyroid tumour cell line (sHPT-1) was established from a hyperplastic gland removed at operation of a patient with sHPT. The cells produced parathyroid hormone and grew with a doubling time of approximately 72 hours. Stabilised nonphosphorylated transcriptionally active β-catenin was expressed. Efficient transfection of siRNA against β-catenin decreased expression of cyclin D1 and MYC, and inhibited cell growth with ensuring cell death. The Wnt coreceptor LRP5 was found expressed with an internal deletion of 142 amino acids (LRP5Δ) in 86% and 100% of pHPT and sHPT tumours, respectively. Stabilising mutation of β-catenin and expression of LRP5Δ was mutually exclusive. Expression of LRP5Δ was required to maintain the nonphosphorylated transcriptionally active ß-catenin level, MYC expression, parathyroid cell growth in vitro, and tumour growth in transplanted SCID mice. Wnt3 ligand and LRP5Δ strongly activated transcription, and LRP5Δ was insensitive to inhibition by DKK1. Aberrant accumulation of β-catenin by stabilising mutation or expression of LRP5Δ appears as a common pathogenic pathway for hyperparathyroid disease. LRP5Δ in particular presents a potential target for therapeutic intervention.

Malignant tumours of the small intestine are rare. Age-standardised incidence in Europe is between 0.5-1.5 per 100 000. As the small intestine represents more than 90 % of the gastrointestinal mucosal surface, it is surprising that it gives rise to less than 2 % of gastrointestinal malignancies. The dominating histological subtypes are carcinoids and adenocarcinomas. We used three population-based registries in Sweden to study survival, second malignant tumours, causes of death, and Crohn’s disease as a risk factor for small intestinal adenocarcinoma and carcinoid. We evaluated tumour site, sex, age, and year of diagnosis as prognostic factors. For adenocarcinomas there was no difference in survival between duodenal and jejunal/ileal tumours. Women with jejunal/ileal adenocarcinomas showed higher probabilities of survival than men, while no such relation was found for duodenal tumours. Old age correlated with poor survival for duodenal tumours, and prognosis has improved in later years. For carcinoids, duodenal tumours had a more favourable prognosis than jejunal/ileal tumours. There was no difference in survival between sexes. Old age correlated with poor survival, and survival has improved in recent years. Female patients with adenocarcinoma had increased risk of acquiring cancer in the genital organs and breasts, and both sexes had increased risks of second tumours in the gastrointestinal tract and skin. Men with carcinoid tumours had increased risk of prostate cancer. Both sexes had increased risk of malignant melanoma and malignancies of endocrine organs. Patients with adenocarcinoma had increased risk of dying from malignant diseases other than the primary small intestinal cancer and from gastrointestinal disease. The cohort with carcinoid had higher than expected risk of dying from malignant disease, gastrointestinal disease, and cardiovascular disease. Patients with Crohn’s disease had increased risk of small intestinal adenocarcinoma and carcinoid, and the risk has increased for patients diagnosed in recent years.

Introduktion: Övervikt och fetma är ett globalt växande folkhälsoproblem vilket leder till enorma ekonomiska samhällskostnader. Fetmakirurgi, bland annat Reglerbart gastriskt band (Adjustable Gastric Banding, AGB), har visat långsiktiga effekter på viktminskning, medan icke-kirurgisk fetmabehandling har visat mindre tydliga effekter. Detta har lett till att fetmakirurgin ökat dramatiskt. Trots detta har vissa kirurgipatienter svårigheter i att upprätthålla viktminskning över tid. Fetmakirurgi kan även leda till senkomplikationer och biverkningar. Flertalet experter argumenterar för att långtidsbehandling är väsentlig för vidmakthållande av beteendeförändring. Dagvårdsbehandling anses vara värd att överväga för patienter med fetma. Den har använts brett inom diabetesvård men ej lika mycket inom fetmabehandling. Syfte: Att strukturera och undersöka population och datamaterial från en redan genomförd men opublicerad, tre år lång interventionsstudie, med tre uppföljningar, om viktminskning och ätbeteende hos patienter med fetma, efter behandling med: Adjustable Gastric Banding, Dagvård alternativt en kombination av de båda behandlingarna. Metod: Datamaterial i 30 pärmar, från patienter (baseline: n= 212) i en redan genomförd men opublicerad interventionsstudie, lästes igenom och strukturerades in i ett index i Microsoft Words. Därefter skapades en databas i Microsoft Excel. I databasen räknades de patienter samman som visat angivna mått på viktminskning (BMI) och ätbeteende (TFEQ) vid något, några eller samtliga av de totalt tre uppföljningstillfällena i studien. Resultat: Efter strukturering och undersökning av datamaterialet framgick att enbart (n=10) av (n=212) fullföljt studien genom uppvisade mått på BMI samt TFEQ vid samtliga av studiens tre uppföljningstillfällen. För att i denna masteruppsats visa resultat från en större studiepopulation presenterades även uppvisade mått (BMI, TFEQ) från patienter som deltagit vid baseline och tredje uppföljningstillfället, men som nödvändigtvis inte deltagit vid uppföljnigstillfälle ett eller två (n=43). BMI och TFEQ presenterades i medelvärde och median för varje behandlingsgrupp. Slutsats: Resultatet visar att majoriteten av de deltagande patienterna inte fullföljde hela programmet. Därför kunde inga effekter av respektive behandling på förändring av vikt och ätbeteende beräknas. / Introduction: Overweight and obesity is a globally growing public health problem leading to enormous economic costs for the society. Obesity surgery, including Adjustable Gastric Banding (AGB), has shown long-term positive effects on weight loss, while non-surgical obesity treatment has shown less evident effects. This has led to a dramatic increase in obesity surgery. Still, some surgery patients have difficulties in maintaining weight loss over time. The majority of experts argue that long-term treatment is essential for maintaining behavioral changes. According to experts, Daycare treatment is worth considering for patients suffering from obesity. It has been used broadly within the diabetes care though not to the same extent in obesity treatment. Aim: To structure and investigate the population and data from an already completed but unpublished three year old intervention study, with three follow ups, of weight loss and eating behavior in patients with obesity after treatment with Adjustable Gastric Banding, Daycare or a combination of the both treatments. Method: Data in 30 binders, from participants (baseline n=212) in an already completed but unpublished intervention study, was read and structured into an index in Microsoft Words. A database in Microsoft Excel was then structured were patients with specified measures for weight loss (BMI) and eating behavior (TFEQ), for one, two or three of the total three follow ups, was counted together. Results: After the structuration and investigation of the material it became evident that due to drop-out or missing data only (n=10) out of (n=212) had fulfilled the study by showing specified measures of BMI and TFEQ at every of the total three follow ups. To, in the present Master thesis, show results from a greater sample, also participants with measures (BMI, TFEQ) from baseline and the third follow up, but not necessary from the first or second follow up (n=43), was included in the presentation. BMI and TFEQ were presented in mean and median for each of the treatment groups. Conclusion: The result shows that a majority of the participants not completed the program. Hence could no effect of the treatments on changes of weight and eating behavior be rated.

Cleft lip and palate (CLP) is a congenital malformation. Assessment, care-planning and treatment in Sweden is executed by a team at six major regional hospitals. Historically, CLP-treatment has undergone many changes. The aim of this study is to map out how CLP-treatment regime has developed in Linköping and Stockholm during, primarily the second half of the 20th century. The focus of the study is on surgery, speech therapy and orthodontic treatment. A study of medical records was conducted of 89 records at the speech-care unit at Linköping University hospital. The different types of clefts included were unilateral and bilateral CLP (UCLP, BCLP) and isolated cleft palate in patients born between 1908 and 1995. Interviews were made with a phoniatrician, a dental orthopaedist and a speech and language pathologist with long experience in CLP-patient care. Results showed, that the total number of operations generally decreased for patients with BCLP and isolated cleft palate. The age when operations were performed varied less after 1975. Time in hospital for surgery became more stable and shorter. The age at the first speech therapy session decreased during the 20th century and the number of sessions at Linköping University hospital decreased for patients born after 1970. The conclusions of this study are: ● age when operating has become more stable. ● time in hospital for surgery has decreased. ● number of treatments, both operations and speech therapy sessions, has decreased. / Läpp-, käk- och gomspalt (LKG) är en medfödd missbildning. Behandling och planering av vård för patienter i Sverige med denna missbildning utförs av specialistteam vid sex av landets stora sjukhus. Vården av personer med LKG har historiskt genomgått förändringar. Syftet med föreliggande studie är att kartlägga hur LKG vården utvecklats i Linköping och Stockholm, främst under senare hälften av 1900-talet. Studien fokuserar på kirurgi, talbehandling och ortodontisk behandling. En journalstudie genomfördes av 89 journaler från Talvårdsavdelningen vid Linköpings Universitetssjukhus. Spalttyperna som ingick i studien var unilateral och bilateral total spalt (U-LKG, B-LKG) samt isolerad gomspalt. Patienterna var födda mellan 1908 och 1995. Intervjuer gjordes med en foniater, en käkortoped och en logoped, som samtliga under flera år var involverade i omhändertagandet av patienter med LKG. I studien framkom att det totala antalet operationstillfällen generellt har minskat för B-LKG och isolerad gomspalt. Sedan 1975 har åldern vid operationerna varierat mindre mellan åren. Även vårdtiderna vid operationerna har stabiliserats samt blivit allt kortare. Åldern vid första talbehandlingen har generellt sjunkit under 1900-talet och antalet talbehandlingar på sjukhuset i Linköping har sjunkit för patienter födda efter 1970. Slutsatser som kan dras av föreliggande studie är att: ● tidpunkterna för operationer har blivit mer stabila. ● vårdtiderna vid operationer har blivit kortare. ● antalet behandlingar, såväl operationer som talbehandlingar, har minskat.

Background: The latest generation of rear-end whiplash protection systems, as found in the WHIPS Volvo and SAHR Saab, have reduced injury rates by almost 50% in comparison with the previous generation of seat/head restraint systems. Occupant behaviour, such as seated posture and seat adjustment settings, may affect the injury risk. Method: Five studies were conducted. Studie I was an injury outcome study based on insurance data. Studies II-IV investigated seat adjustment, occupant backset, and cervical retraction for drivers and occupants in different postures and positions in the car, during stationary and driving conditions. Study V compared the occupant data from studies II and III with a vehicle testing tool, the BioRID dummy, using the protocols of the ISO, RCAR, and the RCAR-IIWPG. Results: Female drivers and passengers had a threefold increased risk for medically-impairing neck injury in rear-end impacts, compared to males. Driver position had a double risk compared with front passenger seat position. Female drivers adjusted the driver seat differently to male drivers; they sat higher and closer to the steering wheel and with more upright back support. The volunteers also adjusted their seat differently to the ISO, RCAR, and RCAR-IIWPG protocol settings; both sexes sat further away from the steering wheel, and seat back angle was more upright then in the protocols. In stationary cars, backset was highest in the rear seat position and lowest in the front passenger seat position. Males had a larger backset than females. Cervical retraction decreased and backset increased for both sexes when posture changed from self-selected posture to a slouched posture. The BioRID II dummy was found to represent 96th percentile female in stature, and a 69th percentile female in weight in the volunteer group. Conclusions: Risks in car rear-end impacts differ by sex and seated position. This thesis indicates the need for a 50th percentile female BioRID dummy and re-evaluation of the ISO, RCAR, and RCAR-IIWPG protocols, and further development of new safety systems to protect occupants in rear-end impacts.

Peritoneal carcinomatosis (PC) is traditionally regarded as a terminal stage of disease with a poor prognosis and systemic chemotherapy is regarded as palliative treatment. In order to improve survival and even to achieve cure for selected patients with PC, cytoreductive surgery and intraperitoneal che-motherapy have been advocated. Despite complete macroscopic removal of tumour, residual microscopic malignant cells might result in recurrence. Intraperitoneal chemotherapy aims to kill residual malignant cells and thereby needs to be distributed in the entire peritoneal cavity. This aggres-sive combined loco-regional treatment has a high risk of morbidity and mor-tality. Whether the increased risks are acceptable to improve survival re-quires investigation and the impact of loco-regional treatment of PC on health-related quality of life (HRQL) needs to bee explored The overall aim of this thesis was to analyse the impact of cytoreductive surgery and intraperitoneal chemotherapy on patients with peritoneal carci-nomatosis. A significant survival improvement (median 32 months) was seen in 18 patients with PC of colorectal origin subjected to loco-regional treatment, in comparison to matched controls treated with systemic chemotherapy (me-dian survival 14 months, Paper I). The results of single-photon emission computer-tomography (SPECT) in 51 patients were correlated to the number of intraperitoneal chemotherapy courses that could be performed without further surgery (Paper II). Postoperative 30-days morbidity and 90-days mortality was investigated in 123 PC-patients after loco-regional treatment. Severe adverse events occurred in 51 (41%) patients. Five patients (4%) had treatment-related mortality. Stoma formation, duration of surgery, periopera-tive blood loss, and extent of PC was associated with morbidity (Paper III). HRQL was investigated in 64 patients. HRQL was negatively affected at 3 months but a partial recovery was seen at 8 months. 30-day morbidity did not have any impact on HRQL at 8 months (Paper IV). This treatment there fore appears justified despite considerable toxicity in view of possible life prolongation.

The results of total knee arthroplasty are inferior in younger patients. The challenge today is therefore to develop designs and concepts that will last at least 25 years. This thesis has evaluated the fixation to bone of modern designs of knee prostheses uring RSA analysis. Coating implant surfaces with hydroxy-apatite have proven to enhance fixation to bone. Addition of screws for fixation of the tibial component enhances the fixation, but has negative side effects such as osteolysis around the screws, in turn leading to a higher risk of component loosening. The magnitude and pattern of migration was studied in a randomized study of uncemented tibial implants coated with hydroxy-apatite with and without additional screw fixation in patients younger than 65 years. The uncemented implants migrated initially more than the cemented implants that constituted the control group. Both uncemented groups stabilized at 3 monthes with no further migration, while the cemented implants showed a continuous migration up to the 2 year follow-up, indicating continuous bone resorption at the implant-bone interface, a fact that might lead to an increased risk of late implant loosening. This may not be a problem in older patients, but may have consequences for long-term fixation in younger patients. There was no difference between the two uncemented groups indicating that screws do not improve fixation. Hydroxy-apatite coated knee implants might be well suited for younger patients. Mobile bearing total knee arthroplasty theoretically uncouples the forces at the implant-bone interface, thus improving fixation of the implant to bone. The magnitude and pattern of migration of a cemented mobile bearing knee arthroplasty and a fixed bearing total knee arthroplasty was compared in a randomized study. The results showed that mobile bearings did not improve fixation. Trabecular metal, a new material recently introduced for total knee arthroplasty, has several theoretical advantages. Trabecular metal tibial implants were evaluated in a randomized study in patients younger than 60 years. The implants displayed the typical migration pattern for uncemented implants with greater migration initially followed by early stabilization. The majority of the trabecular metal implants subsided into the bone with no lift-off. Lift-off has the potential of exposing the interface to joint fluid with the potential risk of bone resorption and late loosening, and is commonly seen in metal-backed implants. The finding of absence of lift-off is regarded beneficial for uncemented fixation. Trabecular metal tibial implants might be suited for younger patients. The optimal mode of fixation of the femoral component is yet to be established. Comparing cemented femoral components with uncemented femoral components in a randomized study in patients younger than 60 years revealed no differences of the magnitude or the pattern of migration. Uncemented femoral component seems equally as good as cemented components in younger patients.