Bakgrund: Forskning har visat på att också syskonens behov måste mötas genom god omvårdnad som en naturlig del inom den pediatriska onkologin. Syfte: Syftet med denna studie var att beskriva upplevelser hos syskon till barn med cancer och att få en bättre förståelse för deras situation. Metod: I denna kvalitativa studie har sju syskon i åldrarna tio till sjutton år genom semistrukturerade djupintervjuer berättat om sin upplevelse som syskon till ett barn med cancersjukdom. Urvalet har begränsats till intervjuer inom Region Uppsalas upptagningsområde. Omvårdnadsprofessor Katie Erikssons teori om hälsa har legat till grund som teoretiskt ramverk. Resultat: I resultatet beskrev syskonen upplevelser av känslor av ensamhet och oro samt en upplevelse av att inte vara förstådd och sedd varken bland jämnåriga eller vuxna. De upplevde sig ha mognat som personer. Samtliga sju syskon beskrev det yttersta sällsynta i att någon frågat hur efter hur de i egenskap av syskon egentligen mår. Slutsats: Att ha känt sig vara ensam och bortglömd var en genomgående upplevelse för de syskon som intervjuats i studien. Närhet, samvaro, inkludering, normalt socialt liv och positivt tänkande visade sig vara värdefulla stödjande faktorer för att öka graden av välbefinnande och hälsa samt minska känslan av oro. Nyckelord: syskons upplevelser, pediatrisk onkologi, hälsa, stöd. / Background: Research has found that siblings need to be taken into account as a natural part in pediatric oncology nursing. Aim: The aim of this study was to describe the experiences of siblings to children with cancer, to gain an increased understanding of their situation. Method: In this qualitative study seven siblings at the age from ten to seventeen have been interviewed using a semi-structured interview guide to describe their situation as siblings to a child with a cancer disease. Geographically the selection was limited to Region Uppsala. Katie Eriksson´s theory on health was used as theoretical framework. Results: Siblings described having experienced feelings of loneliness, anxiety and of not being seen or properly understood among peers and adults. Several siblings accounted for subsequent personal growth and maturity. All siblings interviewed testified to an absence of questions regarding how they themselves were doing. Conclusion: Siblings are to a high degree affected and involved in the crisis that a cancer diagnosis can cause within a family, and there is a need for increased sibling attention and support in the home as well as in the health care system. Key words: Siblings’ experiences, pediatric oncology, health, support.

<p>Sedan 1960 talet har screening för och vaccinering mot cervixcancer blivit allt mer utbrett, trots detta drabbas fortfarande 450 kvinnor varje år av cervixcancer i Sverige. Då incidensen minskar finns risken för att kunskapen om sjukdomen minskar. Syftet var därför att belysa kvinnors upplevelser av att behandlats för cervixcancer för att öka kunskap och förståelse i mötet med kvinnorna. Studien utfördes som en litteraturstudie där 20 artiklar låg till grund för resultatet. Resultatet belyser kvinnors upplevelser av att behandlats för cervixcancer och hur det påverkade vardagen, reproduktiv och sexuell hälsa, deras syn på framtiden samt hur de upplevde sjukvården. Att ha behandlats för cervixcancer var något som drabbade hela människan, såväl fysiskt, psykiskt som sexuellt och inte bara genitalierna där sjukdomen hade sitt ursprung. Det framkom att kvinnorna ville samtala om tabubelagda ämnena men inte alltid vågade ta upp dem själva. Därför är det betydelsefullt att sjuksköterskorna ställer frågor angående de här ämnena. Omvårdnad bör grundas på evidens och därför är det viktigt att forskningen fortskrider för att optimera vården för kvinnor med cervixcancer.</p>

<p>Positron Emission Tomography (PET) has gained an important roll in clinical for diagnosis, staging and prognosis of a range of cancer types. Utilization of PET for monitoring and evaluation of cancer treatment is an attractive but almost new concept. The proper choice of PET-tracer as a biomarker for treatment follow-up is crucial. The important characteristic for a suitable tracer is its ability to reflect the response to a treatment at an early stage, before any morphologically changes occurs. It would be an advantage to screen a battery of PET tracers in a preclinical model and introduce a few potential tracers in clinical trial. </p><p>The most conventional pre-clinical approach in PET-oncology utilizes xenografts in mice or rats and requires a large number of subjects. It would be a great advantage to introduce a less demanding but still reliable preclinical method for a more efficient planning of studies in animal model and then in human trials. </p><p>The Multicellular Tumour Spheroid (MTS) system represents an intermediary level between cells growing as monolayer and solid tumours in experimental animals or patients. It mimics the growth of naturally occurring human tumours before neovascularization and appears to be more informative than monolayer and more economical and more ethical than animal models.</p><p>The aim of this work was to establish, refine and evaluate the application of MTS model as a preclinical approach in PET oncology. The vision was to introduce a preclinical method to probe and select PET tracer for treatment monitoring of anticancer drugs, which can hopefully be applied for optimization in breast cancer treatment.</p><p>In this thesis, a number of basic experiments were performed to explore the character of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) uptake in MTS. FDG as the most established PET tracer was an obvious initial option for the evaluation of the model. For further assess-ment, we studied effects on FDG uptake in MTS treated with five routinely used chemother-apy agents. For association of PET tracer uptake to size change of MTS, we developed a reliable and user-friendly method for size determination of MTS. The next step was to apply the MTS model to screen PET tracers for analysis of early response of chemotherapy in breast cancer. Finally the method was utilized for translational imaging exemplified with a new chemotherapy agent.</p><p>The results were encouraging and the MTS model was introduced and evaluated as a preclini-cal tool in PET oncology. The method was implicated to in vitro quickly assess a therapy profile of existing and newly developed anticancer drugs in order to investigate the effects of candidate drugs on tumour-growth, selection of appropriate PET tracer for treatment monitor-ing and finally understanding relation between growth inhibition and biomarkers as part of translational imaging activities.</p>

Sarcomas of the female genital tract are rare tumors and account for less than 5% of gynecologic malignancies. Traditionally, gynecologic sarcomas have been divided into different tumor types according to their histopathological features. The most common are leiomyosarcoma (LMS), malignant mixed Müllerian tumors (MMMT), endometrial stromal sarcoma (ESS) and (Müllerian) adenosarcoma. The different tumor types are highly aggressive with early lymphatic and/or hematogenous spread. Treatment is difficult and it is believed that sarcomas have a low radio-and chemosensitivity, and the mainstay in treatment is surgical removal of the tumor. The most important prognostic feature has been tumor stage. Nevertheless, there are some early-stage tumors that run a biological course different from that expected and additional prognostic factors indicating high-risk tumors are desirable. The study cohort consists of 49 uterine LMS, 44 uterine MMMTs, 17 uterine ESS, 11 uterine adenosarcomas and 26 ovarian MMMTs. The tumors were analyzed in a retrospective manner for DNA ploidy, S-phase fraction (SPF), p53 and mdm-2 expression, as well as traditional clinical and pathological prognostic factors, such as tumor stage. grade, atypia and mitotic index. Of the 49 LMS, 36 (86%) were non-diploid and 13 (27%) were p53-positive. Among the 44 uterine MMMTs, 30 (68%) were non-diploid and 27 (61%) had an SPF&gt;10%. Twenty-seven (61%) overexpressed p53 and 11 (25%) were mdm-2 positive. Furthermore, 40 (91%) of the uterine MMMTs had a high mitotic count and 42 (95%) had high grade cytologic atypia. All low-grade ESS were DNA diploid and had a low SPF. Among the four high-grade ESS, three (75%) were DNA aneuploid and three (75%) were p53-positive. Among 1 1 adenosarcomas, eight (73%) were non-diploid. All ovarian MMMTs were non-diploid and all but two had an SPF&gt;10%. 19 (73%) ovarian MMMTs were p53positive. The 5-year survival rate was 33% for LMS, 38% for uterine MMMT, 57% for ESS, 69% for adenosarcoma and 30% for ovarian MMMT. Thirty-five (71%) patients with LMS died of disease and two of intercurrent disease. Stage was found to be the most important factor for survival (p=0.007); in addition DNA ploidy (p=0.045) and SPF (p=0.041) had prognostic significance. Twenty-seven (61%) patients with uterine MMMT died of disease and six (14%) died of intercurrent disease. Stage was the only prognostic factor for survival. Nine (53%) patients with ESS died of disease. There was a significant correlation of survival to tumor grade (p=0.007), DNA ploidy (p=0.026), SPF (p=0.048) and stage (p=0.026). Of the 11 patients with adenosarcoma, four (36%) patients died of disease and three (27%) patients died of intercurrent disease. There were no variables that correlated with survival. Eighteen (69%) patients with ovarian MMMT died of disease and two (8%) patients died of intercurrent disease. In a multivariate analysis, only stage reached independent prognostic significance for survival (p=0.023). In summary, stage represents the most important prognostic factor for survival for uterine and ovarian sarcomas. DNA flow cytometry is useful in gaining additional prognostic information for LMS and ESS. P53-and mdm-2 overexpression had no prognostic value for survival rate. Most of the MMMT overexpressed p53 and were non-diploid. Treatment of sarcomatous neoplasms is difficult and the mainstay remains surgical removal of the tumor. For patients with early stage sarcoma there was a high recurrence rate, which suggests that a large proportion of patients may have systemic micrometastasic disease at the time of diagnosis. Recurrent and metastatic uterine sarcoma remains an incurable disease, and treatment must be considered palliative. / On the day of the public defence the status of the articles III and IV was: Accepted for publication. ; Bild/Image 1=p53/mdm-2 interaction ; Bild/Image 2=Leiomysarcoma stage I ; Bild/Image 3=Survival in uterine sarcoma.

Oestrogen is one of the most important hormonal regulators and is known to play a key role in the development and growth of breast cancer. The majority of tumours have a hormone dependent growth, and this is indicated by the presence of oestrogen receptors (ERs). About two thirds of breast cancers occur after the menopause when the ovaries have ceased to produce oestrogen and despite the low levels of circulating oestrogen’s the tumour concentrations of oestrone, oestradiol and their sulfates have been shown to be significant. Patients with hormone dependent tumours are candidates for treatment with the anti-oestrogen tamoxifen, which acts by competing with oestrogen for binding to the ER thereby, diminish the transcription of oestrogen regulated genes. The drug is mainly metabolised by cytochrome P450 enzymes in the liver and to a lesser extent locally in the breast, where upon several produced metabolites have higher affinity for the ER than the mother substance. Patients treated with tamoxifen have in general a prolonged disease-free survival. Even if most patients respond well to tamoxifen about 30-50 % either fail to respond or become resistant by incompletely understood mechanisms. Therefore, the aim of this thesis was to investigate possible mechanisms responsible for tamoxifen resistance. In paper I and II we studied genetic variants of enzymes participating in the metabolism of tamoxifen and assessed whether these variants correlated to breast cancer prognosis and/or to the benefit of tamoxifen. The results indicate an influence of CYP2D6, CYP3A5, and SULT1A1 genotypes in tamoxifen response. Further, tamoxifen has shown to compete with oestrogen for the binding to ER. In paper III we measured the expression levels of enzymes involved in the local synthesis of oestrogens in order to see if they correlated to clinical outcome. The protein expression of stromal aromatase was shown to have a prognostic significance, especially in ER-positive patients. Finally, tamoxifen and its ER-active metabolites have shown to induce both cell cycle arrest and apoptosis and one central mediator in these processes is the tumour suppressor protein p53. The proapoptotic activity of p53 is dependent on a proline rich domain containing a common Pro-to-Arg polymorphism. In paper IV we examined the value of this genetic variant as a predictive marker for anti-cancer therapy and found that patients carrying the Pro-allele might be good responders of tamoxifen therapy. The present thesis further indicates the complexity of the mechanisms underlying tamoxifen resistance. In summary, genetic variants of metabolic enzymes, genetic variants in p53, as well as expression levels of enzymes involved in local oestrogen synthesis, may have influence on breast cancer prognosis and may be useful markers in the prediction of tamoxifen response.

The aim of this thesis was to determine the relevant dose of arbepoetin-alfa (DA) in patients with lymphoproliferative diseases (LPD) and chemotherapy induced anemia (CIA), to study the clinical impact of intravenous (IV) iron supplementation combined with epoetin beta treatment, to identify factors that might predict hemoglobin (Hb) response to treatment with epoetins and to investigate safety of DA. A dose-finding phase II study was able to assess a reasonable DA dose of 2.25 μg/kg once weekly for the treatment of CIA in patients with LPD. Dose-response trends were observed for the different dose cohorts although not statistically significant for any of the endpoints. However a significantly higher proportion of patients achieved Hb response (increase ≥2 g/dL) in the combined DA groups than in placebo (P<0.001). A larger pivotal phase II trial was performed in a similar setting o confirm that the dose 2.25μg/kg once weekly was appropriate and safe. The proportion of patients achieving Hb response was significantly higher in the DA group (60%) than in the placebo group (18%) (P<0,001) and resulted in higher mean changes in Hb than placebo from baseline, 2.66 g/dl versus 0.69 /dl. Also a significantly lower proportion of patients in the DA group (31%) received RBC tranfusions than in the placebo group (48%). The short-term safety of DA with the tested dose was confirmed. The efficacy of DA was consistent for all end points independent of malignancy type or baseline endogenous erythropoietin serum levels. The correction of moderate anemia in truly iron repleted patients with clinically stable LPD not receiving hemotherapy or RBC transfusions with epoetin beta treatment, with or without IV iron treatment was studied in an open label randomized trial. Also the impact on iron kinetics was assessed. The mean change in Hb concentration from baseline to end of treatment (EOT ) was 2.91 versus 1.50 g/dL respectively (P<0.0001). There was a significant (P<0.0001) difference in mean Hb at EOT between the iron and no-iron groups (13.0 g/dL versus 11.8 g/dL). Hb response was achieved by significantly more patients in the iron group (P=0.0012)than in the no-iron group (93% versus 53%) and the median time to achieve a Hb response was 6 weeks in the iron group compared with 12 weeks in the no-iron group. The mean weekly epoetin dose per patient was statistically significant lower in the iron group at week 13 (P =0.029) and at least 25% lower at EOT. To investigate the long-term safety of DA in cancer patients with CIA four previously published double blind, randomized placebo-controlled phase II -III studies were analysed (n = 1.129). Median durations of progression-free survival and overall survival was comparable between DA and placebo for lung cancer (median follow up 15.8 months), for LPD (median follow up 32.6 months) and in the pooled population (follow up 4 months).

Colorectal cancer (CRC) is one of most common cancer diseases worldwide. In Swedenapproximately 5,000 new cases of CRC are generated each year, which makes it the thirdmost common cancer disease among both men and women. The past decades ofimproved treatment strategies have considerably increased the five-year survival for CRCpatients. However more could be achieved in this area, in particular for metastatic CRC,which is the cause of most CRC-related deaths. Therefore it is important to study thebiological response to certain treatments induced in CRC to find valuable predictiveand/or prognostic factors to select patients for better suited treatments. The aim of this thesis was to gain insight into the molecular changes that occurfollowing irradiation or treatment with SN-38 in rectal cancer patients or colon cancercell lines by studying the RNA expression, protein expression, DNA cell cycledistribution and apoptotic response. The expression of phosphatase of regenerating liver(PRL) proteins was investigated in rectal cancers from 125 patients included in arandomized clinical trial of preoperative radiotherapy (RT). Increased expression of PRLswas seen at the invasive margin of primary and metastatic cancers compared with theinner area of the tumors. Moreover, strong PRL staining at the invasive margin correlatedto distant recurrence and worse survival of patients in the RT group but not in non-RTgroup (Paper I). Radiosensitivity was studied by treating KM12C, KM12SM andKM12L4a colon cancer cell lines with radiation. KM12C is of low metastatic naturecompared with the highly metastatic KM12SM and KM12L4a. Upregulation of ΔNp73and PRL-3 might contribute to the radioresistant phenotype in KM12C. In contrast,KM12L4a shows a high frequency of apoptosis and lack of upregulation of ΔNp73, PRL-3 and survivin, which might explain its radiosensitive phenotype (Paper II). KM12C,KM12SM and KM12L4a were treated with SN-38 which inhibits topoisomerase 1 (topo-1). The results show that SN-38 induces G2/S arrest and possess the capacity to triggerapoptosis in the three cell lines (Paper III). To further elucidate SN-38 effect on these celllines, the gene expression profile following SN-38 treatment was studied. Oligonucleotidearrays consisting of ~27,000 spots were hybridized with sample and reference cDNA.Both unsupervised and supervised hierarchical clustering analysis, and functional analysiswere performed. Supervised hierarchical clustering gives a strong signal of 1453discriminated genes, the vast majority being upregulated. Both upregulated anddownregulated genes point toward a favorable impact of SN-38 regarding the apoptoticpathways. For example RhoB and Bax are upregulated together with downregulation ofKras and survivin, which promotes apoptosis (Paper IV). In conclusion, PRLs may be valuable biomarkers for RT resistance, predicting apoor prognosis in rectal cancer patients. Targeting radio-resistance factors, such asΔNp73 and survivin may contribute to an increased sensitivity to RT. SN-38 affects cellproliferation and apoptosis.

Positron Emission Tomography (PET) has gained an important roll in clinical for diagnosis, staging and prognosis of a range of cancer types. Utilization of PET for monitoring and evaluation of cancer treatment is an attractive but almost new concept. The proper choice of PET-tracer as a biomarker for treatment follow-up is crucial. The important characteristic for a suitable tracer is its ability to reflect the response to a treatment at an early stage, before any morphologically changes occurs. It would be an advantage to screen a battery of PET tracers in a preclinical model and introduce a few potential tracers in clinical trial. The most conventional pre-clinical approach in PET-oncology utilizes xenografts in mice or rats and requires a large number of subjects. It would be a great advantage to introduce a less demanding but still reliable preclinical method for a more efficient planning of studies in animal model and then in human trials. The Multicellular Tumour Spheroid (MTS) system represents an intermediary level between cells growing as monolayer and solid tumours in experimental animals or patients. It mimics the growth of naturally occurring human tumours before neovascularization and appears to be more informative than monolayer and more economical and more ethical than animal models. The aim of this work was to establish, refine and evaluate the application of MTS model as a preclinical approach in PET oncology. The vision was to introduce a preclinical method to probe and select PET tracer for treatment monitoring of anticancer drugs, which can hopefully be applied for optimization in breast cancer treatment. In this thesis, a number of basic experiments were performed to explore the character of 2-[fluorine-18]-fluoro-2-deoxy-d-glucose (FDG) uptake in MTS. FDG as the most established PET tracer was an obvious initial option for the evaluation of the model. For further assess-ment, we studied effects on FDG uptake in MTS treated with five routinely used chemother-apy agents. For association of PET tracer uptake to size change of MTS, we developed a reliable and user-friendly method for size determination of MTS. The next step was to apply the MTS model to screen PET tracers for analysis of early response of chemotherapy in breast cancer. Finally the method was utilized for translational imaging exemplified with a new chemotherapy agent. The results were encouraging and the MTS model was introduced and evaluated as a preclini-cal tool in PET oncology. The method was implicated to in vitro quickly assess a therapy profile of existing and newly developed anticancer drugs in order to investigate the effects of candidate drugs on tumour-growth, selection of appropriate PET tracer for treatment monitor-ing and finally understanding relation between growth inhibition and biomarkers as part of translational imaging activities.

Sedan 1960 talet har screening för och vaccinering mot cervixcancer blivit allt mer utbrett, trots detta drabbas fortfarande 450 kvinnor varje år av cervixcancer i Sverige. Då incidensen minskar finns risken för att kunskapen om sjukdomen minskar. Syftet var därför att belysa kvinnors upplevelser av att behandlats för cervixcancer för att öka kunskap och förståelse i mötet med kvinnorna. Studien utfördes som en litteraturstudie där 20 artiklar låg till grund för resultatet. Resultatet belyser kvinnors upplevelser av att behandlats för cervixcancer och hur det påverkade vardagen, reproduktiv och sexuell hälsa, deras syn på framtiden samt hur de upplevde sjukvården. Att ha behandlats för cervixcancer var något som drabbade hela människan, såväl fysiskt, psykiskt som sexuellt och inte bara genitalierna där sjukdomen hade sitt ursprung. Det framkom att kvinnorna ville samtala om tabubelagda ämnena men inte alltid vågade ta upp dem själva. Därför är det betydelsefullt att sjuksköterskorna ställer frågor angående de här ämnena. Omvårdnad bör grundas på evidens och därför är det viktigt att forskningen fortskrider för att optimera vården för kvinnor med cervixcancer.

Service screening with mammography was implemented in Northern Sweden between 1989 and 1998, covering 190,000 women aged 40-74 years constituting the target population in the area. The aim of this thesis was the evaluation of mammography screening in Northern Sweden with special focus on selected screening performance indicators and on the disease outcome. We analysed interval cancer (IC) incidence and episode sensitivity in the Norrbotten Mammography Screening Programme (NMSP) for the period 1989-2002. An overall IC rate at 1.1/1000 and IC rate ratio at 38% was found and epsiode sensitivity was estimated at 62-73%, in concert with reference values of the European guidelines. Radiological classification of the IC cases in three rounds of the NMSP showed that true, occult, missed and minimal signs IC, were present in 48%, 10%, 14% and 28% of the cases. We analysed early death from breast cancer (n=342) in Northern Sweden during the first five years of mammography service screening. Most fatal cases were advanced and incurable on diagnosis. In a few screen-detected cases with favourable prognostic factors the fatal outcome was unexpected. We estimated breast cancer survival by detection mode in 5120 women with breast cancer. We found a significantly favourable survival among IC cases compared to cases among uninvited. We studied breast cancer mortality in relation to mammography screening. Our findings indicated a long-term reduction of breast cancer mortality by 26-30% among women invited to screening and by 31-35% among women screened compared to not screened. We conclude from our evaluation of the mammography screening in Northern Sweden that women benefited from this public health intervention in form of improved survival and reduced mortality.