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With improved surgical techniques and preoperative radiotherapy (RT) the local recurrence rate in rectal cancer patients has been reduced, however the mortality rate is still high and there is a huge variation in the response to preoperative RT in patients with the same tumour stage. To improve patient’s survival, it is of great importance to identify good prognostic and predictive factors that help us to select the best suited patients for preoperative RT in the future. For many years, studies of neoplastic transformation have mainly focused on tumour cells. In recent years, researchers have realised that the stroma around tumour cells and their extracellular matrix components also play an important role in tumour carcinogensesis. The aim of this thesis was to investigate the biological factors, survivin and particularly interesting new cysteine-histidine rich protein (PINCH), histological factors, inflammatory infiltration, fibrosis, necrosis, mucinous content, angiogenesis and lymphangiogenesis as well as their relationships to preoperative RT and to clinical variables in rectal cancer patients who participated in a Swedish rectal cancer trial of preoperative RT. In paper I, the expression of survivin and its relationship to preoperative RT and clinical factors were investigated in 98 primary rectal tumours and adjacent normal mucosa. In all patients, positive survivin expression was independently related to worse survival compared to negative survivin expression in a multivariate analysis. In paper II, PINCH expression and its relationship to RT, clinical, histological and biological factors were investigated at the invasive margin and inner tumour area in 137 primary rectal tumours and in cell line of fibroblasts. In patients without RT, strong PINCH expression was independently related to worse survival in a multivariate analysis. No survival relationship was found in the patients with RT, and there was no difference in PINCH expression between the subgroups of non-RT and RT at the invasive margin/inner tumour area. In patients with RT, strong PINCH expression at the inner tumour area was related to a high level of lymphatic vessel density (LVD). In paper III, the frequency of LVD/blood vessel density (BVD) was analysed at the periphery, the inner tumour area and the invasive margin of 138/140 primary rectal tumours and correlated to RT, clinical, histological and biological factors. In all patients, LVD at the periphery of the tumour was independently related to better survival compared to LVD at the inner tumour area/invasive margin. In all patients, a higher LVD at the periphery was related to negative (wild type) p53 expression. In paper IV, the inflammatory infiltration, fibrosis, necrosis and mucinous content were studied in relation to RT, clinical and biological parameters in preoperative biopsies (n = 153) and in primary tumours (n = 148). In all patients and in the subgroups of non-RT and RT a higher grade of inflammatory infiltration was independently related to improved survival compared to weak inflammatory infiltration in a multivariate analysis. In this thesis, survivin, PINCH, LVD and inflammatory infiltration are independent prognostic factors in rectal cancer patients who participated in a clinical trial of preoperative RT. This information may help us to improve patient’s survival by selecting the best suited patients for preoperative RT in the future.

<p>The purpose of this thesis was to evaluate the diagnostic potential of a new ultrasound contrast agent,Sonazoid^TM, intended for use in patients with suspicion of prostate cancer.</p><p>The sonographic appearance of normal prostatic vascularity in dogs was evaluated before and after injection of Sonazoid,using different Doppler flow detection modes.The use of Sonazoid significantly improved the visibility of the vascular pattern in normal dog prostate,both with colour and power Doppler imaging.There was a significant difference in the depiction of blood flow in the prostate between the two imaging modalities,showing the power Doppler superior to colour Doppler imaging.The contrast revealed a radial,spoke-like intraprostatic pattern,not seen prior to contrast injection.</p><p>Different ultrasound imaging modalities were tested in a small group of young healthy male volunteers to evaluate the visibility of the normal prostate blood flow with and without Sonazoid.</p><p>The ultrasound contrast agent improved the visibility of the normal human prostate vascular anatomy for both colour and power Doppler imaging.Again,the improvement was significantly better for power Doppler than for colour Doppler imaging.Using fundamental B-mode,there was no major difference in the ultrasound appearance of the prost ate vascular it y before and after i njection of Sonazoid.Cont rast dynamic st udies of blood flow wit hi n t he normal gland showed a filling from the periphery towards the centre in all subjects,demonstrating a symmetric, radial vascular pattern.</p><p>A canine prostate model was used to investigate if Sonazoid,could improve the visualisation of prostatic vessels to better delineate areas on normal and decreased blood flow.Both 2D and 3D power Doppler imaging was performed in this study.The visibility of the prostate blood flow improved significantly following injection of Sonazoid for both 2D and 3D power Doppler imaging.There was,however,no major difference in depicting the vascularity using 2D and 3D imaging.After injection of Sonazoid,a disturbance of the radial vascular pattern and a lack of blood flow symmetry between the two prostate lobes were possible to identify.The added information gained by injection of Sonazoid made it possible to identify areas of decreased blood flow not seen prior to contrast injection.</p><p>The vascular pattern of lesions,identified with B-mode imaging in patients with suspicion of prostate cancer,was studied,using Sonazoid.Contrast dynamic inflow in the lesions,compared to the adjacent tissue was investigated in the same study.Prostate cancer lesions appeared hypervasuclar prior to ultrasound contrast agent.Three of six cancer lesions changed from hypervascular to marked hypervascular following injection of Sonazoid,a finding that might be interpreted as a higher level of confidence.None of the non-cancer lesions were assessed as hypervascular after Sonazoid injection,a possible increased value of a negative finding.Four of the cancer lesions enhanced earlier compared to the surrounding prostate tissue,following ultrasound contrast injection.The results indicate that changes in vascular architecture,e.g.induction of angiogenesis by tumour cells,can be observed by ultrasonographically determining the inflow pattern of an intravenously injected ultrasound contrast agent.</p>

The purpose of this thesis was to evaluate the diagnostic potential of a new ultrasound contrast agent,SonazoidTM, intended for use in patients with suspicion of prostate cancer. The sonographic appearance of normal prostatic vascularity in dogs was evaluated before and after injection of Sonazoid,using different Doppler flow detection modes.The use of Sonazoid significantly improved the visibility of the vascular pattern in normal dog prostate,both with colour and power Doppler imaging.There was a significant difference in the depiction of blood flow in the prostate between the two imaging modalities,showing the power Doppler superior to colour Doppler imaging.The contrast revealed a radial,spoke-like intraprostatic pattern,not seen prior to contrast injection. Different ultrasound imaging modalities were tested in a small group of young healthy male volunteers to evaluate the visibility of the normal prostate blood flow with and without Sonazoid. The ultrasound contrast agent improved the visibility of the normal human prostate vascular anatomy for both colour and power Doppler imaging.Again,the improvement was significantly better for power Doppler than for colour Doppler imaging.Using fundamental B-mode,there was no major difference in the ultrasound appearance of the prost ate vascular it y before and after i njection of Sonazoid.Cont rast dynamic st udies of blood flow wit hi n t he normal gland showed a filling from the periphery towards the centre in all subjects,demonstrating a symmetric, radial vascular pattern. A canine prostate model was used to investigate if Sonazoid,could improve the visualisation of prostatic vessels to better delineate areas on normal and decreased blood flow.Both 2D and 3D power Doppler imaging was performed in this study.The visibility of the prostate blood flow improved significantly following injection of Sonazoid for both 2D and 3D power Doppler imaging.There was,however,no major difference in depicting the vascularity using 2D and 3D imaging.After injection of Sonazoid,a disturbance of the radial vascular pattern and a lack of blood flow symmetry between the two prostate lobes were possible to identify.The added information gained by injection of Sonazoid made it possible to identify areas of decreased blood flow not seen prior to contrast injection. The vascular pattern of lesions,identified with B-mode imaging in patients with suspicion of prostate cancer,was studied,using Sonazoid.Contrast dynamic inflow in the lesions,compared to the adjacent tissue was investigated in the same study.Prostate cancer lesions appeared hypervasuclar prior to ultrasound contrast agent.Three of six cancer lesions changed from hypervascular to marked hypervascular following injection of Sonazoid,a finding that might be interpreted as a higher level of confidence.None of the non-cancer lesions were assessed as hypervascular after Sonazoid injection,a possible increased value of a negative finding.Four of the cancer lesions enhanced earlier compared to the surrounding prostate tissue,following ultrasound contrast injection.The results indicate that changes in vascular architecture,e.g.induction of angiogenesis by tumour cells,can be observed by ultrasonographically determining the inflow pattern of an intravenously injected ultrasound contrast agent.

The skeleton is the most common site of prostate cancer bone metastasis, and at present, there are no curable treatments for these patients. To further understand what stimulates tumor cell growth in the bone microenvironment and to find suitable therapies, reliable model systems are needed. For this purpose, we have developed an in vitro co-culture system that can be used to study interactions between tumor cells and murine calvarial bones. To validate the model, we measured the release of collagen fragments and monitored changes in expression levels of genes normally expressed during active bone remodeling. One of the major reasons why prostate cancer cells colonize bone is the abundance of tumor-stimulating factors, such as insulin-like growth factors (IGFs), present in this milieu. We found that the IGF-1 receptor (IGF-1R) was one of the most highly activated receptor tyrosine kinases in tumor cell lines stimulated with bone conditioned media. Since IGF-1 is known to be a strong survival factor for tumor cells, we hypothesized, that concurrent inhibition of IGF-1R signaling can enhance the effects of apoptosis-inducing therapies, such as castration. We used our co-culture model to target human prostate cancer cell lines, PC-3 and 22Rv1, with simvastatin (an inhibitor of the mevalonate pathway and an inducer of apoptosis), in combination with anti-IGF-1R therapy. Tumor cell viability declined with either one of the therapies used alone, and the effect was even more pronounced with the combined treatment. The hypothesis was also tested in rats that had been inoculated with rat prostate cancer cells, Dunning R3327-G, into the tibial bone, and treated with either anti-IGF-1R therapy, castration, or a combination of both therapies. Immunohistochemistry was used to evaluate therapeutic effects on tumor cell proliferation and apoptosis, as well as tumor cell effects on bone remodeling. The tumor cells were found to induce an osteoblastic response, both in vivo in rats, and in vitro using the co-culture model. Interestingly, the therapeutic response differed depending on whether tumor cells were located within the bone marrow cavity or if they had leaked out into the knee joint cavity, highlighting the role of the microenvironment on metastatic growth and therapeutic response. Therapies targeting the IGF-1R have been tested in clinical trials, unfortunately with disappointing results. By immunohistochemical evaluation of bone metastases from patients with castration-resistant prostate cancer, we found a large variance in IGF-1R staining within this group of patients. Hence, we postulate that the effects of anti-IGF-1R therapies could be more beneficial in patients with high tumoral IGF-1R-activity than in IGF-1R negative cases. We also believe that side effects, such as hyperglycemia, associated with anti-IGF-1R therapy, could be reduced if this treatment is administered only to selected patients and for shorter time periods. In a separate study, using whole-genome expression data from bone metastases obtained from prostate cancer patients, we present evidence that a high activity of osteoblasts is coupled to a high activity of osteoclast. Moreover, we found that high bone remodeling activity is inversely related to tumor cell androgen receptor (AR) activity. The results from this study may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered, and could aid in the search for novel therapeutic targets. In summary, we present an in vitro model for studies of the bidirectional interplay between prostate cancer cells and the bone microenvironment. We also demonstrate the importance of IGF-1 in prostate cancer bone metastases and suggest that inhibition of IGF-1R signaling can be used to treat prostate cancer as well as to enhance effects of other treatments such as androgen deprivation therapy. Furthermore, we emphasize the possibility of molecular tumor characterization when designing treatment plans for individual patients, thereby maximizing the therapeutic effects.

Introduktion: På en onkologisk avdelning vårdar sjuksköterskan patienter med cancerdiagnoser och för att ge patienterna en god vård behöver den vara av god kvalitet. Vårdkvalitet innefattar att vården är individanpassad, säker, kunskapsbaserad och ändamålsenlig, effektiv, jämlik samt tillgänglig. Syfte: Syftet var att beskriva omvårdnadens kvalitet relaterat till sjuksköterskans kärnkompetenser på en onkologisk vårdavdelning, ur ett sjuksköterskeperspektiv. Metod: Studien utformades efter Polit och Beck (2012) nio-stegs-modell för litteraturstudier. Databaser som användes var CINAHL och PubMed vilket resulterade i tio vetenskapliga artiklar som litteraturstudiens resultat baserades på. Sex stycken var utifrån kvalitativ metod och fyra utifrån kvantitativ metod som bearbetades deduktivt. De valda artiklarna granskades enligt Polit och Beck (2012) kvalitetsgranskningsmallar. Resultat: Resultatet utgick från sjuksköterskans kärnkompetenser: Personcentrerad vård, samverkan i team, evidensbaserad vård, säker vård och informatik. Resultatet som framgick var att vårdkvaliteten påverkades när sjuksköterskan arbetade efter kompetenserna. Slutsats: Sjuksköterskans arbete för att påverka vårdkvaliteten grundade sig i att besitta evidensbaserad kunskap, agera som en företrädare för patienten, en ledare för vårdteamet samt sträva efter att utforma vården individanpassat.

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Squamous cell carcinoma (SCC) is the most common histological type of cancer in the head and neck region and arises in the epithelial mucosa of the upper aerodigestive tract. Approximately one and a half million people are living with the diagnosis. Despite efforts in prevention and advances in treatment, the 5-year survival rate still lies around 60%, and recurrences and second primary tumors remain a problem. Moreover, treatment responses vary from patient to patient, highlighting the need for individually tailored treatments. To make this possible, biomarkers predicting treatment outcome are needed to better guide treatment decisions. The aim of this thesis was to evaluate the expression of certain proteins and the frequency of certain SNPs (Single nucleotide polymorphisms) in tumor biopsies and cell cultures of head and neck squamous cell carcinomas (HNSCC), and to explore their potential as biomarkers for treatment outcome. Furthermore, we aimed to study the impact of hypoxia on treatment response, epithelial-tomesenchymal transition (EMT), and induction of cancer stem cells (CSC). In papers I and II, we investigated two proteins, survivin and WRAP53β, using immunohistochemistry (IHC) in tumor biopsies from 40 patients categorized as Non-responders or Responders to radiotherapy. High expression of survivin and nuclear expression of WRAP53β were significantly more prevalent in the Responder group. The combination of these two factors correlated strongest to overall survival, but not to a significantly higher extent compared to survivin alone. Moreover, when examined separately, a high percentage of p53-stained cells and the presence of the SNP FGFR4 Gln388Arg correlated to improved overall survival, whereas the SNP XPD Lys751Gln was associated with worse overall survival. The latter three showed no significant correlations to radiotherapy response. In paper III, the two most promising proteins identified in papers I and II were analyzed in a study cohort of 149 tumor biopsies of glottic laryngeal SCC, categorized as T2N0-T3N0. In this patient group, no significant associations between survivin expression and survival could be found. However, expression of cytoplasmic WRAP53β was significantly linked to worse disease-free-survival (DSF) compared to nuclear WRAP53β or negative staining for WRAP53β. Positive expression of p16INK4a was found in 7% of the tumors. The prevalence of p16 INK4a was higher in younger patients (&lt;60) and associated with absence of recurrence and longer DSF. In paper IV, five HNSCC cell lines were cultured in normoxic (20% O2) and hypoxic (1% O2) conditions and changes in treatment response, EMT profile, and expression of CSC markers were examined. As expected, hypoxia induced EMT and to a certain extent expression of CSC markers. Silencing of the hypoxia-inducible-factor-1α (HIF-1α) only partly reversed these effects, suggesting that other mechanisms are involved. Whereas most cell lines became more resistant to treatment in hypoxia, one cell line (LK0412) became more sensitive to cetuximab-treatment in hypoxia, an effect that was revoked by depletion of HIF-1α, suggesting a possible sensitizing effect of HIF-1α to cetuximab-treatment. Taken together, WRAP53β appears to be a promising biomarker candidate for treatment outcome in HNSCC, but further evaluation especially on the subcellular localization of WRAP53β is required. Even though the role of survivin in radiotherapy response in glottic SCC seems to be insignificant, it might have a more important role in other HNSCC subsites. As far as the effects of hypoxia, it appears that hypoxia might have a sensitizing effect on cetuximab-treatment in certain cases, which seems to be HIF1-α –dependent. Further studies are required to clarify the importance of this observation.

Lysosomes, the recycling units of the cell, participate in the signaling pathway to apoptosis, which has stimulated the search for anti-cancer drugs targeting the lysosomal compartment. Lysosomes are, however, often altered in cancer cells. The aim of this thesis was to investigate the involvement of lysosomes during apoptosis in normal and cancer cells. We developed and used flow cytometric methods to measure cytosolic and lysosomal pH in cells. The cytosolic pH of U937 cells decreased, in a caspase-independent way, by 1.4 pH-units during apoptosis. Concomitantly, the lysosomal pH increased from 4.3 to 5.2, suggesting that proton release from lysosomes might be responsible for cytosolic acidification. When studying the lysosomal pH of head and neck squamous cell carcinoma (HNSCC) cell lines and normal oral keratinocytes (NOKs), the pH was significantly increased in three of five HNSCC cell lines, as compared to NOKs. Moreover, high lysosomal pH correlated to low expression of the B subunit of the vacuolar V0/V1-ATPase, a necessary component of the proton pump responsible for lysosomal acidification, and to reduced intrinsic cisplatin sensitivity. Cisplatin-induced apoptosis was, at least partly, dependent on lysosomal cathepsins. When investigating the colony formation ability of the two HNSCC cell lines LK0412 and SqCC/Y1, both were found to give rise to holoclones, indicating the presence of cells with cancer stem cell properties. Holoclone cells from the LK0412 cell line were less sensitive to cisplatin compared to more differentiated paraclone cells. Moreover, we detected differences in intracellular localization of the lysosomal compartment and expression of cathepsins between holo- and paraclone cells. This thesis shows that changes found in the lysosomal compartment of cancer cells, such as alteration of lysosomal pH, might influence the outcome of a drug treatment. In addition, differences in drug sensitivity between subpopulations of tumor cells may affect the outcome of an anticancer therapy. / Programmerad celldöd eller apoptos är en viktig mekanism för att upprätthålla balans mellan kroppens celler. Vid exempelvis cancer fungerar inte styrningen av denna process, vilket leder till att för få celler dör och en tumör kan växa ohämmat. Denna avhandling fokuserar på lysosomen, en mycket sur organell i cellen som är ansvarig för nedbrytning av cellmaterial. Hos cancerceller är lysosomerna ofta förändrade. Vi har undersökt lysosomernas roll under apoptos hos normala celler och hos cancerceller. För att kunna undersöka pH-förändringar under apoptos har vi utvecklat metoder att mäta cytosoliskt och lysosomalt pH med hjälp av en teknik som kallas flödescytometri. I apoptotiska celler ser vi att det cytosoliska pH:t sjunker med 1.4 pH-enheter till pH 5.7 samtidigt som det lysosomala pH:t ökar från 4.3 till 5.5. Detta tyder på att läckage av vätejoner från lysosomerna kan orsaka en försurning av cytosolen under apoptos. Genom att studera normala orala keratinocyter och jämföra dessa mot fem olika cellinjer eeablerade från skivepitelcancer från munhåla har vi också funnit ett samband mellan det lysosomala pH:t och känsligheten för cellgiftet cisplatin. Cisplatinbehandling leder till apoptos hos alla celler men en högre dos krävs hos celler som har ett högt lysosomalt pH. Tumörer tros innehålla ett litet antal sk cancerstamceller, som har förmåga att kontinuerligt kopiera sig själva utan att åldras. Överlevnad av dessa celler tros vara orsaken till att en tumör återkommer efter en behandling. Vi visar i denna avhandling att cellinjer från skivepitelcancer innehåller celler som har cancerstamcellsegenskaper, och att dessa celler kan ha en lägre känslighet mot cisplatin jämfört med mer utvecklade cancerceller. Lysosomerna utgör ett intressant framtida mål för nya cancerläkemedel. I denna avhandling visar vi att förändringar i det lysosomala systemet kan påverka effekten av ett läkemedel och att skillnader mellan olika sub-populationer av celler från samma tumör kan påverka resultatet av en behandling.