<p>Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect.</p><p>Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases.</p><p>Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases.</p><p>In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.</p>

Colorectal cancer is one of the most common malignant diseases in Sweden – more than 5000 new cases are diagnosed each year. The overall five-year survival is about 60% and in cases of recurrence the prognosis is poor. In a phase III study in advanced colorectal cancer the response rate was doubled when 5-FU was given as a bolus injection versus as a short infusion. The toxicity was similar and time to progression was longer in the injection group. However, overall survival was not significantly different. Dose-effect relationships of 5-FU were studied in another phase III study recruiting 312 patients. A decrease from 500 mg/m2 to 400 mg/m2 worsened the treatment results. A low incidence of severe toxicity was seen in both groups. An increase to 600 mg/m2 worsened the toxicity without any improvement of the results. A cytotoxic drug sensitivity test in different tumour types, mainly gastrointestinal cancer, poorly predicted treatment outcome in a phase II study. The conventional Nordic Flv regimen was split in a phase I/II trial. An escalation of dose was possible and the response rate was 20%. Thymidylate synthase (TS) and the gene expression of p53 were investigated by immunohistochemical technique in the primary tumours of 132 patients. None of the markers predicted the later palliative chemotherapy result. However, TS significantly predicted time to recurrence. Serum markers were analysed before and during FLv treatment to early predict outcomes among 87 patients. TPS is promising, both as a predictive marker before start of treatment and after a short period of treatment. In the same setting, CEA had lower predictive value. S-VEGF and S-bFGF did not yield any prognostic information of later outcome. In all studies B-haemoglobin values, performance status and subjective response were strong markers, both for prediction of objective response and for survival.

Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect. Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases. Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases. In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.

In modern, advanced radiotherapy (e.g. intensity modulated photon radiotherapy, IMXT) the delivery time for each fraction becomes prolonged to 10-20 minutes compared with the conventional, commonly 2-5 minutes. The biological effect of this prolongation is not fully known. The large number of beam directions in IMXT commonly leads to a large integral dose in the patient. Electrons would reduce the integral dose but are not suitable for treating deep-seated tumour, due to their limited penetration in tissues. By combining electron and photon beams, the dose distributions may be improved compared with either used alone. One obstacle for using electron beams in clinical routine is that there is no available treatment planning systems that optimise electron beam treatments in a similar way as for IMXT. Protons have an even more pronounced dose fall-off, larger penetration depth and less penumbra widening than electrons and are therefore more suitable for advanced radiotherapy. However, proton facilities optimised for advanced radiotherapy are not commonly available. In some instances electron beams may be an acceptable surrogate. The first part of this study is an experimental in vitro study where the situation in a tumour during fractionated radiotherapy is simulated. The effect of the prolonged fraction time is compared with the predictions by radiobiological models. The second part is a treatment planning study to analyse the mixing of electron and photon beams for at complex target volume in comparison with IMXT. In the next step a research version of an electron beam optimiser was used for the improvement of treatment plans. The aim was to develop a method for translating crude energy and intensity matrices for optimised electrons into a deliverable treatment plan without destroying the dose distribution. In the final part, different methods of treating the spinal canal in medulloblastoma were explored in a treatment planning study that was evaluated with biological models for estimating risks for late radiation effects. The effect on cell survival of prolonging fraction time at conventional doses/fraction is significant in an in vitro system. This effect is underestimated by biological models. Prolonging the fraction time will spare tissues with a fast DNA repair. Thus, there is a risk for sparing tumours. The mixed electron and photon beam technique has the potential to treat deep-seated tumours. Compared with IMXT the number of beams can be reduced and as a consequence, the time for each fraction could be kept shorter. The integral dose in the patient will also be lower. The mixed beam technique could potentially be further improved if automatic optimisation for electrons was available. The results suggest that optimisation and segmentation can be automated, and a deliverable treatment plan can be obtained with simple procedures without destroying the quality of the dose distribution. The integral dose in patients may lead to late radiation side effects. In childhood cancers the risk for development of radiation induced cancers is a reality and the integral dose outside the target volume should be minimised. Based on models for cancer induction, protons show the lowest risk while electrons have some benefit compared with different photon techniques. All methods are able to similarly well treat the target volume.

<p>Breast cancer is one of the most common malignancies in women. Due to early detection and the use of screening programs approximately 60% of all new cases lack lymph node involvement. Today, a substantial proportion of these women will be offered adjuvant systemic chemotherapy. However, better proliferation markers are needed to predict patient outcome and to avoid overtreatment. </p><p>Cyclin A, cyclin E and Ki-67 are all markers for proliferation and involved in the regulation of the cell cycle. Overexpression has been associated with disease recurrence in several studies, but the results have not been consistent. However, none of these studies has investigated aberrant expression of cyclin E (the expression of cyclin E during phases of the cell cycle other than late G1 and early S-phase). Studies have shown that aberrant cyclin E might provide additional prognostic information compared to cyclin E alone.</p><p>The aims of this thesis were 1.to investigate the prognostic value of cyclin A, cyclin E and aberrant cyclin E in early breast cancer. 2.to validate the tissue microarray (TMA) technique for cyclin A and 3.to define the most optimal cut-off values for cyclin A and Ki-67.</p><p>We found that the agreement of TMA and large section results was good with kappa values 0.62-0.75 and that the reproducibility of the two readers’ results was good or even very good, with kappa values 0.71 – 0.87. </p><p>The optimal cut-off value for cyclin A average was 8% and for cyclin A maximum value 11%. The corresponding values for Ki-67 were 15 and 22%. </p><p>Neither cyclin E nor aberrant cyclin E was a prognostic factor in low-risk node negative breast cancer patients. </p><p>Finally, we conclude that cyclin A is a prognostic factor in node negative breast cancer (univariate analysis average value OR=2.9 95% CI 1.8-4.6; maximum value OR=3.7 95% CI 2.3-5.9).</p>

<p>Enterochromaffin-like (ECL) and ghrelin cells, in the human gastric mucosa and in gastric endocrine tumours (GETs), were subclassified with respect to immunohistochemical reaction <i>vs.</i> vesicular monoamine transporter 2 (VMAT-2), ghrelin/obestatin, and histidine decarboxylase (HDC). The immunohistochemical expression of ghrelin/obestatin and HDC in GETs was related/correlated to plasma ghrelin/obestatin and urinary methyl imidazole acetic acid (U-MeImAA) excretion respectively, with the intention of identifying markers for these tumour types. </p><p>ECL cells in the gastric mucosa appear either with VMAT-2 only, or with HDC immunoreactivity only, or they can express both proteins; but in GETs the transporter protein and the enzyme were almost always co-expressed in the same cells. Furthermore, ghrelin and obestatin were co-localized in the same cells in the gastric mucosa and in the tumours. In the gastric mucosa, occasional ghrelin/obestatin cells expressed VMAT-2, but in GETs these proteins were always co-localized. Ghrelin expressing cells were non-immunoreactive to HDC. Plasma ghrelin/obestatin concentrations remained low in patients with GETs, irrespective of the relative incidence of these cells in the mucosa and in tumours. The plasma values were not related/correlated to various clinico-pathological parameters. A malignant ghrelinoma was however an exception. The tumour released high total and active ghrelin concentrations into the blood circulation. The patient suffered from diarrhoea, hypothyroidism and diabetes mellitus, but it is not clear if these conditions were due to hyperghrelinaemia. The excretion U-MeImAA was increased in a few patients with GETs, but this increase was not always related to clinical symptoms.</p><p>In conclusion, ECL cells are an heterogeneous group according to VMAT-2 and HDC immunoreactivity. Ghrelin and obestatin are expressed in the same cells in the gastric mucosa, and a few of these cells display VMAT-2 immunoreactivity. Ghrelinoma is a new gastric tumour entity.</p>

Background: Approximately one in three Swedish people will receive a cancer diagnosis. Cancer primarily affects the elderly but also young people suffer. Young people are in a period of life that could put a strain of the ordinary when they are faced with choices and new challenges. The basic sense of security in everyday life is not so obvious and many suffer from, for example, stress and the feeling of being inadequate in relation to the requirements. It is relevant that the nurses can put themselves into what it is like to be young and afflicted with cancer, with the pressures of life itself and what the disease represents. For the nurse, it is important to try to understand what quality of life, crisis and management means, because it often is crucial for young patients with cancer. Aim: The aim is to increase the understanding of how the young people with cancer handle to live with a fatal disease. Methods: A literature review based on ten qualitative scientific articles. The articles were selected through a systematic literature search in the databases CINAHL, Pubmed and ProQuest Nursing &amp; Allied Health Source. The analysis of the articles was made through comparison of the similarities and differences. Results: In the results three different themes emerged: Being normal, Having access to support and To find a positive or accepting attitude. The result illustrates the most common strategies used by young people to handle living with cancer. There are also a number of subthemes presented attached to these themes which clarifies different aspects of the strategies. Discussion: The discussion clarifies the meaning of the result's main themes. What might it mean to live normally? Barriers to support and management was The lack of information evidencing how important it was to get information, but also how this was one of the shortcomings in health care. The need for support to patient and familyreveals that support from family is not only important for the patient but also something that can sometimes burst from the family side. Age adjustment in health care is discussed as a more age-appropriate care could be beneficial for young people. Although The attitude’s importance addressed in the sense of how important it is to stay positive and how hope can get a person to live longer.

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

Background: Oral Tongue Squamous Cell Carcinoma (OTSCC) is the most frequent and aggressive carcinoma in the head and neck region. Its incidence has increased during the last decades, especially in young patients (≤40 years) mainly female. These young patients have either not been exposed to the traditional risk factors for this disease, or have a much reduced duration of exposure than the typical OTSCC patient. The reasons behind this increasing incidence remain unknown. The aims of this thesis were to analyse the presence and possible role of human papillomavirus (HPV) in oral tongue cancer in correlation with its surrogate marker p16 and its receptor syndecan-1. Other aims were to evaluate expression of EMT (epithelial to mesenchymal transition) - related markers, such as E-cadherin, β-catenin, CK5 and CK19, and to address the potential predictive role of podoplanin in the loco-regional metastatic process. Clinical parameters including age, sex, geographical distribution, relapse, tumour staging and grading were also investigated for a possible correlation with biomarker expression and prediction of survival rate and therapeutic strategy. Materials and methods: More than one hundred samples of OTSCC coming from two University Hospitals of two different countries (Sweden and Italy) were analysed. HPV presence was evaluated by in situ hybridisation for detection of the high-risk HPV 16 and indirectly by immunohistochemistry (IHC) of its surrogate marker p16. Expression of the HPV receptor syndecan-1 and the EMT biomarkers E-cadherin, β-catenin, CK5, CK19 were also evaluated by immunohistochemistry. Samples were scored using a quick score (QS), taking both number and intensity of cells stained into account. Podoplanin expression was investigated at both protein and RNA level. Results: Tumour size and lymph node metastasis correlated to both overall and disease-free survival. Despite variable expression of the syndecan-1 receptor, HPV 16 was not detected in any sample analysed, excluding a possible association with p16, which was expressed in 33% of the cases. All EMT-related markers were commonly expressed in tongue cancer. Data showed E-cadherin to be an independent prognostic factor with higher expression associated with poor overall survival. Notably, E-cadherin, β-catenin and CK5 directly correlated to each other. Multivariate analysis of clinical data demonstrated that age of the patient is an independent prognostic factor with younger patients showing a worse survival rate. Patients younger than 40 years also showed significantly higher expression of podoplanin. Data for geographic distribution revealed a difference in expression of E-cadherin between Swedish and Italian patients. Conclusions: In contrast to SCC of the base of the tongue and the tonsil, HPV is not present in OTSCC, excluding HPV infection as a risk factor. Higher levels of E-cadherin and young age is associated with poor survival in OTSCC patients. The different frequency of EMT markers seen between Swedish and Italian patients suggests an important role for the environment and the geographical area in the onset of different molecular patterns of OTSCC.

No description available.