Late effects of cancer at a young age: Registry-based studies of the health of cancer patients and their off-spring

Modern cancer therapy has resulted in increased survival among patients diagnosed with cancer at a young age. These improvements have led to the investigation of late morbidity and mortality associated with cancer and its treatments. The aim of this study was to evaluate late effects of cancer treated at a young age on the health of patients and their offspring. Utilising the nationwide population-based registries in Finland, we evaluated the risk of hypothyroidism and the probability of parenthood in cancer survivors as well as preterm birth, neonatal outcomes, and the risk of cancer among offspring of patients. The survivor cohort, identified from the Finnish Cancer Registry, consisted of 25,784 cancer patients diag-nosed between ages 0 and 34 in 1953–2004. By linkage to the population register, siblings of these patients were identified for comparison. The prevalence of hypothyroidism was higher among former childhood cancer (aged 0–16) patients than in the general population. The probability of parenthood following early onset cancer was overall significantly reduced compared to siblings. Offspring of female cancer survivors were at an increased risk of preterm birth, this risk being highest among patients diagnosed in childhood and early adulthood (aged 20–34 years). The offspring were not, however, at a significantly increased risk of neonatal death or stillbirth, though they were more likely to need monitoring or intensive care in the neonatal period. The risk of sporadic cancer among offspring of male and female cancer survivors was not elevated in comparison to the general population. The study showed that former cancer patients are at risk of certain adverse endocrine and reproductive health outcomes and should be followed for timely intervention. The offspring of cancer survivors do not appear to be at risk for adverse health outcomes.

ERBB4 mutations in cancer and amyotrophic lateral sclerosis

ErbB receptor tyrosine kinases, epidermal growth factor receptor (EGFR, also known as ErbB1), ErbB2 (HER2 or NEU), ErbB3 (HER3), and ErbB4 (HER4), transduce signals borne by extracellular ligands into central cellular responses such as proliferation, survival, differentiation, and apoptosis. Mutations in ERBB genes are frequently detected in human malignant diseases of epithelial and neural origin, making ErbB receptors important drug targets. Targeting EGFR and ErbB2 has been successful in eg. lung and breast cancer, respectively, and mutations in these genes can be used to select patients that are responsive to the targeted treatment. Although somatic ERBB4 mutations have been found in many high-incidence cancers such as melanoma, lung cancer, and colorectal cancer and germ-line ERBB4 mutations have been linked to neuronal disorders and cancer, ErbB4 has generally been neglected as a potential drug target. Thus, the consequences of ERBB4 mutations on ErbB4 biology are largely unknown. This thesis aimed to elucidate the functional consequences and assess the clinical significance of somatic and germ-line ERBB4 mutations in the context of cancer and amyotrophic lateral sclerosis. The results of this study indicated that cancer-associated ERBB4 mutations can promote aberrant ErbB4 function by activating the receptor or inducing qualitative changes in ErbB4 signaling. ERBB4 mutations increased survival or decreased differentiation in vitro, suggesting that ERBB4 mutations can be oncogenic. Importantly, the potentially oncogenic mutations were located in various subdomains in ErbB4, possibly providing explanation for the characteristic scattered pattern of mutations in ERBB4. This study also demonstrated that hereditary variation in ERBB4 gene can have a significant effect on the prognosis of breast cancer. In addition, it was shown that hereditary or de novo germ-line ERBB4 mutations that predispose to amyotrophic lateral sclerosis inhibit ErbB4 activity. Together, these results suggest that ErbB4 should be considered as a novel drug target in cancer and amyotrophic lateral sclerosis.

Asbestin tunnistaminen keinonenällä

Asbesti on yleisnimike kuitumaisille silikaattimineraaleille. Sillä on monia hyviä ominaisuuksia. Siksi sitä on käytetty useisiin eri käyttötarkoituksiin jo yli 4 000 vuoden ajan. Sisäänhengitettynä asbesti aiheuttaa kuitenkin vakavia terveyshaittoja, mm. asbestoosia, keuhkosyöpää ja mesotelioomaa. Vuosina 1918-1988 Suomessa käytettiin asbestia 300 000 tonnia. Yleisintä käyttö oli 1960-70-lukujen vaihteessa. Sairauksien viive altistumisesta on 10-40 vuotta. Sairauksien esiintyminen onkin nyt suurimmillaan. Suurin osa sairauksista on hyvänlaatuisia keuhkopussin paksuuntumia eli plakkeja. Vuosittain asbestin aiheuttamiin sairauksiin, etupäässä syöpiin, kuolee Suomessa noin 100 ihmistä. Yhteensä altistuneita arvellaan olevan 250 000. Heistä elossa on noin 50 000. Vaarallisuutensa vuoksi asbestin käyttö on useissa maissa kielletty, mutta maailmalla sitä käytetään edelleen suuria määriä. Suomessa asbestin käyttöä rajoitettiin jo 1970-luvulla. Pieniä poikkeuksia lukuun ottamatta täyskielto tuli voimaan 1.1.1994. Suomessa asbestia esiintyy edelleen vanhoissa rakennuksissa. Asbestipurkutyö on luvanvaraista. Asbestitöissä on huolehdittava siitä, että kukaan ei altistu asbestille. Asbestipitoisen materiaalin tunnistaminen silmämääräisesti on vaikeaa. Materiaali luokitellaan asbestipitoiseksi, jos siinä on asbestia yli 1 painoprosenttia tai jos sitä voidaan pölyävyytensä takia pitää vaarallisena. Asbestipitoisen materiaalin kartoituksessa voidaan käyttää rakennussuunnitelmia, vanhoja asiakirjoja kuten urakoitsijan laskuja sekä tuntemusta rakennusajan yleisistä rakennustavoista. Varmuus saadaan kuitenkin vain tutkimalla materiaali esimerkiksi laboratoriokokeissa. Tässä diplomityössä on pyritty selvittämään, voidaanko asbesti tunnistaa ChemPro 100 -keinonenällä. Laite perustuu ioniliikkuvuusspektrometriaan eli eri yhdisteiden erilaiseen liikkuvuuteen kaasumaisessa väliaineessa. Menetelmä on nopea ja yksinkertainen. Tutkimusta varten hankittiin asbestipitoisia materiaaleja, joista saatuja tuloksia vertailtiin toisiinsa. Nykyiset asbestintunnistusmenetelmät ovat monimutkaisia ja hitaita. Jos keinonenä pystyttäisiin kouluttamaan tunnistamaan asbestimateriaali, helpottaisi se asbestikartoituksen tekemistä.

The Possibilities and Dosimetric Limitations of MLC-Based Intensity-Modulated Radiotherapy Delivery and Optimization Techniques

The use of intensity-modulated radiotherapy (IMRT) has increased extensively in the modern radiotherapy (RT) treatments over the past two decades. Radiation dose distributions can be delivered with higher conformality with IMRT when compared to the conventional 3D-conformal radiotherapy (3D-CRT). Higher conformality and target coverage increases the probability of tumour control and decreases the normal tissue complications. The primary goal of this work is to improve and evaluate the accuracy, efficiency and delivery techniques of RT treatments by using IMRT. This study evaluated the dosimetric limitations and possibilities of IMRT in small (treatments of head-and-neck, prostate and lung cancer) and large volumes (primitive neuroectodermal tumours). The dose coverage of target volumes and the sparing of critical organs were increased with IMRT when compared to 3D-CRT. The developed split field IMRT technique was found to be safe and accurate method in craniospinal irradiations. By using IMRT in simultaneous integrated boosting of biologically defined target volumes of localized prostate cancer high doses were achievable with only small increase in the treatment complexity. Biological plan optimization increased the probability of uncomplicated control on average by 28% when compared to standard IMRT delivery. Unfortunately IMRT carries also some drawbacks. In IMRT the beam modulation is realized by splitting a large radiation field to small apertures. The smaller the beam apertures are the larger the rebuild-up and rebuild-down effects are at the tissue interfaces. The limitations to use IMRT with small apertures in the treatments of small lung tumours were investigated with dosimetric film measurements. The results confirmed that the peripheral doses of the small lung tumours were decreased as the effective field size was decreased. The studied calculation algorithms were not able to model the dose deficiency of the tumours accurately. The use of small sliding window apertures of 2 mm and 4 mm decreased the tumour peripheral dose by 6% when compared to 3D-CRT treatment plan. A direct aperture based optimization (DABO) technique was examined as a solution to decrease the treatment complexity. The DABO IMRT technique was able to achieve treatment plans equivalent with the conventional IMRT fluence based optimization techniques in the concave head-and-neck target volumes. With DABO the effective field sizes were increased and the number of MUs was reduced with a factor of two. The optimality of a treatment plan and the therapeutic ratio can be further enhanced by using dose painting based on regional radiosensitivities imaged with functional imaging methods.