Register studies of cancer in the Southern Health Care Region in Sweden

The overall aim was to study different aspect of health care use and health care costs on a population based level for persons with cancer and their partners, and from an individual level to explore the impact of comorbidities in incidence and survival. In the beginning of the study all persons in the Southern Health Care Region in Sweden diagnosed with colon, rectal, breast, prostate and lung cancer during the period 2000 to 2005 were identified via the Swedish Cancer Register. Lately, including the period 2006 to 2007, all persons diagnosed with cancer were analysed with specification of 18 types of cancer. The obtained information was linked to other population based registries. Comorbidity diagnoses for patients and all data for up to 8 eight control persons were also extracted from health care registries in Skåne. Results showed that the major part of health care costs for prostate and lung cancer patients occurred during the first year following the diagnosis. A clear difference was seen between costs for survivors and patients who later died. For patients with prostate cancer health care costs increased with higher Gleason score (rate of aggressiveness) in the year following the diagnosis. Higher health care costs were seen for patients treated with primary radiotherapy and costs were higher for patients with curative treatments compared to those with palliative treatments. For patients with lung cancer the costs totally were declining with higher stage. Highest health care costs were seen for patients treated with endoscopic therapy of the bronchus. Health care costs were higher for operated patients compared to those with treatments only by chemotherapy or radiotherapy. Higher survival in patients with non-small cell lung cancer (NSCLC) was explained by surgery, short waiting time, treatments by chemotherapy or radiotherapy and patients living in a specific geographic area. Lower survival was connected to no treatment, tumour stage, performance status and alcoholic related diseases. Overall a diagnosis of dementia was significantly less common among the cancer cases. Because the effect was seen for all tumour types and especially for patients older than 70 years and since the deficit was more pronounced for patients with tumours situated within the body, the data suggest that malignancies are underdiagnosed for persons with dementia. Diabetes was significantly more common prior to diagnosis in patients with liver, pancreatic, colon and urinary tract/bladder cancer and in patients with breast cancer diagnosed with diabetes 0–4 years prior to the cancer diagnosis. A lower risk of diabetes was seen in patients with prostate carcinoma among individuals with diabetes diagnosed 5–10 years prior to the cancer diagnosis. Obesity was significantly more common in patients with endometrial, colon and kidney cancer and with breast cancer above the age of 60 years in those where obesity was diagnosed close to the diagnosis of cancer. High blood lipids were significantly more common in patients with ovarian cancer and less common in patients with breast cancer. From a public health view avoiding overweight and obesity, as well as preventing type II diabetes mellitus, are important in preventing cancer and other diseases. Measures should be taken early on and should be based on healthy eating and physical activity patterns throughout life. Health care consumption and health care costs for partners increased in the years following the cancer diagnosis of the person with cancer especially for partners to colon, prostate and lung cancer patients. The number of diagnoses increased significantly among partners in the whole sample with the largest increase in psychiatric diagnoses. In the future, new treatments, especially new pharmacy, are to change the relationship between treatments, costs and survival. It is of importance further examine in what way results are affected by how the patient contacts the health care system, the patient´s lifestyle and socioeconomic background or the health care system itself (organisation, competence etc). Furthermore, the new knowledge concerning cancer and comorbidities may provide an insight into the mechanisms of tumour development. Postponing the onset of comorbidity may also prevent/postpone the diagnosis of cancer. Further research is needed to learn more about the situation of the partner and to identify persons at risk of psychiatric morbidity. Knowledge is also needed on how to support the partner in the most efficient way. When planning for care and allocation of resources for care the impact on the partner should also be considered

Clinical implications of HPV in oropharyngeal cancer

Tonsillar cancer incidence has been increasing in Sweden and many other western countries in the last decades despite that other head and neck cancers are decreasing. It is now established that Human Papillomavirus (HPV) can be accredited part of that increase. The aims of this thesis were to investigate any change in incidence of base of tongue cancer, any further increase of tonsillar cancer incidence, what role HPV may have, the prognostic value of HPV as well as the outcome of different treatment regimes on tonsillar cancer. Using the Swedish Cancer Registry, we found that the incidence for both tonsillar and base of tongue cancer has increased from 1970 to 2006-2007, for tonsillar cancer from 0.74/100000 person-years 1970-1979 to 1.65/100000 person-years 2000-2006 in Stockholm County and for base of tongue cancer from 0.15/100000 person-years 1970- 1974 to 0.47/100000 person-years 2005-2007 in Sweden. We analyzed pre-treatment, paraffin-embedded diagnostic tumor biopsies for HPV using PCR technique and found that the proportion of HPV in both tonsillar and base of tongue cancer has increased during the last decade, reaching 93% positivity in tonsillar cancer and 83% positivity in base of tongue cancer in 2006-2007. To evaluate if HPV was transcriptionally active in these biopsies, we also tested for HPV E6 and E7 mRNA, which was positive in the vast majority of cases. For base of tongue cancer, HPV was found to be a significant prognostic factor, with improved overall as well as disease free survival compared to patients with HPV-negative tumors, irrespective of patient age, sex and tumor stage. It has been suggested that patients with HPV positive tumors possibly could be cured by less intense treatment and thus reducing side effects. When analyzing all HPV positive tonsillar cancer patients in Stockholm County, Sweden between 2000 and 2007, we compared survival and development of distant metastasis between groups that had received three different treatment regimes. No significant difference in overall or disease free survival was found between the treatment groups, but a trend of improved survival for intensified treatment was seen that needs to be studied further. The vast majority of HPV positive tonsillar- and base of tongue cancers are HPV16, which means that the commercially available vaccines would protect against it. This highlights the discussion if boys/men should be included in the HPV vaccination program

Cell cycle regulation during gametogenesis in budding yeast

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, June 2013."June 2013." Cataloged from PDF version of thesis.Includes bibliographical references.Sexual reproduction depends on meiosis, the specialized cell division that gives rise to gametes. During meiosis, two consecutive rounds of chromosome segregation follow one round of DNA replication to yield four haploid gametes from one diploid progenitor. In meiosis I, homologous chromosomes segregate and in meiosis 11, sister chromatids split. Much of the same cell cycle machinery controls mitosis and meiosis. However, segregation of homologous chromosomes in meiosis I and progression into meiosis 11 directly after meiosis I necessitate several modifications to the basic cell cycle machinery. In this thesis, I have investigated how cell cycle regulators function during gametogenesis. First, I show that the mitotic exit network, which is a signaling pathway essential for mitotic exit, is dispensable for the meiotic divisions, and in fact signals via a mechanism distinct from mitosis. Second, I present data that the Polo kinase Cdc5, which activates mitotic exit in budding yeast, has gained additional roles during meiosis 1. I show that CDC5 is required for the removal of cohesin from chromosome arms in meiosis I, which is a prerequisite for meiosis I segregation. Despite the central role of CDC5 in regulating meiosis I, CDC5 is dispensable during meiosis 11. In sum, understanding how cell cycle regulators control the specialized meiotic divisions has improved our understanding of how different cell division types are established.by Michelle Andrea Attner.Ph.D

Human Papillomavirus (HPV) 16 E6 Variants in Tonsillar Cancer in Comparison to Those in Cervical Cancer in Stockholm, Sweden

Background: Human papillomavirus (HPV), especially HPV16, is associated with the development of both cervical and tonsillar cancer and intratype variants in the amino acid sequence of the HPV16 E6 oncoprotein have been demonstrated to be associated with viral persistence and cancer lesions. For this reason the presence of HPV16 E6 variants in tonsillar squamous cell carcinoma (TSCC) in cervical cancer (CC), as well as in cervical samples (CS), were explored. Methods: HPV16 E6 was sequenced in 108 TSCC and 52 CC samples from patients diagnosed 2000–2008 in the County of Stockholm, and in 51 CS from young women attending a youth health center in Stockholm. Results: The rare E6 variant R10G was relatively frequent (19%) in TSCC, absent in CC and infrequent (4%) in CS, while the well-known L83V variant was common in TSCC (40%), CC (31%), and CS (29%). The difference for R10G was significant between TSCC and CC (p = 0.0003), as well as between TSCC and CS (p = 0.009). The HPV16 European phylogenetic lineage and its derivatives dominated in all samples (.90%). Conclusion: The relatively high frequency of the R10G variant in TSCC, as compared to what has been found in CC both in the present study as well as in several other studies in different countries, may indicate a difference between TSCC and CC with regard to tumor induction and development. Alternatively, there could be differences with regard to the oral an

Oropharyngeal Cancer Epidemic and Human Papillomavirus

Patients with HPV-positive cancer were young and lacked traditional risk factors

Interventions for the treatment of oral cavity and oropharyngeal cancer:chemotherapy

<b>Background:</b> Oral cavity and oropharyngeal cancers are frequently described as part of a group of oral cancers or head and neck cancer. Treatment of oral cavity cancer is generally surgery followed by radiotherapy, whereas oropharyngeal cancers, which are more likely to be advanced at the time of diagnosis, are managed with radiotherapy or chemoradiation. Surgery for oral cancers can be disfiguring and both surgery and radiotherapy have significant functional side effects, notably impaired ability to eat, drink and talk. The development of new chemotherapy agents, new combinations of agents and changes in the relative timing of surgery, radiotherapy, and chemotherapy treatments may potentially bring about increases in both survival and quality of life for this group of patients.<p></p> <b>Objectives:</b> To determine whether chemotherapy, in addition to radiotherapy and/or surgery for oral cavity and oropharyngeal cancer results in improved survival, disease free survival, progression free survival, locoregional control and reduced recurrence of disease. To determine which regimen and time of administration (induction, concomitant or adjuvant) is associated with better outcomes.<p></p> <b>Search strategy:</b> Electronic searches of the Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE, EMBASE, AMED were undertaken on 28th July 2010. Reference lists of recent reviews and included studies were also searched to identify further trials.<p></p> <b>Selection criteria:</b> Randomised controlled trials where more than 50% of participants had primary tumours in the oral cavity or oropharynx, and which compared the addition of chemotherapy to other treatments such as radiotherapy and/or surgery, or compared two or more chemotherapy regimens or modes of administration, were included.<p></p> <b>Data collection and analysis:</b> Trials which met the inclusion criteria were assessed for risk of bias using six domains: sequence generation, allocation concealment, blinding, completeness of outcome data, selective reporting and other possible sources of bias. Data were extracted using a specially designed form and entered into the characteristics of included studies table and the analysis sections of the review. The proportion of participants in each trial with oral cavity and oropharyngeal cancers are recorded in Additional Table 1.<p></p> <b>Main results:</b> There was no statistically significant improvement in overall survival associated with induction chemotherapy compared to locoregional treatment alone in 25 trials (hazard ratio (HR) of mortality 0.92, 95% confidence interval (CI) 0.84 to 1.00). Post-surgery adjuvant chemotherapy was associated with improved overall survival compared to surgery +/- radiotherapy alone in 10 trials (HR of mortality 0.88, 95% CI 0.79 to 0.99), and there was an additional benefit of adjuvant concomitant chemoradiotherapy compared to radiotherapy in 4 of these trials (HR of mortality 0.84, 95% CI 0.72 to 0.98). Concomitant chemoradiotherapy resulted in improved survival compared to radiotherapy alone in patients whose tumours were considered unresectable in 25 trials (HR of mortality 0.79, 95% CI 0.74 to 0.84). However, the additional toxicity attributable to chemotherapy in the combined regimens remains unquantified.<p></p> <b>Authors' conclusions:</b> Chemotherapy, in addition to radiotherapy and surgery, is associated with improved overall survival in patients with oral cavity and oropharyngeal cancers. Induction chemotherapy is associated with a 9% increase in survival and adjuvant concomitant chemoradiotherapy is associated with a 16% increase in overall survival following surgery. In patients with unresectable tumours, concomitant chemoradiotherapy showed a 22% benefit in overall survival compared with radiotherapy alone.<p></p&gt

Multiple kinases inhibit origin licensing and helicase activation to ensure reductive cell division during meiosis

Meiotic cells undergo a single round of DNA replication followed by two rounds of chromosome segregation (the meiotic divisions) to produce haploid gametes. Both DNA replication and chromosome segregation are similarly regulated by CDK oscillations in mitotic cells. Yet how these two events are uncoupled between the meiotic divisions is unclear. Using Saccharomyces cerevisiae, we show that meiotic cells inhibit both helicase loading and helicase activation to prevent DNA replication between the meiotic divisions. CDK and the meiosis-specific kinase Ime2 cooperatively inhibit helicase loading, and their simultaneous inhibition allows inappropriate helicase reloading. Further analysis uncovered two previously unknown mechanisms by which Ime2 inhibits helicase loading. Finally, we show that CDK and the polo-like kinase Cdc5 trigger degradation of Sld2, an essential helicase-activation protein. Together, our data demonstrate that multiple kinases inhibit both helicase loading and activation between the meiotic divisions, thereby ensuring reductive cell division.National Institutes of Health (U.S.) (Grant GM007287

Chromosomal aberrations and aneuploidy in oral potentially malignant lesions: distinctive features for tongue

<p>Abstract</p> <p>Background</p> <p>The mucosae of the oral cavity are different at the histological level but appear all equally exposed to common genotoxic agents. As a result of this exposure, changes in the mucosal epithelia may develop giving rise to Oral Potentially Malignant Lesions (OPMLs), which with time may in turn progress to Oral Squamous Cell Carcinomas (OSCCs). Therefore, much effort should be devoted to identify features able to predict the likeliness of progression associated with an OPML. Such features may be helpful in assisting the clinician to establish both appropriate therapies and follow-up schedules. Here, we report a pilot study that compared the occurrence of DNA aneuploidy and chromosomal copy number aberrations (CNAs) in the OPMLs from different oral anatomical subsites.</p> <p>Methods</p> <p>Samples from histologically diagnosed OPMLs were processed for high resolution DNA flow cytometry (hr DNA-FCM) in order to determine the relative DNA content expressed by the DNA index (DI). Additionally, array-Comparative Genomic Hybridization (a-CGH) analysis was performed on DNA obtained from diploid nuclei suspensions directly. When aneuploid nuclei were detected, these were physically separated from diploid nuclei on the base of their DI values by means of a DNA-FCM-Sorter in order to improve the a-CGH analysis.</p> <p>Results</p> <p>Tongue OPMLs were more frequently associated with DNA aneuploidy and CNAs than OPMLs arising from all the other mucosal subsites.</p> <p>Conclusions</p> <p>We suggest that the follow-up and the management of the patients with tongue OPMLs should receive a distinctive special attention. Clearly, this hypothesis should be validated in a prospective clinical study.</p