Taxane-containing induction chemotherapy followed by definitive chemoradiotherapy. Outcome in patients with locally advanced head and neck cancer

BACKGROUND Induction chemotherapy followed by definitive chemoradiotherapy is an intensified treatment approach for locally advanced squamous cell carcinoma of the head and neck (HNSCC) that might be associated with high rates of toxicity. MATERIALS AND METHODS The data of 40 consecutive patients who underwent induction chemotherapy with docetaxel-containing regimens followed by intensity-modulated radiotherapy (IMRT) and concomitant systemic therapy for unresectable locally advanced HNSCC were retrospectively analyzed. Primary objectives were RT-related acute and late toxicity. Secondary objectives were response to induction chemotherapy, locoregional recurrence-free survival (LRRFS), overall survival (OS), and influencing factors for LRRFS and OS. RESULTS The median follow-up for surviving patients was 21 months (range, 2-53 months). Patients received a median of three cycles of induction chemotherapy followed by IMRT to 72 Gy. Three patients died during induction chemotherapy and one during chemoradiotherapy. Acute RT-related toxicity was of grade 3 and 4 in 72 and 3 % of patients, respectively, mainly dysphagia and dermatitis. Late RT-related toxicity was mainly xerostomia and bone/cartilage necrosis and was of grade 3 and 4 in 15 % of patients. One- and 2-year LRRFS and OS were 72 and 49 % and 77 and 71 %, respectively. CONCLUSION Induction chemotherapy followed by chemoradiotherapy using IMRT was associated with a high rate of severe acute and late RT-related toxicities in this selected patient cohort. Four patients were lost because of fatal complications. Induction chemotherapy did not compromise the delivery of full-dose RT; however, the use of three cycles of concomitant cisplatin was impaired.

Mental health-care utilization in survivors of childhood cancer and siblings: the Swiss childhood cancer survivor study

PURPOSE We aimed to (1) describe the utilization of mental health-care in survivors and siblings, the association with severity of distress, and visits to other professionals in distressed survivors not utilizing mental health-care; and (2) identify factors associated with utilization of mental health-care in distressed survivors. METHODS Within the Swiss Childhood Cancer Survivor Study, we sent postal questionnaires to all participants aged <16 years at diagnosis (1976-2003), who survived ≥5 years after diagnosis and were aged ≥16 years at study. Survivors and siblings could indicate if they utilized mental health-care in the past year. Psychological distress was assessed with the Brief Symptom Inventory-18 (BSI-18). Participants with scores T ≥ 57 on two of three scales or the Global Severity Index were considered distressed. RESULTS We included 1,602 survivors and 703 siblings. Overall, 160 (10 %) and 53 (8 %), utilized mental health-care and 203 (14 %) and 127 (14 %) were considered distressed. Among these, 69 (34 %) survivors and 20 (24 %) siblings had utilized mental health-care. Participants with higher distress were more likely to utilize mental health-care. Distressed survivors not utilizing mental health-care were more likely to see a medical specialist than nondistressed. In the multivariable regression, factors associated with utilizing mental health-care were higher psychological distress and reporting late effects. CONCLUSIONS Our results underline the importance of developing interventional programs and implementing psychological screening in follow-up of survivors. It is also important to systematically address siblings' needs. In follow-up, patients at risk should be informed about existing possibilities or advised to visit mental health professionals.

Information provision and information needs in adult survivors of childhood cancer

BACKGROUND Knowledge about their past medical history is central for childhood cancer survivors to ensure informed decisions in their health management. Knowledge about information provision and information needs in this population is still scarce. We thus aimed to assess: (1) the information survivors reported to have received on disease, treatment, follow-up, and late effects; (2) their information needs in these four domains and the format in which they would like it provided; (3) the association with psychological distress and quality of life (QoL). PROCEDURE As part of the Follow-up survey of the Swiss Childhood Cancer Survivor Study, we sent a questionnaire to all survivors (≥18 years) who previously participated to the baseline survey, were diagnosed with cancer after 1990 at an age of <16 years. RESULTS Most survivors had received oral information only (on illness: oral: 82%, written: 38%, treatment: oral: 79%, written: 36%; follow-up: oral: 77%, written: 23%; late effects: oral: 68%, written: 14%). Most survivors who had not previously received any information rated it as important, especially information on late effects (71%). A large proportion of survivors reported current information needs and would like to receive personalized information especially on late effects (44%). Survivors with higher information needs reported higher psychological distress and lower QoL. CONCLUSIONS Survivors want to be more informed especially on possible late effects, and want to receive personalized information. Improving information provision, both qualitatively and quantitatively, will allow survivors to have better control of their health and to become better decision makers. Pediatr Blood Cancer 2014;61:312-318. © 2013 Wiley Periodicals, Inc.

General practitioner involvement in follow-up of childhood cancer survivors: a systematic review

BACKGROUND An increasing number of childhood cancer survivors need long-term follow-up care. Different models address this problem, including that of follow-up by general practitioners (GP). We describe models that involve GPs in follow-up for childhood cancer survivors, their advantages and disadvantages, clinics that employ these models, and the elements essential to high-quality, GP-led follow-up care. PROCEDURE We searched four databases (PubMed [including Medline], Embase, Cochrane, and CINAHL) without language restrictions. RESULTS We found 26 publications, which explicitly mentioned GP-led follow-up. Two models were commonly described: GP-only, and shared care between GP and pediatric oncology or late effects clinic. The shared care model appears to have advantages over GP-only follow-up. We found four clinics using models of GP-led follow-up, described in five papers. We identified well-organized transition, treatment summary, survivorship care plan, education of GPs and guidelines as necessary components of successful follow-up. CONCLUSION Scarcity of literature necessitated a review rather than a meta-analysis. More research on the outcomes of GP-led care is necessary to confirm the model for follow-up of childhood cancer survivors in the long term. However, with the necessary elements in place, the model of GP-led follow-up, and shared care in particular, holds promise.

Epoetin and Darbepoetin for Managing Anemia in Patients Undergoing Cancer Treatment: Comparative Effectiveness Update

Objectives: To update the 2006 systematic review of the comparative benefits and harms of erythropoiesis-stimulating agent (ESA) strategies and non-ESA strategies to manage anemia in patients undergoing chemotherapy and/or radiation for malignancy (excluding myelodysplastic syndrome and acute leukemia), including the impact of alternative thresholds for initiating treatment and optimal duration of therapy. Data sources: Literature searches were updated in electronic databases (n=3), conference proceedings (n=3), and Food and Drug Administration transcripts. Multiple sources (n=13) were searched for potential gray literature. A primary source for current survival evidence was a recently published individual patient data meta-analysis. In that meta-analysis, patient data were obtained from investigators for studies enrolling more than 50 patients per arm. Because those data constitute the most currently available data for this update, as well as the source for on-study (active treatment) mortality data, we limited inclusion in the current report to studies enrolling more than 50 patients per arm to avoid potential differential endpoint ascertainment in smaller studies. Review methods: Title and abstract screening was performed by one or two (to resolve uncertainty) reviewers; potentially included publications were reviewed in full text. Two or three (to resolve disagreements) reviewers assessed trial quality. Results were independently verified and pooled for outcomes of interest. The balance of benefits and harms was examined in a decision model. Results: We evaluated evidence from 5 trials directly comparing darbepoetin with epoetin, 41 trials comparing epoetin with control, and 8 trials comparing darbepoetin with control; 5 trials evaluated early versus late (delay until Hb ≤9 to 11 g/dL) treatment. Trials varied according to duration, tumor types, cancer therapy, trial quality, iron supplementation, baseline hemoglobin, ESA dosing frequency (and therefore amount per dose), and dose escalation. ESAs decreased the risk of transfusion (pooled relative risk [RR], 0.58; 95% confidence interval [CI], 0.53 to 0.64; I2 = 51%; 38 trials) without evidence of meaningful difference between epoetin and darbepoetin. Thromboembolic event rates were higher in ESA-treated patients (pooled RR, 1.51; 95% CI, 1.30 to 1.74; I2 = 0%; 37 trials) without difference between epoetin and darbepoetin. In 14 trials reporting the Functional Assessment of Cancer Therapy (FACT)-Fatigue subscale, the most common patient-reported outcome, scores decreased by −0.6 in control arms (95% CI, −6.4 to 5.2; I2 = 0%) and increased by 2.1 in ESA arms (95% CI, −3.9 to 8.1; I2 = 0%). There were fewer thromboembolic and on-study mortality adverse events when ESA treatment was delayed until baseline Hb was less than 10 g/dL, in keeping with current treatment practice, but the difference in effect from early treatment was not significant, and the evidence was limited and insufficient for conclusions. No evidence informed optimal duration of therapy. Mortality was increased during the on-study period (pooled hazard ratio [HR], 1.17; 95% CI, 1.04 to 1.31; I2 = 0%; 37 trials). There was one additional death for every 59 treated patients when the control arm on-study mortality was 10 percent and one additional death for every 588 treated patients when the control-arm on-study mortality was 1 percent. A cohort decision model yielded a consistent result—greater loss of life-years when control arm on-study mortality was higher. There was no discernible increase in mortality with ESA use over the longest available followup (pooled HR, 1.04; 95% CI, 0.99 to 1.10; I2 = 38%; 44 trials), but many trials did not include an overall survival endpoint and potential time-dependent confounding was not considered. Conclusions: Results of this update were consistent with the 2006 review. ESAs reduced the need for transfusions and increased the risk of thromboembolism. FACT-Fatigue scores were better with ESA use but the magnitude was less than the minimal clinically important difference. An increase in mortality accompanied the use of ESAs. An important unanswered question is whether dosing practices and overall ESA exposure might influence harms.

Accelerated partial breast irradiation with interstitial brachytherapy as second conservative treatment for ipsilateral breast tumour recurrence: multicentric study of the GEC-ESTRO Breast Cancer Working Group

PURPOSE To analyse the clinical outcome after salvage lumpectomy and multi-catheter brachytherapy (MCB) for ipsilateral breast tumour recurrence (IBTR). MATERIAL AND METHODS Between 09/00 and 09/10, 217 patients presenting an IBTR underwent lumpectomy and MCB (low, pulsed, or high-dose rate). Survival rates without second local recurrence (2nd LR), distant metastasis (DM), and overall survival (OS) were analysed as well as late effects and cosmetic results. Univariate and multivariate analyses (MVA) based on IBTR data were performed to find prognostic factors for 2nd LR, DM, and OS. RESULTS Median follow-up after the IBTR was 3.9 years [range: 1.1-10.3]. Five and 10-year actuarial 2nd LR rates were 5.6% [range: 1.5-9.5] and 7.2% [range: 2.1-12.1], respectively. Five and 10-year actuarial DM rates were 9.6% [range: 5.7-15.2] and 19.1% [range: 7.8-28.3], respectively. Five and 10-year actuarial OS rates were 88.7% [range: 83.1-94.8] and 76.4% [range: 66.9-87.3], respectively. In MVA, histological grade was prognostic factor for 2nd LR (p=0.008) and OS (p=0.02); while tumour size was prognostic factor for DM (p=0.03). G3-4 complication rate was 11%. Excellent/good cosmetic result was achieved in 85%. CONCLUSION This study suggests that in case of IBTR, lumpectomy plus MCB is feasible and effective in preventing 2nd LR with an OS rate at least equivalent to those achieved with salvage mastectomy.

Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: design of the TEXT and SOFT trials

OBJECTIVES In 2003 the International Breast Cancer Study Group (IBCSG) initiated the TEXT and SOFT randomized phase III trials to answer two questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer: 1-What is the role of aromatase inhibitors (AI) for women treated with ovarian function suppression (OFS)? 2-What is the role of OFS for women who remain premenopausal and are treated with tamoxifen? METHODS TEXT randomized patients to receive exemestane or tamoxifen with OFS. SOFT randomized patients to receive exemestane with OFS, tamoxifen with OFS, or tamoxifen alone. Treatment was for 5 years from randomization. RESULTS TEXT and SOFT successfully met their enrollment goals in 2011. The 5738 enrolled women had lower-risk disease and lower observed disease-free survival (DFS) event rates than anticipated. Consequently, 7 and 13 additional years of follow-up for TEXT and SOFT, respectively, were required to reach the targeted DFS events (median follow-up about 10.5 and 15 years). To provide timely answers, protocol amendments in 2011 specified analyses based on chronological time and median follow-up. To assess the AI question, exemestane + OFS versus tamoxifen + OFS, a combined analysis of TEXT and SOFT became the primary analysis (n = 4717). The OFS question became the primary analysis from SOFT, assessing the unique comparison of tamoxifen + OFS versus tamoxifen alone (n = 2045). The first reports are anticipated in mid- and late-2014. CONCLUSIONS We present the original designs of TEXT and SOFT and adaptations to ensure timely answers to two questions concerning optimal adjuvant endocrine treatment for premenopausal women with endocrine-responsive breast cancer. Trial Registration TEXT: Clinicaltrials.govNCT00066703 SOFT: Clinicaltrials.govNCT00066690.

Late Quaternary palaeoenvironmental reconstruction from Lakes Ohrid and Prespa (Macedonia/Albania border) using stable isotopes

Abstract. Here we present stable isotope data from three sediment records from lakes that lie along the Macedonian- Albanian border (Lake Prespa: 1 core, and Lake Ohrid: 2 cores). The records only overlap for the last 40 kyr, although the longest record contains the MIS 5/6 transition (Lake Ohrid). The sedimentary characteristics of both lakes differ significantly between the glacial and interglacial phases. At the end of MIS 6 Lake Ohrid’s water level was low (high �18Ocalcite) and, although productivity was increasing (high calcite content), the carbon supply was mainly from inorganic catchment rock sources (high �13Ccarb). During the last interglacial, calcite and TOC production and preservation increased, progressively lower �18Ocalcite suggest increase in humidity and lake levels until around 115 ka. During ca. 80 ka to 11 ka the lake records suggest cold conditions as indicated by negligible calcite precipitation and low organic matter content. In Lake Ohrid, �13Corg are complacent; in contrast, Lake Prespa shows consistently higher �13Corg suggesting a low oxidation of 13C-depleted organic matter in agreement with a general deterioration of climate conditions during the glacial. From 15 ka to the onset of the Holocene, calcite and TOC begin to increase, suggesting lake levels were probably low (high �18Ocalcite). In the Holocene (11 ka to present) enhanced productivity is manifested by high calcite and organic matter content. All three cores show an early Holocene characterised by low �18Ocalcite, apart from the very early Holocene phase in Prespa where the lowest �18Ocalcite occurs at ca. 7.5 ka, suggesting a phase of higher lake level only in (the more sensitive) Lake Prespa. From 6 ka, �18Ocalcite suggest progressive aridification, in agreement with many other records in the Mediterranean, although the uppermost sediments in one core records low �18Ocalcite which we interpret as a result of human activity. Overall, the isotope data present here confirm that these two big lakes have captured the large scale, low frequency palaeoclimate variation that is seen in Mediterranean lakes, although in detail there is much palaeoclimate information that could be gained, especially small scale, high frequency differences between this region and the Mediterranean.

Comparing growth trajectories of risk behaviors from late adolescence through young adulthood: An accelerated design

Risk behaviors such as substance use or deviance are often limited to the early stages of the life course. Whereas the onset of risk behavior is well studied, less is currently known about the decline and timing of cessation of risk behaviors of different domains during young adulthood. Prevalence and longitudinal developmental patterning of alcohol use, drinking to the point of drunkenness, smoking, cannabis use, deviance, and HIV-related sexual risk behavior were compared in a Swiss community sample (N = 2,843). Using a longitudinal cohort-sequential approach to link multiple assessments with 3 waves of data for each individual, the studied period spanned the ages of 16 to 29 years. Although smoking had a higher prevalence, both smoking and drinking up to the point of drunkenness followed an inverted U-shaped curve. Alcohol consumption was also best described by a quadratic model, though largely stable at a high level through the late 20s. Sexual risk behavior increased slowly from age 16 to age 22 and then remained largely stable. In contrast, cannabis use and deviance linearly declined from age 16 to age 29. Young men were at higher risk for all behaviors than were young women, but apart from deviance, patterning over time was similar for both sexes. Results about the timing of increase and decline as well as differences between risk behaviors may inform tailored prevention programs during the transition from late adolescence to adulthood.

Late Weichselian local ice dome configuration and chronology in Northwestern Svalbard: early thinning, late retreat

The chronology and configuration of the Svalbard Barents Sea Ice Sheet (SBSIS) during the Late Weichselian (LW) are based on few and geographically scattered data. Thus, the timing and configuration of the SBSIS has been a subject of extensive debate. We present provenance data of erratic boulders and cosmogenic 10Be ages of bedrock and boulders from Northwest Spitsbergen (NWS), Svalbard to determine the thickness, configuration and chronology during the LW. We sampled bedrock and boulders of mountain summits and summit slopes, along with erratic boulders from coastal locations around NWS. We suggest that a local ice dome over central NWS during LW drained radially in all directions. Provenance data from erratic boulders from northern coastal lowland Reinsdyrflya suggest northeastward ice flow through Liefdefjorden. 10Be ages of high-elevation erratic boulders in central NWS (687–836 m above sea level) ranging from 18.3 ± 1.3 ka to 21.7 ± 1.4 ka, indicate that the centre of a local ice dome was at least 300 m thicker than at present. 10Be ages of all high-elevation erratics (>400 m above sea level, central and coastal locations) indicate the onset of ice dome thinning at 25–20 ka. 10Be ages from erratic boulders on Reinsdyrflya ranging from 11.1 ± 0.8 ka to 21.4 ± 1.7 ka, indicate an ice cover over the entire Reinsdyrflya during LW and a complete deglaciation prior to the Holocene, but apparently later than the thinning in the mountains. Lack of moraine deposits, but the preservation of beach terraces, suggest that the ice covering this peninsula possibly was cold-based and that Reinsdyrflya was part of an inter ice-stream area covered by slow-flowing ice, as opposed to the adjacent fjord, which possibly was filled by a fast-flowing ice stream. Despite the early thinning of the ice sheet (25–20 ka) we find a later timing of deglaciation of the fjords and the distal lowlands. Several bedrock samples (10Be) from vertical transects in the central mountains of NWS pre-date the LW, and suggest either ice free or pervasive cold-based ice conditions. Our reconstruction is aligned with the previously suggested hypothesis that a complex multi-dome ice-sheet-configuration occupied Svalbard and the Barents Sea during LW, with numerous drainage basins feeding fast ice streams, separated by slow flowing, possibly cold-based, inter ice-stream areas.

Regulation of survivin gene expression in the human endometrium and endometrial cancer

In the United States, endometrial cancer is the leading cancer of the female reproductive tract. There are 40,100 new cases and 7,470 deaths from endometrial cancer estimated for 2008 (47). The average five year survival rate for endometrial cancer is 84% however, this figure is substantially lower in patients diagnosed with late stage, advanced disease and much higher for patients diagnosed in early stage disease (47). Endometrial cancer (EC) has been associated with several risk factors including obesity, diabetes, hypertension, previously documented occurrence of hereditary non-polyposis colorectal cancer (HNPCC), and heightened exposure to estrogen (25). As of yet, there has not been a dependable molecular predictor of endometrial cancer occurrence in women with these predisposing factors. The goal of our lab is to identify genes that are aberrantly expressed in EC and may serve as molecular biomarkers of EC progression. One candidate protein that we are exploring as a biomarker of EC progression is the cell survival protein survivin.

Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome.

Individuals with Lynch syndrome are predisposed to cancer due to an inherited DNA mismatch repair gene mutation. However, there is significant variability observed in disease expression likely due to the influence of other environmental, lifestyle, or genetic factors. Polymorphisms in genes encoding xenobiotic-metabolizing enzymes may modify cancer risk by influencing the metabolism and clearance of potential carcinogens from the body. In this retrospective analysis, we examined key candidate gene polymorphisms in CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 as modifiers of age at onset of colorectal cancer among 257 individuals with Lynch syndrome. We found that subjects heterozygous for CYP1A1 I462V (c.1384A>G) developed colorectal cancer 4 years earlier than those with the homozygous wild-type genotype (median ages, 39 and 43 years, respectively; log-rank test P = 0.018). Furthermore, being heterozygous for the CYP1A1 polymorphisms, I462V and Msp1 (g.6235T>C), was associated with an increased risk for developing colorectal cancer [adjusted hazard ratio for AG relative to AA, 1.78; 95% confidence interval, 1.16-2.74; P = 0.008; hazard ratio for TC relative to TT, 1.53; 95% confidence interval, 1.06-2.22; P = 0.02]. Because homozygous variants for both CYP1A1 polymorphisms were rare, risk estimates were imprecise. None of the other gene polymorphisms examined were associated with an earlier onset age for colorectal cancer. Our results suggest that the I462V and Msp1 polymorphisms in CYP1A1 may be an additional susceptibility factor for disease expression in Lynch syndrome because they modify the age of colorectal cancer onset by up to 4 years.

Role of germ line p53 mutations in aneuploidy and immortalization of dermal fibroblasts from Li-Fraumeni cancer patients

Pedigree analysis of certain families with a high incidence of tumors suggests a genetic predisposition to cancer. Li and Fraumeni described a familial cancer syndrome that is characterized by multiple primary tumors, early age of onset, and marked variation in tumor type. Williams and Strong (1) demonstrated that at least 7% of childhood soft tissue sarcoma patients had family histories that is readily explained by a highly penetrant autosomal dominant gene. To characterize the mechanism for genetic predisposition to many tumor types in these families, we have studied genetic alterations in fibroblasts, a target tissue from patients with the Li-Fraumeni Syndrome (LFS).^ We have observed spontaneous changes in initially normal dermal fibroblasts from LFS patients as they are cultured in vitro. The cells acquire an altered morphology, chromosomal anomalies, and anchorage-independent growth. This aberrant behavior of fibroblasts from LFS patients had never been observed in fibroblasts from normal donors. In addition to these phenotypic alterations, patient fibroblasts spontaneously immortalize by 50 population doublings (pd) in culture; unlike controls that remain normal and senesce by 30-35 (2). At 50 pd, immortal fibroblasts from two patients were found to be susceptible to tumorigenic transformation by an activated T24 H-ras oncogene (3). Approximately 80% of the oncogene expressing transfectants were capable of forming tumors in nude mice within 2-3 weeks. p53 has been previously associated with immortalization of cells in culture and cooperation with ras in transfection assays. Therefore, patients' fibroblast and lymphocyte derived DNA was tested for point mutations in p53. It was shown that LFS patients inherited certain point mutations in one of the two p53 alleles (4). Further studies on the above LFS immortal fibroblasts have demonstrated loss of the remaining p53 allele concomitant with escape from senescence. While the loss of the second allele correlates with immortalization it is not sufficient to transformation by an activated H-ras or N-ras oncogene. These immortal fibroblasts are resistant to tumorigenic transformation by v-abl, v-src, c-neu or v-mos oncogene; implying that additional steps are required in the tumorigenic progression of LFS patients' fibroblasts.^ References. (1) Williams et al., J. Natl. Cancer Inst. 79:1213, 1987. (2) Bischoff et al., Cancer Res. 50:7979, 1990. (3) Bischoff et al., Oncogene 6:183, 1991. (4) Malkin et al., Science 250:1233, 1990. ^

Delineation of a novel genetic region at 5q11 harboring tumor suppressor gene(s) and identification of the telomeric DNA as a marker for human prostate cancer

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer mortality in American men. The distinction between those cases of prostate cancer destined to progress rapidly to lethal metastatic disease and those with little likelihood of causing morbidity and mortality is a major goal of current research. Some type of diagnostic method is urgently needed to identify which histological prostate cancers have completed the progression to a stage that will produce a life-threatening disease, thus requiring immediate therapeutic intervention. The objectives of this dissertation are to delineate a novel genetic region harboring tumor suppressor gene(s) and to identify a marker for prostate tumorigenesis. I first established an in vitro cell model system from a human prostate epithelial cells derived from tissue fragments surrounding a prostate tumor in a patient with prostatic adenocarcinoma. Since chromosome 5 abnormality was present in early, middle and late passages of this cell model system, I examined long-term established prostate cancer cell lines for this chromosome abnormality. The results implicated the region surrounding marker D5S2068 as the locus of interest for further experimentation and location of a tumor suppressor gene in human prostate cancer. ^ Cancer is a group of complex genetic diseases with uncontrolled cell; division and prostate cancer is no exception. I determined if telomeric DNA, and telomerase activity, alone or together, could serve as biomarkers of prostate tumorigenesis. I studied three newly established human prostate cancer cell lines and three fibroblast cell cultures derived from prostate tissues. In conclusion, my data reveal that in the presence of telomerase activity, telomeric repeats are maintained at a certain optimal length, and analysis of telomeric DNA variations might serve as early diagnostic and prognostic biomarkers for prostate cancer. (Abstract shortened by UMI.)^

High-resolution late-glacial chronology for the Gerzensee lake record (Switzerland): δ18O correlation between a Gerzensee-stack and NGRIP

Oxygen-isotope variations were analyzed on bulk samples of shallow-water lake marl from Gerzensee, Switzerland, in order to evaluate major and minor climatic oscillations during the late-glacial. To highlight the overall signature of the Gerzensee δ18O record, δ18O records of four parallel sediment cores were first correlated by synchronizing major isotope shifts and pollen abundances. Then the records were stacked with a weighting depending on the differing sampling resolution. To develop a precise chronology, the δ18O-stack was then correlated with the NGRIP δ18O record applying a Monte Carlo simulation, relying on the assumption that the shifts in δ18O were climate-driven and synchronous in both archives. The established chronology on the GICC05 time scale is the basis for (1) comparing the δ18O changes recorded in Gerzensee with observed climatic and environmental fluctuations over the whole North Atlantic region, and (2) comparing sedimentological and biological changes during the rapid warming with smaller climatic variations during the Bølling/Allerød period. The δ18O record of Gerzensee is characterized by two major isotope shifts at the onset and at the termination of the Bølling/Allerød warm period, as well as four intervening negative shifts labeled GI-1e2, d, c2, and b, which show a shift of one third to one fourth of the major δ18O shifts at the beginning and end of the Bølling/Allerød. Despite some inconsistency in terminology, these oscillations can be observed in various climatic proxies over wide regions in the North Atlantic region, especially in reconstructed colder temperatures, and they seem to be caused by hemispheric climatic variations.