| 1. |
- Andersson, Anne, 1966-
(författare)
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Long-term side effects after treatment of Hodgkin's lymphoma
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Long-term side effects associated with the treatment of Hodgkin’s lymphoma (HL) have frequently been reported during the last decades. Studies have shown increased mortality in HL survivors. Following Hodgkin’s lymphoma, second malignancies (SM) and cardiovascular disease (CVD) are the most common causes of death in individuals treated for HL. This study investigates the incidence of side effects such as SM, CVD and infections in a cohort diagnosed with HL in Sweden between 1965 and 1995. In addition, this study identifies covariate risk factors for late side effects in order to develop strategies that prevent morbidity and mortality in HL survivors. Methods Using the Swedish Cancer Registry (SCR) at the National Board of Health and Welfare and the Multi-Generation Registry at Statistics (MGR) Sweden, we identified 6946 individuals diagnosed with HL between the years 1965 and 1995, and their first degree relatives (FDR) (n=17 858). In addition we identified the malignancies and inpatient care for CVD and infections for the HL cohort and their FDR. The standard incidence ratio (SIR) was calculated for the risk of SM, CVD and infections. For SM and CVD the risk also was stratified and calculated for family history of disease. The Swedish Hodgkin Intervention and Prevention study (SHIP), a prospective study, invited 702 individuals treated for HL at the age of 45 years or younger and who were treated in the region of Skåne, Uppsala or Umeå. The participants completed a questionnaire and were invited to an out-patient visit to an oncologist with clinical examination and blood tests. Any pathological findings were referred for further investigation. Results An increased risk for SM in HL long-term survivors was observed and seems to increase with the number of FDRs with cancer. There was also an increased risk for inpatient care due to congestive heart failure (CHF) and coronary artery disease (CAD). A family history of CHF and CAD further increased the risk for these diseases. The risk for inpatient care due to infections was increased and remained increased after 20 years or longer. The risk for infections was associated with splenectomy and hypothyroidism. Radiotherapy was an independent risk factor for cardiovascular disease in the cohort of the prospective study. ConclusionLong-term survivors from HL have an increased risk for developing late side effects such as SM, CVD and infections. Since many HL patients are young and the cure rate from the disease is high, it is of great importance to offer focused surveillance programs to selected individuals who are at high risk, e.g. individuals who received radiotherapy as part of their treatment and who have other known risk factors for cardiovascular disease such as hypertension, hypercholesterolemia, family history and smoking.
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| 2. |
- Brandefors, Lena, 1960-
(författare)
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Waldenstrom's macroglobulinemia : population based studies of familial aggregation and prognostic factors
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundWaldenstrom’s macroglobulinemia (WM) is a rare lymphoproliferative disorder with a world-wide incidence of 3-4 patients per million persons per year. In Sweden, the incidence was about three times higher, and approximately 100 patients per year are reported to the Swedish Lymphoma Registry (SLR). Our aim was to study the WM population with focus on incidence and survival in relation to clinical prognostic factors and primary therapies (Paper I-II). We also discussed the diagnostic difficulties in patients with non-WM lymphoplasmacytic lymphoma (LPL). In Paper III-IV, we study familial WM from different aspects to better understand underlying pathogenetic factors.Patients and methodsThe patients in all four studies were collected from SLR. In papers I and II, a total of 1511 patients with WM and non-WM LPL were registered between 2000 and 2014, and medical records were retrieved for 1139 patients (75%). A retrospective review showed that 981 and 33 (after review by haematopathologist) of these patients fulfilled the World Health Organization (WHO) diagnostic criteria for WM and non-WM LPL, respectively. In Paper III and IV, we used SLR and the Northern Lymphoma Registry (NLR) for the years 1997- 2011. We identified 12 families with a family history of WM, IgM monoclonal gammopathy of undetermined significance (MGUS) and/or multiple myeloma (MM).ResultsIn paper I, the overall survival (OS) for WM improved between the two time periods, 2000-2006 and 2007-2014, with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS at the time of diagnosis in asymptomatic patients in no need of therapy were age, poor performance status (PS), haemoglobin ≤115 g/l, and female sex. Elevated lactate dehydrogenase (LDH) level and haemoglobin ≤115 g/l were significant prognostic factors for patients receiving therapy 0-3 months after diagnosis. The level of the IgM monoclonal immunoglobulin (MI) had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival. Paper II describes the differential diagnostic difficulties in non-WM LPL, especially with Marginal Zone Lymphoma (MZL). The non-WM LPL patients had more adverse prognostic factors as elevated LDH, anaemia, and lymphocytosis at diagnosis compared to the patients with WM. Despite this, the OS did not significantly differ between the groups (P = 0.249). The median OS for non-WM LPL was 71 months and the three-year and five-year survival was 71 % and 55%, respectively. The OS and RS were worse for males than females. In Paper III, we showed that age-adjusted incidence in Norrbotten and Västerbotten for WM and non-WM LPL was higher than expected – 17.5 and 14.8 per million person and year, respectively. The corresponding figure for Sweden was 10.5 per million persons per year. Autoimmune diseases or haematological malignancies in the medical history in patients or in their relatives were reported in nine and five of the 12 families, respectively. The relatives showed a high proportion abnormal serum protein electrophoresis (SPE): 12/56 (21%) showed MGUS and 13/56 (25%) showed abnormalities in the immunoglobulin levels (i.e., subnormal levels and poly/oligoclonality). Paper IV describes hyperphosphorylated paratarg 7 (pP-7), a target of 11% of the monoclonal immunoglobulin M (IgM) in WM and MGUS of IgM type, and distribution in Sweden and in familial WM. The frequency of pP-7 seems to be in line or lower in non-familial WM (7.1%) and higher in familial WM (16.7%) in the counties of Norrbotten and Västerbotten than in earlier published studies. Positive analysis for pP-7 was shown up to 10 years before diagnosis of WM.ConclusionWe show that in a rare disease such as WM registry studies might bring new knowledge about incidence, disease characteristic, prognostic factors, treatments, and outcome. We also identified aggregation of families with WM in an effort to better understand the underlying pathogenesis
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| 3. |
- Ghasimi, Soma, 1984-
(författare)
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Genotype-phenotype studies in brain tumors
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Meningioma and glioma are the most common primary brain tumors, but their etiologies are largely unknown. Although meningioma is usually benign, their intracranial location can lead to lethal consequences, and despite progress in surgery, radiotherapy, and chemotherapy the prognosis for patients with glioma remains poor. The only well-established environmental risk factor for meningioma and glioma is ionizing radiation. Evidence for inherited predisposition to meningioma and glioma is provided by a number of rare inherited syndromes where collectively these diseases account for only a small proportion of the twofold increased risk of brain tumors seen in first-degree relatives for meningioma and glioma patients. It is very possible that much of the excess familial risk is a consequence of co-inheritance of multiple low-risk genetic variations. With this in mind, the aims of the studies in this thesis were to discover genetic risk variants influencing the probability of acquiring the disease and to identify the association between risk variants on the tumor phenotype.To identify genetic variants influencing meningioma risk, a comprehensive tagging of the selected genes in a case-control study was performed. We identified nine risk variants inEGF, ERBB2, and LRIG2 genes. However, these findings could not be confirmed in another larger independent dataset. In addition, the study identified a correlation between LRIG2 protein expression and ER status when analyzed with different parameters. In a separate study with a larger sample of meningioma patients, the same correlation between LRIG2 and ER status was observed.To explore the potential association between reported germline risk variants and somatic genetic events, matched tumor and blood samples from glioma patients were analyzed by SNP array. The results identified correlations betweenEGFR gene variants and somatic aberrations within the EGFR locus and CDKN2A/B locus. To further study the relationship between germline risk variants and tumor phenotype, the same patient material was used and analyzed by three different techniques: SNP array, IHC, and FISH. The results revealed EGFR risk variants effecting copy number variation of the EGFR gene and the expression of the IDH1 and p53. Further comparison between different techniques such as SNP array and FISH analysis revealed the difficulty in achieving consistent results with different techniques.To summarize, the glioma studies show a link between genotype and phenotype where genetic risk variants in theEGFR gene were found to be associated with specific somatic aberrations. These associations are biologically interesting because EGFR is involved in multiple cellular processes. Additional studies of the direct functional role of these observations need to be conducted to elucidate the molecular mechanisms underlying the identified association between germline gene variants and somatic aberrations. For the meningioma studies, no significant risk variants influencing the disease were found but a correlation between LRIG2 and ER status was observed. This result suggests a potential role for the LRIG protein in the pathogenesis of meningioma, but more studies are needed to confirm this hypothesizes.
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| 4. |
- Hawranek, Carolina, 1982-
(författare)
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Someone has to tell them : exploring hereditary cancer risk disclosure in Sweden
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Summary in EnglishBackground: An awareness of hereditary susceptibility for breast, ovarian and colorectal cancer in high-risk families enables targeted cancer prevention. A discovered hereditary risk in one family member (proband) may thus be important for several members of that family. Identified at-risk relatives can be offered surveillance to allow early detection or in some cases risk-reducing surgery to lower the risk of disease and premature death. Problem: The current clinical praxis with family-mediated risk disclosure leaves up to half of all at-risk relatives uninformed of their potential cancer risk. Complementary disclosure pathways have demonstrated promising results suggesting new opportunities to develop clinical management of hereditary cancer risk disclosure. However, concerns over legal liability, risk of inducing cancer worry and lack of robust outcome data from randomized trials among other factors, have hampered translation of emerging findings into clinical practice.Aim: This thesis explores perceptions and preferences on the disclosure of risk information concerning hereditary cancer syndromes in the general public and in patients. The work also estimates cancer worry levels in the Swedish population and explores willingness to participate in screening colonoscopy at different hypothetical levels of lifetime risk of colorectal cancer. Methods: Two quantitative and two qualitative studies were designed to address the aims. Data collection included focus groups, a population survey, and semi-structured patient interviews. Quantitative data was analyzed using descriptive statistics and groups were compared using tests and regression analysis. Interview data was analyzed with inductive qualitative content analysis of both manifest and latent content. Focus was placed on participants’ perceptions and preferences and patients’ management of risk disclosure as well as their interaction with genetic healthcare professionals.Results: Study I describes how lay people view the roles and responsibilities involved in risk disclosure. Respondents assumed genetic healthcare professionals (HCPs) would have a clear mandate in leading the risk disclosure process and wanted to be actively involved in shaping this process. They expected healthcare services to provide easy-to-understand, personalized information suitable for themselves and potential relatives. Findings from Study II show a strong public preference to share and receive risk information about hereditary cancer (90% and 89% respectively in a 10% cancer risk scenario). A majority wanted to receive information about a potential hereditary cancer risk from a healthcare professional (80%) and also preferred healthcare services to inform their at-risk relatives (58%). Preferred options for contact were by letter or telephone, followed by digital options. Study III presents novel data on cancer worry levels in a Swedish population-based sample (mean 9.46 of a total 24 on the 6-item cancer worry scale). Female respondents and those with children had higher cancer worry scores, and those with higher worry levels were also more inclined to participate in a screening colonoscopy. For each increasing risk level presented (5, 10 or 70% lifetime risk of colorectal cancer) more respondents reported interest to undergo colonoscopy. Study IV describes patient experiences of family disclosure, which is seen as difficult yet important, and often performed for the sake of others. Patients also describe the feeling unqualified in the role as proband, while others consider it a straightforward task which needs to be done. The patient data also illustrates the difficulties in communicating complex health information and patients’ struggles to navigate benefits and drawbacks of interacting with relatives. Patients also envisioned solutions to perceived barriers and outlined alternatives for healthcare services to better facilitate the risk disclosure process.Conclusion: Findings in this thesis indicate a missing link in the communication between proband, relative and healthcare regarding hereditary cancer risk information. The combined results suggest that risk disclosure would benefit from being more:Standardized – by increasing transparency about the risk disclosure process and harmonize disclosure options to guide probands and healthcare professional in the clinical setting.Systematic – by establishing follow up of risk disclosure as routine care and clearly define communication duties of healthcare professionals and probands early in the process.Situational – by tailoring professional support for risk disclosure and adapting the content and approach to the coping style, behavioral type and need of each family.Clinical implications: This thesis highlights the challenges of risk disclosure in families with increased risk of hereditary cancer and strengthens the argument for shifting towards more healthcare involvement in the process of informing at-risk relatives. The findings complement existing evidence on how hereditary cancer risk disclosure could develop further to better support proactive management of cancer risk in families affected by hereditary cancer.
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| 5. |
- Sjöström, Olle, 1973-
(författare)
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Risk and survival for colorectal cancer in northern Sweden : sociodemographic factors and surveillance programs
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundColorectal cancer (CRC) – i.e., cancer in the colon or rectum – is one of the most common cancers both globally and in Sweden. The risk for CRC is mainly related to age, heredity, and life-style risk factors. Previous studies have also demonstrated that individuals with lower socioeconomic status (SES), living alone, or far from care facilities may have a higher risk for CRC or a worse outcome. In contrast to life-style or sociodemographic-associated risks, an inherited risk for CRC is difficult to modify. However, colonoscopic surveillance programs can be help prevent CRC in families with a known hereditary risk.The Northern Health Care Region (northern Sweden) is the most sparsely populated region in Sweden, and travel distances to care can be long. The population in Northern Sweden is on average older and has lower SES compared with the rest of the country. The impact of these sociodemographic differences on CRC in northern Sweden is not well known. AimThis thesis analyses CRC in a northern Sweden setting with regards to incidence, survival, and associated sociodemographic risk factors, including prevention for individuals with increased hereditary risk.MethodsPapers I and II, cohort studies from the Risk North database, link individual data from health care registers to other sociodemographic registers. In Paper I, the incidence, mortality, and survival for all CRC cases in northern Sweden were compared with the rest of Sweden for the period 2007-2013. Uni- and multivariable Cox regression analysis were used to assess the impact of sociodemographic factors and tumour stage on survival by calculating hazard ratios (HR). In Paper II, we analysed any association between travel time to care and CRC survival in northern Sweden during 2007-2013 using the same type of Cox regression analysis. Papers III and IV are based on a cohort of individuals with a family history of CRC, prospectively recorded from 1995 to 2012 in the colonoscopic surveillance register at the Cancer Prevention Clinic at Umeå University Hospital. In Paper III, we evaluated the cancer preventive effect of the performed colonoscopic surveillance. Observed cases of CRC were compared to a cohort estimate of cases without surveillance. Compliance with surveillance and colonoscopic quality was also analysed. In Paper IV, we examined the cost-effectiveness of the colonoscopic surveillance program in Paper III. A cost-utility analysis with a societal perspective was used and the stability of the results was tested in a sensitivity analysis. ResultsThe age-adjusted incidence in colon cancer was 12.7% lower in northern compared to southern Sweden or 35.9/100 000 vs. 41.1/100 000 person years (p < 0.01). For rectal cancer, the incidence was 10.5% lower in the north (17.6 vs. 19.7 p <0.01). In subgroup analysis, the largest difference in incidence between northern and southern Sweden was found among individuals > 79 years age (colon - 190 vs. 237 ≈ 19.6%, rectal 72.4 vs. 88.0 ≈ 17.7%). For all of Sweden, the incidence in colorectal cancer was higher in males, individuals with lower SES, or individuals living alone. In univariable analyses of survival (all-cause and cause-specific) for colon and rectal cancer patients in all of Sweden, patients with high SES or co-habiting had a significantly better outcome compared to patients with low SES or living alone. HR for death ranged from 0.60 to 0.85 in the better-favoured risk group. No differences in colon or rectal cancer survival between northern and southern Sweden were demonstrated in the univariable analysis. However, in multivariable survival analysis, all-cause survival for colon cancer patients was better in southern Sweden (HR 0.92; 95% CI 0.86 – 0.97). For cause-specific survival for colon cancer or in any analysis for rectal cancer, no differences between northern and southern Sweden were demonstrated. In analysis of travel time, no association between travel time and survival was found. In the evaluation of the colonoscopic surveillance programme, one case of CRC was observed, compared to 9.5-10.5 expected cases. Standardised Incidence Ratio (SIR) between observed and expected cases of CRC was 0.10 (CI 95% 0.0012–0.53) to 0.11 (CI 95% 0.0014–0.59. The compliance to the surveillance program was 90%. The adenoma detection rate was 14%, and 10% of the examinations were incomplete. In the cost-utility analysis, the net cost for surveillance was 233 038 €, while saving 64.8 Quality Adjusted Life Years (QALYs) compared to non-surveillance. The resulting Incremental Cost-Effectiveness Ratio (ICER) was 3596 €/QALY, ranging from -4620 €/QALY in the best-case scenario to 33 779 € /QALY in the worst-case scenario.ConclusionThe incidence of CRC was lower in northern Sweden and most evident in the elderly, raising questions on differences in life-style between northern and southern Sweden in the past. There were considerable sociodemographic disparities in CRC survival in Sweden, including a lower all-cause survival for colon cancer patients in the north. In this study, travel time to care in northern Sweden did not affect survival and the lower all-cause survival in northern Sweden cannot be fully explained. The colonoscopic surveillance of families in northern Sweden with inherited risk for CRC had a good cancer preventive effect, including a high cost-effectiveness. The reasons for the good effect may be high compliance, since the quality of the colonoscopies was moderate.
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| 6. |
- Sjöström, Sara, 1977-
(författare)
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Risk and prognostic factors for malignant glioma
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Glioblastoma is the most common and aggressive type of glioma and associated with poor prognosis. Apart from ionizing radiation and some rare genetic disorders, few aetiological factors have been identified for primary brain tumours. Inverse associations to asthma and low IgG levels for varicella zoster virus have in previous studies indicated that the immune system may play a role in glioma development. Little is known about prognostic factors in glioma. Previous studies have shown an association between age, Karnofsky performance status, O6-methylguanine-DNA methyltransferase (MGMT) hypermethylation, and prognosis. Polymorphisms in different low penetrance genes have in some studies been associated with glioma prognosis.Material and methods: In paper I, we analysed IgG levels for four different viruses, Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella zoster virus (VZV) and adenovirus (Ad), in prediagnostic blood samples from 197 cases with glioma and 394 controls collected from three large cohorts: the Northern Sweden Health and Disease Study; the Malmö Diet and Cancer Study; and the Diet, Cancer and Health cohort from Copenhagen. ELISA was used to measure IgG levels and for EBV response to both the nuclear antigen (EBNA1) and the viral capsid antigen (VCA) was measured, for VCA using immunoflourescence. IgG levels were divided into quartiles and binary logistic regression was used to compare the quartiles in cases and controls. All odds ratios were adjusted for age, sex, and cohort. In paper II-IV, we studied 176 glioblastoma cases from Sweden and Denmark. We collected treatment and follow-up data on the cases. We genotyped 30 tagging SNPs in EGF, 89 in EGFR, 27 in VEGFR2, and 17 in VEGF. We also studied 1458 SNPs in 136 DNA repair genes. Hazard ratios were calculated using Cox regression; the major allele was set as categorical variable and all HR were adjusted for age, sex, country, and treatment. For the DNA repair gene results, we adjusted the p-values for multiple testing. Significant findings were confirmed in separate datasets.Results and Discussion: We found a trend towards higher IgG VZV levels in controls compared to glioma cases, especially when restricting the analyses to only include glioma cases with at least 2 years between blood sample and diagnosis. This finding might indicate that there is an aetiological and not a disease-related association. This confirms previous findings and support that a strong immune system can detect and inhibit growth of small cancer clusters. In EGF, we found seven SNPs in one haplotype block that were significantly associated with glioblastoma survival. Four of the SNPs were available for confirmation; however, none reached statistical significance. One explanation could be age differences in the different cohorts. In EGFR, four SNPs associated with survival were found; however, as 89 polymorphisms were tested this was the expected outcome by chance. In VEGF and VEGFR2, we found two SNPs associated with glioblastoma survival, but they could not be confirmed in the separate dataset, and due to multiple testing, were considered to be false positives. Among the DNA repair genes, we found nine SNPs in three genes-MSH2, RAD51L1 and RECQL4-associated with glioblastoma survival after confirmation and adjustment for age, sex, country, and treatment. After adjusting for multiple testing, one SNP in MSH2 and one in RECQL4 remained significant.Conclusions: Our studies provide additional knowledge to the aetiological and prognostic factors important for glioma, emphasising the possible importance of immune function mechanisms. We found limited evidence for the role of genetic variants in glioma progression genes, and some for DNA repair variants as prognostic factors for glioblastoma survival.
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| 7. |
- Sooman, Linda, 1983-
(författare)
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Prognostic Biomarkers and Target Proteins for Treatment of High-grade Gliomas
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The survival for high-grade glioma patients is poor and the treatment may cause severe side effects. A common obstacle in the treatment is chemoresistance. To improve the quality of life and prolong survival for these patients prognostic biomarkers and new approaches for chemotherapy are needed. To this end, a strategy to evade chemoresistance was evaluated by combining chemotherapeutic drugs with agents inhibiting resistance mechanisms identified by a bioinformatic analysis (paper I). The prognostic value of 13 different proteins was analyzed in this thesis (papers II-IV). Two of them, p38 mitogen-activated protein kinase (MAPK) and protein tyrosine phosphatase non-receptor type 6 (PTPN6, also known as SHP1) were analyzed for their potential as targets in combination chemotherapy (in paper III and IV, respectively). We found that:PTPN6 expression and methylation status may be important for survival of anaplastic glioma patients, p38 MAPK phosphorylation may be a potential negative prognostic biomarker for high-grade glioma patients and FGF2 expression may be a potential negative prognostic biomarker for proneural glioma patients.PTPN6 may be a useful target for combination chemotherapy with cisplatin, melphalan or bortezomib in high-grade gliomas. The following drug combinations; camptothecin combined with an EGFR or RAC1 inhibitor, imatinib combined with a Notch or RAC1 inhibitor, temozolomide combined with an EGFR or FAK inhibitor and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for high-grade gliomas.
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| 8. |
- Späth, Florentin, 1980-
(författare)
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Molecular epidemiology approach : nested case-control studies in glioma and lymphoid malignancies
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Nested case-control studies aim to link molecular markers with a certain outcome. Repeated prediagnostic samples may improve the evaluation of marker-disease associations. However, data regarding the benefit of repeated samples in such studies are sparse. We aimed to assess the relationship between blood levels of various proteins and risk of glioma, B cell lymphoma, and multiple myeloma to gain further understanding of disease etiology and to evaluate the clinical relevance of the studied markers. To this end, marker-disease associations were evaluated considering the natural history of the studied disease and the time between blood sample collection and diagnosis using both single (I-II) and repeated prediagnostic blood samples (III-IV).PATIENTS AND METHODS: We conducted four nested case-control studies and one meta-analysis using samples from three prospective cohorts: the Janus Serum Bank, the Northern Sweden Health and Disease study, and the European Prospective Investigation into Cancer and Nutrition study. The following studied endpoints and relationships were included: I) glioma risk and the association with the receptor tyrosine kinases (soluble) sEGFR and sERBB2; II) B cell lymphoma risk and the association with the immune markers sCD27 and sCD30; III) B cell lymphoma risk and the association with immune markers (CXCL13, sTNF-R1, sCD23, sCD27, and sCD30) and their trends over time; and IV) multiple myeloma risk and the association with ten immune markers and growth factors (MCP-3, MIP-1α, MIP-1β, VEGF, FGF-2, fractalkine, TGF-α, IL-13, TNF-α, and IL-10) and their trends over time.RESULTS: Risk of developing I) glioma was weakly associated with high blood levels of sERBB2. In addition, high levels of both sEGFR and sERBB2 assessed 15 years before diagnosis were associated with glioblastoma risk.Risk of II) B cell lymphoma was associated with high levels of sCD30, whereas high levels of sCD27 were particularly associated with risk of chronic lymphocytic leukemia. Meta-analyses showed consistent results for sCD30 across cohorts and lymphoma subtypes, whereas results for sCD27 were less consistent across cohorts and subtypes.In addition, III) B cell lymphoma risk was associated with levels of CXCL13, sCD23, sCD27, and sCD30 assessed in samples collected 17 years before diagnosis. Marker levels increased in cases closer to diagnosis, particularly for indolent lymphoma with a marked association for chronic lymphocytic leukemia and sCD23. Increasing marker levels closer to diagnosis were also observed for CXCL13 in future diffuse large B cell lymphoma patients.Risk of IV) multiple myeloma was associated with low levels of MCP-3, VEGF, FGF-2, fractalkine, and TGF-α. Levels of these markers decreased in myeloma cases over time, especially for TGF-α. TGF-α assessed at time of the prediagnostic repeated sample seemed to help predict progression to multiple myeloma.CONCLUSIONS: Both the natural history of the studied disease and the time between sample collection and diagnosis are crucial for the evaluation of marker-disease associations. Using repeated blood samples improves the understanding of marker-disease associations and might help to identify useful biomarker candidates.
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