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  • Baecklund, F, et al. (författare)
  • A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival
  • 2014
  • Ingår i: BMC Medical Genetics. - 1471-2350. ; 15, s. 113
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed. Methods: We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of similar to 300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999-2002 and in the United States 2001-2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model. Results: In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0x10(-8)). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 5.24x10(-8)). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival. Conclusions: The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.
  • Blomquist, E, et al. (författare)
  • The potential of proton beam radiation therapy in intracranial and ocular tumours
  • 2005
  • Ingår i: Acta Oncologica. - 0284-186X. ; 44:8, s. 862-70
  • Tidskriftsartikel (refereegranskat)abstract
    • A group of oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy. The estimations have been based on current statistics of tumour incidence, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours and normal tissues. In intracranial benign and malignant tumours, it is estimated that between 130 and 180 patients each year are candidates for proton beam therapy. Of these, between 50 and 75 patients have malignant glioma, 30-40 meningeoma, 20-25 arteriovenous malformations, 20-25 skull base tumours and 10-15 pituitary adenoma. In addition, 15 patients with ocular melanoma are candidates.
  • Chang, E T, et al. (författare)
  • Body mass index and risk of malignant lymphoma in Scandinavian men and women
  • 2005
  • Ingår i: Journal of the National Cancer Institute. - 0027-8874. ; 97:3, s. 210-218
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: The incidence of non-Hodgkin lymphoma and prevalence of obesity are increasing globally. A suggested positive association between obesity and risk of non-Hodgkin lymphoma has prompted us to investigate the relationship between body mass index (BMI) and risk of malignant lymphoma subtypes in a population-based case-control study. METHODS: Telephone interviews were conducted with 3055 case patients with non-Hodgkin lymphoma and 618 case patients with Hodgkin lymphoma diagnosed between October 1, 1999, and August 30, 2002, and 3187 population-based control subjects. The interviews assessed current height, normal adult weight, and other possible risk factors. Multivariable odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for risk of lymphoma were estimated by unconditional logistic regression. All statistical tests were two-sided. RESULTS: BMI was not associated with risk of overall non-Hodgkin lymphoma or of Hodgkin lymphoma (for example, comparing the highly obese group [BMI > or =35.0 kg/m2] with the normal-weight group [BMI = 18.5-24.9 kg/m2], OR for risk of non-Hodgkin lymphoma = 0.9, 95% CI = 0.6 to 1.3; P(trend) across all categories of BMI = .27). BMI was also not associated with risk of any non-Hodgkin lymphoma subtype evaluated, although there was some evidence of a positive association with risk of diffuse large B-cell lymphoma (for example, comparing the highly obese group with the normal-weight group, OR for diffuse large B-cell lymphoma = 1.5, 95% CI = 0.9 to 2.4; P(trend) =.05). CONCLUSIONS: Excess weight does not appear to be associated with an increased risk of malignant lymphoma in general, or with a risk of most major lymphoma subtypes. Hence, the growing incidence of obesity is unlikely to be an important contributor to the increasing incidence of non-Hodgkin lymphoma worldwide.
  • Kjersem, JB, et al. (författare)
  • Let-7 miRNA-binding site polymorphism in the KRAS 3`UTR; colorectal cancer screening population prevalence and influence on clinical outcome in patients with metastatic colorectal cancer treated with 5-fluorouracil and oxaliplatin +/- cetuximab.
  • 2012
  • Ingår i: BMC Cancer. - 1471-2407. ; 12:1, s. 534
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Recent studies have reported associations between a variant allele in a let-7 microRNA complementary site (LCS6) within the 3 untranslated region (3 UTR) of KRAS (rs61764370) and clinical outcome in metastatic colorectal cancer (mCRC) patients receiving cetuximab. The variant allele has also been associated with increased cancer risk. We aimed to reveal the incidence of the variant allele in a colorectal cancer screening population and to investigate the clinical relevance of the variant allele in mCRC patients treated with 1st line 5-fluorouracil-oxaliplatin (Nordic FLOX) +/- cetuximab.METHODS: The feasibility of the variant allele as a risk factor for CRC was investigated by comparing the LCS6 gene frequencies in 197 CRC patients, 1060 individuals with colorectal polyps, and 358 healthy controls. The relationship between clinical outcome and LCS6 genotype was analyzed in 180 mCRC patients receiving Nordic FLOX and 355 patients receiving Nordic FLOX + cetuximab in the NORDIC-VII trial (NCT00145314). RESULTS: LCS6 frequencies did not vary between CRC patients (23%), individuals with polyps (20%), and healthy controls (20%) (P=0.50). No statistically significant differences were demonstrated in the NORDIC-VII cohort even if numerically increased progression-free survival (PFS) and overall survival (OS) were found in patients with the LCS6 variant allele (8.5 (95% CI: 7.3-9.7 months) versus 7.8 months (95% CI: 7.4-8.3 months), P=0.16 and 23.5 (95% CI: 21.6-25.4 months) versus 19.5 months (95% CI: 17.8-21.2 months), P=0.31, respectively). Addition of cetuximab seemed to improve response rate more in variant carriers than in wild-type carriers (from 35% to 57% versus 44% to 47%), however the difference was not statistically significant (interaction P = 0.16).CONCLUSIONS: The LCS6 variant allele does not seem to be a risk factor for development of colorectal polyps or CRC. No statistically significant effect of the LCS6 variant allele on response rate, PFS or OS was found in mCRC patients treated with 1st line 5-fluorouracil-oxaliplatin +/- cetuximab.
  • Pettersson, D, et al. (författare)
  • Tumour regression in the randomized Stockholm III Trial ofradiotherapy regimens for rectal cancer
  • 2015
  • Ingår i: British Journal of Surgery. - 0007-1323. ; 102:8, s. 972-978
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundThe Stockholm III Trial randomized patients with primary operable rectal cancers to either short-course radiotherapy (RT) with immediate surgery (SRT), short-course RT with surgery delayed 4-8 weeks (SRT-delay) or long-course RT with surgery delayed 4-8 weeks. This preplanned interim analysis examined the pathological outcome of delaying surgery. MethodsPatients randomized to the SRT and SRT-delay arms in the Stockholm III Trial between October 1998 and November 2010 were included, and data were collected in a prospective register. Additional data regarding tumour regression grade, according to Dworak, and circumferential margin were obtained by reassessment of histopathological slides. ResultsA total of 462 of 545 randomized patients had specimens available for reassessment. Patients randomized to SRT-delay had earlier ypT categories, and a higher rate of pathological complete responses (11<bold></bold>8 versus 1<bold></bold>7 per cent; P=0<bold></bold>001) and Dworak grade 4 tumour regression (10<bold></bold>1 versus 1<bold></bold>7 per cent; P<0<bold></bold>001) than patients randomized to SRT without delay. Positive circumferential resection margins were uncommon (6<bold></bold>3 per cent) and rates did not differ between the two treatment arms. ConclusionShort-course RT induces tumour downstaging if surgery is performed after an interval of 4-8 weeks.
  • Rutqvist, L E, et al. (författare)
  • A systematic overview of radiation therapy effects in rectal cancer.
  • 2003
  • Ingår i: Acta oncologica (Stockholm, Sweden). - 0284-186X. ; 42:5-6, s. 476-92
  • Tidskriftsartikel (refereegranskat)abstract
    • A systematic review of radiation therapy trials in several turnout types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for breast cancer is based on data from 29 randomized trials, 6 meta-analyses and 5 retrospective studies. In total, 40 scientific articles are included, involving 41204 patients. The results were compared with those of a similar overview from 1996 including 285982 patients. The conclusions reached can be summarized as follows: There is strong evidence for a substantial reduction in locoregional recurrence rate following postmastectomy radiation therapy to the chest wall and the regional nodal areas. There is strong evidence that postmastectomy radiation therapy increases the disease-free survival rate. There are conflicting data regarding the impact of postmastectomy radiotherapy upon overall survival. There is strong evidence that breast cancer specific survival is improved by postmastectomy radiotherapy. There is strong evidence for a decrease in non-breast cancer specific survival after postmastectomy radiotherapy. There is some evidence that overall survival is increased by optimal postmastectomy radiation therapy. There is strong evidence that postmastectomy radiotherapy in addition to surgery and systemic therapy in mainly node-positive patients decreases local recurrence rate and improves survival. There is moderate evidence that the decrease in non-breast cancer specific survival is attributed to cardiovascular disease in irradiated patients. There are conflicting data whether breast conservation surgery plus radiotherapy is comparable to modified radical mastectomy alone in terms of local recurrence rate. There is strong evidence that breast conservation surgery plus radiotherapy is comparable to modified radical mastectomy alone in terms of disease-free survival and overall survival. There is strong evidence that postoperative radiotherapy to the breast following breast conservation surgery results in a statistically and clinically significant reduction of ipsilateral breast recurrences followed by diminished need for salvage mastectomies. There is strong evidence that the omission of postoperative radiotherapy to the breast following breast conservation surgery has no impact on overall survival. In one meta-analysis including three randomized studies a survival advantage is demonstrated by Bayesian statistics. There is strong evidence that the addition of a radiation boost after conventional radiotherapy to the turnout bed after breast conservation surgery significantly decreases the risk of ipsilateral breast recurrences but has no impact on overall survival after short follow-up. There is strong evidence for the use of postoperative radiotherapy to the breast following breast conservation surgery for DCIS (ductal breast cancer in situ). Radiotherapy leads to a clinically and statistically significant reduction of both non-invasive and invasive ipsilateral breast recurrences. There is insufficient evidence to define the optimal integration of systemic adjuvant therapy and postoperative radiotherapy. There are limited data on radiotherapy-related morbidity in breast cancer. No conclusions can be drawn.
  • Sahlberg, SH, et al. (författare)
  • The effect of a dimeric Affibody molecule (ZEGFR:1907)2 targeting EGFR in combination with radiation in colon cancer cell lines
  • 2012
  • Ingår i: International Journal of Oncology. - 1019-6439. ; 40:1, s. 176-184
  • Tidskriftsartikel (refereegranskat)abstract
    • The epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer and is therefore an attractive target for treatment. (ZEGFR:1907)2 is a newly developed dimeric affibody molecule with high affinity to the extracellular part of EGFR. In this study, we evaluated the cytotoxic effects of (ZEGFR:1907)2 in combination with external radiation and the possible inhibitory effects in the EGFR signalling pathways in the colon cancer cell lines HT-29 and HCT116. The effects were compared with an EGFR antibody (cetuximab) and the tyrosine kinase inhibitors (erlotinib and sunitinib). These cell lines are genotypically different with respect to e.g. KRAS and BRAF mutational status, recently shown to be of clinical significance for therapeutic effects. Both cell lines express approximately 100,000-150,000 EGFRs per cell but differ in the radiation response (HCT116, SF2=0.28 and HT-29, SF2=0.70). Exposure to (ZEGFR:1907)2 produced a small, but significant, reduction in survival in HCT116 but did not affect HT-29 cells. Similar results were obtained after exposure to EGF and the EGFR antibody cetuximab. The EGFR tyrosine kinase targeting inhibitor erlotinib and the multi-tyrosine kinase inhibitor sunitinib reduced survival in both cell lines. However, none of the drugs had any significant radiosensitizing effects in combination with radiation. Akt and Erk are central proteins in the EGFR downstream signalling and in the cellular response to ionizing radiation. The activation of Akt (Ser 473) and Erk (Thr202/Tyr204) by radiation was both dose- and time-dependent. However the activation of EGFR was not clearly affected by radiation. Neither (ZEGFR:1907)2 nor any of the other drugs were able to completely inactivate Akt or Erk. On the contrary, erlotinib stimulated Akt phosphorylation in both cell lines and in HCT116 cells Erk was activated. Overall the results illustrate the complexity in response to radiation and drugs in cells with differential phenotypic status.
  • Smedby, KE, et al. (författare)
  • Autoimmune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype
  • 2006
  • Ingår i: Journal of the National Cancer Institute. - 0027-8874. ; 98:1, s. 51-60
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms. METHODS: In a population-based case-control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes. RESULTS: Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjögren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype. CONCLUSIONS: Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.
  • Smedby, K E, et al. (författare)
  • Malignant lymphomas in coeliac disease evidence of increased risks for lymphoma types other than enteropathy-type T cell lymphoma.
  • 2005
  • Ingår i: Gut. - 0017-5749. ; 54:1, s. 54-9
  • Tidskriftsartikel (övrigt vetenskapligt)abstract
    • Background: Numerous studies have reported on the association between coeliac disease and the otherwise uncommon enteropathy-type T cell lymphoma (ETTL). A systematic risk assessment of more prevalent lymphoma entities, such as B cell and non-intestinal lymphomas, in coeliac disease has not been performed. Aims: In light of the increasing number of patients diagnosed with coeliac disease and the unknown aetiology of malignant lymphomas, we aimed to estimate the distribution and risk of lymphoma subtypes in coeliac disease. Methods: We reviewed and reclassified 56 cases of incident malignant lymphomas occurring in a Swedish population based cohort of 11 650 patients hospitalised with coeliac disease. The observed numbers of lymphoma subtypes were compared with those expected in the Swedish population. Results: The majority (n = 32, 57%) of lymphomas in the cohort were not intestinal T cell lymphomas. Significantly increased risks were observed for B cell non-Hodgkin lymphoma (NHL) (standardised incidence ratio (SIR) 2.2 (95% confidence interval (CI) 1.2-3.6); 11 non-intestinal and five intestinal) and for lymphomas of non-intestinal origin (SIR 3.6 (95% CI 2.3-5.2), 11 B and 14 T cell). Furthermore, 44% of patients with B cell NHL had a history of other autoimmune/inflammatory diseases. The relative risks for T cell NHL (SIR 51 (95% CI 35-68); n = 37) and for primary gastrointestinal lymphomas (SIR 24 (95% CI 16 34); five B and 25 T cell) were markedly increased, as anticipated. Conclusion: Most lymphomas complicating coeliac disease are indeed related to the disease and are not of the ETTL-type. There was a remarkable aggregation of autoimmune/inflammatory disorders, female sex, coeliac disease, and B cell lymphoma.
  • Tarpgaard, LS, et al. (författare)
  • Plasma YKL-40 in Patients with Metastatic Colorectal Cancer Treated with First Line Oxaliplatin-Based Regimen with or without Cetuximab RESULTS from the NORDIC VII Study
  • 2014
  • Ingår i: PLoS ONE. - 1932-6203. ; 9:2, s. e87746
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: We aim to test the hypothesis that high plasma YKL-40 is associated with short progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated with first-line oxaliplatin and 5-flourouracil with or without cetuximab. Patients and Methods: A total of 566 patients in the NORDIC VII Study were randomized 1:1:1 to arm A (Nordic FLOX), arm B (Nordic FLOX + cetuximab), or arm C (Nordic FLOX + cetuximab for 16 weeks followed by cetuximab alone as maintenance therapy). Pretreatment plasma samples were available from 510 patients. Plasma YKL-40 was determined by ELISA and dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects. Results: Pretreatment plasma YKL-40 was elevated in 204 patients (40%), and median YKL-40 was higher in patients with mCRC than in healthy subjects (age adjusted, P < 0.001). Patients with elevated YKL-40 had shorter PFS than patients with normal YKL-40 (7.5 vs. 8.2 months; hazard ratio (HR) = 1.27 95% confidence interval (CI) 1.05-1.53 P = 0.013) and shorter OS (16.8 vs. 23.9 months; HR = 1.33, 1.04-1.69, P = 0.024). Multivariate Cox analysis demonstrated that elevated pretreatment YKL-40 was an independent biomarker of short OS (HR = 1.12, 1.01-1.25, P = 0.033). The ratio of the updated plasma YKL-40 (i.e. level after 1, 2, 8 weeks of treatment, and at end of treatment compared to the baseline level) was associated with OS (HR = 1.27, 1.06-1.52, P = 0.011). Conclusions: Plasma YKL-40 is an independent prognostic biomarker in patients with mCRC treated with first-line oxaliplatin-based therapy alone or combined with cetuximab.
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