uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Glimelius, Ingrid
Publications (10 of 36) Show all publications
Hollander, P., Rostgaard, K., Ekström-Smedby, K., Molin, D., Loskog, A., de Nully Brown, P., . . . Glimelius, I. (2018). An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome. European Journal of Haematology, 100(1), 88-97
Open this publication in new window or tab >>An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome
Show others...
2018 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 1, p. 88-97Article in journal (Refereed) Published
Abstract [en]

Objective: The classical Hodgkin lymphoma (cHL) tumor microenvironment shows anongoing inflammatory response consisting of varying degrees of infiltrating eosinophils,mast cells, macrophages, regulatory T lymphocytes (Tregs), and activated lymphocytes surrounding the malignant cells. Herein, different immune signatures are characterized and correlated with treatment outcome.

Methods: Tumor-infiltrating leukocytes were phenotyped in biopsies from 459 patients with cHL. Time to progression (TTP) (primary progression, relapse, or death from cHL) and overall survival were analyzed using Cox proportional hazards regression.

Results: The leukocyte infiltration in the microenvironment was highly diverse between patients and was categorized in 4 immune signatures (active, anergic, innate, or mixed). A high proportion of Tregs (anergic) resulted in shorter TTP (median 12.9-year follow-up) in age-adjusted analyses (hazard ratio = 1.82; 95% confidence interval 1.05-3-15). Epstein-Barrvirus (EBV)-positive cases had higher proportions of macrophages and activated lymphocytes than EBV negative, but neither of those leukocytes predicted prognosis.

Conclusions: Abundant Tregs (anergic signature) indicate a shorter TTP, particularly in younger patients. This is probably due to a reduced ability of the immune system to attack the tumor cells. Our data warrant further investigation if these suggested immune signatures could predict outcome of immunotherapy such as immune checkpoint inhibitors.

Keyword
Hodgkin lymphoma, Regulatory T lymphocytes, Tumor microenvironment
National Category
Cancer and Oncology
Research subject
Pathology; Oncology
Identifiers
urn:nbn:se:uu:diva-335491 (URN)10.1111/ejh.12987 (DOI)000418451500012 ()29064587 (PubMedID)
Funder
Swedish Cancer Society, CAN 2016/440, CAN 2016/607, CAN 2016/552
Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2018-01-29Bibliographically approved
Englund, A., Glimelius, I., Rostgaard, K., Smedby, K. E., Eloranta, S., Molin, D., . . . Hjalgrim, L. L. (2018). Hodgkin lymphoma in children, adolescents and young adults - a comparative study of clinical presentation and treatment outcome.. Acta Oncologica, 57(2), 276-282
Open this publication in new window or tab >>Hodgkin lymphoma in children, adolescents and young adults - a comparative study of clinical presentation and treatment outcome.
Show others...
2018 (English)In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 276-282Article in journal (Refereed) Published
Abstract [en]

Background: Hodgkin lymphoma (HL) treatment protocols for children, adolescents and young adults traditionally differ, but the biological and clinical justification for this remains uncertain.

Material and methods: We compared age-dependent clinical presentation and treatment and outcome for 1072 classical HL patients 0–24 years diagnosed in Denmark (1990–2010) and Sweden (1992–2009) in pediatric (n = 315, Denmark <15 years, Sweden <18 years) or adult departments (n = 757). Distribution of clinical characteristics was assessed with Pearson’s chi2-test and Mantel–Haenszel trend test. The Kaplan–Meier method was used for survival analyses. Hazard ratios (HR) were used to compare the different treatment groups and calculated using Cox regression.

Results: Children (0–9 years) less often presented with advanced disease than adolescents (10–17 years) and young adults (18–24 years) (stage IIB-IV: children 32% vs. adolescents 50%, and adults 55%; p < .005). No variation in overall survival (OS) was seen between pediatric and adult departments or by country. Danish pediatric patients received radiotherapy (36%) less frequently than Swedish pediatric patients (71%) (p < .0001). Ten-year event-free survival (EFS) was lower among Danish pediatric patients (0–14 years) (0.79; 95% confidence interval (CI) 0.70–0.86) than among Swedish pediatric patients (0–17 years) (0.88; 95% CI 0.83–0.92), HR (1.93; 95% CI 1.08–3.46). A similar pattern was seen between adult patients in the two countries: Denmark 10-year EFS 0.85 (95% CI 0.81–0.88), Sweden 0.88 (95% CI 0.84–0.91), adjusted HR 1.51 (95% CI 1.03–2.22).

Conclusion: Adolescents and young adults shared similar clinical presentation suggesting a rationale of harmonized treatment for these groups. Both adult and pediatric protocols provided high OS with no significant difference between the departments. The less frequent use of radiotherapy in Danish pediatric patients corresponded to a lower EFS, but comparable OS in all groups confirmed effective rescue strategies for the relapsing patients.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-343244 (URN)10.1080/0284186X.2017.1355563 (DOI)000423473200016 ()28760045 (PubMedID)
Funder
Swedish Childhood Cancer Foundation, KF2014-0003; FTJH11/002Swedish Cancer Society, 2012/774; 2016/440
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-03-09Bibliographically approved
Hollander, P., Kamper, P., Smedby, K. E., Enblad, G., Ludvigsen, M., Mortensen, J., . . . Glimelius, I. (2017). High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome. Blood Advances, 1(18), 1427-1439
Open this publication in new window or tab >>High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome
Show others...
2017 (English)In: Blood Advances, ISSN 2473-9529, Vol. 1, no 18, p. 1427-1439Article in journal (Refereed) Published
Abstract [en]

Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Identifying patients with a high risk of treatment failure could support the use of PD-1 inhibitors as front-line treatment. Our aim was to investigate the prognostic impact of PD-1, programmed death-ligand 1 (PD-L1), and PD-L2 in the tumor microenvironment in diagnostic biopsies of patients with cHL. Patients from Denmark and Sweden, diagnosed between 1990 and 2007 and ages 15 to 86 years, were included. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1, PD-L1, and PD-L2, and the proportions of positive cells were calculated. Event-free survival (EFS; time to treatment failure) and overall survival (OS) were analyzed using Cox proportional hazards regression. High proportions of both PD-1(+) (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.86) and PD-L1(+) (HR 5 1.89; 95% CI, 1.08-3.30) leukocytes in the microenvironment were associated with inferior EFS in a multivariate analysis (adjusted for white blood cell count >15 x 10(9)/L, hemoglobin <105 g/L, albumin <40 g/L, B symptoms, extranodal involvement, stage, bulky tumor, nodular sclerosis subtype, Epstein-Barr virus status, lymphocyte count <0.6 x 10(9)/L, sex, and country). A high proportion of PD-L1(+) leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI, 1.15-10.37). This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1(+) and PD-L1(+) leukocytes in the tumor microenvironment.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-332667 (URN)10.1182/bloodadvances.2017006346 (DOI)000407339200010 ()
Funder
Swedish Cancer Society, CAN2016/440
Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2017-12-19Bibliographically approved
Glimelius, I., Eloranta, S., Ekberg, S., Chang, E. T., Neovius, M. & Smedby, K. E. (2017). Increased healthcare use up to 10 years among relapse-free Hodgkin lymphoma survivors in the era of intensified chemotherapy and limited radiotherapy. American Journal of Hematology, 92(3), 251-258
Open this publication in new window or tab >>Increased healthcare use up to 10 years among relapse-free Hodgkin lymphoma survivors in the era of intensified chemotherapy and limited radiotherapy
Show others...
2017 (English)In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 92, no 3, p. 251-258Article in journal (Refereed) Published
Abstract [en]

With today's excellent cure rates for Hodgkin lymphoma (HL), the number of long-term survivors is increasing. This study aims to provide a global assessment of late adverse effects for workingage HL survivors treated with contemporary protocols (combination chemotherapy and limited radiotherapy). From Swedish nationwide registers we identified 1017 HL survivors diagnosed in 2000-2009, aged 18-60 years (median 32) and surviving at least one year post-diagnosis, and 4031 age-,sex-, and calendar-year-matched population comparators. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) for outpatient visits and inpatient bed-days after the first year up to 14 years post-diagnosis (through 2013) were estimated across treatment subgroups, considering relapse-free time and using negative binomial regression. Scheduled outpatient visits for HL were excluded. The rate of outpatient visits was nearly double (IRR = 1.8, 95% CI: 1.6-2.0) that among comparators and higher rates persisted up to 10 years post-diagnosis. The rate of inpatient bed-days among relapse-free survivors was more than three-fold (IRR = 3.6, 95% CI: 2.74.7) that of comparators and the increase persisted up to four years post-diagnosis. Patients requiring 6-8 chemotherapy courses had higher rates of outpatient visits (IRR = 1.4, 95% CI: 1.11.7) and bed-days (IRR-4.7, 95% CI: 2.9-7.8) than patients treated with 2-4 courses+radiotherapy. Previously seldom reported reasons for the excess healthcare use included chest pain, keratitis, asthma, diabetes mellitus, and depression. Contemporary treatment, chemotherapy in particular, was associated with excess healthcare use among HL survivors during the first decade postdiagnosis. The reasons for healthcare visits reflected a wide range of disorders, indicating the need of broad individualized care in addition to specific screening programs.

Place, publisher, year, edition, pages
WILEY, 2017
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-321157 (URN)10.1002/ajh.24623 (DOI)000398905200013 ()28006849 (PubMedID)
Available from: 2017-05-02 Created: 2017-05-02 Last updated: 2017-05-02Bibliographically approved
Glimelius, I. & Diepstra, A. (2017). Novel treatment concepts in Hodgkin lymphoma. Journal of Internal Medicine, 281(3), 247-260
Open this publication in new window or tab >>Novel treatment concepts in Hodgkin lymphoma
2017 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 3, p. 247-260Article, review/survey (Refereed) Published
Abstract [en]

Treatment of classical Hodgkin's lymphoma (HL) has been a success story, with cure of localized disease with radiotherapy in the 1930s, cure of advanced stages with combination chemotherapy with/without radiotherapy in the mid-1960s and continuous improvements since then. Nonetheless, at present approximately 2% of patients with classical HL are primarily refractory to conventional therapy with only 50% becoming long-term survivors. Another 13% of patients relapse, with only 60% being alive 10 years postrecurrence (as exemplified in this review in a Swedish cohort of 18- to 65-year-old patients diagnosed during the period 1992-2009). Recently, novel targeted drugs were approved for refractory/relapsed HL and here we review results of trials that form the basis for these approvals as well as new trials. In summary, brentuximab vedotin can be used in refractory patients (i) as a complement to high-dose chemotherapy with autologous stem cell transplantation (SCT) improving the chances of being able to proceed to an allogenic SCT and cure, (ii) as consolidation after autologous SCT and (iii) as palliative life-prolonging treatment. However, we have yet to determine whether this drug provides the greatest benefit in first- or second-line treatment, as consolidation or in refractory disease or relapse. Trials of immune checkpoint inhibitors, such as those targeting programmed death 1 (nivolumab and pembrolizumab), and thus not primarily the tumour cells, have shown overall response rates of >65%. Long-term results and data from Phase III trials are still lacking, but nivolumab recently gained approval in refractory patients already treated with brentuximab vedotin and autologous SCT. Other novel treatments of interest include T cells with a chimeric antigen receptor and combination therapies with histone deacetylase inhibitors.

Place, publisher, year, edition, pages
WILEY, 2017
Keyword
brentuximab vedotin, checkpoint inhibitors, chimeric antigen receptor T cells, Hodgkin's lymphoma, relapse/refractory disease, targeted drugs
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-321063 (URN)10.1111/joim.12582 (DOI)000394893800003 ()27991731 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-05-04 Created: 2017-05-04 Last updated: 2017-05-04Bibliographically approved
Baecklund, F., Foo, J.-N., Askling, J., Eloranta, S., Glimelius, I., Liu, J., . . . Smedby, K. E. (2017). Possible Interaction Between Cigarette Smoking and HLA-DRB1 Variation in the Risk of Follicular Lymphoma. American Journal of Epidemiology, 185(8), 681-687
Open this publication in new window or tab >>Possible Interaction Between Cigarette Smoking and HLA-DRB1 Variation in the Risk of Follicular Lymphoma
Show others...
2017 (English)In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 185, no 8, p. 681-687Article in journal (Refereed) Published
Abstract [en]

Follicular lymphoma (FL) risk is strongly associated with germline genetic variation in human leukocyte antigen (HLA) class II. Cigarette smoking has been suggested to increase FL risk, primarily among women. We hypothesized that amino acids in HLA-antigen D-related beta 1 subunit (DRB1) interact with smoking in FL risk, as shown for rheumatoid arthritis. We analyzed 373 patients with FL and 818 controls from 2 population-based case-control studies in Sweden and Denmark (1999-2003). Haplotypes in HLA-DRB1 were imputed at amino acid positions 11, 13, 28, 30, and 70-74 (shared epitope). We estimated the relative risk of FL as odds ratios with 95% confidence intervals for different smoking status/haplotype combinations. Interaction was defined as departure from additivity of effects and quantified by the attributable proportion (AP). Relative to never-smokers carrying no shared epitope alleles, smoking was associated with the risk of FL among all subjects (for former smokers, odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.10, 4.41; ORcurrent = 3.56, 95% CI: 1.60, 7.92) and women (ORformer = 2.95, 95% CI: 1.18, 7.37; ORcurrent = 5.63, 95% CI: 2.07, 15.3) carrying 2 shared epitope alleles but not among those carrying zero or 1 shared epitope allele. Smoking and shared epitope status interacted significantly as measured by AP (overall, AP = 0.6, 95% CI: 0.15, 1.0; for women, AP = 0.5, 95% CI: 0.005, 1.0). These results suggest a possible interaction between smoking and HLA-DRB1-associated antigen presentation in FL risk and provide a model to further unravel FL etiology.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2017
Keyword
etiology, follicular lymphoma, HLA-DRB1, interaction, smoking
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-324635 (URN)10.1093/aje/kww118 (DOI)000400981000009 ()28369180 (PubMedID)
Funder
Swedish Cancer Society, 2009/1084, 2012/774
Available from: 2017-06-16 Created: 2017-06-16 Last updated: 2017-06-16Bibliographically approved
Hollander, P., Kamper, P., Smedby, K. E., Enblad, G., Mortensen, J., Amini, R.-M. -., . . . Glimelius, I. (2016). High Expression Of Programmed Cell Death Receptor 1 In The Tumor Microenvironment Is Associated With Inferior Event Free Survival In Classical Hodgkin Lymphoma. Paper presented at 10th International Symposium on Hodgkin Lymphoma, OCT 22-25, 2016, Cologne, Germany. Haematologica, 101(S5), 1-2
Open this publication in new window or tab >>High Expression Of Programmed Cell Death Receptor 1 In The Tumor Microenvironment Is Associated With Inferior Event Free Survival In Classical Hodgkin Lymphoma
Show others...
2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no S5, p. 1-2Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-316329 (URN)000392549000003 ()
Conference
10th International Symposium on Hodgkin Lymphoma, OCT 22-25, 2016, Cologne, Germany
Available from: 2017-05-23 Created: 2017-05-23 Last updated: 2017-05-23Bibliographically approved
Wahlin, B. E., Overgaard, N., Peterson, S., Digkas, E., Glimelius, I., Lagerlof, I., . . . Molin, D. (2016). Hodgkin Lymphoma In Sweden Since 2000: Better Survival Only In Elderly Women - A Swedish Lymphoma Registry Study. Haematologica, 101, 22-22
Open this publication in new window or tab >>Hodgkin Lymphoma In Sweden Since 2000: Better Survival Only In Elderly Women - A Swedish Lymphoma Registry Study
Show others...
2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 22-22Article in journal (Other academic) Published
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-316331 (URN)000392549000051 ()
Available from: 2017-05-12 Created: 2017-05-12 Last updated: 2017-05-12Bibliographically approved
Everhov, Å. H., Ekberg, S., Hirschberg, A. L., Bergmark, K., Rådestad, A. F., Glimelius, I. & Smedby, K. E. (2016). Lost workdays in uterine cervical cancer survivors compared to the general population: impact of treatment and relapse.. Journal of cancer survivorship, 10(3), 514-523
Open this publication in new window or tab >>Lost workdays in uterine cervical cancer survivors compared to the general population: impact of treatment and relapse.
Show others...
2016 (English)In: Journal of cancer survivorship, ISSN 1932-2259, E-ISSN 1932-2267, Vol. 10, no 3, p. 514-523Article in journal (Refereed) Published
Abstract [en]

PURPOSE: The aim of the present study was to examine the risk of lost workdays due to sick leave and disability pension by treatment modality and relapse in a population-based cohort of cervical cancer survivors versus matched comparators.

METHODS: We identified 1971 cervical cancer patients aged ≤60 years (median 42) at diagnosis in Sweden 2003-2009 and 9254 population comparators. Information on sociodemographic and clinical characteristics, sick leave, and disability pension was retrieved from nationwide prospective registers. Differences in the annual mean number of lost workdays were calculated by linear regression, and hazard ratios (HRs) of disability pension were calculated by Cox regression analysis, with follow-up through September 2013.

RESULTS: Cervical cancer patients had more lost workdays annually than comparators up to 8 years following diagnosis. Relapse-free patients had more lost workdays than comparators up to 4 years. Risk of disability pension during follow-up was increased among the relapse-free patients treated with hysterectomy (HR 1.8 [95 % confidence interval (CI) 1.1-2.8]), hysterectomy plus chemotherapy and/or radiotherapy (HR 2.5 [95 % CI 1.2-5.4]), or chemotherapy and/or radiotherapy alone (HR 3.0 [95 % CI 1.3-6.8]), compared with the population. Women treated with fertility-sparing surgery did not have more lost workdays than the population beyond the first year and were not at increased risk of disability pension.

CONCLUSION: We observed a long-standing increased risk of lost workdays among cervical cancer patients, overall, as well as among relapse-free patients.

IMPLICATIONS FOR CANCER SURVIVORS: Extensive but not limited treatment was associated with increased risk of lost workdays, possibly reflecting an association between treatment side effects and work ability.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-270347 (URN)10.1007/s11764-015-0496-1 (DOI)000376032700009 ()26563951 (PubMedID)
Available from: 2015-12-27 Created: 2015-12-27 Last updated: 2017-12-01Bibliographically approved
Weibull, C. E., Eloranta, S., Smedby, K. E., Björkholm, M., Kristinsson, S. Y., Johansson, A. L., . . . Glimelius, I. (2016). Pregnancy and the Risk of Relapse in Patients Diagnosed With Hodgkin Lymphoma. Journal of Clinical Oncology, 34(4), 337-+
Open this publication in new window or tab >>Pregnancy and the Risk of Relapse in Patients Diagnosed With Hodgkin Lymphoma
Show others...
2016 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, no 4, p. 337-+Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Many patients and clinicians are worried that pregnancy after the diagnosis of Hodgkin lymphoma (HL) may increase the risk of relapse despite a lack of empirical evidence to support such concerns. We investigated if an association exists between pregnancy and relapse in women with a diagnosis of HL.

MATERIALS AND METHODS: Using Swedish healthcare registers combined with medical records, we included 449 women who received a diagnosis of HL between 1992 and 2009 and who were age 18 to 40 years at diagnosis. Follow-up started 6 months after diagnosis, when the patients' condition was assumed to be in remission. Pregnancy-associated relapse was defined as a relapse during pregnancy or within 5 years after delivery. Hazard ratios (HRs) with 95% CIs were estimated by using the Cox proportional hazards model.

RESULTS: Among the 449 women, 144 (32%) became pregnant during follow-up. Overall, 47 relapses were recorded, of which one was a pregnancy-associated relapse. The adjusted HR for the comparison of the pregnancy-associated relapse rate to the non-pregnancy-associated relapse rate was 0.29 (95% CI, 0.04 to 2.18). The expected number of relapses in women with a recent pregnancy, given that they would experience the same relapse rate as that of women without a recent pregnancy, was 3.76; the observed-to-expected ratio was 0.27 (95% exact CI, 0.01 to 1.51).

CONCLUSION: We found no evidence that a pregnancy after diagnosis increases the relapse rate among women whose HL is in remission. Survivors of HL need to consider a range of factors when deciding about future reproduction. However, given the results of this study, the risk of pregnancy-associated relapse does not need to be considered.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-270343 (URN)10.1200/JCO.2015.63.3446 (DOI)000374331500012 ()26668344 (PubMedID)
Funder
Swedish Cancer SocietyThe Karolinska Institutet's Research Foundation
Available from: 2015-12-27 Created: 2015-12-27 Last updated: 2017-12-01Bibliographically approved
Organisations

Search in DiVA

Show all publications