| 1. |
- Abdulla, Maysaa
(författare)
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Prognostic signficance of tumor cell markers in diffuse large B-cell lymphoma with special emphasis on lymphoma localization
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diffuse large B-cell lymphoma (DLBCL) is the most common type of high-grade B-cell lymphoma with different clinical, morphological, immunophenotypical, and molecular features. DLBCL is curable in 60-70% of patients when treated with standard immunochemotherapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).The main aim of this thesis is to identify prognostic factors in DLBCL by studying tumor markers (paper I and II), site of disease (paper III) and tumor microenvironment markers in primary DLBCL of the CNS (PCNSL) (paper IV) in order to better identify different risk groups of DLBCL patients.In papers I-III, we studied DLBCL patients treated homogeneously with R-CHOP. The negative prognostic impact of double protein expression of MYC and BCL2 so called “double-expressor lymphoma” (DEL) was a common finding in the three papers. In paper I, we detected DEL in 27% of patients, distributed with no significant difference between the germinal center derived B-cell subgroup (GCB) in 52% of cases and the non-GCB subgroup in 37% of cases. There was no significant difference in survival between GCB and non-GCB patients. The diagnosis in most of the patients with DEL was made on core needle biopsy in this paper. This finding was more thoroughly investigated in paper III with attention paid to the site of biopsy. In paper II, we evaluated the concordance of cell of origin (COO) assignment between gene expression profile (GEP) and immunohistochemistry (IHC) to identify the best predictor of survival in a DLBCL cohort including patients from Sweden and Denmark. The overall concordance between the two methods was 83%. We found that ABC/non-GCB subtype identified by both GEP and IHC is associated with the worst outcome. This finding indicates the importance of precise risk stratification in the era of precision medicine. DEL was more common in ABC patients categorized by GEP. In paper III, we identified abdominal lymph node involvement by radiological examination in 63% of DLBCL patients with an inferior survival, adverse clinical characteristics and significantly more frequent DEL. These findings may indicate a distinct biological behavior in patients with abdominal nodal disease. In paper IV, we demonstrated a significant association between IDO1 and PD-L1 in PCNSL patients. This finding indicates the crucial immunosuppressive role of these two molecules. In addition, in PCNSL low frequencies of MYC and BCL2 translocations and high frequency of BCL6 translocation was observed and DEL was detected in 49% of cases. Contrary to our results in systemic DLBCL in papers I-III, there was no significant prognostic impact of DEL in PCNSL.
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| 2. |
- Abu Sabaa, Amal
(författare)
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Clinical and Molecular Studies of Diffuse Large B-cell Lymphoma
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The general aim of this thesis was to study the prognostic clinical and biological markers of Diffuse Large B-cell Lymphoma (DLBCL).Paper I: Utilizing population-based data for patients with DLBCL in Sweden, the study aimed to establish whether event free survival at 24 months (EFS24) was a reproducible milestone. The disease-free survival for lymphoma patients was compared with that of age and sex matched Swedish general population. We demonstrated that overall survival was similar to age and sex matched general population only for younger patients (<60 years of age) achieving ES24. Patients older than that had worse prognosis. Death was mainly linked to cardiovascular disease and secondary malignancies.Paper II: Plasma samples collected via the bio bank U-CAN were analyzed using multiplex extension assay (PEA) utilizing preselected protein panels to examine the possibility of distinguishing lymphomas, leukemias and controls. The study confirmed that PEA technology could be used not only to effectively screen for large number of plasma protein biomarkers in low plasma sample volumes (1 µL), but even to discriminate between controls and different haematological malignancies. Paper III: Plasma protein pattern evolution in DLBCL patients was highlighted by PEA analysis of plasma proteins at different time points under treatment with Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Significant distinctions in protein patterns at diagnosis compared to controls and striking differences in protein levels before and after treatment in patient who responded to treatment were evident. The three top proteins were TCL1A, CXCL13 and IL2RA. Paper IV: An interesting protein that emerged from the above studies was TCL1A. This plasma protein was analyzed in plasma samples by PEA. Validation by plasma enzyme immunosorbent assay (ELISA) was attempted. The cytoplasm and nucleus bound form of TCL1A were analyzed with the help of immunohistochemistry in tissue microarray samples. The study included 178 patients of which 125 received R-CHOP. Clinical risk factor analysis showed no significant correlation with tissue IHC. Significantly higher levels of plasma TCL1A were seen in male patients (measured by ELISA and PEA) and in patients with Ann Arbor stages II-IV (measured by PEA). Survival analysis showed no statistical significance.
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| 3. |
- Adde, Magdalena, 1960-
(författare)
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Aggressive B-cell Lymphomas : Studies of Treatment, FDG-PET Evaluation and Prognostic Factors
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- To improve outcome in young, high-risk lymphoma patients, treatment was intensified, adding etoposide and rituximab to standard CHOP treatment. Granulocyte-colony stimulating factor (G-CSF) enabled treatment bi-weekly. Results were promising: overall (OS) and event-free survival (EFS) 79% and 60% respectively, median follow up 27 months. Single infusion Ara-C, contrary to expectations, did not prevent relapse in CNS. DLBCL were classified as germinal center (GC) or non-GC derived, using immunohistochemical markers, CD10, BCL6 and MUM1. We investigated the outcome for both phenotypes after adding rituximab to chemotherapy. For 106 patients treated with CHOP alone, the GC phenotype displayed significantly better OS and EFS. In contrast, GC phenotype did not predict outcome in 95 patients treated with immunochemotherapy . Thus, addition of rituximab seems to eliminate the prognostic value of immunohistochemically defined GC phenotypes in DLBCL. To improve evaluation and find non-responders, mid-treatment FDG-PET CT was incorporated into clinical routine for patients with high-risk aggressive lymphoma. For those with positive PET, biopsy followed by treatment intensification was recommended. Twenty-five patients were examined, five with positive PET. Two of these had lymphoma in the biopsy. Two had a negative biopsy, and one had a false positive investigation. Seven patients had increased uptake of uncertain significance. Two patients with uncertain PET, and two with negative PET have relapsed, giving a negative predictive value of 85%. In case of relapse of aggressive lymphoma or if not obtaining CR, high dose chemotherapy with autologous stem cell support (HDT) is standard treatment. HDT outcome for 38 patients with transformed follicular lymphoma was compared to outcome for 79 patients with de novo B-cell lymphoma. At median follow-up of 11.5 years both OS and EFS were superior in the transformed group, OS 67% and 33%, EFS 55% and 27% respectively. Treatment related mortality was less than reported in other studies.
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| 4. |
- Cederblad, Lena, 1959-
(författare)
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Aspects on Head and neck Cancer with special reference to Salivary Gland Tumours and Single Nucleotide Polymorphism
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A thesis on Head and neck cancer focusing on dose planning, salivary gland carcinoma and Single nucleotide polymorphism.For dose planning PET/CT (Positron emissions tomography/computed tomography) with tracer gave more precise information in comparison dose planning with CT. More primary tumours and metastases were found with the acetate tracer than with glucose tracer. Acetate PET/CT also showed larger volume of tumours attributed to lipid metabolism.In a retrospective study salivary gland cancer 5-year overall survival (OS) was 53 %. Salivary gland carcinoma consists of many histopathological groups, the two largest groups being mucoepidermoid carcinoma (MEC) and adenoid cystic carcinoma (ASCC). For ACC, having the best 5-year OS, it was 70 percent. Facial palsy, advanced stage disease, lymph node metastases worsened prognosis. ACC and polymorphous low grade carcinoma (PLGA) expressed c-myc and cyclin D1 to a larger extent than MEC.In squamous cell carcinoma of the head and neck we examined the occurrence of Single Nucleotide polymorphism, SNP. We found that the SNPs in male and female patients differed from each other. In male patients the SNPs were associated with immune response while in female patients the association was to SNPs concerning inflammation. This means that different pathways were engaged in cancer development for men and women. We also found that the SNPs in patients were different from those expressed in the healthy controls.
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| 5. |
- Delforoush, Maryam, 1980-
(författare)
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Potential New Drugs in Lymphoma
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lymphomas are malignant tumours arising from cells in the lymphatic system. They are classified as B-cell lymphomas, T-cell lymphomas and Hodgkin lymphoma (HL). Of the B-cell lymphomas, one of the most common is diffuse large B-cell lymphoma (DLBCL). Many patients with lymphomas can be successfully treated however patients who relapse or are refractory have a poor prognosis, warranting further investigations to identify potential targets and develop novel drugs.Picropodophyllin (PPP), a potent and selective inhibitor of IGF-1R, inhibits malignant cell growth with low or no toxicity on normal cells in preclinical models. In paper I, we investigated the potential benefits of using PPP against DLBCL and found that the anti-tumor effects of PPP might possibly be explained by IGF-1R-unrelated mechanism(s). However, the inhibitory effects of PPP on lymphoma cells together with its low toxicity in vivo makes it a promising drug candidate for treatment. Melflufen, a derivative of melphalan, is currently being evaluated in a clinical phase I/II trial in relapsed or refractory multiple myeloma. In paper II, we confirmed previous reports of superior potency of melflufen over melphalan. Being active in cell lines and primary cultures of lymphoma cells as well as in a xenograft model in mice, melflufen considered being a candidate for further evaluation in treatment. bAP-15, a novel inhibitor of proteasome activity, inhibits ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase L5 (UCHL5). In paper III, we investigated the activity of b-AP15 in DLBCL and HL cell lines and compared the results to standard drugs used in treatment. Results showed inhibition of the proteasome and growth inhibition/cytotoxicity with IC50-values in the micromolar range. Treatment failure and lack of clinical benefit of proteasome inhibitors like bortezomib in DLBCL patients inspired us investigating for possible new targets, with major focus on proteasome inhibitors in DLBCL. In paper IV, we suggested that UCHL5 and/or USP14, as new targets for proteasome inhibitors in DLBCL, be further evaluated.The findings in this thesis suggest that PPP, Melflufen and b-AP15 are potential candidates for clinical drug development and UCHL5 and/or USP14 are new potential targets for proteasome inhibitors in DLBCL.
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| 6. |
- Englund, Annika
(författare)
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Hodgkin Lymphoma in children, adolescents and young adults
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hodgkin lymphoma (HL) is a heterogeneous condition varying from engaging one single lymph node site to a widespread condition. The prognosis with contemporary treatment is excellent for the vast majority. However, the treatment might cause severe late adverse effects in a proportion of the affected individuals.We evaluated all children and adolescents diagnosed in Sweden and registered in the Swedish Childhood Cancer Register over a period of 25 years. The incidence has been stable and the overall survival (OS) is very good, comparable to the best results in the world. Approximately ten percent encountered a relapse, but even after relapse the chances of survival were good. During the study period there were no detectable changes in survival estimates. The use of radiotherapy has decreased.Epstein Barr virus (EBV) and numbers of eosinophils, mast cells and macrophages in the tumors were investigated in 98 cases. Young children were more likely to express EBV. In patients with advanced disease the mast cell and macrophage counts were higher and they also had more affected laboratory parameters. Patients with Nodular Lymphocyte Predominant Hodgkin Lymphoma did not express EBV in the tumor, had significantly lower numbers of eosinophils, mast cells and macrophages and less affected laboratory parameters compared to classical HL.Outcome and clinical presentation were investigated in a cohort of children, adolescents and young adults in Sweden and Denmark and treatment in pediatric and adult departments was compared. OS and event-free survival (EFS) did not differ between the three age groups nor between pediatric and adult treatment. However, the Danish pediatric patients had lower EFS, which corresponded to less use of radiotherapy. Adolescents and young adults shared similar characteristics, while children presented differently with less advanced disease and male preponderance.Hospitalization rates and outpatient visits after end of treatment were evaluated to see whether the excess need of resources described in the literature is evenly distributed among the survivors or whether it is limited to a smaller group. Most of the patients had a low burden of health care use and the relapsing patients were the main drivers of the excess need.
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| 7. |
- Gholiha, Alex R.
(författare)
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Immunologic Markers in the Tumor Microenvironment of Classical Hodgkin Lymphoma
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In classical Hodgkin lymphoma (cHL), cytokine regulation and cellular composition of the tumor microenvironment (TME) is crucial for tumor cell survival. In paper I, we examined the presence of CD138+ plasma cells and IgG4+ plasma cells in diagnostic cHL biopsies with immunohistochemistry (IHC). We found that increasing proportions of CD138+ plasma cells in the TME were associated with B-symptoms and inferior survival. IgG4+ plasma cells in the TME were a rare finding. In paper II, we investigated IL-6+ leukocytes and IL-6+ Hodgkin-Reed-Sternberg (HRS) cells in the TME of primary cHL. We observed that an IL-6+ leukocyte proportion of ≤ 1% in the TME was an independent adverse prognostic marker for event-free and overall survival. Further, the presence of IL-6+ leukocytes correlated with an increased proportion of CD138+ plasma cells and CD68+macrophages in the TME. IL-6+ HRS cells correlated with increased proportions of CD68+macrophages, PD-L1+ leukocytes, and PD-L1+HRS cells. In paper III, we investigated CD47 surface glycoprotein expression on HRS cells in the TME. CD47 is mainly known to promote antiphagocytic signaling via interaction with the SIRPa protein on phagocytic cells. IHC for CD47 was performed on diagnostic cHL biopsies. Cases with high CD47 expression on HRS cells had an inferior survival in univariate and multivariate analyses, adjusting for established prognostic factors compared with patients with low CD47 expression on HRS cells. In paper IV, using the Proximity Extension Assay (PEA) method, we identified 17 distinguishing immunologic proteins in cHL when comparing cHL diagnostic tissue lysates with reactive lymph node lysates from controls. In addition, 8 of these 17 proteins were elevated in cHL plasma compared with plasma from controls. Several of the identified proteins have established evidence in cHL as PD-L1, IL-6, CCL17, LAG3, and several proteins were introduced as new potential targets. In conclusion, our findings increase our knowledge regarding several immunological elements within the TME of cHL introducing clinicopathological associations of prognostic and potential therapeutic future implications.
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| 8. |
- Glimelius, Ingrid, 1975-
(författare)
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Hodgkin Lymphoma – an Interplay Between Tumour Cell and Microenvironment
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hodgkin lymphoma (HL) is a malignant disorder characterised by few tumour cells surrounded by a massive infiltrate of inflammatory cells, fibrosis, and microvessels. Therefore, it is a good model in which to study the interplay between tumour cells and the microenvironment. In a population-based series, stage IIB had poor prognosis, equivalent to the most advanced stage (stage IV). The most prominent negative prognostic factor was tumour bulk in the mediastinum (often large fibrotic tumours). The tumour cells expressed interleukin-9 (IL-9) in their cytoplasm in half of the cases. These cases had an over representation of nodular sclerosis histology (characterised by fibrotic bands) and infiltration of eosinophils and mast cells in the tumours. Despite this, IL-9 expression was not a negative prognostic factor. A role of inflammatory cells is to contribute to angiogenesis. Yet, a correlation between high microvessel count and high mast cell number in HL tumours was not identified, in contrast to other lymphomas. However, a correlation to poor prognosis was seen for cases with high microvessel count. Eosinophils contain eosinophil cationic protein (ECP). ECP was cytotoxic to cells from two HL cell lines of B-cell origin and one HL line of T-cell origin. At high concentrations, the cytotoxic effect was not as pronounced for the line of T-cell origin. If the in vitro cell lines are representative of HL in vivo, eosinophils may have different roles in different HL tumours. In addition to the effect from tumour cells, host-related factors contribute to the inflammatory infiltrate in HL. A history of asthma and hives, and carrying the ECP434GG genotype were associated with elevated numbers of eosinophils, whereas, history of tobacco smoking was associated with lower numbers. HL is a complex tumour consisting of recruited and subverted normal cells, fibrosis and angiogenesis: these constitute the microenvironment, which likely supports tumour cell growth, and differs between patients.
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| 9. |
- Hedström, Gustaf
(författare)
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Prognostic Markers in Diffuse Large B-cell Lymphoma : How Bad can it be
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diffuse large B-cell lymphoma (DLBCL), which is the most common type of lymphoma, is characterised by its aggressiveness and poor outcome without adequate treatment and also for its biological and clinical heterogeneity. It is therefore highly desirable to gain a more profound understanding of the underlying biology of the disease, as well as predictive factors for the guidance of treatment. The studies presented here attempt to gain an overall grasp on DLBCL, from the epidemiological level down to the genomic level.The tumour microenvironment consists of both tumour cells and normal infiltrating cells in a delicate interplay. By assessing the number of infiltrating mast cells (MCs) in the microenvironment, a correlation between low numbers of MCs and poorer prognosis of DLBCL was found.However, malignant cells are not only affected by environmental conditions but also by intrinsic factors, such as small non-coding microRNAs. A low expression level of microRNA-129 was found to correlate with poor survival of DLBCL and the finding remained significant even for rituximab-treated patients.An even smaller intracellular genomic unit is one single nucleotide. The single nucleotide polymorphism 309 (SNP309) is a T to G change in the promotor region of MDM2, a regulatory protein in the p53 pathway, which results in increased transcription of MDM2 and thus decreased levels of p53. It was found that homozygous T allele patients had longer overall survival, as well as disease-specific survival and disease-free survival. However, treatment with rituximab eliminated the predictive value of the SNP309 polymorphism.In the last project presented in this thesis we used epidemiological methods to analyse all DLBCL cases diagnosed 2000-2013 in Sweden. Here it was possible to categorically show that higher age is an adverse prognostic factor, and most importantly, this starts from a young age.In conclusion, within this thesis I have applied different laboratory and analysis techniques to examine DLBCL biology in relation to the clinic. I have identified potential new prognostic markers, contributed to an enhanced understanding of DLBCL biology and described epidemiological data from one of the largest DLBCL cohorts ever presented. All of these aspects provide important information for a deeper understanding of the disease DLBCL.
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| 10. |
- Hellström, Vivan
(författare)
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The clinical perspective on malignancies in renal transplanted patients
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Post-transplant malignancies cause significant morbidity and mortality. In this thesis we investigated malignancies in renal transplanted patients from a clinical viewpoint. The use of regional tumour registries considerably improved identification of pre- and post-transplant malignancies, which are generally underreported in transplant registries.Despite previously adequate cancer treatments with favourable prognosis, patients with pre-transplant malignancies showed higher incidence of post-transplant cancer and reduced survival compared to a 1:3 ratio matched control group of patients without a previous cancer from the Collaborative Transplant Study in Europe. A careful oncological surveillance pre-transplant and post-transplant is recommended.A multidisciplinary team evaluated the immunosuppressive and oncological treatment in a clinical prospective observational study of 120 renal transplanted patients with post-transplant malignancies. In two-thirds of the patients immunosuppression was possible to change to mTOR inhibitors with anti-tumour effects. Oncological treatment was adjusted in 50% of patients with solid or haematological tumours. MDT assessments are essential for optimizing treatment of post-transplant malignancies.Number of previous cutaneous squamous cell carcinoma (SCC) posed the most significant risk variable in predicting subsequent SCCs during a two-years study of 73 transplanted patients with at least one SCC.Incidence of transplant-derived tumours is 5 times higher than anticipated. Three of eleven cancers in urinary tract and two of four cancers in the transplants were transplant-derived. Five of eleven cancers of the urinary tract were BK-virus positive. Allograft immune response against these tumours offer new options for cancer treatment such as immunomodulatory or anti-viral treatment in combination with modified immunosuppression.
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