Purpose To investigate the proportion of patients with lymphoma with persistent clinically relevant cognitive impairment, and its relation to treatment, fatigue, and psychological distress.Methods... Show morePurpose To investigate the proportion of patients with lymphoma with persistent clinically relevant cognitive impairment, and its relation to treatment, fatigue, and psychological distress.Methods Patients with diffuse-large-B-cell-lymphoma (DLBCL), follicular-lymphoma (FL), and chronic-lymphocytic-leukemia (CLL)/small-lymphocytic-lymphoma (SLL), diagnosed between 2004-2010 or 2015-2019, were followed up to 8 years post-diagnosis. Sociodemographic and clinical data were obtained from the Netherlands Cancer Registry and the Population-based HAematological Registry for Observational Studies. The EORTC QLQ-C30 was used to assess cognitive functioning and fatigue, and the HADS to assess psychological distress. Individual growth curve models were performed. Results were compared with an age- and sex-matched normative population.Results A total of 924 patients were included (70% response rate). Persistent cognitive impairment was twice as high in patients (30%) compared to the normative population (15%). Additionally, 74% of patients reported co-occurring symptoms of persistent fatigue and/or psychological distress. Patients with FL (- 23 points, p < 0.001) and CLL/SLL (- 10 points, p < 0.05) reported clinically relevant deterioration of cognitive functioning, as did the normative population (FLnorm - 5 points, DLBCLnorm - 4 points, both p < 0.05). Younger age, higher fatigue, and/or psychological distress at inclusion were associated with worse cognitive functioning (all p's < 0.01). Treatment appeared less relevant.Conclusion Almost one-third of patients with lymphoma report persistent cognitive impairment, remaining present up to 8 years post-diagnosis. Early onset and co-occurrence of symptoms highlight the need for clinicians to discuss symptoms with patients early.Implications for Cancer Survivors Early recognition of cognitive impairment could increase timely referral to suitable supportive care (i.e., lifestyle interventions) and reduce (long-term) symptom burden. Show less
The objective is to assess the performance of seven semiautomatic and two fully automatic segmentation methods on [F-18]FDG PET/CT lymphoma images and evaluate their influence on tumor... Show moreThe objective is to assess the performance of seven semiautomatic and two fully automatic segmentation methods on [F-18]FDG PET/CT lymphoma images and evaluate their influence on tumor quantification. All lymphoma lesions identified in 65 whole-body [F-18]FDG PET/CT staging images were segmented by two experienced observers using manual and semiautomatic methods. Semiautomatic segmentation using absolute and relative thresholds, k-means and Bayesian clustering, and a self-adaptive configuration (SAC) of k-means and Bayesian was applied. Three state-of-the-art deep learning-based segmentations methods using a 3D U-Net architecture were also applied. One was semiautomatic and two were fully automatic, of which one is publicly available. Dice coefficient (DC) measured segmentation overlap, considering manual segmentation the ground truth. Lymphoma lesions were characterized by 31 features. Intraclass correlation coefficient (ICC) assessed features agreement between different segmentation methods. Nine hundred twenty [F-18]FDG-avid lesions were identified. The SAC Bayesian method achieved the highest median intra-observer DC (0.87). Inter-observers' DC was higher for SAC Bayesian than manual segmentation (0.94 vs 0.84, p < 0.001). Semiautomatic deep learning-based median DC was promising (0.83 (Obs1), 0.79 (Obs2)). Threshold-based methods and publicly available 3D U-Net gave poorer results (0.56 <= DC <= 0.68). Maximum, mean, and peak standardized uptake values, metabolic tumor volume, and total lesion glycolysis showed excellent agreement (ICC >= 0.92) between manual and SAC Bayesian segmentation methods. The SAC Bayesian classifier is more reproducible and produces similar lesion features compared to manual segmentation, giving the best concordant results of all other methods. Deep learning-based segmentation can achieve overall good segmentation results but failed in few patients impacting patients' clinical evaluation. Show less
Most lymphomas and leukemias are neo¬plasms of B cells. Due to the many different B cell development stages from which these neoplasms arise, the resulting diseases are quite heterogeneous, which... Show moreMost lymphomas and leukemias are neo¬plasms of B cells. Due to the many different B cell development stages from which these neoplasms arise, the resulting diseases are quite heterogeneous, which amongst other things is manifested in different tumor growth location, proliferation potential and surface antigen repertoire. Neverthe¬less, some population characteristics are found in almost all B cell malignancies as the cell-of-origin is identical. One of these is the cell surface antigen CD20. Originally used as a marker to distinguishing B cells from other lymphocytes, it quickly became a target for immunotherapy. Immuno-therapy is a treatment that makes use of immune system components to fight cancer, in this case by the injection of a monoclonal antibody specifically targeting one protein: CD20. The addition of CD20-targeting an¬tibodies to an anti-tumor treatment allows your immune system to recognize CD20-ex¬pressing B cells (diseased and healthy), and dispose of them. Overall, after several decades of research and therapeutic experience with antibodies targeting CD20, new functional discoveries as well as therapeutic advances are still being made, and CD20 therefore remains a highly attractive and fruitful target for the therapy of B cell malignancies as well as certain B-cell mediated autoimmune diseases. Show less
Xin, B.T.; Schimmack, G.; Du, Y.; Florea, B.I.; Marel, G.A. van der; Driessen, C.; ... ; Overkleeft, H.S. 2016
This thesis describes a study on primary diffuse large B cell lymphoma of bone with large patient numbers in chapter 2. The tumor presents mostly in the long bones. The clinical outcome is usually... Show moreThis thesis describes a study on primary diffuse large B cell lymphoma of bone with large patient numbers in chapter 2. The tumor presents mostly in the long bones. The clinical outcome is usually favorable. We found a trend towards worse survival for the immunoblastic tumor subtype. In chapter three, We studied the MRI characteristics of 29 bone lymphoma patients. The majority of the patients displayed a combination of definite cortical abnormalities and extension to the soft tissue, but up to 31% of the patients showed MRI features that looked radiologically non-aggressive or even benign. In chapter four, we determined the prognostic significance of BCL-6, CD10, MUM1, BCL-2, p53, CD30 and CD44. Applying the Hans__ algorithm, we concluded that 19 out of a cohort of 36 cases displayed a germinal center-like phenotype. No significant influence on survival was found. In chapter five, we investigated genomic alterations in nine cases. We found several recurrent genomic aberrations, but none had statistically significant prognostic influence. The most frequent finding was five cases with gain of 1q (five out of nine cases) and 2p16.1 amplification (four out of nine cases). In chapter six we investigated 50 cases for involvement of aberrant NF-_B activation by performing immunohistochemical stainings. In a minority (19%) of cases, we found substantial nuclear staining of p50. The nuclear expression of p50 was not preferentially detected in non-germinal center or germinal center type cases, or related to an inferior prognosis. Show less
De resultaten beschreven in dit proefschrift verschaffen nieuwe inzichten in verschillende aspecten van de behandeling van inflammatoire darmziekten. Uit grote studies is gebleken dat mutaties in... Show moreDe resultaten beschreven in dit proefschrift verschaffen nieuwe inzichten in verschillende aspecten van de behandeling van inflammatoire darmziekten. Uit grote studies is gebleken dat mutaties in genen die betrokken zijn bij het autofagie proces (autophagos: __zelf-eten__), geassocieerd zijn met de ziekte van Crohn. In dit proefschrift wordt beschreven hoe deze mutatie in dendritische cellen leidt tot hyperactivatie van het immuunsysteem. Dit mechanisme kan mogelijk een nieuw aangrijpingspunt verschaffen voor nieuwe therapie voor pati_nten die een mutatie hebben in dit gen. Anti-tumor-necrosis-factor-alpha (anti-TNF_) therapie neemt een steeds belangrijkere plaats in in de behandeling van IBD; het werkingsmechanisme is echter niet geheel duidelijk. In dit proefschrift wordt beschreven hoe regulatoire macrophagen met immuunsuppressieve en wondgenezende eigenschappen ge_nduceerd worden door anti-TNF_ therapie. Dit werkingsmechanisme kan nieuwe aangrijpingspunten verschaffen voor toekomstige therapie_n. Tevens wordt in dit proefschrift een experimentele behandeling van Crohn met mesenchymale stamcellen (MSCs) beschreven. Deze behandeling is haalbaar en veilig gebleken, hetgeen aanleiding geeft tot verder onderzoek naar de effectiviteit van MSCs in de behandeling van Crohn. Tot slot werd het v__rkomen van kwaadaardige lymfomen onderzocht in IBD pati_nten in Nederland. Deze lymfomen bleken niet vaker voor te komen in de totale groep IBD pati_nten vergeleken met gezonde mensen, wel werd een verhoogde incidentie gezien in bepaalde leeftijdsgroepen. Daarnaast bleek het ontstaan van een EBV positief lymfoom (epstein Barr virus) sterk geassocieerd te zijn met het gebruik van azathioprine, een ander immuunsuppressieve therapie. Samenvattend beschrijft dit proefschrift verschillende aspecten van IBD therapie, en worden nieuwe inzichten en aangrijpinspunten verschaft Show less
Diffuse large B cell lymphoma is the most common type of non-Hodgkin lymphoma of which 40% present at extra-nodal sites including immune privileged sites such as the testis and the central nervous... Show moreDiffuse large B cell lymphoma is the most common type of non-Hodgkin lymphoma of which 40% present at extra-nodal sites including immune privileged sites such as the testis and the central nervous system (CNS). Loss of Human Leucocyte Antigen (HLA) expression has been described in many different tumour types as a mechanism to evade anti-tumour immune responsen. In testicular and CNS lymphomas HLA class I and II expression was very commonly observed in contrast to nodal, stomach and skin lymphomas that expressed HLA in most of the cases. Loss of HLA-DR and DQ expression was often due to homozygous deletions of the corresponding genes. Loss of class I expression was often caused by loss of Beta-2-microglobulin expression and hemizygous deletions. Despite their immune privileged status, the testicular and CNS lymphomas showed high numbers of activated cytotoxic T cells, suggesting that these lymphomas are highly immunogenic. DNA-typing for HLA-DR and DQ polymorphisms in testicular and nodal lymphomas revealed a positive association of testicular lymphomas with HLA-DRB1*12 and a negative association of nodal lymphomas with HLA-DRB1*07. Both testicular and nodal lymphomas showed a positive association with HLA-DRB1*15. No significant relationship was found between the different haplotypes and the occurrence of homozygous deletions in the testicular lymphomas. Show less
Primary cutaneous lymphoma form a seperate group of non-Hodgkin lymphoma. Apart from the usual nodal presentation of a lymphoma, less frequently a lymphoma develops in an extranodal site. The skin... Show morePrimary cutaneous lymphoma form a seperate group of non-Hodgkin lymphoma. Apart from the usual nodal presentation of a lymphoma, less frequently a lymphoma develops in an extranodal site. The skin is, after the gastrointestinal tract, the most frequent site of extranodal lymphoma. If the skin is the primary site of involvement, i.e. no extracutaneous sites are involved at diagnosis, these lymphomas are called primary cutaneous lymphoma. In this thesis different types of primary cutaneous lymphoma are evaluated and discussed. In chapter 2 a large group of primary cutaneous CD30+ lympoproliferations is described and compared with a group of systemic CD30+ ALCL with skin localisations. Lymphomatoid papulosis and primary cutaneous CD30+ CTCL are closely related conditions and should be considered as a spectrum, with a comparable, excellent, prognosis. Multiagent chemotherapy (MAC) could not induce long lasting remissions, in fact all patients treated with MAC developed one or more (cutaneous) relapses. Therefor MAC is only indicated in case of extracuteneous localisations. In chapter 3 a group of CD30-negative T-cell lymphomas presenting in the skin that could not be diagnosed as MF, SS or SPTL are evaluated. In this group there were few survivors, apart from a rare group of patients with primary cutaneous lymphoma with small-medium sized CD4+/CD8-neoplastic T-cells (less than 30% large cells). In particular, patients with localized disease had an excellent prognosis. In chapter 4 haematological malignancies presenting in the skin and expressing CD56 were collected, both from the Dutch cutaneous lymphoma group and literature. In general these types of malignancies had a poor prognosis, except for patients with primary cutaneous CD30+ LPD, that showed a similar good prognosis as CD56-negative cases. Most cases belonged to the group of nasal-type NK/T-cell lymphoma and the group of CD4+, CD56+ hematodermic neoplasm (formerly also designated as blastic NK-cell lymphoma. In addition, CD56 was expressed in some SPTL, rare primary cutaneous CD30-negative large T-cell lymphomas, skin localisations of acute myeloid leukemia and CD30+ CTCL. In most of these groups CD56 expression did not affect prognosis. However, in SPTL CD56 expression proved a marker for gamma/delta T-cell origin and these cases showed a poorer prognosis as compared to SPTL with an alpha/beta phenotype (that were usually CD56-negative). In the new WHO-EORTC classification the category of SPTL only includes cases with an alpha/beta-positive phenotype, whereas cases with a gamma/delta positive phenotype are included in the provisional category of cutaneous gamma/delta-positive T-cell lymphoma. In chapter 5 a rare case of lymphomatoid papulosis with CD56-expression was presented and the frequency of co-expression of CD56 in primary cutaneous CD30+ LPD was analyzed. CD56 expression was found in approximately 10% of CD30+ LPD (both LyP and primary CD30+ CTCL). However, these CD56+ cases were not found to have a different prognosis from CD56 negative cases. In chapter 6 a European multicenter study on primary cutaneous large B-cell lymphomas is presented. Patients with primary cutaneous large B-cell lymphoma of the leg showed a poorer prognosis as patients with primary cutaneous follicle center cell lymphoma (PCFCCL). Moreover, round cell morphology was identified as a poor prognostic parameter. Although this was closely related to presentation on the leg(s), also in the group of PCFCCL the presence of a predominance of cells with round nuclei (centroblasts and immunoblasts) was associated with a poorer prognosis. The results of this study contributed to a new category in the WHO-EORTC classification, designated primary cutaneous large B-cell lymphoma (PCLBCL), leg-type, indicating that both patients with the classical presentation on the leg(s) as patients showing the same morphology and immunophenotype (bcl-2+, Mum-1/ IRF4+) on other sites are included in this group. Presentation with multifocal lesions proved to be a poor prognostic parameter for PCLBCL-leg-type, but not for PCFCCL. In chapter 7 treatment results in multifocal primary CBCL were analyzed. The main question in this study was if PCFCCL presenting with multifocal skin lesions should be treated with MAC. The study showed that MAC is only indicated in PCLBCL, leg-type and not in (multifocal) PCFCCL. Radiotherapy on multiple sites appeared equally effective as MAC in these patients. In chapter 8 the frequency of CNS-involvement in CBCL patients of the Dutch cutaneous lymphoma group. was evaluated. The frequency was low. Only 4/140 patients with a primary CBCL developed CNS involvement in the course of their disease. Interestingly 3 of these 4 patients were PCFCCL, a lymphoma usually with an excellent prognosis. Only 4 disease related deaths were reported in this group of which 3 with CNS involvement. The reason for this relatively high prevalence of CNS involvement in PCFCCL is unclear. The studies presented in this thesis have provided important information, which has contributed to the recent development of the WHO-EORTC classification. Moreover, they have contributed to updated guidelines for the treatment of the different types of primary cutaneous lymphomas, as presented in TABLE 2 in chapter 9. Show less
