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Background: Accurate regulation of DNA methylation is necessary for normal cells to differentiate, develop and function. TET2 catalyzes stepwise DNA demethylation in hematopoietic cells. Mutations in the TET2 gene predispose to hematological malignancies by causing DNA methylation overload and aberrant epigenomic landscape. Studies on mice and cell lines show that the function of TET2 is boosted by vitamin C. Thus, by strengthening the demethylation activity of TET2, vitamin C could play a role in the prevention of hematological malignancies in individuals with TET2 dysfunction. We recently identified a family with lymphoma predisposition where a heterozygous truncating germline mutation in TET2 segregated with nodular lymphocyte-predominant Hodgkin lymphoma. The mutation carriers displayed a hypermethylation pattern that was absent in the family members without the mutation. Methods: In a clinical trial of 1 year, we investigated the effects of oral 1 g/day vitamin C supplementation on DNA methylation by analyzing genome-wide DNA methylation and gene expression patterns from the family members. Results: We show that vitamin C reinforces the DNA demethylation cascade, reduces the proportion of hypermethylated loci and diminishes gene expression differences between TET2 mutation carriers and control individuals. Conclusions: These results suggest that vitamin C supplementation increases DNA methylation turnover and provide a basis for further work to examine the potential benefits of vitamin C supplementation in individuals with germline and somatic TET2 mutations.

Background: Immune-related adverse events (irAEs) are frequently encountered by patients during immune checkpoint inhibitor (ICI) treatment and are associated with better treatment outcomes. The sequencing of radiotherapy (RT) and ICIs is widely used in current clinical practice, but its effect on survival has remained unclear. Methods: In a real-world multicenter study including 521 patients who received ICI treatment for metastatic or locally advanced cancer, RT schedules and timing, irAEs, time to progression, overall survival, and treatment responses were retrospectively reviewed. Results: Patients who received previous RT and developed irAE (RT +/AE +) had the best overall response rate (ORR 44.0%). The ORR was 40.1% in the RT −/AE + group, 26.7% in the RT −/AE − group and 18.3% in the RT + /AE − group (p < 0.001). There was a significantly longer time to progression (TTP) in the RT + /AE + group compared to the RT −/AE − and RT + /AE − groups (log rank p = 0.001 and p < 0.001, respectively), but the trend toward longer TTP in the RT + /AE + group did not reach statistical significance in pairwise comparison to that in the RT −/AE + group. Preceding RT timing and intent had no statistically significant effect on TTP. In a multivariate model, ECOG = 0 and occurrence of irAEs remained independent positive prognostic factors for TTP (HR 0.737; 95% CI 0.582–0.935; p = 0.012, and HR 0.620; 95% CI 0.499–0.769; p < 0.001, respectively). Conclusions: Better ORR and a trend toward longer TTP were demonstrated for patients with RT preceding ICI treatment and development of irAEs, which suggests that RT may boost the therapeutic effect of immunotherapy in patients with metastatic cancers.

The purpose of this RNA sequencing study was to investigate the biological mechanism underlying how the transcription factors (TFs) Twist1 and Zeb1 influence the prognosis of mycosis fungoides (MF). We used laser-captured microdissection to dissect malignant T-cells obtained from 40 skin biopsies from 40 MF patients with stage I–IV disease. Immunohistochemistry (IHC) was used to determinate the protein expression levels of Twist1 and Zeb1. Based on RNA sequencing, principal component analysis (PCA), differential expression (DE) analysis, ingenuity pathway analysis (IPA), and hub gene analysis were performed between the high and low Twist1 IHC expression cases. The DNA from 28 samples was used to analyze the TWIST1 promoter methylation level. In the PCA, Twist1 IHC expression seemed to classify cases into different groups. The DE analysis yielded 321 significant genes. In the IPA, 228 significant upstream regulators and 177 significant master regulators/causal networks were identified. In the hub gene analysis, 28 hub genes were found. The methylation level of TWIST1 promoter regions did not correlate with Twist1 protein expression. Zeb1 protein expression did not show any major correlation with global RNA expression in the PCA. Many of the observed genes and pathways associated with high Twist1 expression are known to be involved in immunoregulation, lymphocyte differentiation, and aggressive tumor biology. In conclusion, Twist1 might be an important regulator in the disease progression of MF.

Primary central nervous system lymphoma (PCNSL) is an aggressive brain disease where lymphocytes invade along perivascular spaces of arteries and veins. The invasion markedly changes (peri)vascular structures but its effect on physiological brain pulsations has not been previously studied. Using physiological magnetic resonance encephalography (MREGBOLD) scanning, this study aims to quantify the extent to which (peri)vascular PCNSL involvement alters the stability of physiological brain pulsations mediated by cerebral vasculature. Clinical implications and relevance were explored. In this study, 21 PCNSL patients (median 67y; 38% females) and 30 healthy age-matched controls (median 63y; 73% females) were scanned for MREGBOLD signal during 2018–2021. Motion effects were removed. Voxel-by-voxel Coefficient of Variation (CV) maps of MREGBOLD signal was calculated to examine the stability of physiological brain pulsations. Group-level differences in CV were examined using nonparametric covariate-adjusted tests. Subject-level CV alterations were examined against control population Z-score maps wherein clusters of increased CV values were detected. Spatial distributions of clusters and findings from routine clinical neuroimaging were compared [contrast-enhanced, diffusion-weighted, fluid-attenuated inversion recovery (FLAIR) data]. Whole-brain mean CV was linked to short-term mortality with 100% sensitivity and 100% specificity, as all deceased patients revealed higher values (n = 5, median 0.055) than surviving patients (n = 16, median 0.028) (p < .0001). After adjusting for medication, head motion, and age, patients revealed higher CV values (group median 0.035) than healthy controls (group median 0.024) around arterial territories (p ≤ .001). Abnormal clusters (median 1.10 × 10₅mm₃) extended spatially beyond FLAIR lesions (median 0.62 × 10₅mm₃) with differences in volumes (p = .0055).

Aim: The purpose of the study was to evaluate the clinical impact of fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) followed by a new biopsy from the site with maximum standardized uptake value (SUVmax) in case of high maximal SUV values, in detecting clinically unsuspected histologic transformations (HT) of follicular lymphoma (FL). Methods: This retrospective study included all the patients who had undergone FDG-PET/CT during primary diagnosis or relapse of FL between 2010 and 2020 at Oulu University Hospital. Results: The diagnosis changed from an indolent disease to a transformed lymphoma in >10% (7/63) of the patients who underwent diagnostic FDG-PET/CT. The HT risk associated with high SUVmax (>10) was 24% (7 of 29 performed biopsies). Four out of these seven patients with verified HT had no previous clinical suspicion of transformation. Conclusion: Our results suggest that a rebiopsy based on a high SUVmax in diagnostic FDG-PET/CT is valuable in detecting clinically unsuspected HT of FL.

Background: We report here the first population-based incidence rates and prognosis of primary central nervous system lymphoma (PCNSL) in Finland. Methods: Finnish Cancer Registry data by histological diagnosis and tumor location (2007–2017) for cases with diffuse large B-cell lymphoma. Results: During 2007–2017, 392 new cases of PCNSL were reported (195 males, 197 females). The average age-adjusted incidence was 0.68/100,000 person-years. Incidence for males was 0.74/100,000 and for females 0.63/100,000, respectively. The incidence was highest, 2.93/100,000, among people aged 75–79 years. Concerning all cases in 2007–2017 the 2-year age-adjusted relative survival rate was 33% and the corresponding 5-year survival rate was 26%. Among patients under the age of 70, the age-adjusted 5-year relative survival rate increased from 36% in 2007–2012 to 43% for 2013–2017. Among patients aged 70+ the corresponding survival rates were poor, 7 and 9%. Conclusions: PCNSL incidence in Finland is among the highest reported in the world. The annual increase in incidence was 2.4%. The prognosis is still dismal, especially in elderly patients.

Background: Autologous stem cell transplantation (auto-SCT) is a treatment option for patients with primary central nervous system lymphoma (PCNSL). Methods: In this prospective multicenter study, the effects of blood graft cellular content on hematologic recovery and outcome were analyzed in 17 PCNSL patients receiving auto-SCT upfront. Results: The infused viable CD34⁺ cell count > 1.7 × 10⁶/kg correlated with more rapid platelet engraftment (10 vs. 31 days, P = 0.027) and with early neutrophil recovery (day + 15) (5.4 vs. 1.6 × 10⁹/L, P = 0.047). A higher number of total collected CD34⁺ cells > 3.3 × 106/kg infused predicted worse 5-year progression-free survival (PFS) (33% vs. 100%, P = 0.028). In addition, CD3⁺CD8⁺ T cells > 78 × 10⁶/kg in the infused graft impacted negatively on the 5-year PFS (0% vs. 88%, P = 0.016). Conclusions: The cellular composition of infused graft seems to impact on the hematologic recovery and PFS post-transplant. Further studies are needed to verify the optimal autograft cellular content in PCNSL.

Approximately 1,300 patients develop non-Hodgkin lymphoma (NHL) in Finland each year. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL; in 2018, a total of 661 patients were identified with this disease in Finland. DLBCL is one of the most aggressive lymphoid cancers and, in most cases, leads to death without treatment. Rituximab has significantly improved the prognosis, and treatment is curative in 70% of patients. Nevertheless, the disease does not respond as expected to treatment or relapses soon after a complete response in some patients. The prognosis for these patients is poor. It is essential to recognize primary refractory diseases at the earliest possible stage to avoid the adverse effects of ineffective treatments and to allow intensification when needed. Radiotherapy (RT) has long-term adverse effects that can appear years or even decades after treatment. The criteria for radiotherapy in DLBCL patients are currently unclear, and conventional criteria for RT, such as primary bulky or residual tumor, were defined in the pre-rituximab era. This study demonstrates that bulky tumor has a significant impact on the prognosis of patients with the limited-stage disease. However, RT to bulky sites was not able to improve the outcome. PET-negative bulky or residual tumor do not seem to affect the prognosis. Hybrid positron emission tomography and -computed tomography (PET-CT) is a commonly used method for response evaluation in DLBCL and aims to identify patients with an insufficient response. However, PET-CT has a high rate of false positivity, resulting in the possibility of error. Treatment should be intensified in patients with active lymphoma tissue behind a positive PET finding, and it is therefore crucial to identify patients with PET-positivity due to other reasons. For these patients, biopsy guided by PET-CT provides more accurate information. Primary central nervous system lymphoma (PCNSL) is a rare disease. In nearly all re, Tiivistelmä Non-Hodgkin lymfoomiin sairastuu vuosittain Suomessa n. 1300 potilasta. Yleisin alatyyppi on Diffuusi suurisoluinen B-solulymfooma (DLBCL) johon v. 2018 sairastui 661 potilasta. DLBCL kuuluu nopeakasvuisiin imukudossyöpiin, jotka hoitamattomana johtavat useimmiten kuolemaan. Nykyisillä hoidoilla n. 70 % paranee. Hoidon aikana etenevässä tai nopeasti hoidon päättymisen jälkeen uusineessa tautitilanteessa ennuste on kuitenkin huono. Potilaiden ennusteen kannalta olisi tärkeää löytää ensilinjan hoidolle riittämättömästi reagoivat taudit mahdollisimman varhaisessa vaiheessa, jotta vältetään tehottoman hoidon haittavaikutukset ja toisaalta voidaan tehostaa hoitoa tarvittaessa. Sädehoidolla on pitkäaikaishaittoja, jotka voivat ilmaantua useita vuosia, jopa vuosikymmeniä, hoidon jälkeen. Sädehoidon kriteerit DLBCL potilailla eivät ole tällä hetkellä yksiselitteiset ja ne on määritelty ennen rituksimabin vakiintumista. Tässä tutkimuksessa lähtötilanteessa todetulla kookkaalla (yli 7,5 cm) kasvaimella oli potilaan ennustetta heikentävä vaikutus paikallisessa tautitilanteessa, mutta sädehoidolla tälle alueelle ei voitu parantaa ennustetta. PET-TT:ssä negatiivisella jäännöskasvaimella ei ollut ennustevaikutusta. PET-TT:tä käytetään yleisesti hoidon vastearviossa. Tavoitteena on tunnistaa potilaat, joiden tauti ei reagoi riittävästi tavanomaiselle hoidolle mutta väärien positiivisten tulosten määrä on kuitenkin korkea. Olisi tärkeää tunnistaa ne potilaat, joiden PET-positiivisuuden aiheuttavat muut syyt. Koepala jäännöskasvaimesta voi antaa lisätietoa näissä tilanteissa. Primaari aivolymfooma (PCNSL) on harvinainen ja huonoennusteinen tautimuoto. Lähes kaikissa rekisteripohjaisissa tutkimuksissa pitkäaikaisselviytyjiä on hyvin vähän. Useat faasi II-tutkimukset ovat osoittaneet lupaavia alkuvaiheen tuloksia metotreksaatti-pohjaisella hoidolla. Seurantatulokset ovat kuitenkin olleet huonot erityisesti uusineessa tai ensilinjan hoidolle vastaamattomassa tautitilanteess

Findings regarding the role of sex in follicular lymphoma (FL) are contradictory and the prognostic value of sex among patients with early progression of disease (POD) remains unclear. We collected real-life data from nine hospitals in Finland and Spain including 1020 FL patients to study the influence of sex on disease outcome. The median follow-up duration was 67 months (range 0–226 months). Female patients showed better progression-free survival (PFS) (hazard ratio [HR], 0.720; 95% confidence interval [CI], 0.588–0.881), disease-specific survival (DSS) (HR, 0.653; 95% CI, 0.448–0.951), and overall survival (OS) (HR, 0.653; 95% CI, 0.501–0.853) than male patients. However, there were no significant sex differences in prognosis in patients with early POD. This study strengthens the understanding that male sex is an adverse prognostic factor for FL. However, this difference does not apply to patients with early POD.

Although overall survival in diffuse large B cell lymphomas (DLBCL) has improved, central nervous system (CNS) relapse is still a fatal complication of DLBCL. For this reason, CNS prophylaxis is recommended for patients at high risk of CNS disease. However, no consensus exists on definition of high-risk patient and optimal CNS prophylaxis. Systemic high-dose methotrexate in combination with R-CHOP has been suggested as a potential prophylactic method, since methotrexate penetrates the blood-brain barrier and achieves high concentration in the CNS. In this retrospective analysis, we report treatment outcome of 95 high-risk DLBCL/FL grade 3B patients treated with R-CHOP or its derivatives with (N = 57) or without (N = 38) CNS prophylaxis. At a median follow-up time (51 months), CNS relapses were detected in twelve patients (12.6%). Ten out of twelve (83%) of CNS events were confined to CNS system only. Median overall survival after CNS relapse was 9 months. Five-year isolated CNS relapse rates were 5% in the prophylaxis group and 26% in the group without prophylaxis. These findings suggest that high-dose methotrexate-containing prophylaxis decreases the risk of CNS failure.

Lymphomas are a heterogeneous group of malignancies of the lymphoid cells with almost a hundred different subtypes. In recent decades, there has been a major improvement in treatment results, and nowadays, only one-third of patients die due to lymphoma. As treatment results have improved, more attention has been paid to the adverse effects of treatment, which may be serious or even lead to death. The aim of this study was to describe treatment methods with a smaller risk of late adverse effects without impairing the treatment results. Follicular lymphoma (FL) is the second most common type of lymphoma in adults. Its prognosis is good, but relapses are common, and treatment must often be repeated, which causes a carcinogenic burden to the patient. Secondary malignancies are a significant late-onset adverse effect of lymphoma treatments. Currently, there are several treatment options available for FL. However, the risks of secondary malignancies associated with different treatment methods are not totally clear. In the present study, a higher risk for secondary haematological malignancies was observed after multiple lines of treatment. For secondary solid tumours, on the other hand, the greater risk was associated with the use of bendamustine. Diffuse large B-cell lymphoma is the most common lymphoma subtype. Patients are elderly and therefore more vulnerable to treatment-related adverse effects. Moreover, cardiac comorbidities are common in elderly patients, which may limit the use of certain treatment options. In this study, treatment results with standard therapy R-CHOP were retrospectively compared to those obtained with R-CEOP and R-CIOP, which are known to be less cardiotoxic. Treatment with R-CEOP was comparable to standard therapy, whereas results with R-CIOP were inferior. Nodular lymphocyte predominant Hodgkin lymphoma is a rare lymphoma subtype. These patients are traditionally treated with the same methods as those with classical Hodgkin lymphoma, Tiivistelmä Lymfoomat ovat heterogeeninen joukko imukudoksen syöpiä ja lähes sata erilaista alatyyppiä on tunnistettu. Lymfoomien hoitotuloksissa on tapahtunut merkittävää edistystä viime vuosikymmenien aikana ja tällä hetkellä vain noin kolmannes potilaista menehtyy tautiin. Hoitotulosten parantuessa on alettu kiinnittää enemmän huomiota myös hoitojen aiheuttamiin haittoihin, jotka saattavat olla huomattavan hankalia ja johtaa jopa potilaan menehtymiseen. Tutkimuksen tarkoituksena oli kuvata hoitomuotoja, joilla hoidon haittojen riski olisi pienempi ilman, että lymfooman hoitotulokset heikkenevät. Follikulaarinen lymfooma on aikuisten toiseksi yleisin lymfoomatyyppi. Taudin ennuste on hyvä, mutta uusiutuminen on yleistä ja tällöin hoitoja joudutaan toistamaan, mikä aiheuttaa potilaille merkittävän karsinogeenisen altistuksen. Mahdollisia hoitomuotoja on useita eikä eri hoitomuotojen aiheuttamaa sekundaarisen syövän riskiä vielä tarkasti tunneta. Tässä tutkimuksessa selvisi, että sekundaaristen hematologisten syöpien riski kasvoi hoitolinjojen lukumäärän kasvaessa. Bendamustiinin käyttö oli yhteydessä suurempaan kiinteiden kasvainten riskiin. Diffuusi suurisoluinen B-solulymfooma on yleisin lymfooman alatyyppi. Potilaat ovat iäkkäitä, mikä lisää riskiä saada hoitojen haittavaikutuksia. Lisäksi iäkkäillä potilailla sydänsairaudet ovat yleisempiä, mikä voi rajoittaa sydäntoksisten hoitovaihtoehtojen käyttöä. Tässä tutkimuksessa verrattiin sydänturvallisempien R-CEOP ja R-CIOP sytostaattiyhdistelmien tehoa R-CHOP standardihoitoon. R-CEOP.lla saadut hoitotulokset olivat verrattavissa standardihoitoon, mutta R-CIOP.lla saadut hoitotulokset olivat heikompia. Nodulaarinen lymfosyyttivaltainen Hodgkinin lymfooma on harvinainen Hodgkinin lymfooma. Näitä potilaita on perinteisesti hoidettu samoilla hoitomuodoilla kun muita Hodgkinin lymfoomia, vaikka taudit ovat biologialtaan hyvin erilaisia. Hodgkinin lymfooman hoidossa käytettävät hoidot ovat huomattavan toksisia. Tutkimuks

Diffuse large B-cell lymphoma (DLBCL) is the single most common lymphoid malignancy in Western world. Excess oxidative stress and antioxidative enzyme expression have previously been associated with adverse disease presentation and poor prognosis in DLBCL. The present study evaluated the clinical relevance of two antioxidant enzymes—peroxiredoxin 6 (Prx6) and thioredoxin-1 (Trx)—, one oxidative stress marker—8-hydroxydeoxyguanosine (8-OHdG)—, and four antioxidative, response-related transcription factors nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2), Kelch ECH associating protein 1 (Keap1) and BTB (broad complex (BR-C), tramtrack (ttk), bric-a-brac/poxvirus (bab)) domain and Cap’n’collar (CNC) homolog 1 (Bach1) in DLBCL patients and cell culture (Trx). The pre-treatment blood serum levels of Prx6 were found to be significantly lower among DLBCL patients compared to healthy controls, and these levels were observed to rise to the controls’ levels after treatments. Low Prx6 levels were associated with neutropenic infections; thus, Prx6 might be a potential marker for selecting patients to receive white blood cell growth factors. All tissue assessed transcription factors, excluding Bach1, had prognostic implications among high-risk DLBCL patients. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 were related to poor overall survival. Nuclear Nrf2 and Bach1 expressions were associated with adverse clinical features in DLBCL. Lymphoma cell’s cytoplasmic Trx expression was associated with superior survival with DLBCL patients who received etoposide-containing, high-dose chemotherapy or R-CHOEP. In the cell culture model, knockdown of Trx resulted in sensitization of lymphoma cells to doxorubicin and decreased the response to etoposide. Trx appears to be predict the response to etoposide (R-CHOEP)., Tiivistelmä Diffuusi suurten B-solujen lymfooma (DLBCL) on yleisin yksittäinen imusolmukesyöpä länsimaissa. Runsas oksidatiivinen stressi ja antioksidatiivisten entsyymien ilmentyminen on aiemmin yhdistetty huonoon taudinkuvaan ja ennusteeseen DLBCL:ssä. Tässä tutkimuksessa arvioitiin kahden antioksidatiivisen entsyymin peroksiredoksiini 6 (Prx6) ja tioredoksiini-1 (Trx), yhden oksidatiivisen stressin markkerin 8-hydroksideoksyguanosiinin (8-OHdG) sekä neljän antioksidatiivivasteeseen liittyvän transkriptiotekijän tumafaktori erytoidi 2-liittyvä faktori 1 (Nrf1) ja faktori 2 (Nrf2), Kelch ECH assosioituva proteiini 1 (Keap1) ja BTB (broad complex (BR-C), tramtrack (ttk), bric-a-brac/poxvirus (bab)) domeeni ja Cap’n’collar (CNC) homologi 1 (Bach1) kliinistä merkitystä DLBCL-potilailla sekä soluviljelyssä (Trx). Hoitoja edeltävien Prx6-seerumipitoisuuksien havaittiin olevan huomattavasti pienempiä verrattuna terveisiin kontrolleihin. Nämä pitoisuudet nousivat hoitojen jälkeen kontrollien tasolle. Matala seerumin Prx6 assosioitui neutropeenisiin infektioihin, minkä vuoksi Prx6 voisi olla potentiaalinen markkeri valkosolukasvutekijän käyttöön. Kaikilla kudoksesta arvioiduilla transkriptiotekijöillä, pois lukien Bach1, oli ennusteellista merkitystä korkean riskin DLBCL-potilaille. Matala Nrf1-tumaekspressio, korkea Nrf1-sytoplasmaekspressio, korkea Nrf2-tumaekspressio ja matala Keap1-sytoplasmaekspressio liittyivät huonoon kokonaiselinaikaan. Nrf2- ja Bach1-tumaekspressiot assosioituvat huonompaan taudinkuvaan DLBCL:ssä. Lymfoomasolujen Trx-sytoplasmaekspressio liittyi parempaan ennusteeseen DLBCL-potilailla, jotka saivat hoidoksi etoposidia sisältävän korkea-annoshoidon tai R-CHOEP-kuurin. Soluviljelymallissa Trx:n tuotannon kumoaminen aiheutti lymfoomasolujen herkistymistä doksorubisiinille ja resistenssiä etoposidille. Trx vaikuttaa ennustavan vastetta etoposidille (R-CHOEP-hoidolle).

Summary Follicular lymphoma (FL) is the most common indolent lymphoma. Currently there are many comparable treatment options available for FL. When selecting the most optimal therapy it is important to consider possible late effects of the treatment as well as survival. Secondary haematological malignancy (SHM) is a severe late effect of treatments, but the incidence of SHMs is still largely unknown. The goal of the present study was to determine the incidence of SHMs and how therapeutic decisions interfere with this risk. The study included 1028 FL patients with a median follow‐up time of 5·6 years. The 5‐year risk of SHM was 1·1% and the risk was associated with multiple lines of treatment (P = 0·016). The 5‐year risk of SHM was 0·5% after the first‐line treatment and 1·6% after the second‐line. The standardized incidence ratio (SIR) was 6·2 (95% confidence interval 3·4–10·5) for SHM overall. This retrospective study found that the risk of SHM was low after first‐line treatment in FL patients from the rituximab era. However, the risk of SHM increases with multiple lines of treatment. Therapeutic approaches should aim to achieve as long a remission as possible with first‐line treatment, thereby postponing the added risk of SHM.

Aims: Oxidative stress markers and antioxidant enzymes have previously been shown to have prognostic value and associate with adverse outcome in patients with diffuse large B cell lymphoma (DLBCL). Nuclear factor erythroid 2-related factor 1 (Nrf1) and factor 2 (Nrf2) are among the principal inducers of antioxidant enzyme production. Kelch ECH associating protein 1 (Keap1) is a negative regulator of Nrf2, and BTB (BR-C, ttk and bab) domain and CNC homolog 1 (Bach1) represses the function of both factors. Their significance in DLBCL prognosis is unknown. Methods: Diagnostic biopsy samples of 76 patients with high-risk DLBCL were retrospectively stained with immunohistochemistry for Nrf1, Nrf2, Keap1 and Bach1, and correlated with clinical data and outcome. Results: Nuclear Nrf2 and nuclear Bach1 expression were associated with adverse clinical features (anaemia, advanced stage, high IPI, high risk of neutropaenic infections), whereas cytoplasmic Nrf1 and Nrf2 were associated with favourable clinical presentation (normal haemoglobin level, no B symptoms, limited stage). None of the evaluated factors could predict survival alone. However, when two of the following parameters were combined: high nuclear score of Nrf2, low nuclear score of Nrf1, high cytoplasmic score of Nrf1 and low cytoplasmic score of Keap1 were associated with significantly worse overall survival. Conclusions: Nrf1 and Nrf2 are relevant in disease presentation and overall survival in high-risk DLBCL. Low nuclear expression of Nrf1, high cytoplasmic expression of Nrf1, high nuclear expression of Nrf2 and low cytoplasmic expression of Keap1 are associated with adverse outcome in this patient group.

Background: Hypoxia-inducible factors (HIFs) and prolyl hydroxylase domain (PHD) proteins control cellular oxygen homeostasis and a wide range of other processes. Materials and Methods: We immunohistochemically assessed the expression of HIF1α, HIF2α, PHD1, PHD2 and PHD3 in 115 cases of classical Hodgkin’s lymphoma, all treated in the first line with doxorubicin, bleomycin, vinblastine and darcabazine (ABVD) chemotherapy. Results: In advanced-stage patients treated with involved-field radiotherapy (IFRT), nuclear HIF1α expression in reactive cellular infiltrate predicted prolonged relapse-free survival (RFS) (p=0.026). Strong cytoplasmic PHD1 expression in Reed–Sternberg cells was associated with poor RFS among patients treated with IFRT and advanced-stage patients treated with ABVD and IFRT (p=0.0028 and p=0.0058, respectively). In Cox regression analysis, PHD1 was a more significant predictor of relapse (risk ratio=18.383; 95% confidence interval(CI)=1.521–222.246; p=0.022) than the International Prognostic Score. Conclusion: HIF and PHD expression appear to be novel prognostic biomarkers in classical Hodgkin’s lymphoma.

Clinical practice points Testicular cancer with brain metastases is related to poor prognosis because the penetration of chemotherapeutic agents is decreased by the blood–brain barrier. The standard treatment of brain metastases—whole brain radiation therapy combined with chemotherapy—is related to a limited increase in survival and considerable deleterious cognitive effects. The blood–brain barrier can be transiently disrupted using hyperosmolar intra-arterial mannitol injection. When combined with intra-arterial chemotherapy, therapeutic intratumoral concentrations can be attained. In experienced centers, blood–brain barrier disruption therapy is relatively safe with a low incidence of catheter-related complications. Blood–brain barrier disruption therapy is a promising treatment modality for brain metastases as an alternative to whole brain radiation therapy.

Diffuse large B‐cell lymphoma (DLBCL) is the most common type of lymphoma. The standard therapy for DLBCL is R‐CHOP. The current 5‐year overall survival is 60% to 70% using standard frontline therapy. However, the use of doxorubicin and its cardiotoxicity is a major clinical problem and preexisting cardiac disease may prevent the use of doxorubicin. Age greater than 65 years is a significant risk factor for anthracycline‐induced cardiotoxicity, and therefore, the use of R‐CHOP is often withheld from elderly patients. The feasibility of replacing doxorubicin with either epirubicin or etoposide in patients who have risk factors for heart complications is analyzed here. Clinical data of 223 DLBCL patients were retrospectively collected from hospital records. Fifty‐five patients were treated with R‐CHOP, 105 with R‐CIOP (epirubicin instead of doxorubicin), 17 with R‐CEOP (etoposide instead of doxorubicin), and 31 with R‐CHOEP. Matched‐pair analysis was carried out between 30 patients treated with R‐CEOP and R‐CHOP. For all patients, the 2‐year progression‐free survival (PFS) was 73.6%. In patients treated with R‐CHOP, the 2‐year PFS was 84.2%, with R‐CIOP 64.4%, with R‐CEOP 87.7%, and with R‐CHOEP 83.2%. In matched‐pair analysis, the 2‐year PFS was 92.3% with R‐CHOP and 86.2% with R‐CEOP. The 2‐year disease specific survival was 100% with R‐CHOP and 86.2% with R‐CEOP. In conclusion, R‐CEOP offers reasonable PFS and disease specific survival in the treatment of DLBCL and good disease control can be achieved in elderly patients. Elderly patients with impaired cardiac function could benefit from the use of R‐CEOP instead of R‐CHOP. The results with R‐CIOP were unsatisfactory, and we do not recommend using this protocol in elderly patients with cardiac disease.

Sirtuins (SIRTs) are a family of histone deacetylases, which widely regulate cellular metabolism and are also involved in DNA repair. Rap1-interacting factor 1 (Rif1) and O⁶-alkylguanine DNA alkyltransferase (MGMT) are DNA-repair enzymes, which may potentially be involved in resistance to treatment of classical Hodgkin lymphoma (HL). We assessed the expression levels of (previously unstudied) SIRT1, SIRT4, SIRT6, Rif1, and MGMT immunohistochemically in 85 patients with untreated classical HL. Aberrant distributions of SIRT1, SIRT4, and SIRT6 were detected in Hodgkin neoplastic Reed–Sternberg (RS) cells compared with reactive elements. Low-level expression of both Rif1 and SIRT6 predicted dismal relapse-free survival in radiotherapy-treated patients (multivariate analysis; HR 8.521; 95% CI 1.714–42.358; p = .0088). Expression levels of SIRT1, 4, and 6 were abnormally distributed in RS cells, suggesting a putative role of aberrant acetylation in classical HL carcinogenesis. Rif1 and SIRT6 may also have substantial prognostic and even predictive roles in classical HL.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are two of the most common lymphomas in the Western world. DLBCL is an aggressive disease with a good response to treatment; about 75% of patients achieve permanent remission after first-line treatment. In patients with relapses or primary refractory disease, prognosis is dismal; only 10–20% of them can be cured, even with aggressive treatments. FL is an indolent lymphoma with a very good response to treatment and slow progression. Median survival with modern treatments is over 15 years. Nevertheless, some patients have short remissions and succumb to disease. Oxidative stress, TP53 mutations, and translocations of MYC, Bcl-2 and Bcl-6 have been linked in many neoplasms to aetiology and poor prognosis. This thesis concerns oxidative stress and redox-state-regulating enzymes in DLBCL and FL, and TP53 mutations and translocations of MYC, Bcl-2 and Bcl-6 in DLBCL. High expression levels of the antioxidant enzyme thioredoxin and a marker of oxidative stress, nitrotyrosine, were related to poor prognosis in DLBCL. In FL, high-level expression of peroxiredoxin was associated with good prognosis. TP53 mutations in specific regions LSH and L3 and concurrent translocation of Bcl-2 were associated with poor prognosis in DLBCL. Not all TP53 mutations predicted survival. High expression levels of Bcl-2 and MYC were associated with poor prognosis in DLBCL. Based on the results presented here, antioxidant function may have protective roles, but also may cause resistance to treatment. TP53 mutations have prognostic roles in DLBCL, but should be further defined. Novel therapies could be developed in connection with these mechanisms., Tiivistelmä Diffuusi suurisoluinen B-solulymfooma (DLBCL) ja follikulaarinen lymfooma (FL) ovat kaksi yleisintä lymfoomaa länsimaissa. DLBCL on aggressiivinen syöpä, joka reagoi hyvin hoitoihin, jopa 75 % paranee. Kuitenkin potilailla, joilla syöpä uusiutuu hoitojen jälkeen tai etenee hoidon aikana, on erittäin huono ennuste, noin 10–20 % näistä potilaista voidaan parantaa. FL on hyväennusteinen lymfooma, joka yleensä reagoi hyvin hoitoihin. Mediaani elossaoloaika kaikilla FL potilailla on yli 15 vuotta taudin toteamisesta. Osalla potilaista FL kuitenkin on aggressiivisempo. Oksidatiivinen stressin, TP53- mutaatioiden, MYC, Bcl-2 ja Bcl-6 -translokaatioiden on todettu olevan huonoon ennusteeseen yhteydessä olevia tekijöitä monissa syövissä, kuten lymfoomissa. Tämä väitöskirja tutki oksidatiivisen stressin ja hapetus-pelkistys reaktioon liittyvien entsyymien osuutta R-CHOP-hoidetuissa DLBCL:ssa ja FL:ssa immunohistokemian (IHC) avulla. DLBCL:ssa tutkittiin lisäksi TP53 mutaatioita, MYC, Bcl-2 ja Bcl-6 translokaatioiden roolia taudin kulussa. Korkea ekspressio oksidatiivisen stressin merkkiainetta nitrotyrosiinia ja antioksidantti thioredoksiinia olivat yhteydessä huonoon ennusteeseen DLBCL:ssa. FL:ssa runsas ilmentyminen antioksidativiisiin entsyymeihin kuuluvia peroksiredoksiineja olivat yhteydessä hyvään ennusteeseen. TP53 mutaatiot LSH ja L3 alueella ja Bcl-2 -translokaatiot yhdessä olivat yhteydessä huonoon ennusteeseen DLBCL:ssa. Kaikki TP53-mutaatiot eivät olleet assosioituneet huonoon ennusteeseen. DLBCL:ssa Bcl-2 ja MYC -proteiinien runsas ilmentyminen IHC:llä arvioituna liittyi huonoon ennusteeseen. Tulosten perusteella solujen hapetus-pelkistystilaa säätelevillä entsyymeillä voi olla dualistinen rooli, osittain suojeleva ja osittain vahingoittava lymfoomissa. TP53 -mutaatioilla voi olla ennusteellista merkitystä, mutta tämä vaatii lisää tutkimuksia.

Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography (DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 μV followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for blood-brain barrier disruption augmented drug delivery.