Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) in hematological malignancies

Abstract Gelatinases (MMP-2 and MMP-9) play a key role during invasion and metastazising of malignant cells and they have been shown to be associated to invasive phenotype and poor prognosis in several solid tumours. However little is known about their role in hematological malignancies. In the present work, gelatinase expression and its clinicopathological correlations were studied with immunohistochemical staining in 10 cases representing normal bone marrow aspirate smears, 123 cases representing diagnostic bone marrow samples of patients with different leukaemias (35 AML, 7 CLL, 6 CML, 75 ALL), 67 diagnostic paraffin-embedded lymph node biopsies from patients with Hodgkin's lymphoma and 57 biopsies from patients with non-Hodgkin's lymphomas. The lymphoma samples were also stained with factor VIII antibody to evaluate the extent of new vessel formation and the non-Hodgkin's lymphoma cases also with tissue inhibitor of metalloproteinases -1 (TIMP-1) antibody. CLL did not express either of the MMP enzymes, while CML in the chronic phase expressed strongly both of the enzymes. In ALL, gelatinase expression was weak and detectable in pediatric cases in only 12.7% and in the adults in 65% of the cases. In adult ALL, MMP-2 expression correlated strongly with an extramedullary and invasive pattern of disease presentation. In AML MMP-2 positivity had markedly favorable prognostic and predictive power. In lymphoma studies, no correlations could be detected between gelatinase expression and the clinical parameters of invasion. MMP-9 positivity was related to the presence of B symptoms, which difference was statistically significant in Hodgkin's lymphoma. In Hodgkin's lymphoma, strong MMP-9 expression also implicated decreased neovascularization. In both lymphoma types, strong MMP-9 expression correlated with unfavorable prognosis, which difference was statistically significant in non-Hodgkin's lymphomas and remained as a tendency in Hodgkin's lymphoma. MMP-2 had statistically significant association with a favorable prognosis in Hodgkin's lymphoma. Combination of the results of both stainings further increased prognostic power. All together these findings implicate that gelatinases could be used as prognostic tools in AML and lymphomas albeit this needs to be verified in larger materials

Interim and end-of-treatment PET-CT suffers from high false-positive rates in DLBCL:biopsy is needed prior to treatment decisions

Abstract The application of positron emission tomography (PET)-computed tomography (CT) in treatment response evaluation has increased in diffuse large B-cell lymphoma (DLBCL), although its predictive value is controversial. We retrospectively analyzed the rate of false-positive PET-CTs performed as interim (n = 94) and end-of-treatment (n = 8) assessments among 102 DLBCL patients treated during 2010–2017 at Oulu University Hospital. In PET-CT Deauville score ≥4 was regarded as positive. A biopsy was performed on 35 patients, and vital lymphoma tissue was detected from nine patients. Positive biopsy findings were associated with poor disease outcomes in this study. This difference was statistically significant: 2-year failure-free survival (FFS) was 44% in patients with a positive biopsy versus 83% for those with a negative biopsy (p = 0.003). The corresponding overall survival (OS) rates were 53% versus 95% (p = 0.010). In the multivariate analyses, a negative biopsy was an independent protective factor in FFS (Hazard Ratio (HR) 0.093 (95% confidence interval [CI] 0.017–0.511); p = 0.006) unrelated to the International Prognostic Index (IPI) (HR 1.139 [95% CI 0.237–5.474] p = 0.871) or stage (HR 1.365 [95% CI 0.138–13.470]; p = 0.790). There was no statistically significant difference in OS according to the PET results, but the FFS rate was significantly higher in patients with a negative PET. The value of PET-CT as an evaluation method suffers from a high false-positive rate, and it is inadequate alone for the justification of treatment decisions. Biopsy results provide more reliable prognostic information for the evaluation of treatment response and outcome and should be used to assess patients with positive PET-CT scans

Significance of bulky mass and residual tumor:Treated with or without consolidative radiotherapy—To the risk of relapse in DLBCL patients

Abstract Bulky and residual tumor are considered to increase the risk of relapse in diffuse large B‐cell lymphoma (DLBCL) patients. Radiotherapy is conventionally used to reduce the risk, but the evidence is controversial. We performed a retrospective analysis to evaluate the significance of bulky and residual tumor treated with or without radiotherapy in DLBCL patients. We analyzed 312 DLBCL patients treated from 2010‐2017 in Oulu University Hospital. A bulky tumor was detected in 123 patients and 55 of these patients (44.3%) received consolidative radiation therapy (RT) to the bulky tumor. Residual tumor meeting the required criteria was found in 138 (39.3%) patients, and 65 (45.5%) of these patients received consolidative RT to the site of residual tumor. iPET‐CT scans were performed in 102 patients. In multivariate analyses, bulky was an independent risk factor in limited stage patients in progression free survival (HR 6.43 [95%CI 1.609‐25.710]; P = .008) not related to International prognostic index (HR 1.35 [95% CI 0.256‐7.124]; P = .724) or age (HR 1.62 [95% CI 0.468‐5.638]; P = .445). This was not seen in advanced stage patients or in patients with residual tumor. Radiotherapy to the bulky or residual tumor was not able to improve the long‐term PFS of patients. In this study, it appears that performing iPET is the most convincing method in improving evaluation and in finding patients with increased risk of relapse. Evidently, patients with negative iPET will not benefit from including RT in the treatment after metabolic complete response (CR), and patients with primary refractory disease are most likely in the group of positive iPET

Environmental response in gene expression and DNA methylation reveals factors influencing the adaptive potential of Arabidopsis lyrata

Abstract Understanding what factors influence plastic and genetic variation is valuable for predicting how organisms respond to changes in the selective environment. Here, using gene expression and DNA methylation as molecular phenotypes, we study environmentally induced variation among Arabidopsis lyrata plants grown at lowland and alpine field sites. Our results show that gene expression is highly plastic, as many more genes are differentially expressed between the field sites than between populations. These environmentally responsive genes evolve under strong selective constraint — the strength of purifying selection on the coding sequence is high, while the rate of adaptive evolution is low. We find, however, that positive selection on cis-regulatory variants has likely contributed to the maintenance of genetically variable environmental responses, but such variants segregate only between distantly related populations. In contrast to gene expression, DNA methylation at genic regions is largely insensitive to the environment, and plastic methylation changes are not associated with differential gene expression. Besides genes, we detect environmental effects at transposable elements (TEs): TEs at the high-altitude field site have higher expression and methylation levels, suggestive of a broad-scale TE activation. Compared to the lowland population, plants native to the alpine environment harbor an excess of recent TE insertions, and we observe that specific TE families are enriched within environmentally responsive genes. Our findings provide insight into selective forces shaping plastic and genetic variation. We also highlight how plastic responses at TEs can rapidly create novel heritable variation in stressful conditions

Treatment of diffuse large B‐cell lymphoma in elderly patients:replacing doxorubicin with either epirubicin or etoposide (VP‐16)

Abstract 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

Role of seed germination in adaptation and reproductive isolation in Arabidopsis lyrata

Abstract Seed germination is an important developmental and life history stage. Yet, the evolutionary impact of germination has mainly been studied in the context of dormancy, or for its role in reproductive isolation between species. Here, we aim to examine multiple consequences of genetic divergence on germination traits between two Arabidopsis lyrata subspecies: ssp. petraea (Eurasia) and ssp. lyrata (North America). Postdormancy germination time, a potentially adaptive trait, showed differentiation between the populations, and quantitative trait loci (QTL) mapping revealed that the trait variation is mainly controlled by two antagonistic loci. These QTL areas contain several candidate genes with known function in postdormancy germination in A. thaliana. The sequence variation of three genes was consistent with differential selection, and they also included fixed nonsynonymous substitutions with potential to account for the phenotypic differentiation. We further show that the divergence between the subspecies has led to a slight but significant reduction in hybrid germination proportions, indicating incipient reproductive isolation. Comparison of reciprocal F1 and F2 progenies suggests that Bateson–Dobzhansky–Muller incompatibilities likely act through uniparentally inherited factors. Examination of genomewide transmission ratio distortion further revealed that cytonuclear interactions cause substantial pregermination inviability in the hybrids. These results confirm that seed germination has adaptive potential beyond the dormancy stage and that hybrid seed inviability can be one of the first reproductive barriers to arise during divergence

Case report: chemotherapy in conjunction with blood–brain barrier disruption for a patient with germ cell tumor with multiple brain metastases

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

Blood graft and outcome after autologous stem cell transplantation in patients with primary central nervous system lymphoma

Abstract 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

Lymfoomahoitojen jälkeiset pitkäaikaishaitat, niiden ehkäisy ja seuranta

Tiivistelmä Myöhäishaitat ovat edelleen tavallisia lymfoomahoitojen jälkeen, ja niiden riski jatkuu koko elämän. Vaikka hoitojen kehittyminen on vähentänyt haittoja, varsinkin sekundaarisyövät sekä sydän- ja verisuonitaudit aiheuttavat ylikuolleisuutta. Perusterveydenhuollon tuleekin olla tietoinen mahdollisista ongelmista ja hoitaa riskitekijöitä tehokkaasti. Psykososiaalisten haittojen ehkäisemiseksi tarvitaan lisää tukea potilaille. Suomen Lymfoomaryhmä on tehnyt suosituksen myöhäishaittojen ehkäisemiseksi ja seuraamiseksi.Abstract Prediction and follow-up of long-term side-effects after lymphoma treatment Post-treatment prognosis of lymphoma patients is generally good. However, patients are at risk of developing treatment-related side-effects over time, including secondary malignancies, cardiovascular diseases, infertility and osteoporosis among others. Lymphoma patients are at an increased risk permanently after their treatment. Patients also experience psychosocial side-effects (like fatigue) which can be more long-lasting than physical symptoms. The recommendations of the Finnish Lymphoma Group for surveillance of these patients are presented

Cardiovascular effects of mannitol infusion:a comparison study performed on mouse and human

Abstract Monitoring blood-brain barrier (BBB) opening is of great interest in terms of brain drug delivery in the treatment of brain lymphoma and maybe in the future in other diseases like dementia. A method involving BBB disruption (BBBD) by mannitol infusion has been developed in University of Portland, USA, and then exploited in Oulu University Hospital in treatment of primary CSN lymphoma. Proper opening of the BBB is crucial for the treatment, yet there are no methods available for its real-time clinical monitoring. Recently, we presented a combined method using direct-current electroencephalography (DC-EEG) and near-infrared spectroscopy (NIRS) for monitoring BBBD in human. Carotid artery mannitol infusion generated a strongly lateralized DC-EEG response and in NIRS a prolonged increase in the oxy/deoxyhemoglobin ratio. This study explores further BBBD, by focusing on monitoring its cardiovascular effects, when measured in human and mouse. For this, we used photoplethysmography (PPG) and opto-electro-mechanical sensors to gather the signals in human and mouse. Mannitol infusion in human causes strong fluctuations in blood pressure, heart rate and PPG signals, and here we discuss how the acquired signals in mouse model compares to human data. In addition, we present our scale-free monitoring concept that enables monitoring physiological signals similarly when performing experiments in mouse and human neuroimaging setups. By combining microscopic and macroscopic imaging in mouse setup enables us to study correlations between mechanistic cellular data and clinical functional data. Further, this allows us to validate and optimize macroscopic sensing and imaging techniques aimed to be used in human imaging