Impact of stem cell source on allogeneic stem cell transplantation outcome in hematological malignancies

BACKGROUND/AIM: Peripheral blood (PB) is used more frequently as a source of stem cells (SCs) for allogeneic transplantation. However, the influence of cell source on the clinical outcome of SC transplantation is not yet well established. The aim of this study was to compare the results of PBSC transplantation (PBSCT) with bone marrow transplantation (BMT) on the basis of engraftment, frequency and severity of immediate (mucositis, acute Graft versus Host Disease--aGvHD) and delayed (chronic GvHD--cGvHD) complications, as well as transplant-related mortality (TRM), transfusion needs, relapses and overall survival (OS). METHODS: We analyzed 158 patients, women/men ratio 64/94 median age 29 (range 9-57), who underwent allogeneic SC transplantation between 1989 and 2009. All included patients had diseases as follows: acute myeloid leukemia (AML)--39, acute lymphoblastic leukemia (ALL) 47, chronic myeloid leukemia (CML)--32, myelodysplastic syndrome (MDS)--10, Hodgkin's lymphoma (HL)- 2, multiple myeloma (MM) 3, granulocytic sarcoma (GrSa) 3, severe aplastic anemia (sAA)--22. The patients underwent transplantations were divided into two groups: BMT group (74 patients) and PBSCT group (84 patients). Each recipient had HLA identical sibling donor. SCs from bone marrow were collected by multiple aspirations of iliac bone and from PB by one "Large Volume Leukapheresis" (after recombinant human granulocyte colony stimulating factor, rHuG-CSF) application (5-12 microg/kgbm, 5 days). Conditioning regimens were applied according to primary disease, GvHD prophylaxis consisted of combination of a cyclosporine A and methotrexate. Results. Engraftment, according to the count of polymorphonuclear and platelets, were significantly (p < 0.001) faster in the PBSCT vs BMT group. The needs for transfusion support were significantly (P < 0.01) higher in the BMT group. Those patients had more frequently oropharingeal mucositis grade 3/4 (33.3% vs 10.0%, p < 0.05). There were no significant differences in the incidence of aGvHD and cGvHD between the two groups. The patients who underwent PBSCT had more frequently extensive cGvHD in comparison with the BMT group (29.1% vs 11.29%, p < 0.05). SC source (SCS) had no significant influence on the TRM (21.62% vs 23.8%, p = 0.64) and the incidence of relapses (21.6% vs 29.7%, p = 0.32). Finally, the patients treated by BMT hd a significantly better OS (logrank 2.33, p < 0.05). Conclusion. SCs harvesting from PB resulted in improved cell yield, faster engraftment, as well as in a decrease of immediate transplantation related complications with a reduced treatment cost. Allogeneic PBSCT were associated with more frequent extensive cGvHD, while the influence of SCS in TRM and relapses was not observed. Finally, the long-term OS was better in the patients treated by BMT. To verify impact of SC source on transplantation (PBSCT vs BMT) overall efficacy, more larger randomized clinical studies are needed.     

Proton MR spectroscopy and diffusion-weighted imaging of intracranial germ cell tumors: Implications for differentiation from other lesions

Introduction

Intracranial germ cell tumors (GCT) are extremely rare brain neoplasms, with imaging characteristics being often non-specific. Considering such imaging limitation in establishing their exact histology, the aim of this paper is to integrate conventional, physiologic and metabolic magnetic resonance imaging (MRI) with histology of these tumors, with the goal of proposing some new insights that could aid in their diagnosis.

Materials and methods

We have retrospectively analyzed preoperative imaging findings in 9 patients with histology proven intracranial germ cell tumors. In all patients conventional magnetic resonance imaging in conjunction with diffusion-weighted imaging (DWI) and proton magnetic resonance spectroscopy (MRS) was performed.

Results

Based on imaging characteristics on conventional sequences germinoma cannot be differentiated from nongerminoma. DWI offered the potential for differentiation of germinomas from non-germinomas since solid part of germinomas demonstrated restricted diffusion with ADC values under 1.0 × 10⁻³ mm²/s, whereas nongerminoma showed elevated diffusion with ADC values above 1.3 × 10⁻³ mm²/s. Short echo MRS demonstrated characteristic spectra in germinomas: increased Cho, decreased NAA and prominent broad lipid resonances.

Conclusion

DWI and MRS imaging findings provide additional information that can facilitate evaluation of intracranial germ cell tumors.     

From dermatological conditions to COVID‐19: Reasoning for anticoagulation,suppression of inflammation,and hyperbaric oxygen therapy

COVID‐19 generates a complex systemic inflammatory response that can lead to death due to wide macrophage activation, endothelial damage, and coagulation in critically ill patients. SARS‐CoV‐2‐induced lung injury due to inflammatory mediated thrombosis could be similar to the livedoid vasculopathy in the skin, supporting a translational comparison of these clinical settings. In this article, we discuss anticoagulation, suppression of inflammatory response, and hyperbaric oxygen therapy in the context of severe COVID‐19 and livedoid vasculopathy.     

Oxidative stress in schizophrenia patients treated with long-acting haloperidol decanoate

In this study the role of oxidative stress in schizophrenia was investigated by evaluating the relationship of oxidative stress markers with neurochemistry, psychopathology, and extrapyramidal symptoms. Antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and concentrations of malondialdehyde, protein carbonyls, nitrite, nitrate, glutathione, dopamine, noradrenaline, adrenaline, and serotonin were measured in 52 outpatients with DSM-IV diagnosis of schizophrenia treated with haloperidol decanoate. Psychopathology and extrapyramidal symptoms were assessed by positive and negative syndrome scale, global assessment of functioning, abnormal involuntary movement scale, Simpson Angus scale, and Barnes akathisia rating scale. Haloperidol dose was positively correlated with plasma protein carbonyls. Longer duration of illness was associated with decreased levels of glutathione peroxidase. Increased activity of superoxide dismutase was associated with increased levels of catalase, glutathione peroxidase, glutathione reductase and reduced glutathione, and decreased concentration of malondialdehyde, indicating joint action of various antioxidative systems. Increased levels of nitrite and noradrenaline were associated with decreased level of malondialdehyde. Akathisia was greater in patients with decreased catalase activity, indicating involvement of impaired antioxidant defense in developing extrapyramidal symptoms. These results confirm the hypothesis that oxidative stress is involved in pathophysiology of schizophrenia and severity of extrapyramidal symptoms.     

Mutant Ataxin-1 Inhibits Neural Progenitor Cell Proliferation in SCA1

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (Q) repeat tract in the protein ataxin-1 (ATXN1). Beginning as a cerebellar ataxic disorder, SCA1 progresses to involve the cerebral cortex, hippocampus, and brainstem. Using SCA1 knock-in mice that mirror the complexity of the human disease, we report a significant decrease in the capacity of adult neuronal progenitor cells (NPCs) to proliferate. Remarkably, a decrease in NPCs proliferation can be observed in vitro, outside the degenerative milieu of surrounding neurons or glia, demonstrating that mutant ATXN1 acting cell autonomously within progenitor cells interferes with their ability to proliferate. Our findings suggest that compromised adult neurogenesis contributes to the progressive pathology of the disease particularly in areas such as the hippocampus and cerebral cortex where stem cells provide neurotropic factors and participate in adult neurogenesis. These findings not only shed light on the biology of the disease but also have therapeutic implications in any future stem cell-based clinical trials.     

The role of T-type calcium channels in peripheral and central pain processing

It is well established that the voltage-gated calcium (Ca2+) channels can modulate neuronal activity in the peripheral and central nervous system causing a variety of behavioral and neuro-endocrine changes in humans and animals. While much attention was focused on the modulation of high voltage-activated (HVA)-type Ca2+ channels, the role of low voltage-activated (LVA) or transient (T) type Ca2+ channels in sensory processing, and in particular pain processing (nociception) is much less certain. However, recent evidence strongly suggests that modulation of both central and peripheral T-type Ca2+ channels influences somatic and visceral nociceptive inputs and that modulation of T-type Ca2+ currents results in significant alteration of pain threshold in a variety of animal pain models. Therefore, T-type Ca2+ channels in peripheral and central neurons, although previously unrecognized, may be important targets for analgesic therapeutic agents including endogenous compounds. Currently available pain therapies remain insufficient with limited efficacy and numerous side effects. Hence, studies of selective and potent modulators of neuronal T-type Ca2+ channels may greatly aid in revealing roles for these channels in sensory pathways (nociception in particular) and in the development of novel and potentially more effective and safer pain therapies. In the present review, we summarize the putative role of peripheral and central T-type Ca2+ channels in nociception and our recent in vivo and in vitro studies focusing primarily on 5alpha- and 5beta-reduced neuroactive steroids and redox agents that are potent modulators of neuronal T-type Ca2+ channels.     

Regulation of oligodendrocyte precursor maintenance by chondroitin sulphate glycosaminoglycans

Chondroitin sulfate proteoglycans (CSPGs) have been proven to inhibit morphological maturation of oligodendrocytes as well as their myelination capabilities. Yet, it remained unclear, whether CSPGs and/or their respective chondroitin sulfate glycosaminoglycan (CS‐GAG) side chains also regulate the oligodendrocyte lineage progression. Here, we initially show that CS‐GAGs detected by the monoclonal antibody 473HD are expressed by primary rat NG2‐positive oligodendrocyte precursor cells (OPCs) and O4‐positive immature oligodendrocytes. CS‐GAGs become down‐regulated with ongoing oligodendrocyte differentiation. Enzymatic removal of the CS‐GAG chains by the bacterial enzyme Chondroitinase ABC (ChABC) promoted spontaneous differentiation of proliferating rat OPCs toward O4‐positive immature oligodendrocytes. Upon forced differentiation, the enzymatic removal of the CS‐GAGs accelerated oligodendrocyte differentiation toward both MBP‐positive and membrane forming oligodendrocytes. These processes were attenuated on enriched CSPG fractions, mainly consisting of Phosphacan/RPTPβ/ζ and to less extent of Brevican and NG2. To qualify CS‐GAGs as universal regulators of oligodendrocyte biology, we finally tested the effect of CS‐GAG removal on OPCs from different sources such as mouse cortical oligospheres, mouse spinal cord neurospheres, and most importantly human‐induced pluripotent stem cell‐derived radial glia‐like neural precursor cells. For all culture systems used, we observed a similar inhibitory effect of CS‐GAGs on oligodendrocyte differentiation. In conclusion, this study clearly suggests an important fundamental principle for complex CS‐GAGs to regulate the oligodendrocyte lineage progression. Moreover, the use of ChABC in order to promote oligodendrocyte differentiation toward myelin gene expressing cells might be an applicable therapeutic option to enhance white matter repair. GLIA 2016;64:270–286     

Comparison of the influence of thyroglobulin antibodies on serum thyroglobulin values from two different immunoassays in post surgical differentiated thyroid carcinoma patients

Measurement of serum thyroglobulin (Tg) is a highly specific test in the management of patients with differentiated thyroid cancer (DTC) after surgical treatment. The aim of our study was to evaluate and compare Tg levels in these patients found by radioimmunoassay (RIA) and immunoradiometric assay (IRMA) and to assess the influence of Tg antibodies (TgAbs) on the values obtained for Tg concentration. Both Tg and TgAb were determined postoperatively in the serum of 71 DTC patients using RIA Tg‐PEG (INEP) and Tg IRMA (CIS) for Tg, together with TgAb (CIS) for circulating endogenous anti‐TgAbs. The obtained concentrations were evaluated statistically. We found a significant difference of Tg concentrations between paired samples from the IRMA and RIA, although the intermethod comparison yielded satisfactory concordance of the twoassays (Spearman correlation coefficient ?0.792). Positive TgAb was found in 28.2% of the serum samples analyzed. Spearman rank correlation analysis revealed a significant negative relationship between serum TgAb and Tg level measured by IRMA (P=0.02), but not by RIA (P=0.417). On the other hand, our clinical data revealed that 1/18 and 3/18 patients with proven lymph node metastasis had Tg values below the detection limit by RIA and IRMA assay, respectively. Their sera were TgAb positive. We concluded that RIA was less prone to influence of TgAb than IRMA. As the presence of TgAbs may interfere in Tg measurement irrespective of the method selected for determination, this should be considered during the clinical management of these patients. J. Clin. Lab. Anal. 23:341–346, 2009. © 2009 Wiley‐Liss, Inc.     

Differential effects of NMDA and AMPA/kainate receptor antagonists on superoxide production and MnSOD activity in rat brain following intrahippocampal injection

The involvement of NMDA and AMPA/kainate receptors in the induction of superoxide radical production in the rat brain was examined after injection of kainate, non-NMDA receptor agonist, kainate plus 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), selective AMPA/kainate receptor antagonist, or kainate plus 2-amino-5-phosphonopentanoic acid (APV), selective NMDA receptor antagonist. Competitive glutamate receptor antagonists were injected with kainate unilaterally into the CA3 region of the rat hippocampus. We investigated superoxide production and mitochondrial MnSOD activity after injection. The measurements took place at different times (5, 15 min, 2, 48 h and 7 days) in the ipsi- and contralateral hippocampus, forebrain cortex, striatum, and cerebellum homogenates. Used glutamate antagonists APV and CNQX both expressed sufficient neuroprotection in sense of decreasing superoxide production and increasing MnSOD levels, but with differential effect in mechanisms and time dynamics. Our findings suggest that NMDA and AMPA/kainate receptors are differentially involved in superoxide production. Following intrahippocampal antagonists injection they, also, interpose different neuroprotection effect on the induction of MnSOD activity in distinct brain regions affected by the injury, which are functionally connected via afferents and efferents. It suggests that MnSOD protects the cells in these regions from superoxide-induced damage and therefore may limit the retrograde and anterograde spread of neurotoxicity.