AUCTORES
Globalize your Research
Review Article | DOI: https://doi.org/10.31579/2642-973X/168
1Dental Surgeon (DDSc),
-Oncologist (MSc), Specialized in Clinical Oncology, Cytology and Histopathology, Dept. of Pathological Anatomy, Medical School, University of Athens, Athens, Greece.
-Resident in Maxillofacial and Oral Surgery, 401 General Military Hospital of Athens, Athens, Greece.
-PhD in Oncology (cand).
-Registrar in Dentistry, NHS of Greece.
2MD, Registrar in Pathology, Ilioupoli Health Centre - NHS of Greece, Athens, Greece.
*Corresponding Author: Nikolaos Andreas Chrysanthakopoulos, Dental Surgeon (DDSc), Oncologist (MSc), Specialized in Clinical Oncology, Cytology and Histopathology, Dept. of Pathological Anatomy, Medical School, University of Athens, Athens, Greece. Resident in Maxillofacial.
Citation: Nikolaos A. Chrysanthakopoulos, Vassiliki Vazintari, (2026), Molecular Biology of the two Less Common Vascular Brain Neoplasms in Adults – A Comprehensive Review, J. Brain and Neurological Disorders, 9(2): DOI:10.31579/2642-973X/168.
Copyright: © 2026, Nikolaos Andreas Chrysanthakopoulos. This is an open-access article distributed under the terms of The Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 09 January 2026 | Accepted: 13 February 2026 | Published: 09 March 2026
Keywords: brain neoplasms; hemangioblastoma; primary central nervous system; lymphoma; molecular biology; genetics; epigenetics
Brain neoplasms are a significant cause of morbidity and mortality worldwide, affecting individuals across an extensive range of demographics. In adults, the most common primary intracranial tumors are gliomas, whereas less common vascular brain neoplasms include hemangioblastomas (HBs) and primary central nervous system lymphomas (PCNSLs). HB is a highly vascular tumor comprising 3% of all Central Nervous System (CNS) tumors. Approximately 25% of these cases are hereditary, resulting from von Hippel-Lindau (VHL) disease - an autosomal dominant disorder - whereas the remainder develop sporadically. These tumors are characterized by a remarkably high prevalence of recurrent somatic mutations (50%) and Loss of Heterozygosity (LOH) at the gene locus on chromosome 3p (72%). Mutations in ARID1B have also been revealed in HB cases. PCNSL is typically a diffuse large B-cell lymphoma (DLBCL). Several genomic alterations have been detected, including the expression of BCL2 and BCL6, mutations in genes encoding p53, ATM, and MYD88, as well as chromosomal deletions, repeated losses, and insertions. Its molecular biology remains a complex field where basic research is essential to meet clinical expectations regarding antitumor efficacy. Modern investigations have focused on understanding the biology and pathogenesis of these tumors to develop new agents for personalized, targeted molecular treatment. The current study presents a comprehensive review of contemporary knowledge regarding the molecular features of these neoplasms. It focuses on the primary intracellular signaling pathways involved in their pathogenesis, genomic and epigenetic characteristics, and the predictive value of molecular indices according to the 2021 WHO classification.
Brain neoplasms affect a wide diversity of individuals and result in significant morbidity and mortality worldwide. Among these, two less common vascular brain neoplasms in adults are hemangioblastomas (HBs) and primary central nervous system lymphomas (PCNSLs). PCNSL is typically a diffuse large B-cell lymphoma (DLBCL) [1]. It primarily affects elderly individuals, with a median age of 66-67 years, whereas it is rare in young individuals [2] and infrequent in the pediatric population [3]. PCNSL accounts for less than 5% of all primary brain tumors and typically affects the brain, spinal cord, leptomeninges, and eyes [4]. The cellular origin remains to be elucidated, as it is unclear whether PCNSL originates within the CNS or is a systemic lymphoma that escapes from the host’s immune system to proliferate in the CNS “sanctuary” [5].
Various genomic alterations have been identified in PCNSL, such as the expression of BCL2, BCL6 [6-8], and IRF4/MUM1 [5], as well as non-synonymous somatic mutations in MYD88, PIM1, and BTG2 [5,9-14]. Non-conservative mutations have also been recorded in the TP53, ATM, PTEN, JAK3, and PIK2CA loci [5,15]. Structural alterations include deletions at chromosomes 6p21 and 6q21-23 [16,17], affecting PRDM1, PTPRK, and A20/TNFAIP3, recurrent chromosomal losses at 9p21 [16], and insertions on chromosome 12q, harboring CDK4, MDM2, STAT6, and GLI1 [16-20], as well as insertions on the long arms of chromosomes 1, 7, and 18 [18].
Other genomic alterations include CARD11 [5,9-13,21] and MALT1 [22] mutations and overexpression. Copy number alterations (CNAs) and translocations on chromosome 9p24, involving the programmed death-ligand 1 (PD-L1) and 2 (PD-L2) loci [23], are frequent. Homozygous loss of HLA class II genes and CDKN2A [24], recurrent BCL6 translocations [25,26], and TBL1XR1 variations [27] are also common. PCNSL biology is mediated by the JAK/STAT signaling pathway [8,23,28,29]. Furthermore, micro-RNAs (mi RNAs) play a critical role, tumor-suppressive miRNAs, such as miR-193b, miR199a, miR-145, and miR-214, are often downregulated [30], whereas miR-17-5p is notably upregulated [30,31].
Epigenetic silencing via DNA hypermethylation has been detected at loci including MGMT, DAPK, and RFC, as well as the CDKN2A (p16 INK4a/p14ARF) locus [32,33], alongside promoter methylation of CDKN1B and RB1 [18,20]. In cases localized to the splenium, TERT promoter mutations are present [34,35]. Inflammatory markers also play a role, as BCA-1 (CXCL-13) is highly expressed [36-38], and Interleukin (IL)-4 signaling may be critical for pathogenesis and progression [8]. HB is a highly vascular, benign tumor accounting for 3% of all CNS tumors, 1-2.5% of all primary intracranial tumors [39], 7-8% of posterior cranial fossa tumors [40], and 7-10% of spinal cord tumors. Its pathology is characterized by neoplastic “stromal” cells embedded within a dense network of vascular channels [41,42]. HBs develop either sporadically or as a manifestation of von Hippel-Lindau (VHL) disease, an autosomal dominant disorder, in approximately 25% of cases [40]. While 75% of HBs are sporadic, the majority of these cases do not carry observable germline VHL alterations. Sporadic cases typically present as solitary lesions, whereas VHL patients tend to develop multiple HBs [43-45].
The histogenesis of HBs remains uncertain. It has been hypothesized that they originate from embryologically arrested “hem angioblast” stem cells [41,46]. Consequently, the WHO classification categorizes HB as a “neoplasm of uncertain histogenesis” [47,48]. These tumors are primarily diploid with few chromosomal abnormalities [49,50]. The presence of VHL mutations has been estimated at10% to 44% in sporadic HB cases [51]. The frequency of chromosome 3 aneuploidy ranges from 18% to 69% in these sporadic tumors [49,50]. Mutations in the VHL tumor suppressor gene, located on chromosome 3p25.3 appear to play a role in both sporadic and VHL disease-related tumors [52-54], however the genetic factors explaining the clinical heterogeneity of the HBs remain unknown. Despite CNA in a small subset of cases [53], the HBs exome is remarkably simple, lacking additional oncogenic driver mutations [52,54]. HBs are characterized by a notably high prevalence of recurrent somatic mutations (50%) and LOH of the gene locus on chromosome 3p (72%). These genomic alterations are responsible for biallelic VHL inactivation in 47% of cases, and an inactivating alteration in at least one allele in 78% of sporadic HBs [52]. Mutations in the ARID1B gene have also been recorded. This gene acts as a tumor suppressor in various types of cancers [55,56].
Further analysis is needed to determine whether such sub clonal variations are functionally essential in supporting the sporadic development of HBs [57]. Epigenetic alterations in sporadic and VHL-associated HBs were detected through the molecular characterization of the VHL promoter [53], raising the possibility that DNA methylation patterns could lead to the identification of relevant biological subgroups. Over the past decade, notable progress in genomic research has improved the classification and management of brain tumors. However, despite these molecular advancements, improvements in overall survival rates and quality of life remain suboptimal. This article provides a comprehensive review of the molecular features of HB and PCNSL, focusing on intracellular signaling pathways, genomic and epigenetic characteristics, and their roles in pathogenesis.
PCNS Lymphoma
Epidemiological data and Classification
PCNSL accounts for 4-6% of all extranodal lymphomas, approximately 2% of all CNS tumors, and up to 1% of all lymphomas [58]. Moreover, its overall incidence rate is 0.5 cases per 100,000-person years, representing 3% to 4% of all newly diagnosed intracranial neoplasms [59]. The median age at diagnosis is 65 years old. The tumor is frequently detected in individuals with acquired immune deficiencies, such as AIDS or post-transplant conditions in immuno-compromised patients, in which the tumor cells are typically Epstein-Barr virus (EBV)-positive [60]. It is also associated with congenital immune deficiencies, such as X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, or ataxia telangiectasia [61]. Approximately 90% of PCNSL cases are diffuse large B cell lymphomas (DLBCLs), and their immunohistochemical analysis typically demonstrates a non-germinal center B-cell-like (non-GCB) immunophenotype [62-64]. In contrast, a small subcategory of patients is diagnosed with T-cell, marginal zone, Burkitt, or lymphoblastic lymphomas [65].
According to gene expression profiling, tumor cells are most closely related to late GC (exit) B-cells [6]. Currently, the 2021 WHO Classification categorizes PCNSLs primarily as DLBCL, as previously mentioned, without further grading, in contrast to other common primary brain tumors [1].
PCNSL histogenetic origin
Under normal circumstances, the CNS is an immunologically privileged site devoid of B-cells. Therefore, the cellular origin of PCNSL remains to be elucidated. One proposed mechanism suggests that a malignant B-cell clone arising systemically might express specific adhesion molecules that facilitate homing to the CNS. There, the tumor cells proliferate and undergo additional mutations in the absence of modulatory control by the host’s immune system. It remains unknown whether PCNSL originates within the CNS or is part of a systemic lymphoma that escapes the immune system to multiply in the CNS ‘sanctuary’ [5]. B-cells recruited to the brain during an inflammatory response may remain for extended periods and eventually undergo malignant transformation while localized within the CNS. Alternatively, B-cells may transform into a malignant state outside the CNS, for example, during a GC response in a secondary lymphoid organ [5].
It is possible that both mechanisms play a role. However, the selective homing of a malignant B-cell solely to the brain cannot be easily explained and remains difficult to validate experimentally. To date, no specific cell adhesion molecule, chemokine or cytokine has been identified that predicts selective B-cell homing to the brain in PCNSL, nor have significant differences in adhesion molecule expression been found between PCNSL and systemic lymphomas [18].
The B-cell differentiation process may provide insights into the histogen etic origin of PCNSL. The primary phase involves the assembly of the V, D, and J sections of the immunoglobulin (Ig) heavy and light chain genes in the bone marrow [9]. Following successful assembly, naïve B-cells exit the bone marrow for the next phase of maturation, where they interact with antigens in the GCs of secondary lymphoid organs, to improve their B-cell receptor (BCR) binding affinity. The process of somatic hypermutation (SHM) in the first 1.5-2.0 kb of the V region genes is regulated within the GCs [10]. This process and affinity maturation require specific antigens, antigens-presenting cells (APC) and T- cells, and the presence of BCL6 [11]. SHM may either increase or decrease BCR affinity, leading to the selection of B-cell clones for further rounds of SHM. Eventually, these cells either undergo apoptosis or exit the GCs [12]. After SHM, B-cells may undergo Ig class-switch recombination, substituting the BCRμ constant region with downstream regions to generate various antibody classes [5].
Sequence analysis of Ig variable region genes in PCNSL has detected high frequencies of somatic mutations. These findings indicate that PCNSLs originate from mature B-cells that have been exposed to antigens and have undergone T-cell-dependent affinity maturation within a GC microenvironment [66]. Morphologically, PCNS cells resemble Centro blasts, and the presence of SHMs in rearranged Ig segments demonstrates their prior involvement in a GC reaction [13].
Expression of B cell markers such as CD19, CD20, and CD79a, is present in almost all PCNSLs. CD10 is present in 10-20% of cases, while plasma cell markers (CD38, CD 138) are generally absent. Further immunopheno type characterization has shown that these tumors process overlapping features of GC and activated B-cell differentiation. Specifically, immunohistochemical analyses have demonstrated that the majority of brain lymphomas express MUM-1, an activated B-cells marker, and BCL-6, a GCs marker [40], as previously confirmed [8]. BCL-2 and BCL-6 are expressed in 56%-93% and 60%-80% of PCNSL cases, respectively [6]. BCL-6 serves as the dominant regulator of the GC reaction and suppresses the exit of B-cells exit from the GCs [23]. Strong IRF4/MUM1 expression is observed in approximately 90% of PCNSLs, indicating that the tumor cells are transitioning out of the GC. Since IRF4/MUM1 expression is more frequently associated with memory B-cells than with GC-B cells, the CD10-BCL6+IRF4/MUM1+ phenotype suggests that further B-cell maturation is impaired. This corresponds to a late GC exit phenotype and is associated with a poor prognosis [5].
Biological analyses have demonstrated that PCNSL is at the late B-cell GC exit phase and exhibits constitutive Nuclear Factor-kB (NF-kB) activity. This activity is driven by mutations in BCR pathway genes, the Toll-like receptor (TLR) pathway (notably MYD 88), and CARD11 [5, 9-13]. Recently, DLBCL has been categorized into distinct molecular clusters. PCNSL has been closely associated with the MCD subtype (defined by the co-occurrence of MYD88L265P and CD79B mutations) or the cluster 5 (C5) DLBCL. Both classifications converge on the presence of recurrent MYD88L265P, PIM1, CD 79B, and BTG2 mutations, as well as Ig heavy locus (IgH)-BCL6 translocations. Other hallmarks include copy number gains at 3q12.3 and 9p24. (involving PD-L1/PD-L2) and copy losses at 6p21-22 (human leukocyte antigen, HLA, locus), 6q21, and 9p21.3 (CDK N2A biallelic loss) [5,26]. Although recent reports have suggested a significant role for the tumor microenvironment in PCNSL pathogenesis, a comprehensive survey examining its interaction with mutation and methylation events is currently lacking [5,14-17].
PCNSL genomic alterations
During SHM phases, B-cell differentiation requires DNA double-strand breaks, consequently, the failure to accurately repair these breaks may lead to the emergence of malignant cells. PCNSL cells frequently harbor translocations affecting Ig and Ig-related genes, most notably BCL6 [23]. Constitutive BCL-6 activity, often caused by mutations in its promoter, can exert significant tumorigenic effects. The Cancer and Leukemia Group B (CALGB) 50202 trial demonstrated that BCL-6 overexpression is associated with poorer survival and refractory disease status [27]. Although these findings have been supported by other studies [67], various retrospective analyses have yielded conflicting results [5,8].
Next-Generation Sequencing (NGS) has revealed that over 80% of non-conservative mutations occur within loci encoding proteins such as TP53, ATM, PTEN, JAK3, PIK2 CA, PTPN11, CTNNB1, and KRAS [15]. Specifically, mutations in the TP53 and ATM genes may be critically involved in the PCNSL molecular pathophysiology. Furthermore, non-synonymous somatic mutations in MYD88, PIM1, and Btg2 have been detected at high frequency via whole-exome sequencing in PCNSL samples [14]. Deletions and insertions of genetic material are highly frequent in PCNSL. Comparative genomic hybridization (CGH) has identified several critical genetic abnormalities. The most common genomic alteration involves the deletion of the chromosome 6p21 region, which harbors the HLA locus [17]. Deletions on chromosome 6q are also frequent, particularly at the 6q21-23 [16] locus. This region contains PTPRK, a protein tyrosine phosphatase implicated in cell adhesion signaling, PRDM1, a tumor suppressor and regulator of B-cell differentiation, and A20 (TNFAIP3), a negative regulator of the NF-kB signaling pathway.
While 6q deletions are associated with adverse outcomes in follicular lymphoma [68], they are present in 66% of PCNSL specimens. Reduced expression of PTPRK, a candidate tumor suppressor, is associated with 6q22-23 deletion, suggesting its role in PCNSL progression. LOH analysis has also shown that 6q aberrations predict shorter survival. Recurred chromosomal losses have also been recorded at the 9p21 locus [16], which contains CDKN2A and other genes involved in cell cycle regulation.
Chromosomal gains on chromosome 12 are very common, specifically at the 12q locus harboring CDK4, MDM2, STAT6, and GLI1 [16,18-20]. Distinct alterations also occur on the long arms of chromosomes 1, 7, and 18 [18], whereas DNA copy number losses are frequently found on chromosome 6 and the short arms of chromosomes 17 and 18. CNAs and translocations on chromosome 9p24, involving the PD-L1 and -2 genes, are frequent, suggesting that immune escape is critical to PCNSL pathophysiology [23]. Homozygous loss of HLA class II [24] and CDKN2A, along with TBL1XR1 variants, are common features that align PCNSL with the recently described [27] “MCD”, “C5”, or “MYD 88-like” subtypes, which are hypothesized to originate from long-lived memory B-cells [27,69-71].
Less research has been conducted on molecular pathogenesis of PCNSL compared with systemic. A molecular aberration in PCNSL that has been reproducibly detected is homozygous deletion or promoter hypermethylation of the CDKN2A gene, which is responsible for P14ARF production. Growth arrest mediated by P14ARF is p53-dependent as p14ARF binds to MDM2, a mediator of p53 stabilization.TP53 mutations are infrequent genomic events in PCNSL, in contrast to systemic lymphomas in which TP53 gene inactivation may be observed in 20% to 40% of tumors. These findings indicate that early alterations of CDKN2A in PCNSL contribute to tumor development and reduce the selective pressure for secondary TP53 mutations [19]. Deletion of CDKN2A, CDKN1B, and RB1 have also been reported in PCNSL cases [18,19].
The Janus kinase (JAK/STAT) signaling pathway plays a central role in the biology of PCNSL, according to molecular analyses. Transcript and protein levels of Il-4 and Il-10 which act as mediators of the JAK/ STAT intracellular signaling pathway and promote B cell proliferation, are upregulated in the tumor microenvironment, as well as in the vitreous and cerebrospinal fluid (CSF) [8]. These cytokines have been associated with tumor response and disease progression [8,28]. The upregulation of Il-4 and Il-10 and activation of downstream JAK/STAT signaling are linked to aberrant MYD88 activation, which is involved in TLR signaling [29]. Increased intratumoral levels of JAK1 transcripts have also been observed in PCNSL [23,28]. Approximately 55% of PCNSL cases harbor mutations within the Toll/IL-1 receptor (TIR) domain of MYD 88, most commonly the L265P mutation, which results from a leukine-to-proline at position 265 and contributes to lymphomagenesis, particularly in PCNSL and activated DLBCL [72].
A L265P substitution in MYD88 is observed in 38%-50% of PCNSL cases, and CD79B is mutated in approximately 20% of cases [17]. Other studies have reported MYD88 mutation frequencies ranging from 38% and 94% in PCNSL cases [27,73,74], which may reflect selection bias due to small cohort sizes, given the rarity of the disease. MYD88 encodes a signaling adaptor protein that regulates NF-kB activation and the JAK/STAT3 signaling pathway following stimulation of TLRs, Il-1/Il-18 receptors, and Interferon-β (IFN-β) production. The MYD88 L265P mutation and loss of CDKN2A have been identified as early mutational events in PCNSL [75]. Although TP53 alterations play a relatively minor role in PCNSL pathogenesis, the CDKN2A/B locus encodes multiple proteins that regulate key cell-cycle control pathways, including the p53 pathway (via p14 ARF) and the RB1 pathway (via p16 INK4a), underscoring the importance of p53-associated mechanisms in PCNSL biology [76].
The CD 79B gene encodes a subunit of the BCR complex that is essential for BCR signaling, and subsequent NF-kB activation. Approximately 40% of PCNSL cases harbor mutations within the immunoreceptor tyrosine-based activation motif of CD79B, most commonly at tyrosine 196 (Y196), leading to chronic active BCR signaling and sustained NF-kB pathway signaling activation [77]. In contrast, systemic DLBCL exhibits lower frequencies of MYD88 and CD79B in the active B-cell (ABC) subtype, with reported rates of 8%-37% for MYD88 and 12%-22% for CD79B mutations [29,78].
The BCR pathway transmits its signals to the CARD11-BCL10-MALT1 (CBM) signalosome complex. Less common mutations as well as overexpression of CARD11 [21] and MALT1 [22] have also been observed in PCNSL cases. Bruton tyrosine kinase (BTK) serves as a key mediator linking BCR and TLR signaling pathways to downstream NF-kB activation. In more than 90% of PCNSL tissue samples, components of the BCR, TLR, or NF-kB signaling path ways are altered. The BCR and TLR pathways, along with their downstream target NF-kB, are frequently affected by SHM, particularly in genes encoding MYD88 and CD79B. NF-kB signaling appears to be the dominant pathway involved in PCNSL pathogenesis [26,79,80], playing a critical role in transcriptional regulation and cell survival. Constitutively activation of NF-kB promotes cellular proliferation, inhibits apoptosis, and sustains the viability of activated ABC DLBCL [80]. NF-kB activity is further enhanced by mutations or deletions of tumor necrosis factor alpha induced protein 3 (TNFAIP3) [73]. The majority of PCNSLs are of the non-GCB-DLBCL subclass and share many genetic aberrations with non-CNS ABC-DLBCL within the same signaling pathways. SHM has been reported to contribute to PCNSL pathogenesis, with a higher mutational load than in systemic DLBCL [13]. SHM targets identified in PCNSL include proto-oncogenes such as PIM1, PAX5, BTG2, and OSBPL10 [13,26].
Despite extensive genetic studies of PCNSL [5,26,75,81], reports on global gene expression profiling remain limited. Available studies indicate that PCNSL exhibit distinct gene expression profiles, which differentiate them from systemic ABC-DLBCL. These differences are particularly evident in the expression of Ig constant genes, highlighting the role of B-cell maturation in the classification of PCNSL and other lymphomas, similar to approaches used in leukemia and multiple myeloma [82].
MYC, a transcription factor commonly upregulated in DLBCL via translocation, drives cell proliferation and regulates cell development, differentiation, and apoptosis, partly through downregulation of BCL2 [83,84]. In PCNSL, microRNAs associated with the MYC signaling pathway have been reported, with tumor-suppressor microRNAs such as miR-193b, miR-199a, miR-145, and miR-214 being downregulated [30].
Epigenetic alterations in PCNSL
Epigenetic silencing through DNA methylation is also involved in the pathogenesis of PCNSL. DNA hypermethylation has been found in various loci such as CDKN2A, p16 INK4a, DAPK, p14ARF, MGMT, and RFC [32,33]. Array-based DNA methylation profiling identified 194 distinctively methylated genes when comparing PCNSL patients to controls. A significantly enriched CpG content was also observed in these differentially methylated genes. However, no differences in methylation patterns between PCNSL and systemic DLBCL cases were recorded [85]. Additionally, promoter methylation of RB1 and CDKN1B has been found in PCNSL cases [18,20].
PCNSL are highly proliferative neoplasms [86]. TERT activation leads to unlimited proliferation, and activating TERT promoter mutations are frequent in various human cancers [34]. Mutations at two hotspot positions (-124G>A and -146G>A) result in enhanced TERT promoter activity. Bruno et al. have found that these TERT promoter mutations were present in PCNSL located in the splenium [35].
MicroRNAs may also play a critical role in the PCNSL pathogenesis as they do in other malignant neoplasms. MiR-17-5p, which targets the proapoptotic gene E2F1, was significantly upregulated in nine PCNSL cases compared with nodal DLBCL cases [87]. It has also been reported that miRNA upregulation is associated with overexpression induced by inflammatory cytokines (miR-155), inhibition of terminal B cell differentiation (miR-30b/c, miR-9), or the MYC pathway (miR-92, miR-17-5p, miR-20a) [30].
Nevertheless, Deckert et al. [5] reported contradictory outcomes. Specifically, they observed that miR-155 exhibited the lowest expression level compared with other mi-RNAs implicated in PCNSL. CSF analysis from PCNSL patients demonstrated that miR-19, miR-21, and miR-92 were expressed at significantly higher levels than in controls with inflammatory CNS diseases, highlighting the potential of these miRNAs as clinical bio-markers [31].
The role of tumor microenvironment in PCNS pathogenesis
Under normal conditions, the brain is immunologically “quiet”, whereas some PCNSL specimens exhibit signs of inflammatory reactions, included activated macrophages and reactive T-cell infiltration. In the CNS perivascular area, T cells residing near blood vessels may interact with perivascular antigen-presenting macrophages. Subsequent invasion of the CNS parenchyma requires antigen stimulation. In the absence of antigen, T cells may remain confined to the perivascular region [88]. Activated perivascular infiltration by CD8 T cells may be associated with favorable outcomes, suggesting the potential efficacy of immunotherapy in enhancing T-cell-mediated immune-surveillance [89].
Inflammatory activation may precede or accompany PCNSL [90]. Chemokines regulate leukocyte trafficking, proliferation and adhesion, contributing to the organization of normal lymphoid structures. A recent study reported high expression of the B-cell-attracting chemokine BCA-1(CXCL-13) in PCNSL. This chemokine promotes B-cell homing to secondary lymphoid organs. BCA-1 binds to its receptor, CXCR5, which is also expressed by B-cells in PCNSL, and may facilitate the extranodal localization of CNS lymphomas. Although BCA-1 is expressed by lymphoma cells, it is not produced by tumor endothelia in PCNSL and therefore, does not contribute to the angiotropic growth pattern of these those tumors [36].
Mechanisms underlying the intracerebral tropism and dissemination of lymphoma cells are central to PCNSL pathogenesis and may involve chemokines such as CXCL-13, and CXCL12 (SDF-1). The diagnostic relevance of Il-10 and CXCL-13 concentration in CNS lymphomas has been demonstrated [37,38]. Elevated CFS levels of CXCL-13 and Il-10 are also associated with poor prognosis in PCNSL patients [36,91].
Furthermore, ectopic expression of the B-cell growth factor Il-4 was also detected in PCNSL [8]. Il-4 may function as an autocrine growth factor for lymphoma cells and as a paracrine factor due to its unique expression by tumor-associated endothelia in PCNSL. Il-4 is not expressed in the normal brain vasculature or in malignant astrocytic neoplasms. These findings support the hypothesis that Il-4 play a critical role in PCNSL pathogenesis and progression and may contribute to the angiotropic growth pattern of lymphoma cells within the CNS. Additionally, the activated form of the transcription factor STAT6, a mediator of Il-4-dependent gene expression, is expressed by tumor cells and tumor-associated endothelia in PCNSL, providing further evidence for the functional significance of Il-4 signaling in PCNSL [92].
Hemangioblastoma
Epidemiological data
Hemangioblastoma (HB) is a highly vascular tumor, accounting for 3% of all CNS tumors, 1-2.5% of primary intracranial tumors [39], 7-8% of posterior cranial fossa tumors [40], and 7-10% of spinal cord tumors. It is generally benign, characterized by neoplastic “stromal” cells embedded with in a dense network of vascular channels [41]. Cystic HBs are more commonly located in the cerebellar hemispheres and, more broadly, in a limited subset of CNS regions, including retina, brainstem, and spinal cord [39-41].
HBs may arise sporadically or as part of von Hippel-Lindau (VHL) disease, an autosomal dominant disorder, which accounts for approximately 25% of cases [40]. About 75% of HBs are sporadic, and somatic VHL mutations have been detected in only a small subset of these tumors [42]. In contrast to familial VHL disease, most sporadic HBs do not exhibit detectable germline or somatic alterations in VHL [43,44]. Sporadic cases typically present as solitary lesions, whereas VHL patients often develop multiple HBs [45]. Two possible explanations have been proposed for the difference in VHL mutation frequency between familial and sporadic HBs. The first suggests that sporadic HBs may arise from alterations in hypoxia-sensing pathway other than VHL, producing a histologically-identical phenotype with excessive angiogenesis. A candidate gene is TCEB1, which encodes.
VHL-binding partner belonging C. Genomic sequencing of clear cell renal carcinoma has shown somatic mutations in TCEB1 in a minority of cases lacking VHL mutations. The second explanation is that earlier bulk sequencing techniques were technically limited and may have underestimated the full extent of VHL inactivation [93]. Despite their classification as benign WHO grade 1 tumor [94], HBs are associated with significant morbidity due to the cumulative effects of the primary tumor or development of peritumoral cysts, which are often large [95]. In some cases, tumor recurrence or progression may occur [96] and, more rarely, leptomeningeal dissemination has been reported [97].
HB cell of origin
It remains unclear whether HBs originate from an embryologically arrested “hem angioblast” stem cell that has subsequently differentiates into the distinct cellular component supporting the tumor architecture [41,46]. A series of immunohistochemical and ultrastructural studies have failed to clarify the origin of the stromal cells. Consequently, HBs remain classified as tumors of ‘‘uncertain histogenesis’’ [47]. Decades ago, it was hypothesized that HBs arise from a ‘‘congenital anlage”, with histologic features reflecting an “embryologic type of the tumor cell [48]. Stein et al. [98] suggested an Angio mesenchymal origin for HB, based on developmental biology observations originally described by Sabin [99]. Sabin [99] and Murray [100] investigated the morphologic evolution of embryonic Angio mesenchymal tissue into hem angioblasts. However, the hem angioblast itself remained an ‘‘hypothetical’’ cell until Choi et al. [101] reported the identification of a common precursor for hematopoietic and endothelial cells. The generation of hem angioblasts from embryonic stem cells [101] enabled detailed analysis of gene and protein expression during embryonic hematopoiesis and vasculogenic.
Consequently, several proteins have been identified that are directly associated with pre-mesangioblast and hemangioblastic differentiation [102]. These include growth factors, transcription factors and transmembrane receptors such as brachyury, Scl, Csf-1R, Gata-1, Flk-1, and Tie-2 [103]. Various hypotheses regarding HB histogenesis have been proposed implicated glial, endothelial, arachnoid, neuroendocrine, fibro-histiocytic cells, embryonic choroid plexus, neuroectodermal cells, or heterogeneous cell populations [104]. These unresolved interpretations have led to the current WHO classification of HBs as neoplasms of ‘‘uncertain histogenesis’’ [47]. Although earlier immunohistochemical studies were unable to definitively identify the origin of stromal cells, the complex immunophenotype combined with their unique morphology may suggest that these cells lack a direct cytologic counterpart in mature brain tissue or in tissues outside the CNS.
Other investigators, based on the morphologic heterogeneity of HBs, have focused on the cytogenetic relationship between stromal and vascular cells. Some studies [105,106] have suggested differentiation of stromal cells into vascular cells, whereas others detected no transition of stromal cells into ‘Vaso formative’ elements and suggested that vascular and stromal cells represent distinct cytologic components [107,108]. However, another report identified ultrastructural evidence of Weibel-Palade body formation within the cytoplasm of stromal cells, suggesting vascular differentiation potential of these cells [109].
Proteins expressed during early hem angioblast differentiation have recently identified, including Scl, also known as Tal-1, which regulates proliferation and self-renewal of multipotent hematopoietic cells [110] and acts as a regulator of erythroid cells differentiation [111], as well as brachyury, a transcription factor essential for posterior mesoderm formation, differentiation, and axial development in vertebrates [103]. Additional proteins involved to vasculogenesis, Flk-1 and Tie-2, and hematopoiesis, Csf-1R and Gata-1, have also been associated with hemangioblast development [103]. Flk-1, also known as kdr, is a receptor tyrosine kinase whose ligand is Vascular Endothelial Growth Factor (VEGF), a key mediator of endothelial cell differentiation. The Tie-2 receptor tyrosine kinase plays an important role in angiogenesis, particularly in vascular network formation. Csf-1R is a transmembrane protein tyrosine kinase receptor for Csf-1, a macrophage-specific growth factor. Gata-1 is a tissue-specific transcription factor essential for erythroid and megakaryocytic development [112]. Notably, these proteins were consistently expressed in HB stromal cells, an observation that strongly supports the hypothesis that embryonic progenitor cells with hemangioblastic differentiation potential represent the cytologic counterpart of the stromal cell population.
Another model suggests that stromal cells are genetically distinct due to VHL deficiency and promote reactive angiogenesis by recruiting normal endothelial cells through pseudo-hypoxia-mediated paracrine signaling. This model contrasts with the alternative hypothesis of an embryologically arrested, heritable “hemangioblast” clone that transdifferentiates into the diverse cellular components comprising the tumor [46,113]. Accordingly, it has been suggested that HBs are primarily comprised of developmentally arrested hemangioblastic stem cells with the capacity to differentiate into primitive vascular structures and RBCs, analogous to embryonic angioblastic mesenchyme [39].
In areas of blood island differentiation within HBs, co-expression of Erythropoietin (Epo) and its receptor (Epo-R) has been demonstrated [114]. Epo-R is expressed during early embryonic blood island formation in mice between embryonic days 8.0 to 9.5 [115] and is upregulated during early blood island differentiation [115]. Epo is a HIF target protein and is upregulated following HIF activation in VHL-deficient stromal cells. Consequently, it has been suggested that the concurrent expression of developmental proteins and HIF target proteins may establish autocrine and paracrine signaling loops that promote tumor growth. Following the observation of consistent Tie-2 expression in stromal cells, co-expression of Ang-1, another HIF target protein was investigated [116].
These findings led to the identification of a potential Tie-2/Ang-1 autocrine/paracrine loop in HB stromal cells. This discovery was preceded by the demonstration of three additional potential autocrine/paracrine loops, transforming growth factor-α (TGF-α), another HIF target protein [117], and its receptor [118], Flk-1 and its HIF-regulated ligand VEGF [119], and stromal cell-derived factor-1 (SDF-1) with its receptor CXCR4 [120]. Moreover, the Tie-2/Ang-1 autocrine/paracrine loop has also been identified in other human neoplasms [121].
Molecular Biology of HB
Despite the presence of CNAs in a small subset of cases [53], the HB exome is notably simple and lacks additional oncogenic driver mutations [52,54]. These tumors are largely diploid with few chromosomal abnormalities [49,50], and have served as prototypic lesions for studying genomic drivers of hypoxia-mediated metabolism in cancer [42]. VHL mutations are detected in approximately 10% to 44% of sporadic HBs [51]. The reported frequency of chromosome 3 aneuploidy in sporadic tumors ranges from 18% to 69% [49,50]. However, only one report identified concurrent somatic VHL mutation and LOH of VHL in one of 13 sporadic HBs [50], while another detected missense mutation with VHL deletion by comparative genomic hybridization in two of 16 sporadic HB cases [49]. These findings may be explained by low VHL mutant allele fractions restricted to the neoplastic “stromal” cell population in sporadic HBs, in contrast to familial tumors, which are characterized by heterozygous germline VHL mutations.
Mutations of the VHL tumor suppressor gene, located on chromosome 3p 25.3 appear to play a role in both sporadic and VHL disease-associated tumors [52-54]. However, the genetic determinants underlying the clinical heterogeneity of HBs remain largely unknown. Loss of chromosome 3p or the entire chromosome 3 represents the most common cytogenetic abnormality in HBs. Other recurrent abnormalities include losses of chromosome regions 1p11-p31, chromosome 9,12 (q24.13), and 18q, as well as gains of chromosome regions 1 (p36.32), 7 (p11.2), and chromosome 19 [122].
Transcriptomic and lipidomic analyses of cystic and solid HBs have identified dysregulation of lipid metabolism-related genes in cyst-forming tumors [123], however the under-lying molecular mechanisms remain unclear. In a recent study by Takayanagi et al., molecular characterization of the VHL promoter revealed epigenetic differences between sporadic and VHL-associated HBs [53], raising the possibility that DNA methylation alterations may define biologically relevant subgroups.
Mutations in ARID1B, a tumor suppressor gene implicated multiple cancer types [55,56], have also been reported. Further studies are required to determine whether these sub clonal variants are functionally significant in driving sporadic HB development [57]. HBs are composed of vascular and ‘‘stromal’’ cells. The neoplastic “stromal” cells account for approximately 10-20% of the total tumor cell population, while the remainder consists of vascular endothelial cells, pericytes, and other nucleated cells, such as lymphocytes, present within the vascular channels [104]. LOH analyses of micro dissected stromal cells have demonstrated that these cells represent the neoplastic, VHL-deficient component of HBs [104,114,124].
As previously discussed, the high prevalence of recurrent somatic VHL mutations (approximately50%) and LOH at the chromosome 3p (approximately 72%) leads to biallelic VHL inactivation in 47% of sporadic HBs and inactivation of at least one VHL allele in 78% of cases [52]. Biallelic VHL loss results in impaired degradation of HIF-1α, which subsequently drives aberrant transcription of hypoxia-responsive genes, including VEGF and PDGFB [125]. Consequently, the tumor mass is composed predominantly of non-neoplastic endothelial cells and surrounding pericytes, with only a minor fraction consisting of neoplastic “stromal” cells that harbor the driver genetic alterations. Thus, HB tumorigenesis appears to be consisted of a small subpopulation of neoplastic stromal cells that recruit and interact with various non-neoplastic cellular components to generate the characteristic tumor architecture [39,126].
The Notch signaling pathway appears to be involved in HB pathogenesis [127]. Additional candidate genes implicated in HB development include EGFR, PTCH, RB1, PTPN11, FLT3, IRF4, FGFR1, CHEK2, PRDM16, MKL1, GPHN, FOXP1, GPC3, IKZF1, HOXA9, HOXA11, HOXC13, HOXC11, HOXD11, and HOXD13 [122]. Copy number gains involving miR-551a (located within the PRDM16 locus), as well as gains of miR-196a-2 and miR-196b, have also been identified in HB samples [122].
PCNSL and HB consist Ute a complex group of diseases characterized by marked genomic, biological and clinical heterogeneity. Neoplastic subtypes harboring alterations in genes that play critical roles in CNS development have been identified, and murine models based on several of these findings have been established. Significant progress has been made in elucidating the molecular pathogenesis of PCNSL leading to the clinical use of targeted therapeutic agents, including those aimed at inhibiting NF-kB pathway activation. However, further investigation is required to clarify the spectrum and functional significance of molecular alterations responsible for uncontrolled cell proliferation in the majority of these neoplasms.
| Hemangioblastoma | Molecular alterations |
| Tumor suppressor genes inactivation | VHL (located on chromosome 3p25-26) [52-57] |
| Functional VHL protein (pVHL) loss | Overproduction of VEGF [112, 119], PDGFB [124,125], Epo [114,115] |
| Copy Number Variations (CNVs) | Chromosome 12q (including PTPN11 gene), 1p11-p31, 3p13 (FOXP1), 6q, 8p11.22 (FGFR1), 12q24.13,13q12.2 (FLT3),18q,22q13.1 (MKL1), 22q12.1 (CHEK2) loss [122], Chromosome 1p36.32 and 7p11.2 gains (inclu-ding EGFR gene) [59], chromosome 19, 2q31.1 (HOXD11, HOXD13, HOXD1, 1HOXD13) 9q22.32 (PTCH),12q13.13 (HOXC 13, HOXC11), Xq26.2 (GPC3) gain [122] |
| Loss of Heterozygosity (LOH) | Chromosome 6q (sometimes concurrent with 3p loss, possible involvement of ZAC1 tumor sup-pressor gene) [107,114,123] |
| Gene mutations | ARID1B gene [55-57] |
| Signaling pathways alterations | EGFR overexpression [122], Notch receptor/ effector [removed]especially NOTCH1, NOTCH4, HES1, HESS5) [127] |
| Candidate genes genomic aberrations | PRDM16, PTPN11, HOXD11, HOXD13, FLT3, FGFR1, FOXP1, GPC3, HOXC13, HOXC11, MKL1, IRF4, GPHN, IKZF1, RB1, HOXA9, HOXA11 and several microRNA, including hsa-miR-196a-2, and miR-551a [122] |
Table 1: Molecular alterations in Hemangioblastoma.
| Primary Central Nervous System Lymphoma | Molecular alterations |
| Point mutation (non-Somatic Hypermutation (SHM)/a (aberrant) SHM | Genes coding for ATM, TP53, PTEN, PIK3CA, JAK3, CTNNB1, PTPN11, KRAS [5,15], PIM1, BTG2 [5,13, 14, 26], MYD88 [5,10-14], CD79B [29,77,78], MALT1 [22], CARD11 [5,9-13,21], OSBPL10 [13,26] |
| SHM/aSHM | BCL6 promoter substitution [6-8], PIM1, PAX5 [35, 36,39,79], RhoH/TTF, MYC proto-oncogene activation [90,91], IGH (Immunoglobulin Heavy) locus translocation [90,99] |
| Genetic material gain | 12q (STAT6, MDM2, CDK4, MDM2, GLI1) [16-20], 1q, 7q, 18q [18] leading to NF-kB activation |
| Genetic material loss | 6p21 (HLA) immune escape [16,17], 9p21 (CDKN2A) proliferation [5,16,25,26], 6q21-23 [5,16,17,26] (PRDM1 tumor activation, A20 (TNFAIP3 NF-kB activation) [75,82] |
| DNA hypermethylation | CDKN2A [19,25,32,33,84-86], DAPK, p14ARF, p16 INK4A, RFC, MGMT no expression [32,33], CDKN1B, RB1 [18- 20], TERT promoter mutations [34,35] |
| Deletion | CDKN2A [18,19,25,32,33,84,85], RB1, CDKN1B [18-20] |
Table 2: Molecular alterations in Primary Central Nervous System Lymphoma.
Conflict of interest and source of funding statement: The Authors declare that they have no conflict of interests The study was self-funded by the author and co-Authors.
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.
The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.
Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.
Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.
Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.
Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”
Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner
My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.
My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.
My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.
I would like to offer my testimony in the support. I have received through the peer review process and support the editorial office where they are to support young authors like me, encourage them to publish their work in your esteemed journals, and globalize and share knowledge globally. I really appreciate your journal, peer review, and editorial office.
Dear Agrippa Hilda- Editorial Coordinator of Journal of Neuroscience and Neurological Surgery, "The peer review process was very quick and of high quality, which can also be seen in the articles in the journal. The collaboration with the editorial office was very good."
I would like to express my sincere gratitude for the support and efficiency provided by the editorial office throughout the publication process of my article, “Delayed Vulvar Metastases from Rectal Carcinoma: A Case Report.” I greatly appreciate the assistance and guidance I received from your team, which made the entire process smooth and efficient. The peer review process was thorough and constructive, contributing to the overall quality of the final article. I am very grateful for the high level of professionalism and commitment shown by the editorial staff, and I look forward to maintaining a long-term collaboration with the International Journal of Clinical Case Reports and Reviews.
To Dear Erin Aust, I would like to express my heartfelt appreciation for the opportunity to have my work published in this esteemed journal. The entire publication process was smooth and well-organized, and I am extremely satisfied with the final result. The Editorial Team demonstrated the utmost professionalism, providing prompt and insightful feedback throughout the review process. Their clear communication and constructive suggestions were invaluable in enhancing my manuscript, and their meticulous attention to detail and dedication to quality are truly commendable. Additionally, the support from the Editorial Office was exceptional. From the initial submission to the final publication, I was guided through every step of the process with great care and professionalism. The team's responsiveness and assistance made the entire experience both easy and stress-free. I am also deeply impressed by the quality and reputation of the journal. It is an honor to have my research featured in such a respected publication, and I am confident that it will make a meaningful contribution to the field.
"I am grateful for the opportunity of contributing to [International Journal of Clinical Case Reports and Reviews] and for the rigorous review process that enhances the quality of research published in your esteemed journal. I sincerely appreciate the time and effort of your team who have dedicatedly helped me in improvising changes and modifying my manuscript. The insightful comments and constructive feedback provided have been invaluable in refining and strengthening my work".
I thank the ‘Journal of Clinical Research and Reports’ for accepting this article for publication. This is a rigorously peer reviewed journal which is on all major global scientific data bases. I note the review process was prompt, thorough and professionally critical. It gave us an insight into a number of important scientific/statistical issues. The review prompted us to review the relevant literature again and look at the limitations of the study. The peer reviewers were open, clear in the instructions and the editorial team was very prompt in their communication. This journal certainly publishes quality research articles. I would recommend the journal for any future publications.
Dear Jessica Magne, with gratitude for the joint work. Fast process of receiving and processing the submitted scientific materials in “Clinical Cardiology and Cardiovascular Interventions”. High level of competence of the editors with clear and correct recommendations and ideas for enriching the article.
We found the peer review process quick and positive in its input. The support from the editorial officer has been very agile, always with the intention of improving the article and taking into account our subsequent corrections.
My article, titled 'No Way Out of the Smartphone Epidemic Without Considering the Insights of Brain Research,' has been republished in the International Journal of Clinical Case Reports and Reviews. The review process was seamless and professional, with the editors being both friendly and supportive. I am deeply grateful for their efforts.
To Dear Erin Aust – Editorial Coordinator of Journal of General Medicine and Clinical Practice! I declare that I am absolutely satisfied with your work carried out with great competence in following the manuscript during the various stages from its receipt, during the revision process to the final acceptance for publication. Thank Prof. Elvira Farina
Dear Jessica, and the super professional team of the ‘Clinical Cardiology and Cardiovascular Interventions’ I am sincerely grateful to the coordinated work of the journal team for the no problem with the submission of my manuscript: “Cardiometabolic Disorders in A Pregnant Woman with Severe Preeclampsia on the Background of Morbid Obesity (Case Report).” The review process by 5 experts was fast, and the comments were professional, which made it more specific and academic, and the process of publication and presentation of the article was excellent. I recommend that my colleagues publish articles in this journal, and I am interested in further scientific cooperation. Sincerely and best wishes, Dr. Oleg Golyanovskiy.
Dear Ashley Rosa, Editorial Coordinator of the journal - Psychology and Mental Health Care. " The process of obtaining publication of my article in the Psychology and Mental Health Journal was positive in all areas. The peer review process resulted in a number of valuable comments, the editorial process was collaborative and timely, and the quality of this journal has been quickly noticed, resulting in alternative journals contacting me to publish with them." Warm regards, Susan Anne Smith, PhD. Australian Breastfeeding Association.
Dear Jessica Magne, Editorial Coordinator, Clinical Cardiology and Cardiovascular Interventions, Auctores Publishing LLC. I appreciate the journal (JCCI) editorial office support, the entire team leads were always ready to help, not only on technical front but also on thorough process. Also, I should thank dear reviewers’ attention to detail and creative approach to teach me and bring new insights by their comments. Surely, more discussions and introduction of other hemodynamic devices would provide better prevention and management of shock states. Your efforts and dedication in presenting educational materials in this journal are commendable. Best wishes from, Farahnaz Fallahian.
Dear Maria Emerson, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews, Auctores Publishing LLC. I am delighted to have published our manuscript, "Acute Colonic Pseudo-Obstruction (ACPO): A rare but serious complication following caesarean section." I want to thank the editorial team, especially Maria Emerson, for their prompt review of the manuscript, quick responses to queries, and overall support. Yours sincerely Dr. Victor Olagundoye.
Dear Ashley Rosa, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews. Many thanks for publishing this manuscript after I lost confidence the editors were most helpful, more than other journals Best wishes from, Susan Anne Smith, PhD. Australian Breastfeeding Association.
Dear Agrippa Hilda, Editorial Coordinator, Journal of Neuroscience and Neurological Surgery. The entire process including article submission, review, revision, and publication was extremely easy. The journal editor was prompt and helpful, and the reviewers contributed to the quality of the paper. Thank you so much! Eric Nussbaum, MD
Dr Hala Al Shaikh This is to acknowledge that the peer review process for the article ’ A Novel Gnrh1 Gene Mutation in Four Omani Male Siblings, Presentation and Management ’ sent to the International Journal of Clinical Case Reports and Reviews was quick and smooth. The editorial office was prompt with easy communication.
Dear Erin Aust, Editorial Coordinator, Journal of General Medicine and Clinical Practice. We are pleased to share our experience with the “Journal of General Medicine and Clinical Practice”, following the successful publication of our article. The peer review process was thorough and constructive, helping to improve the clarity and quality of the manuscript. We are especially thankful to Ms. Erin Aust, the Editorial Coordinator, for her prompt communication and continuous support throughout the process. Her professionalism ensured a smooth and efficient publication experience. The journal upholds high editorial standards, and we highly recommend it to fellow researchers seeking a credible platform for their work. Best wishes By, Dr. Rakhi Mishra.
Dear Jessica Magne, Editorial Coordinator, Clinical Cardiology and Cardiovascular Interventions, Auctores Publishing LLC. The peer review process of the journal of Clinical Cardiology and Cardiovascular Interventions was excellent and fast, as was the support of the editorial office and the quality of the journal. Kind regards Walter F. Riesen Prof. Dr. Dr. h.c. Walter F. Riesen.
Dear Ashley Rosa, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews, Auctores Publishing LLC. Thank you for publishing our article, Exploring Clozapine's Efficacy in Managing Aggression: A Multiple Single-Case Study in Forensic Psychiatry in the international journal of clinical case reports and reviews. We found the peer review process very professional and efficient. The comments were constructive, and the whole process was efficient. On behalf of the co-authors, I would like to thank you for publishing this article. With regards, Dr. Jelle R. Lettinga.
Dear Clarissa Eric, Editorial Coordinator, Journal of Clinical Case Reports and Studies, I would like to express my deep admiration for the exceptional professionalism demonstrated by your journal. I am thoroughly impressed by the speed of the editorial process, the substantive and insightful reviews, and the meticulous preparation of the manuscript for publication. Additionally, I greatly appreciate the courteous and immediate responses from your editorial office to all my inquiries. Best Regards, Dariusz Ziora
Dear Chrystine Mejia, Editorial Coordinator, Journal of Neurodegeneration and Neurorehabilitation, Auctores Publishing LLC, We would like to thank the editorial team for the smooth and high-quality communication leading up to the publication of our article in the Journal of Neurodegeneration and Neurorehabilitation. The reviewers have extensive knowledge in the field, and their relevant questions helped to add value to our publication. Kind regards, Dr. Ravi Shrivastava.
Dear Clarissa Eric, Editorial Coordinator, Journal of Clinical Case Reports and Studies, Auctores Publishing LLC, USA Office: +1-(302)-520-2644. I would like to express my sincere appreciation for the efficient and professional handling of my case report by the ‘Journal of Clinical Case Reports and Studies’. The peer review process was not only fast but also highly constructive—the reviewers’ comments were clear, relevant, and greatly helped me improve the quality and clarity of my manuscript. I also received excellent support from the editorial office throughout the process. Communication was smooth and timely, and I felt well guided at every stage, from submission to publication. The overall quality and rigor of the journal are truly commendable. I am pleased to have published my work with Journal of Clinical Case Reports and Studies, and I look forward to future opportunities for collaboration. Sincerely, Aline Tollet, UCLouvain.
Dear Ms. Mayra Duenas, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews. “The International Journal of Clinical Case Reports and Reviews represented the “ideal house” to share with the research community a first experience with the use of the Simeox device for speech rehabilitation. High scientific reputation and attractive website communication were first determinants for the selection of this Journal, and the following submission process exceeded expectations: fast but highly professional peer review, great support by the editorial office, elegant graphic layout. Exactly what a dynamic research team - also composed by allied professionals - needs!" From, Chiara Beccaluva, PT - Italy.
Dear Maria Emerson, Editorial Coordinator, we have deeply appreciated the professionalism demonstrated by the International Journal of Clinical Case Reports and Reviews. The reviewers have extensive knowledge of our field and have been very efficient and fast in supporting the process. I am really looking forward to further collaboration. Thanks. Best regards, Dr. Claudio Ligresti
Dear Chrystine Mejia, Editorial Coordinator, Journal of Neurodegeneration and Neurorehabilitation. “The peer review process was efficient and constructive, and the editorial office provided excellent communication and support throughout. The journal ensures scientific rigor and high editorial standards, while also offering a smooth and timely publication process. We sincerely appreciate the work of the editorial team in facilitating the dissemination of innovative approaches such as the Bonori Method.” Best regards, Dr. Matteo Bonori.
I recommend without hesitation submitting relevant papers on medical decision making to the International Journal of Clinical Case Reports and Reviews. I am very grateful to the editorial staff. Maria Emerson was a pleasure to communicate with. The time from submission to publication was an extremely short 3 weeks. The editorial staff submitted the paper to three reviewers. Two of the reviewers commented positively on the value of publishing the paper. The editorial staff quickly recognized the third reviewer’s comments as an unjust attempt to reject the paper. I revised the paper as recommended by the first two reviewers.
Dear Maria Emerson, Editorial Coordinator, Journal of Clinical Research and Reports. Thank you for publishing our case report: "Clinical Case of Effective Fetal Stem Cells Treatment in a Patient with Autism Spectrum Disorder" within the "Journal of Clinical Research and Reports" being submitted by the team of EmCell doctors from Kyiv, Ukraine. We much appreciate a professional and transparent peer-review process from Auctores. All research Doctors are so grateful to your Editorial Office and Auctores Publishing support! I amiably wish our article publication maintained a top quality of your International Scientific Journal. My best wishes for a prosperity of the Journal of Clinical Research and Reports. Hope our scientific relationship and cooperation will remain long lasting. Thank you very much indeed. Kind regards, Dr. Andriy Sinelnyk Cell Therapy Center EmCell
Dear Editorial Team, Clinical Cardiology and Cardiovascular Interventions. It was truly a rewarding experience to work with the journal “Clinical Cardiology and Cardiovascular Interventions”. The peer review process was insightful and encouraging, helping us refine our work to a higher standard. The editorial office offered exceptional support with prompt and thoughtful communication. I highly value the journal’s role in promoting scientific advancement and am honored to be part of it. Best regards, Meng-Jou Lee, MD, Department of Anesthesiology, National Taiwan University Hospital.
Dear Editorial Team, Journal-Clinical Cardiology and Cardiovascular Interventions, “Publishing my article with Clinical Cardiology and Cardiovascular Interventions has been a highly positive experience. The peer-review process was rigorous yet supportive, offering valuable feedback that strengthened my work. The editorial team demonstrated exceptional professionalism, prompt communication, and a genuine commitment to maintaining the highest scientific standards. I am very pleased with the publication quality and proud to be associated with such a reputable journal.” Warm regards, Dr. Mahmoud Kamal Moustafa Ahmed
Dear Maria Emerson, Editorial Coordinator of ‘International Journal of Clinical Case Reports and Reviews’, I appreciate the opportunity to publish my article with your journal. The editorial office provided clear communication during the submission and review process, and I found the overall experience professional and constructive. Best regards, Elena Salvatore.
Dear Mayra Duenas, Editorial Coordinator of ‘International Journal of Clinical Case Reports and Reviews Herewith I confirm an optimal peer review process and a great support of the editorial office of the present journal
Dear Editorial Team, Clinical Cardiology and Cardiovascular Interventions. I am really grateful for the peers review; their feedback gave me the opportunity to reflect on the message and impact of my work and to ameliorate the article. The editors did a great job in addition by encouraging me to continue with the process of publishing.
Dear Cecilia Lilly, Editorial Coordinator, Endocrinology and Disorders, Thank you so much for your quick response regarding reviewing and all process till publishing our manuscript entitled: Prevalence of Pre-Diabetes and its Associated Risk Factors Among Nile College Students, Sudan. Best regards, Dr Mamoun Magzoub.
International Journal of Clinical Case Reports and Reviews is a high quality journal that has a clear and concise submission process. The peer review process was comprehensive and constructive. Support from the editorial office was excellent, since the administrative staff were responsive. The journal provides a fast and timely publication timeline.
Dear Maria Emerson, Editorial Coordinator of International Journal of Clinical Case Reports and Reviews, What distinguishes International Journal of Clinical Case Report and Review is not only the scientific rigor of its publications, but the intellectual climate in which research is evaluated. The submission process is refreshingly free of unnecessary formal barriers and bureaucratic rituals that often complicate academic publishing without adding real value. The peer-review system is demanding yet constructive, guided by genuine scientific dialogue rather than hierarchical or authoritarian attitudes. Reviewers act as collaborators in improving the manuscript, not as gatekeepers imposing arbitrary standards. This journal offers a rare balance: high methodological standards combined with a respectful, transparent, and supportive editorial approach. In an era where publishing can feel more burdensome than research itself, this platform restores the original purpose of peer review — to refine ideas, not to obstruct them Prof. Perlat Kapisyzi, FCCP PULMONOLOGIST AND THORACIC IMAGING.
Dear Grace Pierce, International Journal of Clinical Case Reports and Reviews I appreciate the opportunity to review for Auctore Journal, as the overall editorial process was smooth, transparent and professionally managed. This journal maintains high scientific standards and ensures timely communications with authors, which is truly commendable. I would like to express my special thanks to editor Grace Pierce for his constant guidance, promt responses, and supportive coordination throughout the review process. I am also greatful to Eleanor Bailey from the finance department for her clear communication and efficient handling of all administrative matters. Overall, my experience with Auctore Journal has been highly positive and rewarding. Best regards, Sabita sinha
Dear Mayra Duenas, Editorial Coordinator of the journal IJCCR, I write here a little on my experience as an author submitting to the International Journal of Clinical Case Reports and Reviews (IJCCR). This was my first submission to IJCCR and my manuscript was inherently an outsider’s effort. It attempted to broadly identify and then make some sense of life’s under-appreciated mysteries. I initially had responded to a request for possible submissions. I then contacted IJCCR with a tentative topic for a manuscript. They quickly got back with an approval for the submission, but with a particular requirement that it be medically relevant. I then put together a manuscript and submitted it. After the usual back-and-forth over forms and formality, the manuscript was sent off for reviews. Within 2 weeks I got back 4 reviews which were both helpful and also surprising. Surprising in that the topic was somewhat foreign to medical literature. My subsequent updates in response to the reviewer comments went smoothly and in short order I had a series of proofs to evaluate. All in all, the whole publication process seemed outstanding. It was both helpful in terms of the paper’s content and also in terms of its efficient and friendly communications. Thank you all very much. Sincerely, Ted Christopher, Rochester, NY.
