Coexistence of BCR∷ABL1 translocation and JAK2V617F mutations in indian patients with myeloproliferative neoplasms: A case series.

ABSTRACT: BCR∷ABL1 translocation and JAK2V617F mutations are canonical variants of myeloproliferative neoplasms (MPNs). Traditionally considered mutually exclusive, they may rarely coexist. We report the clinicopathological profile and treatment outcomes of four MPN patients with coexistence of these disease-defining genetic variants. Both mutations were detected simultaneously in three patients who did not harbor tell-tale signs of CML and were evaluated for both BCR∷ABL1 and JAK2V617F based on clues from hemogram, peripheral-blood and bone-marrow examination. All were treated with imatinib and hydroxyurea and attained major molecular response after 2-7 months. In another patient, JAK2V617F was detected 15 years after the diagnosis of CML at the time of evaluation of loss of hematological and molecular response. She was treated with dasatinib but no hematologic or molecular response was attained after 6 months despite good compliance. In conclusion, BCR∷ABL1 and JAK2V617F may rarely coexist in MPN with variable temporal evolution, clinicopathological profile, and treatment response.

Primary Uterine Alveolar Soft Part Sarcoma in a Postmenopausal Woman: Histopathologic and Immunohistochemical Characteristics of a Rare Case.

BACKGROUND: Primary uterine alveolar soft part sarcoma (ASPS) is a rare, indolent mesenchymal malignancy with less than 40 patients documented in the literature. CASE: We report an example of ASPS in a 61-year-old postmenopausal woman. Macroscopically, the uterus showed multiple nodular masses. Microscopic examination revealed tumor arranged in nests and alveolar pattern. The tumor cells were moderately to markedly pleomorphic, epithelioid to polygonal, with eccentrically placed nuclei, vesicular chromatin, prominent macro-nucleoli, and moderate to abundant eosinophilic cytoplasm. PAS-positive and diastase-resistant intracytoplasmic crystals were also seen in some tumor cells. On immunohistochemistry, the tumor cells showed diffuse positivity for vimentin and nuclear positivity for TFE3, a surrogate marker for ASPS. These were negative for SMA, desmin, CD10, h-caldesmon, cyclin D1, EMA, Melan A, and CD34. SMARCB1 expression was retained. Based on the histopathology and IHC, a final diagnosis of uterine ASPS was rendered. CONCLUSIONS: Knowledge of the characteristic histopathologic and immunohistochemical features can help accurately diagnose such rare tumors. Knowledge of the characteristic histopathologic and immunohistochemical features can help accurately diagnose such rare sarcoma in an uncommon site with an unusual age.

SGK-1 Signalling Pathway is a Key Factor in Cell Survival in Ischemic Injury.

Serum and glucocorticoid-regulated kinases (SGK) are serine/threonine kinases that belong to AGC. The SGK-1, which responds to stress, controls a range of ion channels, cell growth, transcription factors, membrane transporters, cellular enzymes, cell survival, proliferation and death. Its expression is highly controlled by various factors such as hyperosmotic or isotonic oxidative stress, cell shrinkage, radiation, high blood sugar, neuronal injury, DNA damage, mechanical stress, thermal shock, excitement, dehydration and ischemia. The structural and functional deterioration that arises after a period of ischemia when blood flow is restored is referred to as ischemia/ reperfusion injury (I/R). The current review discusses the structure, expression, function and degradation of SGK-1 with special emphasis on the various ischemic injuries in different organs such as renal, myocardial, cerebral, intestinal and lungs. Furthermore, this review highlights the various therapeutic agents that activate the SGK-1 pathway and slow down the progression of I/R injuries.

Therapeutic implications of phosphorylation- and dephosphorylation-dependent factors of cAMP-response element-binding protein (CREB) in neurodegeneration.

Neurodegeneration is a condition of the central nervous system (CNS) characterized by loss of neural structures and function. The most common neurodegenerative disorders (NDDs) include Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), motor neuron disorders, psychological disorders, dementia with vascular dementia (VaD), Lewy body dementia (DLB), epilepsy, cerebral ischemia, mental illness, and behavioral disorders. CREB (cAMP-response element-binding protein) represent a nuclear protein that regulates gene transcriptional activity. The primary focus of the review pertains to the exploration of CREB expression and activation within the context of neurodegenerative diseases, specifically in relation to the phosphorylation and dephosphorylation events that occur within the CREB signaling pathway under normal physiological conditions. The findings mentioned have contributed to the elucidation of the regulatory mechanisms governing CREB activity. Additionally, they have provided valuable insights into the potential mediation of diverse biological processes, such as memory consolidation and neuroprotective effects, by various related studies. The promotion of synaptic plasticity and neurodevelopment in the central nervous system through the targeting of CREB proteins has the potential to contribute to the prevention or delay of the onset of neurodegenerative disorders. Multiple drugs have been found to initiate downstream signaling pathways, leading to neuroprotective advantages in both animal model studies and clinical trials. The clinical importance of the cAMP-response element-binding protein (CREB) is examined in this article, encompassing its utility as both a predictive/prognostic marker and a target for therapeutic interventions.

Cytological spectrum of testicular malignancies with histopathological correlation: A retrospective analysis.

BACKGROUND: Testicular malignancy is the most common solid organ cancer occurring in young men. The most common testicular malignancy is germ cell tumor. Extragonadal malignancies such as lymphomas are rare. Testicular fine-needle aspiration cytology (FNAC) in cancer is a bit controversial amidst fear of tumor seeding along the needle tract. Nevertheless, its largely safe, cost-effective technique providing a quick and fairly reliable diagnosis. METHODS: A retrospective analysis of testicular malignancies on FNAC over a period of 9 years with cyto-histological correlation wherever possible was carried out. FNAC slides and cell blocks with immunocytochemistry wherever done were retrieved. RESULTS: A total of 74 cases were obtained. The age ranged from 1 year to 65 years. Infiltration by leukemia was the most common malignancy detected in pediatric population, while germ cell tumors were common amongst young adults and middle-aged men. In elderly, metastatic carcinoma, infiltration by lymphoma were identified. On FNAC, 38 cases were of leukemic infiltration, 27 of germ cell tumors (subtyped as mixed germ cell tumors-15 cases, seminoma-11 cases, and yolk sac tumor-1 case) with two cases each of non-Hodgkin lymphoma, Leydig cell tumor, metastatic adenocarcinoma, and one case each of metastatic small cell carcinoma, rhabdomyosarcoma, and malignant neoplasm. Histological correlation was available in 15/74 cases. Only 3 cases were discordant. Seeding of tumor along the needle tract was not seen. CONCLUSION: The current study deciphers the cytological spectrum of testicular malignancies on FNAC and highlights its importance as a reliable modality for a prompt diagnosis of testicular tumors guiding patient management.

Emerging Targets for Modulation of Immune Response and Inflammation in Stroke.

The inflammatory and immunological responses play a significant role after stroke. The innate immune activation stimulated by microglia during stroke results in the migration of macrophages and lymphocytes into the brain and are responsible for tissue damage. The immune response and inflammation following stroke have no defined targets, and the intricacies of the immunological and inflammatory processes are only partially understood. Innate immune cells enter the brain and meninges during the acute phase, which can cause ischemia damage. Activation of systemic immunity is caused by danger signals sent into the bloodstream by injured brain cells, which is followed by a significant immunodepression that encourages life-threatening infections. Neuropsychiatric sequelae, a major source of post-stroke morbidity, may be induced by an adaptive immune response that is initiated by antigen presentation during the chronic period and is directed against the brain. Thus, the current review discusses the role of immune response and inflammation in stroke pathogenesis, their role in the progression of injury during the stroke, and the emerging targets for the modulation of the mechanism of immune response and inflammation that may have possible therapeutic benefits against stroke.

Vitamin D as therapeutic modulator in cerebrovascular diseases: a mechanistic perspectives.

Vitamin D deficiency has been linked to several major chronic diseases, such as cardiovascular and neurodegenerative diseases, diabetes, and cancer, linked to oxidative stress, inflammation, and aging. Vitamin D deficiency appears to be particularly harmful to the cardiovascular system, as it can cause endothelial dysfunctioning and vascular abnormalities through the modulation of various downstream mechanisms. As a result, new research indicates that therapeutic approaches targeting vitamin D inadequacies or its significant downstream effects, such as impaired autophagy, abnormal pro-inflammatory and pro-oxidant reactions, may delay the onset and severity of major cerebrovascular disorders such as stroke and neurologic malformations. Vitamin D modulates the various molecular pathways, i.e., Nitric Oxide, PI3K-Akt Pathway, cAMP pathway, NF-kB Pathway, Sirtuin 1, Nrf2, FOXO, in cerebrovascular disorder. The current review shows evidence for vitamin D's mitigating or slowing the progression of these cerebrovascular disorders, which are significant causes of disability and death worldwide.

Brain-Derived Neurotrophic Factor: A Novel Dynamically Regulated Therapeutic Modulator in Neurological Disorders.

The growth factor brain-derived neurotrophic factor (BDNF), and its receptor tropomyosin-related kinase receptor type B (TrkB) play an active role in numerous areas of the adult brain, where they regulate the neuronal activity, function, and survival. Upregulation and downregulation of BDNF expression are critical for the physiology of neuronal circuits and functioning in the brain. Loss of BDNF function has been reported in the brains of patients with neurodegenerative or psychiatric disorders. This article reviews the BDNF gene structure, transport, secretion, expression and functions in the brain. This article also implicates BDNF in several brain-related disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, major depressive disorder, schizophrenia, epilepsy and bipolar disorder.

Liposarcoma of tongue: A case report.

ABSTRACT: Liposarcoma (LS) is one of the most common malignant tumors. However, oral LS is an extremely rare lesion that is often clinically misdiagnosed as a benign lesion because of its asymptomatic and indolent clinical course. In oral cavity, the tongue is the most frequent site for its occurrence.

Therapeutic and mechanistic intervention of vitamin D in neuropsychiatric disorders.

Vitamin D deficiency is believed to affect between 35 and 55% of the world's population, making it a hidden pandemic. In addition to its role in bone and calcium homeostasis, vitamin D has also been linked in preclinical and clinical research to brain function. These outcomes have also been used for a variety of neuropsychiatric and neurodevelopmental problems. Nevertheless, these individuals are more prone to develop signs of cognitive decline. This review will emphasize the association between vitamin D and neuropsychiatric illnesses such as autism, schizophrenia, depression, and Attention Deficit Hyperactivity Disorder (ADHD). While numerous research show vitamin D's essential role in cognitive function in neuropsychiatric illnesses, it is too early to propose its effect on cognitive symptoms with certainty. It is necessary to conduct additional research into the associations between vitamin D deficiency and cognitive abnormalities, particularly those found in autism, schizophrenia, depression, and ADHD, to develop initiatives that address the pressing need for novel and effective preventative therapeutic strategies.

Targeting ferroptosis in ischemia/reperfusion renal injury.

Renal I/R injury is a severe medical condition contributing to acute kidney injury (AKI), leading to rapid kidney dysfunction and high mortality rates. It is generally observed during renal transplantation, shock, trauma, and urologic and cardiovascular surgery, for which there is no effective treatment. Cell death and damage are commonly linked to I/R. Cell death triggered by iron-dependent lipid peroxidation, such as ferroptosis, has been demonstrated to have a significant detrimental effect in renal IRI models, making it a new type of cell death currently being researched. Ferroptosis is a nonapoptotic type of cell death that occurs when free iron enters the cell and is a critical component of many biological processes. In ferroptosis-induced renal I/R injury, iron chelators such as Deferasirox, Deferiprone, and lipophilic antioxidants are currently suppressed lipid peroxidation Liproxstatin-1 (Lip-1), Ferrostatin-1 along with antioxidants like vitamin and quercetin. Ferroptosis has been considered a potential target for pharmaceutical intervention to alleviate renal IRI-associated cell damage. Thus, this review emphasized the role of ferroptosis and its inhibition in renal IRI. Also, Pharmacological modulation of ferroptosis mechanism in renal I/R injury has been conferred. Graphical abstract.

Therapeutic Insights on Ferroptosis in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder that alters either motor or non-motor activities. Dopamine-based medications can help alleviate symptoms at an early stage, but the disease worsens due to fewer neuroprotective drugs. PD's pathogenic mechanism involves α-synuclein accumulations, lipid peroxidation damage, iron deposition, and enhanced oxidative stress. An iron-dependent method of programmed cell death known as ferroptosis, which results from the dangerous accumulation of lipid peroxides, is similar to PD. The interesting fact is that α-synuclein has been functionally connected to iron or lipid metabolism, suggesting that dysregulated α-syn may interact with other PD clinical traits associated with ferroptosis. Treatments aimed at restoring dopamine levels in the brain are already available; however, they only alleviate symptoms and do not stop the progression of neurodegeneration. Ferroptosis-related mechanisms that could be targeted for treatment will be discussed in this review. Researchers have found that anti-ferroptosis molecules such as iron chelators and anti-oxidants protect the brains of PD animal models and humans. The ferroptosis pathway in PD and the treatment prospects of addressing the molecular pathways engaged in ferroptosis are both examined in this review.

Neuroprotective Effect of Piclamilast-Induced Post-Ischemia Pharmacological Treatment in Mice.

Various studies have evidenced the neuroprotective role of PDE4 inhibitors. However, whether PDE4 inhibitor, Piclamilast pharmacological post-treatment is protective during cerebral ischemia reperfusion-induced injury remains unknown. Therefore, this study design included testing the hypothesis that Piclamilast administered at the beginning of a reperfusion phase (Piclamilast pPost-trt) shows protective effects and explores & probes underlying downstream mechanisms. Swiss albino male mice were subjected to global ischemic and reperfusion injury for 17 min. The animals examined cerebral infarct size, biochemical parameters, inflammatory mediators, and motor coordination. For memory, assessment mice were subjected to morris water maze (MWM) and elevated plus maze (EPM) test. Histological changes were assessed using HE staining. Piclamilast pPost-trt significantly reduced I/R injury-induced deleterious effects on biochemical parameters of oxidative stress, inflammatory parameters, infarct size, and histopathological changes, according to the findings. These neuroprotective effects of pPost-trt are significantly abolished by pre-treatment with selective CREB inhibitor, 666-15. Current study concluded that induced neuroprotective benefits of Piclamilast Post-trt, in all probability, maybe mediated through CREB activation. Hence, its neuroprotective effects can be further explored in clinical settings.

Therapeutic implications of sonic hedgehog pathway in metabolic disorders: Novel target for effective treatment.

Hedgehog, a developmental morphogen, and its downstream signalling have recently been associated with metabolic control. Sonic hedgehog signalling (Shh) is a significant pathway that regulates various events during the growth and development of embryos. The dysregulation of the Shh pathway has been implicated in many physiological and pathological processes, including adipocyte differentiation, cancer, diabetes and obesity. Researchers have proved that pharmacological modulation of the Shh pathway might help to improve better outcomes in metabolic disorders. A systemic review was conducted through various search engines to understand the molecular nature of Shh Pathway in Metabolic Disorders and its therapeutic implication in the future. However, we could find that by studying the crosstalk between various pathways, such as Wnt/ ß-catenin, TGF (transforming growth factor ß), mTOR, and notch with Sonic hedgehog, a close link between the pathogenesis of different metabolic disorders. Understanding the importance of these molecular interlinking networks will provide a rational basis that influences its activity. This article discusses the changes and modifications that happen due to up-or down-regulation of various transcription factors in the Shh pathway. The study attempts to provide a complete overview of the main signalling events involved with canonical and non-canonical Hedgehog signalling and the increasingly complicated regulatory modalities related to Hedgehog for regulating metabolism. Further, it investigates the possible approaches needed to treat metabolic disorders for better results.

Efficacy and safety of CD24Fc in hospitalised patients with COVID-19: a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Non-antiviral therapeutic options are required for the treatment of hospitalised patients with COVID-19. CD24Fc is an immunomodulator with potential to reduce the exaggerated inflammatory response to tissue injuries. We aimed to evaluate the safety and efficacy of CD24Fc in hospitalised adults with COVID-19 receiving oxygen support. METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 study at nine medical centres in the USA. Hospitalised patients (age ≥18 years) with confirmed SARS-CoV-2 infection who were receiving oxygen support and standard of care were randomly assigned (1:1) by site-stratified block randomisation to receive a single intravenous infusion of CD24Fc 480 mg or placebo. The study funder, investigators, and patients were masked to treatment group assignment. The primary endpoint was time to clinical improvement over 28 days, defined as time that elapsed between a baseline National Institute of Allergy and Infectious Diseases ordinal scale score of 2-4 and reaching a score of 5 or higher or hospital discharge. The prespecified primary interim analysis was done when 146 participants reached the time to clinical improvement endpoint. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT04317040. FINDINGS: Between April 24 and Sept 22, 2020, 243 hospitalised patients were assessed for eligibility and 234 were enrolled and randomly assigned to receive CD24Fc (n=116) or placebo (n=118). The prespecified interim analysis was done when 146 participants reached the time to clinical improvement endpoint among 197 randomised participants. In the interim analysis, the 28-day clinical improvement rate was 82% (81 of 99) for CD24Fc versus 66% (65 of 98) for placebo; median time to clinical improvement was 6·0 days (95% CI 5·0-8·0) in the CD24Fc group versus 10·0 days (7·0-15·0) in the placebo group (hazard ratio [HR] 1·61, 95% CI 1·16-2·23; log-rank p=0·0028, which crossed the prespecified efficacy boundary [α=0·0147]). 37 participants were randomly assigned after the interim analysis data cutoff date; among the 234 randomised participants, median time to clinical improvement was 6·0 days (95% CI 5·0-9·0) in the CD24Fc group versus 10·5 days (7·0-15·0) in the placebo group (HR 1·40, 95% CI 1·02-1·92; log-rank p=0·037). The proportion of participants with disease progression within 28 days was 19% (22 of 116) in the CD24Fc group versus 31% (36 of 118) in the placebo group (HR 0·56, 95% CI 0·33-0·95; unadjusted p=0·031). The incidences of adverse events and serious adverse events were similar in both groups. No treatment-related adverse events were observed. INTERPRETATION: CD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19. FUNDING: Merck & Co, National Cancer Institute, OncoImmune.

Therapeutic implications of cyclooxygenase (COX) inhibitors in ischemic injury.

INTRODUCTION: Ischemia-reperfusion injury (IRI) is the inexplicable aggravation of cellular dysfunction that results in blood flow restoration to previously ischemic tissues. COX mediates the oxidative conversion of AA to various prostaglandins and thromboxanes, which are involved in various physiological and pathological processes. In the pathophysiology of I/R injuries, COX has been found to play an important role. I/R injuries affect most vital organs and are characterized by inflammation, oxidative stress, cell death, and apoptosis, leading to morbidity and mortality. MATERIALS AND METHODS: A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out to understand the Nature and mechanistic interventions of the Cyclooxygenase modulations in ischemic injury. Here, we have discussed the COX Physiology and downstream signalling pathways modulated by COX, e.g., Camp Pathway, Peroxisome Proliferator-Activated Receptor Activity, NF-kB Signalling, PI3K/Akt Signalling in ischemic injury. CONCLUSION: This review will discuss the various COX types, specifically COX-1 and COX-2, which are involved in developing I/R injury in organs such as the brain, spinal cord, heart, kidney, liver, and intestine.

Mechanistic Insight on Autophagy Modulated Molecular Pathways in Cerebral Ischemic Injury: From Preclinical to Clinical Perspective.

Cerebral ischemia is one of the most devastating brain injuries and a primary cause of acquired and persistent disability worldwide. Despite ongoing therapeutic interventions at both the experimental and clinical levels, options for stroke-related brain injury are still limited. Several evidence suggests that autophagy is triggered in response to cerebral ischemia, therefore targeting autophagy-related signaling pathways can provide a new direction for the therapeutic implications in the ischemic injury. Autophagy is a highly conserved lysosomal-dependent pathway that degrades and recycles damaged or non-essential cellular components to maintain neuronal homeostasis. But, whether autophagy activation promotes cell survival against ischemic injury or, on the contrary, causes neuronal death is still under debate. We performed an extensive literature search from PubMed, Bentham and Elsevier for various aspects related to molecular mechanisms and pathobiology involved in autophagy and several pre-clinical studies justifiable further in the clinical trials. Autophagy modulates various downstream molecular cascades, i.e., mTOR, NF-κB, HIF-1, PPAR-γ, MAPK, UPR, and ROS pathways in cerebral ischemic injury. In this review, the various approaches and their implementation in the translational research in ischemic injury into practices has been covered. It will assist researchers in finding a way to cross the unbridgeable chasm between the pre-clinical and clinical studies.

Calpain Inhibitors as Potential Therapeutic Modulators in Neurodegenerative Diseases.

It is considered a significant challenge to understand the neuronal cell death mechanisms with a suitable cure for neurodegenerative disorders in the coming years. Calpains are one of the best-considered "cysteine proteases activated" in brain disorders. Calpain is an important marker and mediator in the pathophysiology of neurodegeneration. Calpain activation being the essential neurodegenerative factor causing apoptotic machinery activation, it is crucial to develop reliable and effective approaches to prevent calpain-mediated apoptosis in degenerating neurons. It has been recently seen that the "inhibition of calpain activation" has appeared as a possible therapeutic target for managing neurodegenerative diseases. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was conducted. The present article reviews the basic pathobiology and role of selective calpain inhibitors used in various neurodegenerative diseases as a therapeutic target.

Neuropeptides: Potential neuroprotective agents in ischemic injury.

AIM: Ischemic damage to the brain is linked to an increased rate of morbidity and mortality worldwide. In certain parts of the world, it remains a leading cause of mortality and the primary cause of long-term impairment. Ischemic injury is exacerbated when particular neuropeptides are removed, or their function in the brain is blocked, whereas supplying such neuropeptides lowers ischemic harm. Here, we have discussed the role of neuropeptides in ischemic injury. MATERIALS & METHODS: Numerous neuropeptides had their overexpression following cerebral ischemia. Neuropeptides such as NPY, CGRP, CART, SP, BK, PACAP, oxytocin, nociception, neurotensin and opioid peptides act as transmitters, documented in several "in vivo" and "in vitro" studies. Neuropeptides provide neuroprotection by activating the survival pathways or inhibiting the death pathways, i.e., MAPK, BDNF, Nitric Oxide, PI3k/Akt and NF-κB. KEY FINDINGS: Neuropeptides have numerous beneficial effects in ischemic models, including antiapoptotic, anti-inflammatory, and antioxidant actions that provide a powerful protective impact in neurons when combined. These innovative therapeutic substances have the potential to treat ischemia injury due to their pleiotropic modes of action. SIGNIFICANCE: This review emphasizes the neuroprotective role of neuropeptides in ischemic injury via modulation of various signalling pathways i.e., MAPK, BDNF, Nitric Oxide, PI3k/Akt and NF-κB.

Solitary cutaneous metastasis from an ovarian high-grade serous carcinoma at the initial presentation: Cytologic diagnosis of a rare manifestation.

Cutaneous metastasis can rarely be the first manifestation of visceral malignancies and is commonly seen in advanced-stage malignancies. It is infrequently seen in patients with ovarian malignancies and may develop either late in the course of the disease or at the initial presentation. Such cases are often associated with poor prognosis, and a prompt, precise tissue diagnosis is essential for appropriate patient management and better clinical outcome. Herein, we present a case of cutaneous metastasis in a young woman with an undiagnosed abdominopelvic mass that was diagnosed as metastatic high-grade serous carcinoma (HGSC) on fine-needle aspiration cytology (FNAC) supplemented by immunocytochemistry (ICC) on the cell block. The index case documents a unique and rare metastatic presentation of ovarian HGSC, as non-Sister Mary Joseph anterior abdominal wall nodule, at the initial presentation. Additionally, it highlights the utility of minimally-invasive FNA combined with ICC in prompt and accurate preoperative diagnosis of an underlying ovarian malignancy.