While the largest proportion of different microbiome-derived proteins, lipoproteins and nucleic acids provide essential microorganism-specific gene products necessary to support microbial structure, function and viability, many of these same components are also shed from the outer cell wall of different Gram-negative bacterial species into surrounding biofluids which eventually enter the systemic circulation. Several of these microbial-derived secreted molecular species represent some of the most pro-inflammatory and noxious neurotoxins known. These neurotoxins disrupt cell-cell adhesion and easily translocate across aged or damaged plasma membranes and into the systemic circulation, brain, and CNS and PNS compartments. For example, microbial lipoprotein glycoconjugates such as Gram-negative bacteria-derived lipopolysaccharide (LPS), bacterial amyloids and more recently small non-coding RNA (sncRNA) microbial-derived neurotoxins have been found by many independent research groups to reside within the brain cells and CNS tissues of aged patients affected with Alzheimer’s disease (AD). This ‘Commentary’ will highlight the most recent findings on these microbial-derived secreted toxins, their neurotropic properties and the potential contribution of these neurotoxic and pro-inflammatory microbial exudates to age-related inflammatory neurodegeneration, with specific reference to the human GI-tract abundant Gram-negative anaerobe Bacteroides fragilis and to AD wherever possible.The microbiome contained within the human gastrointestinal (GI)-tract constitutes a highly complex, dynamic and interactive internal prokaryotic ecosystem that possesses a staggering diversity, speciation and complexity. This repository of microbes comprises the largest interactive source and highest density of microbes anywhere in nature, collectively constituting the largest ‘diffuse organ system’ in the human body. Through the extracellular fluid (ECF), cerebrospinal fluid (CSF), lymphatic and glymphatic circulation, endocrine, systemic and neurovascular circulation and/or central and peripheral nervous systems  microbiome-derived signaling strongly impacts the health, well-being and vitality of the human host. Recent data from the Human Microbiome Initiative (HMI) and the Unified Human Gastrointestinal Genome (UHGG) consortium have classified over  This paper will also highlight and comment upon recent work from peer-reviewed studies that advance the concept of microbiome-derived bacterial factors, such as microbial-secreted neurotoxins, are critical in driving pro-inflammatory degenerative neuropathology such as those widely observed in the aged AD brain and CNS.The human gastrointestinal (GI)-tract microbiome forms a highly complex and interactive internal prokaryotic ecosystem that possesses a staggering diversity, speciation and complexity. This dynamic repository of microbes comprises the largest interactive source and highest density of microbes anywhere in nature, collectively constituting the largest ‘diffuse organ system’ anywhere in the human body that is at least as metabolically active as the liver –10. Throequences ,5. WhileHomo sapiens contains a highly dynamic and interactive community of microorganisms known as ‘the human microbiome’ consisting mostly of aerobic and anaerobic bacteria, archaebacteria, fungi, protozoa, viruses and other microorganisms. The human microbiome forms a significant fraction of the human ‘metaorganism’ with considerable commensal and/or symbiotic benefit to the human host [Bacteroidetes, the largest phylum of anaerobic Gram-negative bacteria in deeper regions of the GI-tract microbiome, while generally beneficial to the host when confined to the interior of the GI-tract, have potential to secrete a remarkably complex array of pro-inflammatory neurotoxins that include microbial surface lipopolysaccharide (LPS), highly immunogenic bacterial amyloids, proteolytic peptides, proteinases, lipoproteins and regulatory nucleic acids consisting mostly of small non-coding RNA (sncRNA). The deleterious neurotoxic effects of these bacterial exudates become more significant as GI-tract and blood-brain barriers (BBB) become altered, leaky and/or dysfunctional in their permeability with aging and disease, including primarily, gastrointestinal, systemic vascular and neurovascular disease [Common to all higher eukaryotes, man host –10. Both disease –15.~99.5% of all of the resident microbes of the human GI-tract microbiome consist of facultative and/or obligate anaerobic bacteria from just 2 of the major bacterial divisions Firmicutes and Bacteroides; these form the ‘bacterial core’ the human GI-tract microbiome [~3.5 cm diameter ~7 m long human GI-tract varies in pH and oxygen availability along its length; microbes in the deeper and more anaerobic regions of the small intestine are the most enriched in obligate anaerobic microbial species [Bacteroides fragilis [Bacteroidetes and in particular the species Bacteroides fragilis: (i) is among the most studied and genetically understood human GI-tract resident microorganisms [3, the highest density of any microbial colonization known in nature [B. fragilis are present at about one-hundred times the abundance of Gram-negative bacilli of the phylum Proteobacteria and the genus-species Escherichia coli [B. fragilis can secrete: (i) a particularly potent, pro-inflammatory and unique LPS subtype (BF-LPS); (ii) bacterial proteolipids, endo/exotoxins and a highly neurotoxic zinc-metalloproteinase known as B. fragilis-toxin (BFT) or fragilysin; and (iii) more recently, bacterial-derived miRNA-like sncRNAs now known to serve a number of critical pathological functions. Recent developments in the analysis and characterization of these 3 major classes of B. fragilis-derived neurotoxins are briefly reviewed and commented upon below.Approximately crobiome –18. The  species ,20. In dfragilis –23. The rganisms ,23; (ii)rganisms ,25;  inhia coli ; (v) liehia coli –30; (vi)hia coli ; (vii) nhia coli ; and . Normally LPS protects Gram-negative bacteria from environmental, chemical and physical stress, and is also recognized by the host innate-immune system upon infection inducing potent pathophysiological effects, strong inflammatory signaling and neuronal cell membrane damage. LPS is typically shed from the outer membrane of Gram-negative bacteria and consist of a hydrophobic lipid-A domain attached to a core oligosaccharide (core-OS) and a distal O-antigen  ,34–41. LB. fragilis [Dietary deficiency-induced neurotoxicity of LPS are mediated in part by macrophages and microglia through the actions of tumor necrosis factor alpha (TNFα), interleukin-1β (IL-1β) and reactive oxygen species (ROS), which may be three of the most important endogenous mediators of the toxic pathophysiological effects of LPS –41. Eachfragilis ,42,48–50fragilis ,39,45–48Aβ42) peptides that accumulate in AD-affected brain [LPS can be therefore considered as a leading example of a highly immunogenic, Gram-negative bacterial-derived amphipathic neurotoxic glycoconjugate, and it has been recently convincingly shown by multiple research laboratories that a diet-inducible BF-LPS accumulates in AD-affected neurons to ultimately deregulate homeostatic gene expression patterns ,45,48–52ed brain ,45.Bacteria thrive in dense multicellular communities held together by an extracellular matrix, and the major proteolipid component of this matrix are highly stable and structured bacterial amyloids and lipoproteins ,53. Whilin vitro studies of human neural cells in primary culture. For example human miRNA-like sncRNAs have been recently demonstrated: (i) to contribute to the virulence of bacterial outer membrane proteins [via a common LPS-ROS-NF-kB-microRNA signaling pathway relevant to pathological gene expression changes as are observed in AD [Very recently microbiome-derived microRNA-like sncRNAs have been shown to be directly involved in the support of multiple pathogenic AD-relevant processes in both human brain and CNS tissues and proteins ; (ii) toproteins ; (iii) aed in AD ,14,15,49ed in AD ; and (v)ed in AD ; Interesed in AD ,12,59,60~200 thousand diverse, non-redundant prokaryotic genomes that generate ~200 million proteins [viability, some of these components are also beginning to be observed to be shed from the outer cell wall of Gram negative bacteria, and also from other microbial species, into the surrounding biofluids that eventually find their way across the GI-tract and blood-brain barriers (BBB) into the brain and CNS. These secreted biopolymers are extremely pro-inflammatory and highly toxic to neuronal structure and function and the homeostatic signaling functions of human neural cells. Other aspects related to GI-tract microbiome complexity and diversity are that: (i) this large microbial repository altogether actively generate extremely pathogenic pro-inflammatory and pathogenic neurochemical cocktails detrimental to the overall function and survival of neurons and CNS and/or PNS tissues; and (iii) while secreted LPS, amyloids, other lipoproteins and sncRNA are generally quite soluble as monomers over time they self-associate into highly insoluble fibrous protein aggregates that appear within and around neurons and throughout the neocortex and brain parenchyma. These have long been implicated in the progressive degenerative neuropathology of several progressive, age-related disorders of the human CNS including PD, PrD and AD. The evolving data-driven concept that each human individual possesses an individualistic GI-tract microbiome that varies in microbial abundance, complexity and speciation may predispose individual humans to differential susceptibility to different forms of age-related neurological disease [Recent and ongoing research is significantly expanding our understanding of the role of GI-tract microbiome-derived secreted pro-inflammatory neurotoxic exudates in PD, PrD and AD and strengthening the idea that GI-tract microorganisms and/or their secretory components contribute to progressive, age-related inflammatory neurodegeneration. This enormous repository of GI-tract microbiome-derived neurotoxins are derived from over proteins ,61,62. W disease ,61–63.This further implies that each human possesses a unique metagenomic microbial profile which may be exploitable for microbiotic augmentation, personalized medicine and/or the implementation of individually-directed therapeutic strategies useful in the clinical management of inflammatory neurodegenerative disorders such as AD and other types of age-related neurological disease.


Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses an antibody-photoabsorber (IRDye700DX) conjugate (APC) that is activated by NIR light irradiation. A major benefit of NIR-PIT is that only APC-bound cancer cells that are exposed to NIR light are killed by NIR-PIT; thus, minimal damage occurs in adjacent normal cells. NIR-PIT has now been applied to many cancers expressing various cell-surface target proteins using monoclonal antibodies designed to bind to them. Moreover, NIR-PIT is not limited to tumor antigens but can also be used to kill specific host cells that create immune-permissive environments in which tumors grow. Moreover, multiple targets can be treated simultaneously with NIR-PIT using a cocktail of APCs. NIR-PIT has great potential to treat a wide variety of cancers by targeting appropriate tumor cells, immune cells, or both, and can be augmented by other immunotherapies.Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses an antibody-photoabsorber (IRDye700DX) conjugate (APC) that is activated by NIR light irradiation. In September 2020, the first APC and laser system were conditionally approved for clinical use in Japan. A major benefit of NIR-PIT is that only APC-bound cancer cells that are exposed to NIR light are killed by NIR-PIT; thus, minimal damage occurs in adjacent normal cells. These early trials have demonstrated that in addition to direct cell killing, there is a significant therapeutic host immune response that greatly contributes to the success of the therapy. Although the first clinical use of NIR-PIT targeted epidermal growth factor receptor (EGFR), many other targets are suitable for NIR-PIT. NIR-PIT has now been applied to many cancers expressing various cell-surface target proteins using monoclonal antibodies designed to bind to them. Moreover, NIR-PIT is not limited to tumor antigens but can also be used to kill specific host cells that create immune-permissive environments in which tumors grow. Moreover, multiple targets can be treated simultaneously with NIR-PIT using a cocktail of APCs. NIR-PIT can be used in combination with other therapies, such as immune checkpoint inhibitors, to enhance the therapeutic effect. Thus, NIR-PIT has great potential to treat a wide variety of cancers by targeting appropriate tumor cells, immune cells, or both, and can be augmented by other immunotherapies. TM) is a newly developed cancer treatment that induces selective immunogenic cell death in targeted cells [TM, Rakuten Medical Inc., San Diego, CA, USA) targeting EGFR and utilizing a near infrared laser system  was approved for clinical use in September 2020. Although NIR-PIT has been primarily developed to use antibodies against cancer membrane antigens, it can also kill normal host cells, especially those that promote cancer cell growth, by inhibiting the immune system locally [Near-infrared photoimmunotherapy (NIR-PIT)  and was approved in March 2011 to treat patients with late-stage melanoma. This class of immune checkpoint inhibitor (ICI) has continued to expand over the last decade, with many ICIs being approved. Although these agents have been highly effective in some patients, immunotherapy-related side effects, termed immune-related adverse events (irAEs), have been widely reported in various organs. irAEs occur because ICIs activate immunity throughout the body, not just in the tumor. These side effects can cause syndromes that mimic autoimmune disease in normal organs. Ideally, a comprehensive cancer therapy would selectively kill tumor cells and activate local tumor immunity. None of the existing major therapies, surgery, radiation, or chemotherapy do this. Tumor- and immune cell-targeted NIR-PIT can kill tumor cells selectively and deplete local immune suppressor cells in the tumor beds. This leads to dramatically more active immune responses against tumors without inducing irAEs in non-target tissues.Numerous NIR-PIT for cancer and immune cells have been attempted over the past decade, resulting in numerous research reports. This review summarizes these efforts and serves to compile this work into one review to provide an update on NIR-PIT against various effective molecular targets.TM) showed selective dedicated cytotoxicity on target cells based on a photo-induced ligand release reaction rather than ROS after the systemic intravenous injection of IR700-based APCs with various antibodies. Additionally, NIR-PIT is a hybrid therapy of direct cancer cell killing induced by NIR light exposure combined with rational immune activation. Therefore, NIR-PIT is totally different from the old “photoimmunotherapy” and is now defined as IlluminoxTM.Historically, the term “photoimmunotherapy” meant targeted photodynamic therapy using antibodies conjugated with conventional photosensitizers such as hematoporphyrin based on cytotoxicity induced by reactive oxygen species (ROS) in the 1980s . VariousNanosized particles were used as carriers of photosensitizers due to the large loading capacity . Nanosiz+ T cells [NIR-PIT utilizes an antibody conjugated with the NIR photon-absorbing silicon phthalocyanine dye IR700 ,9,10. Wh T cells ,21. TherInitially, NIR-PIT was developed to target cells expressing EGFR, human epidermal growth factor receptor-2 (HER2), and prostate-specific membrane antigen (PSMA) . Since tEGFR, belonging to the erythroblastosis oncogene B (ErbB) family, is a transmembrane tyrosine kinase receptor . PhysiolHER2, also known as HER2/neu, c-erbB2, or ERBB2, is a membrane tyrosine kinase and another member of the ErbB family . HER2 waCD44, a non-kinase transmembrane glycoprotein, is a well-known marker of cancer stem cells (CSCs) and mediates intercellular adhesion, regulating epithelial to mesenchymal transition and cancer progression . VariousPSMA is a well-established cell membrane marker of prostate cancer, and is expressed highest in poorly differentiated, metastatic, and hormone-refractory prostate cancer . The expCarcinoembryonic antigen (CEA), a glycoprotein involved in cell adhesion, is already used as a tumor marker in various cancers, and the expression levels of CEA are related to prognosis in colorectal cancer patients ,80,81. MMalignant pleural mesothelioma (MPM) is a malignant tumor that originates from mesothelial cells and has an extremely poor prognosis ,88. PodoMesothelin (MSLN) is a cell-surface glycoprotein and tumor differentiation marker expressed in several tumors, including lung cancer, pancreatic cancer, ovarian cancer, and MPM . MSLN caGlycoprotein A33 antigen (GPA33) could be another target of NIR-PIT in colorectal cancer because it is highly expressed in over 95% of human colorectal cancers, more than 60% of gastric cancers, and 50% of pancreatic cancers . AdditioTumor-associated calcium signal transducer 2 (TROP2) is a 46kD glycoprotein that plays a multifunctional cellular role, including transducing of cytoplasmic calcium. TROP2 is overexpressed in many epithelial cancers, including gastrointestinal tumors, cholangiocarcinoma, and prostate and pancreatic cancer . FurtherCadherin-17 (CDH-17), a cell surface biomarker specific for gastrointestinal cancers, is a cell−cell adherent junctional molecule and plays an important role in cancer cell adhesion, progression, and metastasis . MoreoveDelta-like protein 3 (DLL3) is a potential therapeutic target molecule for small cell lung cancer (SCLC) and other neuroendocrine tumors that is minimally expressed in normal tissues . HoweverGlypican-3 (GPC3), a 65-kDa membrane-bound heparin sulfate proteoglycan that is highly expressed in hepatic cell carcinoma (HCC) but not in normal tissue, is being evaluated as a potential therapeutic target for HCC ,111. GPCGastrointestinal stromal tumors (GISTs) are the most common submucosal tumors (SMTs) of the alimentary tract . SMTs arLymphoma is a diverse group of B-cell, T-cell, and natural-killer cell tumors, but the majority of lymphomas (approximately 90%) are of B-cell origin . MalignaMycosis fungoides is a rare cancer, however, it is the most common subtype of cutaneous T-cell lymphoma . It is rCD146 has been identified as a melanoma cell adhesion molecule. The expression of CD146 in melanoma is high and is found in 70% of primary melanomas and 90% of their lymph node metastases . Wei et Non-antibody mediated NIR-PIT has proven to be more difficult than antibody mediated NIR-PIT. However, there are some advantages of using non-antibody targeting agents such as galactosyl serum albumin (GSA), because GSA as a target is ubiquitous among ovarian cancers, whereas it is difficult to find a single antibody that will bind to all types of ovarian cancers. GSA is comprised of galactose molecules conjugated via carboxyl groups to an albumin molecule, and it binds to β-D-galactose receptors, also called H-type lectins, which are overexpressed on the surface of many ovarian tumors . AlthougPD-1 (CD279) is a T-cell immune checkpoint that suppresses autoimmunity, leading to immune tolerance of cells expressing programmed death-ligand 1  . UpregulCancer immunotherapy is aimed at activating or boosting the activation of the immune system to attack cancer cells through endogenous immunity mechanisms . The pio+CD25+Foxp3+ Tregs has been considered an essential step for enhancing anticancer immune reactions [+CD25+Foxp3+ Tregs in tumor beds to induce the activation of antitumor effector cells [+ T and NK cells and activation of antigen-presenting cells. Furthermore, the therapeutic effects of CD25-targeted NIR-PIT extended to distant non-treated tumors in a tumor-specific manner, because activated CD8+ T and NK cells were increased in the non-treated tumor after this therapy.Within the tumor tissue, T cells and natural killer (NK) cells that can recognize cancer cells are often present in large numbers, but their cytotoxic function is suppressed by nearby immunosuppressor cells such as Tregs ,141. Coneactions ,143. Howeactions . Further+ T cells and NK cells [2 NIR-PIT was more effective than anti-CD25-IgG NIR-PIT in suppressing tumor growth and inducing abscopal effects in vivo. The faster clearance of anti-CD25-F(ab’)2-IR700 and the absence of antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cellular cytotoxicity (CDC) contributed to the therapeutic efficacy of CD25-targeted NIR-PIT by minimizing the circulating APCs with their ability to block the IL-2 receptor. Thus, local CD25-targeted NIR-PIT produces tumor type-specific, systemic antitumor effects, which alter the growth of distant tumors of the same tumor type. Since expression and regulation of CD25 has been well investigated and known, local CD25-targeted NIR-PIT is a promising method for reducing immunosuppression caused by Tregs and thus augmenting effector cell-mediated cancer cell killing.CD25 is also known as the IL-2 receptor α-chain. The IL-2 receptor is expressed not only on Tregs but also on activated lymphocytes such as CD8NK cells . RemainiNK cells . Okada e+ T cells and resulting in T-cell activation in regional lymph nodes. Furthermore, CTLA4-targeted NIR-PIT induced an abscopal effect in over half of the tumor-bearing mice. It is believed that residual anti-CTLA4-IR700 might enhance antitumor immunity by promoting T-cell priming. Thus, CTLA4-targeted NIR-PIT is a promising antitumor therapy. However, CTLA4 exists in the cytoplasm in both normal and cancer cells to a much larger extent than CTLA4 expressed on the cellular membrane. Therefore, it is still unclear how the effects of CTLA4-targeted NIR-PIT affect these cells with the large reserve of intracellular CTLA4.A monoclonal antibody against CTLA4 was approved as an immune checkpoint inhibitor for clinical use in 2011. CTLA4 and CD28 are expressed on T cells and share the binding ligands CD80 and CD86 ,148. CD2Tumor-associated macrophages (TAMs) play essential roles in tumor invasion and metastasis, and contribute to drug resistance . TAM lev+ cells in reducing tumor and stroma growth; however, serious side effects have been observed in these approaches, such as cachexia and anemia [Cancer-associated fibroblasts (CAFs) are the most abundant cell population in the tumor microenvironment (TME), and are thought to play an essential role in tumor progression, angiogenesis, metastasis, and immunosuppression ,157,158.d anemia . Since rd anemia . Thus, td anemia .CD47, a cell-surface protein that prevents cancer cell phagocytosis via the “don’t eat me” signaling, is highly expressed on several human cancers, including acute myeloid leukemia, non-Hodgkin’s lymphoma, and bladder cancer . CD47-taAngiogenesis is regulated principally by interactions between vascular endothelial growth factors (VEGFs) and vascular endothelial growth factor receptors (VEGFRs), and plays a key role in cancer growth and metastasis in various malignant tumors ,164. TheWhen no good target antigen exists on a cancer cell, gene transfer technology could be used to make cells express an artificial target antigen, which could then be easily targeted with an APC. For example, HER2-targeted NIR-PIT has promising antitumor effects in HER2-positive cancers . HoweverNIR-PIT can simultaneously target two or more kinds of cells by co-injecting two or more different APCs, followed by exposure to NIR light. The combination approach for NIR-PIT is greatly advantageous, as it allows for targeting a broader spectrum of tumors more effectively, irrespective of enrichment of any one specific target. The combination NIR-PIT using panitumumab-IR700 and trastuzumab-IR700 was more efficacious than either monotherapy alone in a bladder cancer xenograft model . FurtherWe reviewed various antibodies that have been used for NIR-PIT, emphasizing the broad spectrum of tumor antigens that can be targeted and introducing targeting of cells in the tumor microenvironment . NIR-PIT


Discrimination between radiation necrosis versus recurrent glioblastoma contrast-enhancing lesions remains imprecise but is paramount for prognostic and therapeutic evaluation. We examined whether patients with radiation necrosis exhibit distinct patterns of blood oxygenation-level dependent functional magnetic resonance imaging (fMRI) cerebrovascular reactivity (BOLD-CVR) and studied eight patients with primary and secondary brain tumors and a multidisciplinary clinical and radiological diagnosis of radiation necrosis and fourteen patients with a first diagnosis of glioblastoma. The contrast-enhancing lesion was derived from high-resolution T1-weighted MRI and rendered the volume-of-interest (VOI). From this primary VOI, an additional 3 mm concentric expanding VOIs up to 30 mm were created for a detailed perilesional BOLD-CVR. Mean intralesional BOLD-CVR values were markedly lower in radiation necrosis. Perilesionally, a characteristic BOLD-CVR pattern was observed for radiation necrosis. In this preliminary analysis, distinctive intralesional and perilesional BOLD-cerebrovascular re-activity patterns are found for radiation necrosis.Background: Current imaging-based discrimination between radiation necrosis versus recurrent glioblastoma contrast-enhancing lesions remains imprecise but is paramount for prognostic and therapeutic evaluation. We examined whether patients with radiation necrosis exhibit distinct patterns of blood oxygenation-level dependent fMRI cerebrovascular reactivity (BOLD-CVR) as the first step to better distinguishing patients with radiation necrosis from recurrent glioblastoma compared with patients with newly diagnosed glioblastoma before surgery and radiotherapy. Methods: Eight consecutive patients with primary and secondary brain tumors and a multidisciplinary clinical and radiological diagnosis of radiation necrosis, and fourteen patients with a first diagnosis of glioblastoma underwent BOLD-CVR mapping. For all these patients, the contrast-enhancing lesion was derived from high-resolution T1-weighted MRI and rendered the volume-of-interest (VOI). From this primary VOI, additional 3 mm concentric expanding VOIs up to 30 mm were created for a detailed perilesional BOLD-CVR tissue analysis between the two groups. Receiver operating characteristic curves assessed the discriminative properties of BOLD-CVR for both groups. Results: Mean intralesional BOLD-CVR values were markedly lower in radiation necrosis than in glioblastoma contrast-enhancing lesions . Perilesionally, a characteristic BOLD-CVR pattern was observed for radiation necrosis and glioblastoma patients, with an improvement of BOLD-CVR values in the radiation necrosis group and persisting lower perilesional BOLD-CVR values in glioblastoma patients. The ROC analysis discriminated against both groups when these two parameters were analyzed together . Conclusions: In this preliminary analysis, distinctive intralesional and perilesional BOLD-cerebrovascular reactivity patterns are found for radiation necrosis. In patients undergoing post-surgical radiotherapy for glioblastoma, the appearance of new contrast-enhancing lesions on clinical follow-up imaging poses a significant diagnostic challenge, as radiation necrosis and recurrent glioblastoma share similar radiological features on contrast-enhanced T1-weighted magnetic resonance imaging (MRI) ,3,4.However, reliable discrimination between radiotherapy-induced tissue changes versus tumor recurrence is paramount for prognostic purposes and therapeutic decision-making.18F-(fluoroethyl)-l-tyrosine positron emission tomography (FET-PET) }) regression was applied to determine the goodness of fit, resulting in a model generating steepness of the curve  and SPSS Statistics 23 .A sigmoidal fit Eight consecutive patients with primary or secondary brain tumors and multidisciplinary diagnosis of radiation necrosis  were enrolled, with a mean age of 55 years (36–77). Further relevant clinical details can be reviewed in p = 0.04).For the radiation necrosis group, mean BOLD-CVR values in the contrast-enhancing lesion were markedly lower than for the contrast-enhancing lesion in the newly diagnosed glioblastoma group . These data are illustrated in For the ROC curve analysis, the area under the curve showed a good ability of the intralesional BOLD-CVR in classifying the patients .2-radiation necrosis: 0.99; R2-glioblastomas: 0.99; see also The sigmoidal fit model described well the mean CVR rates in the two groups  in order to recruit sufficient blood flow.Moreover, tumor cells are also found beyond the borders of a contrast-enhancing lesion without damaging the BBB, due to the infiltrative and aggressive behavior of such lesions ,31. Suchp = 0.04) and a more rapid CVR increase around the lesion. On the other hand, the glioblastoma group showed smaller circum-lesional variations without statistical difference between investigated VOIs  has also shown some impressive results, and recent investigations have detected different ratios of metabolites in the tumors and radiation necrosis areas. Specifically, choline (Cho)/creatinine (Cr) and cho/N-acetyl-aspartate (NAA) were higher in recurrent tumors ,36. Here18Fluoroethyl18Fluoroethyl-l-Tyrosine PET (FET-PET) radiotracer uptake was found to be significantly lower in patients with pseudo-progression than in glioblastomas with a sensitivity of 100% and a specificity of 96%, and also, time to peak (TTP) in tracer uptake was significantly lower in pseudoprogression [With regard to PET imaging, gression .n = 8) and glioblastoma (n = 14) is a relevant limitation; however, it is suitable for a proof of concept study. Moreover, a definitive diagnosis of radiation necrosis is possible only with histological confirmation, which was not available here. However, the reliable inclusion criteria for radiation necrosis patients allow for a representative clinical diagnosis of radiation necrosis [The small cohort of patients with radiation necrosis (necrosis . AdditioIn patients with recurrent glioblastoma, the contrast-enhancing lesion most likely harbors both tumor tissue combined with radiation-induced changes. Therefore, our results need to be interpreted with caution and have no clinical merit based on this dataset. We selected newly diagnosed glioblastoma patients as a reference to be able to maximally exploit the different biological features between radiation necrosis and glioblastoma tissue. The goal of the study was to test the hypothesis of BOLD-CVR as a viable tool to characterize radiation necrosis: the potentials of BOLD-CVR in differentiating the hemodynamic features of suspected radiation necrosis versus tumor tissue to delineate a possible pattern should be studied in greater detail in future validation studies.In this preliminary analysis, distinctive intralesional and perilesional BOLD-CVR patterns are found for radiation necrosis. The properties of BOLD-CVR as an adjunct tumor imaging parameter to identify radiation necrosis is promising but requires further evaluation.


Moreover, heparin may present anti-SARS-CoV-2 potential once it can impact viral infectivity and alter SARS-CoV-2 Spike protein architecture. Another feasible approach is the administration of the glucocorticoid dexamethasone. Although glucocorticoid's administration for viral infection managing is controversial, there is increasing evidence demonstrating that dexamethasone treatment is capable of drastically diminishing the death rate of patients presenting with Acute Respiratory Distress Syndrome (ARDS) that required invasive mechanical ventilation. Importantly, dexamethasone may be detrimental by impairing viral clearance and inducing hyperglycemia and sodium retention, hence possibly being deleterious for diabetics and hypertensive patients, two major COVID-19 risk groups. Therefore, while heparin's multitarget capacity shows to be strongly beneficial for severe COVID-19 patients, dexamethasone should be carefully administered taking into consideration underlying medical conditions and COVID-19 disease severity. Therefore, we suggest that the multitarget impact of heparin as an anti-viral, antithrombotic and anti-inflammatory drug in the early stage of the COVID-19 could significantly reduce the need for dexamethasone treatment in the initial phase of this disease. If the standard treatment of heparins fails on protecting against severe illness, dexamethasone must be applied as a potent anti-inflammatory shutting-down the uncontrolled and exacerbated inflammation.COVID-19 is spreading worldwide at disturbing rates, overwhelming global healthcare. Mounting death cases due to disease complications highlight the necessity of describing efficient drug therapy strategies for severe patients. COVID-19 severity associates with hypercoagulation and exacerbated inflammation, both influenced by ACE2 downregulation and cytokine storm occurrence. In this review, we discuss the applicability of the anticoagulant heparin and the anti-inflammatory corticosteroid dexamethasone for managing severe COVID-19 patients. The upregulated inflammation and blood clotting may be mitigated by administrating heparin and its derivatives. Heparin enhances the anticoagulant property of anti-thrombin (AT) and may be useful in conjunction with fibrinolytic drugs for severe COVID-19 patients. Besides, heparin can also modulate immune responses, alleviating TNF-α-mediated inflammation, impairing IL-6 production and secretion, and binding to complement proteins and leukotriene B Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease COVID-19), is rapidly spreading worldwide, being the cause of death of more than two million individuals globally in March of 2021 . Severe COVID-19 occurs due to complications, mostly affecting the lungs 9, is rap, impact Severe COVID-19 patients tend to show elevated circulating amounts of the proinflammatory mediators Interleukin-6 (IL-6), IL-8, IL-1β, and Monocyte Chemoattractant Protein-1 (MCP-1) . Even thThe hypercoagulable state characteristic of COVID-19 severity is illustrated by the consistently elevated D-dimer levels , dissemiInflammatory and coagulation processes interplay intimately in many ways, including through Tissue Factor (TF), thrombin-dependent PAR activation, Toll-like Receptors (TLRs), and complement system . ElevateThe emerging association between thromboembolic events and COVID-19 raised new insights about the physiopathology of the pandemic disease. Countless therapeutic targets were proposed through the knowledge of unbalanced procoagulant/anticoagulant factors that leads to the impairment of endogenous antithrombotic activity during SARS-CoV-2 infection –20. The Heparin is a polysaccharide originally isolated from mammalian animal tissue in 1916 . ThereafBoth UFH and LMWH have the ability of binding to anti-thrombin (AT) glycoprotein, enhancing AT inactivation of potent enzymes in the coagulation pathway, such as Factor Xa and Factor IIa (Thrombin). The heparin dependence of AT to prevent blood clot formation makes the drug an indirect antithrombotic agent and the absence of intrinsic fibrinolytic activity impairs thrombi breakdown when they are already shaped , 26. BesReports have shown that COVID-19 patients presented increased levels of procoagulation biomarkers and severe immune dysfunction that can lead to disseminated intravascular coagulation (DIC), increased risk for venous thromboembolism (VTE), and organ failure, which reflects in a high hospital mortality rate of 1:31 with a confidence interval (CI) of 95% –32. UsinIt is important to emphasize the importance of indicating LMWH and UFH for both prophylaxis and early treatment, once these drugs are not able to promote fibrinolysis of pre-existing thrombi formed in the tissue. Aware of this fact, the combination of heparin and fibrinolytic drugs could be effective for the treatment of severe cases, once thrombolysis also presents clinical benefits against severe pulmonary embolism .Beyond the expected effects of heparins on preventing clots formation through indirect inhibition of the coagulation pathway, other properties provided by these drugs can be the key for the positive data about their efficacy compared to single-target drugs. The exacerbated inflammation that is also found in severe COVID-19 cases is mediated especially through the uncontrolled production of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-8, monocyte chemoattractant protein-1 (MCP-1), and TNF-α in the cytokine release syndrome , 42. Res4), a potent pro-inflammatory mediator that is closely related to neutrophil activation  and Herpes Simplex Virus (HSV) , 59. Thihan LMWH , 64. It han LMWH . In thisAlthough antiviral evidence of both LMWH and UFH against SARS-CoV-2 are still preliminary, the other protective activities against COVID-19 complications are clear. The ideal therapeutic approach for treating such complex diseases is also using a multi-target molecule that restores different SARS-CoV-2-affected pathways. The anticoagulant, anti-inflammatory, and potential antiviral effects provided by heparins increase the perspectives of using these medications for creating a better prognosis for COVID-19 affected individuals . ConsideBased on available clinical data, around 20% of SARS-CoV-2-infected patients developed Acute Respiratory Distress Syndrome (ARDS), characterized by pulmonary pathological alterations as elevated dead space and decreased oxygenation –69. The Consistently manifested by ARDS patients, pulmonary hyaline membrane formation impairs gas exchange, limits surfactant action, favors lung fibrosis, and induces lung microvascular thrombi , 73. OthGlucocorticoids (GCs) are steroid hormones derived from cholesterol metabolism. Both endogenous and synthetic forms of GCs share the same lipophilic chemical structure that allows the molecule to exert a broad range of endocrine effects in the organism . CurrentDexamethasone mechanisms of action are characterized by exclusive binding to the classical cytosolic GC receptor (cGCR), which provides the majority of anti-inflammatory effects . The druAs previously discussed, endogenous GCs are central for metabolic homeostasis and systemic inflammatory events during tissue repair and pathogens elimination . Due to At first, it was not clear whether patients diagnosed with COVID-19 could take advantage of the use of dexamethasone, especially taking into account the above-mentioned points . ReportsFaced with the complex scenario of severely ill patients with COVID-19, diverse protocols employing complementary treatments  have beeThe preliminary results of a large randomized, controlled, open-label trial conducted in the United Kingdom are in favor of dexamethasone use. In this trial, Dexamethasone arm constituted 2,104 patients receiving 6 mg dexamethasone  once daily for up to 10 days and 4,321 patients receiving standard care. Dexamethasone reduced mortality by 35% in patients receiving invasive mechanical ventilation. Besides, the prospective meta-analysis from the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group recommended the independent use of corticosteroids in patients with COVID-19. An important correlation between the administration of systemic GCs and reduced mortality was found among critically ill patients with COVID-19 . SelvaraAlthough dexamethasone promising performance for severe COVID-19, there are still concerns regarding this anti-inflammatory drug prescription for indiscriminately cases. Until now, the available data suggests a beneficial role of dexamethasone treatment on hospitalized patients, especially for those who received intensive oxygen therapy , 109. A Strongyloides hyperinfection, a neglected nematode disease, brought the current concern about dexamethasone application without concomitant vermifuge use  decrease of SARS-CoV-2 host cell entry, (II) inhibition of pro-inflammatory cytokines and chemokines, (III) inhibition of vascular permeability and leukocyte migration.Despite the controversial role of corticosteroids in treating severe infectious diseases, several clinical studies have provided increasing evidence that dexamethasone could function widely as an available treatment for the most severely ill patients with COVID-19. However, many clinically important questions remain open, and determination of optimal initiation period, dosing, and duration of the dexamethasone treatment might be considered to avoid serious adverse effects during COVID-19 management.While UFH or LMWH are indicated as prophylactic agents for the initial phase of the disease, which could impair clots formation in addition to abrogate viral cell entry, dexamethasone must be prescribed only for severe cases, when the disease reaches a highly inflammatory state. Taking this into account, we suggest that the multitarget impact of heparin as an anti-viral, antithrombotic and anti-inflammatory drug in the early stage of the COVID-19 could significantly reduce the need for dexamethasone treatment in the initial phase of this disease. If the standard treatment of heparins fails on protecting against severe illness, dexamethasone must be applied as a potent anti-inflammatory shutting-down the uncontrolled and exacerbated inflammation.Overall, the association of anti-coagulant heparin and the corticosteroid dexamethasone could be a very effective and promising therapeutic tool in avoiding COVID-19 complications when used for severely ill patients.GP-d-N, HB-d-M, SF, GK, and KM wrote different sections of the manuscript. KM revised, wrote, and prepared the manuscript. IS prepared the figures. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Acute kidney injury (AKI) is a severe complication of coronavirus disease (COVID-19) that negatively affects its outcome. Concern had been raised about the potential effect of renin–angiotensin–aldosterone system (RAAS) blockades on renal outcomes in COVID-19 patients. However, the association between RAAS blockade use and incident AKI in COVID-19 patients has not been fully understood. We investigated the association between RAAS blockade exposure and COVID-19-related AKI in hospitalized patients through meta-analysis. Electronic databases were searched up to 24th December 2020. Summary estimates of pooled odds ratio (OR) of COVID-19-related AKI depending on RAAS blockade exposure were obtained through random-effects model. The random-effect meta-analysis on fourteen studies  showed that RAAS blockade use was significantly associated with increased risk of incident AKI in hospitalized COVID-19 patients . Additional analysis showed that the association of RAAS blockade use on COVID-19-related AKI remains significant even after stratification by drug class and AKI severity. RAAS blockade use is significantly associated with the incident AKI in hospitalized COVID-19 patients. Therefore, careful monitoring of renal complications is recommended for COVID-19 patients with recent RAAS blockade use due to the potential risk of AKI. To date, around 3.2 M people have died due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection worldwide, and almost 20% of the total deaths have occurred in the United States. (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Despite extensive global efforts to identify potential therapeutics for COVID-19 patients5, the vast majority have not resulted in clinically meaningful improvement. While waiting for the worldwide vaccination and the establishment of herd immunity, and with a limited therapeutic armamentarium, a better understanding of the risk factors associated with severe/fatal COVID-19 course and meticulous medical attention to mitigate these risk factors are crucial in improving its clinical outcome.Coronavirus disease (COVID-19) is a protean viral illness with a potentially life-threatening course, that has caused unforeseen and unprecedented socioeconomic burdens. The clinical course of COVID-19 varies widely from asymptomatic infection to deadly severe acute respiratory distress syndrome, multi-organ failures, and death6. The pathogenesis of AKI in COVID-19 patients is likely multifactorial, including direct injury through viral tropism leading to endothelial dysfunction, coagulopathy, and complement activation as well as indirect injury through organ crosstalk, dehydration, and exposure to nephrotoxins while receiving COVID-19 treatment7. Several risk factors for COVID-19-induced AKI have been addressed in recent studies including older age, male sex, severity of COVID-19, and the levels of ferritin, creatine kinase, and brain natriuretic peptide9. Notably, concern had been raised about the use of renin–angiotensin–aldosterone system (RAAS) blockade and its potential risk on incident AKI in COVID-19 patients based on its potential effect on the reduction of glomerular filtration rate as well as increased susceptibility and severity of COVID-19 by enhancing angiotensin-converting enzyme 2 (ACE2) which is a functional receptor protein for SARS-CoV-27.Acute kidney injury (AKI) is one of the most common complications of COVID-19, which has been found to be significantly related to poorer clinical outcome and increased risk of mortality in COVID-19 patients10. On the other hand, an alternative hypothesis has suggested that RAAS blockade may mitigate viral entry into cells by restoring ACE1/ACE2 imbalance11. Beyond these speculative assumptions, several clinical studies have shown no clear association between RAAS inhibitor use and the incidence of COVID-19 or mortality15. However, the safety data regarding RAAS blockade use on COVID-19-related renal dysfunction are relatively scarce. Several recent studies have shown the potential detrimental effects of angiotensin-converting-enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use on the development of AKI in COVID-19 patients18, but these studies have limitations due to the small number of participants.RAAS inhibitors are known to affect ACE2 expression and activity, which can hypothetically increase the risk of SARS-CoV2 infection by facilitating viral entryACEIs and ARBs are widely used antihypertensive medications, and their use is most prevalent in the elderly and chronic kidney disease patients, who belong to the highest risk groups for the development of COVID-19-related mortalities and multiorgan failure. Thus, further investigation of the potential association of RAAS blockade exposure with the development of AKI in COVID-19 patients is crucial to provide proper guidance to healthcare providers in order to prevent unnecessary exposure or discontinuation of RAAS inhibitors in COVID-19 patients. Therefore, we conducted a systematic review and meta-analysis of the association between RAAS blockade use and AKI development in laboratory-confirmed or clinically diagnosed COVID-19 patients.Published articles reporting incident AKI in COVID-19 patients and their use of ACEIs or ARBs from January 1, 2020 to December 24, 2020 were identified by searching PubMed, Embase, Cochrane, and Scopus. A search update was conducted on January 15, 2021. An example search strategy used for PubMed was as follows: (COVID-19 OR SARS-CoV-2 OR coronavirus) AND  AND (English[Language]). For inclusion, studies were required to meet the following criteria: (1) case–control, retrospective or prospective cohort, or descriptive studies published in English; (2) human subjects with laboratory-confirmed or clinically diagnosed COVID-19; and (3) reported data on pharmacological RAAS blockade exposure either before or during hospitalization and the incidence of AKI. The timing of the initiation of RAAS blockade use relative to the hospitalization date was not specified prior to analysis. Review articles, case reports, or case series reporting fewer than 10 patients or non-peer-reviewed publications were excluded. Any duplicate data among the included studies were identified by assessing whether specific studies were conducted in the same hospitals in overlapping time frames or by contacting investigators when deemed appropriate. Study selection and data extraction were conducted by two investigators (S.A.L. and R.P.) in tandem, and any discrepancies were resolved via a third reviewer’s (J.H.Y.) mediation. Although this study’s protocol was not registered in PROSPERO, no relevant protocols for this topic were found in this database during the writing of this review. Of note, the authors did not seek specific institutional review board or ethics committee approval for this study because the study was conducted using publicly available data obtained from online databases.Study quality was assessed using the Newcastle–Ottawa Scale (NOS) for retrospective studies. The NOS scale demonstrated good study quality (7–8) in all selected studies . The summary estimate of the incidence of AKI depending on RAAS blockade exposure is presented as ORs and their 95% confidence intervals (CIs). Additional analysis of the incidence of AKI depending on ACEIs/ARB use and AKI severity were performed in the same way. The pooled ORs with 95% CIs were calculated using the random-effects model with the restricted maximum-likelihood estimator assuming high heterogeneity in characteristics among the included studies. Between-study heterogeneity was assessed using the I2 statistic and Cochran’s Q test with P < 0.10. Additional univariate meta-regression was performed to find potential covariates affecting the association between RAAS blockade use and COVID-19-related AKI which can also be the source of high heterogeneity. The meta-regression included clinical factors such as age, sex, region, level of care, underlying comorbidities, and sample size. Contour-enhanced funnel plot and Egger’s test were used to detect publication bias. We also performed trim-and-fill method to evaluate the effect of missing studies and recalculated pooled OR with 95% CIs that included the hypothetical studies if deemed appropriate.The author, type of study, location where the study was performed, date of publication, median/mean age, number of AKI cases, RAAS blockade use, definition of AKI, and diagnosis criteria of COVID-19 were extracted from each included study. Meta-analysis was performed using the package ‘meta’ and ‘metafor’ of the R-project  that did not contain the data of interest.Following the initial database search and screening, 60 full-text articles were assessed for eligibility; among them, 44 studies were excluded for specific reasons Fig. . Of the . was excluded in the additional meta-analysis regarding the incidence of AKI depending on ACEIs/ARB use due to overlapping data with Ng et al. All studies used the Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the definition of AKI. Furthermore, RAAS blockade exposure was determined based on the medication history at the time of admission in most studies; however, Cheng et al. and Kolhe et al. defined the exposure as drug administration during hospitalization. The criteria for COVID-19 diagnosis were based on laboratory confirmation using polymerase chain reaction in 14 studies and laboratory confirmation or clinical suspicion of COVID-19 in two studies .Table P = 0.003) with high heterogeneity (79.65%) , substantially weakening the significant association found in the original analysis. No significant publication bias was found on the association between ARB use and incidence of COVID-19-related AKI based on Egger’s test  .Next, the association between RAAS blockade use and COVID-19-related AKI was analyzed after stratification of AKI by severity. The random-effect meta-analysis of pooled OR showed that the use of RAAS blockade was significantly associated with moderate-to-severe AKI compared to no/mild AKIin hospitalized COVID-19 patients  as well as via individual manuscript review. This could have originated from variations in the dosage/timing of RAAS blockade use as well as different definitions of COVID-19 diagnosis, even though most of the studies followed molecular diagnosis for COVID-19 confirmation. To better understand the origin of substantial heterogeneity between studies, we performed univariate meta-regression, which did not show any significant association with effect sizes. However, other covariates such as race, the dosage of drugs, or frequency of cardiovascular disease could not be included in the meta-regression due to missing values in included studies. Multiple meta-regression could not be performed due to multiple missing covariate data among the included studies. Lastly, subgroup analyses on each potential confounding factor were limited because most of the studies simply described the overall prevalence of each factor in the total study population while no specific data was provided depending on the RAAS blockade exposure, which remains a potential weakness of our study.Our study has several limitations. A limited number of studies remained after the initial screening because most published studies regarding incident AKI with SARS-CoV-2 infection lacked specific data on recent RAAS blockade usage. Moreover, most included studies are observational retrospective studies and could only provide crude odds ratio on AKI incidence according to RAAS blockade exposure. Therefore, this meta-analysis may not be used to derive any conclusions regarding the cause-and-effect relationship between RAAS blockade and AKI in COVID-19 patients, and may also be affected by recall, selection, and publication bias. Inherent to the nature of the meta-analysis, significant heterogeneity was found both via statistical methods (IIn conclusion, exposure to RAAS inhibitors appears to be associated with a higher risk of COVID-19-related AKI. Because of the reliance of our analysis on observational studies, a causal relationship cannot be ascribed to RAAS blockade and AKI in COVID-19 and practice-changing recommendations cannot be made on the basis of our data. Nonetheless, our study warrants further randomized controlled studies and meta-analyses on the effect of RAAS blockade on kidney outcomes to better define the risk/benefit of RAAS blockade use in AKI patients with COVID-19.Supplementary Information.


BackgroundA personal history of depression prior to breast cancer diagnosis and its effect on post-diagnosis quality of life (QOL) in women undergoing breast reconstruction is relatively unknown. We performed the current study to determine if depression alters QOL for patients who undergo breast reconstruction by assessing the pre-to-post-operative change in patient-reported BREAST-Q scores.MethodologyWe conducted a single-center, post-hoc analysis of 300 patients with completed BREAST-Q data who underwent breast reconstruction from November 2013 to November 2016 following a diagnosis of breast cancer. Patients completed the BREAST-Q at four time points: pre-operatively, six weeks following tissue expander (TE) insertion for patients undergoing staged reconstruction, and six and 12 months following the final reconstruction. Medical records were reviewed to identify patients who had a pre-cancer diagnosis of clinical depression and/or anti-depressant medication use. BREAST-Q scores were compared between groups and within groups. Groups compared were the depression (n = 50) and no depression (n = 250) patients, along with anti-depressant (n = 36) and no anti-depressant (n = 14) use in the depression group.ResultsWithin-group Sexual Well-being scores at the six-week post-TE follow-up for patients in the depression group  were significantly lower (p < 0.01) than the scores for patients in the no depression group . There were no statistically significant differences in BREAST-Q scores in other domains. When compared to patients diagnosed with depression who were not taking anti-depressants, anti-depressant medication use did not result in statistically significant higher BREAST-Q scores, although Satisfaction With Breasts six months post-operatively, Psychosocial Well-being at six weeks post-TE, Sexual Well-being at six weeks post-TE and six months post-operatively were clinically higher in patients taking anti-depressants for depression.ConclusionsPatients with a diagnosis of depression prior to breast cancer had lower BREAST-Q Sexual Well-being scores in the six-week TE group with or without anti-depressant medication. Patients with a pre-cancer diagnosis of depression considering TEs may benefit from additional counseling prior to breast reconstruction or electing a different method of breast reconstruction. Anti-depressant medications may provide clinically higher BREAST-Q scores in patients with a pre-cancer diagnosis of depression. Adding an anti-depressant medication to a patient’s treatment plan may provide additional benefits. Larger samples are required to properly determine the impact of anti-depressant medications on BREAST-Q scores in patients with a pre-cancer diagnosis of depression. In 2018, the Centers for Disease Control and Prevention reported that 8.1% of all U.S. adults aged 20 and older had a diagnosis of depression, with women being nearly two times more likely than men to be diagnosed .Breast cancer is the most prevalent cancer among women and the second leading cause of cancer mortality in the United States. An estimated one out of every eight U.S. women will be diagnosed during their lifetime ,5. BreasWomen with a history of depression have been shown to have a higher risk for recurrence of depression following breast cancer diagnosis . HoweverTo our knowledge, no study has examined the differences in pre- and post-operative patient-reported outcomes (PROs) in patients undergoing breast reconstruction with a pre-cancer diagnosis of depression. We performed the current study to determine if BREAST-Q scores differ between patients with and without a pre-cancer diagnosis of depression by looking at PROs at various time points throughout the reconstruction process. Additionally, we examined if anti-depressant medication use in patients diagnosed with depression impacted patient-reported QOL and satisfaction reported in the BREAST-Q.Study designThis study was approved by the institutional review board at The Johns Hopkins Hospital (IRB00039871). The STROBE guidelines are adhered to throughout this paper. We performed a post-hoc analysis of a prospectively collected cohort of 300 patients from a single institution who underwent breast reconstruction following a diagnosis of breast cancer with completed BREAST-Qs at designated time points from November 2013 to November 2016. Patients were included if they were ≥18 years of age; underwent immediate or staged (tissue expander [TE] insertion) or delayed (mastectomy followed by reconstruction on a later date) breast reconstruction; and had completed BREAST-Qs at the designated time points: pre-operatively (baseline), six weeks following TE insertion (only for staged reconstruction patients), and six and twelve months following final reconstruction. Included patients in the study may have received implant-based or autologous breast reconstruction. We reviewed patient medical records to identify individuals with a pre-cancer diagnosis of clinical depression and/or anti-depressant medication use indicated for the treatment of depression.We categorized patients as having depression if pre-breast cancer Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM V) criteria clinical diagnosis of depression could be identified in their medical records. We defined no depression as the absence of this diagnosis and no history of taking anti-depressant medication for the indication of depression prior to breast cancer diagnosis. We further subdivided patients in the depression group into one of two groups: those who were (medication use) and those who were not (medication non-use) taking anti-depressant medications at the time of pre-cancer diagnosis and throughout the reconstruction process, and recorded anti-depressant medication use as relevant. Daily medication adherence was confirmed by all patients included in the study. Psychotherapy and other non-medication therapies were not evaluated in this study. We excluded patients taking an anti-depressant medication in the absence of a clinical diagnosis of depression from the depression group.We assessed patient QOL and satisfaction using five domains within the BREAST-Q breast reconstruction module (Appendix): (1) Satisfaction With Breasts; (2) Psychosocial Well-being; (3) Sexual Well-being; (4) Physical Well-being: Chest; and (5) Physical Well-being: Abdomen. For each domain, items were summed and converted to a 0-100 scale, with greater values indicating higher satisfaction and better QOL .Outcomes analyzedOur primary outcome of interest was the difference in BREAST-Q reconstruction module scores between patients with depression and with no depression at our four study time points: (1) pre-operatively (baseline); (2) six weeks post-TE insertion (for staged reconstruction), (3) six months after final reconstruction, and (4) 12 months after final reconstruction. Our secondary outcome of interest was the difference in BREAST-Q scores between depressed patients with medication use and depressed patients with medication non-use.Data management and statistical analysisPatient and BREAST-Q data were prospectively entered into and managed using the Research Electronic Database Capture . We performed descriptive statistics to compare patient demographics. Categorical variables and continuous variables were compared using the Fischer’s Exact test and the Mann-Whitney U test, respectively. We reported medians and interquartile ranges (IQRs) for BREAST-Q scores using the Mann-Whitney U test to compare the depression and no depression patient groups. We used the same statistical guidelines for the subgroup analysis within the depression group based on medication use/non-use. We depicted changes in scores within the depression, no depression, medication use, and medication non-use groups from pre-operative to the four different time points during mastectomy and reconstruction using longitudinal graphs. Statistical significance was observed at p < 0.05. Clinical significance was determined by a minimal important difference (MID) of 0.5 the standard deviation (SD) between median BREAST-Q scores . All staDemographicsPatient demographic variables are summarized in Table A total of 300 patients were eligible for study inclusion having completed BREAST-Qs at the pre-operative and six- and 12-month post-operative time points. Of these 300 patients, 50 (17%) had depression and 250 (83%) had no depression. The only significant difference between the depression and no depression groups was in the percentage of smokers . Reconstruction type did not differ significantly between groups, with 205 (68%) patients undergoing staged reconstruction involving TE placement. Of these, 32 (16%) had a pre-cancer history of depression and 173 (84%) had none; all of these patients completed BREAST-Qs for the six-week post-TE time point.Within the depression group (n = 50), 36 (72%) patients were and 14 (28%) patients were not taking anti-depressant medications from the time before a diagnosis of breast cancer throughout the study. There were no significant demographic differences between groups based on medication use/non-use.Anti-depressant medicationsFive classes of anti-depressant medications were used by patients in the depression group Table .These included 22 selective serotonin reuptake inhibitors (SSRI), eight selective serotonin and norepinephrine reuptake inhibitors (SNRI), two tricyclic anti-depressants (TCA), one monoamine oxidase inhibitors (MAOI), six miscellaneous classes, and three combinations of more than one class. SSRIs were observed as the most frequently used class of anti-depressant medications . Among the 22 SSRIs, escitalopram  and sertraline  were most frequently used. Medications were further categorized as those causing sexual dysfunction  and non-dysfunction  to explore the impact of medication-induced sexual dysfunction on BREAST-Q Sexual Well-being scores.BREAST-Q scoresWe found no statistically significant differences in pre-operative baseline BREAST-Q scores between the depression and no depression groups across all five domains Table . HoweverFigure The no depression group demonstrated significant within-group from pre-operative to six-month post-final reconstruction increases for Satisfaction With Breasts , Psychosocial Well-being , and decreases for Physical Well-being: Chest , and Physical Well-being: Abdomen . The no depression group demonstrated significant within-group from pre-operative to 12-month post-final reconstruction increases for Satisfaction With Breasts , Psychosocial Well-being , and decreases for Physical Well-being: Abdomen . Within-group Physical Well-being: Abdomen scores increased for both the depression and no depression groups from six to 12 months after final reconstruction time points.Subgroup analysis of the depression group comparing medication non-use n = 14, 28%) with medication use  did not show any statistically significant between-group differences in BREAST-Q scores across any domains , Sexual Well-being , and Physical Well-being: Chest   Table .In this study of PROs using the BREAST-Q, our results show that women who had a diagnosis of depression prior to a breast cancer diagnosis reported significantly lower Sexual Well-being scores than women with no diagnosis of depression at the six-week post-TE insertion time point. Because some anti-depressants are associated with sexual dysfunction, we subgrouped the anti-depressant medication users to determine if medication use disproportionately influenced the Sexual Well-being domain. Although we found no statistically significant differences, we found that patients using anti-depressants associated with sexual dysfunction had clinically significantly lower BREAST-Q scores at the six-week post-TE insertion time point for Sexual Well-being. These patients may benefit from additional counseling from healthcare professionals prior to and following TE insertion to help them progress to the six-month post-final reconstruction time point when their self-reported QOL is comparable to patients without depression or depressed patients using anti-depressants that do not cause sexual dysfunction.This is an important consideration when assessing Sexual Well-being scores. Breast surgery may adversely change a woman’s perception of her own sexuality, leading to additional decreases in scores among women on anti-depressants associated with sexual dysfunction. A study by Mathias et al. (2006) evaluated the use of the anti-depressant bupropion, which is not associated with sexual dysfunction, on sexual function scores using the Arizona Sexual Experience Scale (ASEX) in women receiving adjuvant therapy for breast cancer. The use of this medication improved patients’ libido, sexual excitability, and ability to achieve orgasm . In our Healthcare providers managing baseline depression may consider switching patients to an anti-depressant that does not cause sexual dysfunction or providing additional counseling for patients newly diagnosed with breast cancer. SSRIs are the most commonly prescribed anti-depressants with 56% of the 36 patients in our study taking an SSRI. Paroxetine is a commonly prescribed SSRI that inhibits the metabolism of the enzyme CYP2D6. This enzyme is necessary for the metabolism of the prodrug tamoxifen, a selective estrogen receptor modulator (SERM), commonly prescribed for breast cancer . PreventOne in five women will experience an episode of depression within their lifetime  The riskOne may assume that a patient’s QOL assessed by PRO tools may correlate with lower scores in patients with depression. However, a study by Salibasic et al. (2018) demonstrated no difference in a patient’s QOL scores before and after mastectomy in patients with or without significantly increased levels of depression, as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core30 and BR23 questionnaires . While tThis study has several limitations. Although the BREAST-Q data were collected prospectively, this study employed a retrospective analysis of data. BREAST-Q data for some domains and time points were incomplete as not all patients fully completed all questionnaires. The six-week time point was only collected for patients with staged tissue expansion. Due to our relatively small sample size, we included patients who underwent either TE-based or immediate autologous breast reconstruction; larger future studies should consider parsing out these groups to control for QOL differences relating to the timing of final breast reconstruction. Additionally, we categorized four patients with no prior diagnosis of depression who were taking an anti-depressant for another indication into the no depression group. Not all patients taking anti-depressants associated with sexual dysfunction were assessed clinically for symptomatic sexual dysfunction. Patients taking these anti-depressants may exhibit different adverse effects. In addition, sexual dysfunction may have been present throughout the entire study population secondary to anti-hormonal therapy for breast cancer, post-menopausal states, or psychologically from breast cancer or breast surgery. Finally, while we used non-parametric statistical analyses to report medians and IQRs, we assessed clinical significance and the MID using means and one-half of the SD, as previously described in the literature.Larger multi-center studies are needed to further elucidate the role of a prior diagnosis of depression and anti-depressant medication use with PROs using the BREAST-Q questionnaire. Although the BREAST-Q has been validated, it has not been specifically tested in patients with mood disorders or who take medications for mood disorders. This may limit the utility of the BREAST-Q in certain populations. In addition, psychological interventions may be equal or more efficacious than anti-depressants alone in this population, as psychological interventions can be tailored to patients’ concerns . Multimodal combinations of anti-depressants and psychological interventions may provide the best treatment strategy. Our findings provide a window to new information that may contribute to better patient care and the opportunity for future prospective studies.Patients with a pre-cancer diagnosis of depression had lower BREAST-Q Sexual Well-being scores at the six-week TE time point than patients without a diagnosis of depression. This was evident even for patients with depression on anti-depressant medications. Patients with a pre-cancer diagnosis of depression considering TEs may benefit from additional counseling prior to breast reconstruction or electing a different method of breast reconstruction. Anti-depressant medications may provide clinically higher BREAST-Q scores in patients with a pre-cancer diagnosis of depression. Adding an anti-depressant medication to a patient’s treatment plan may provide additional benefits.


COX-2). Preliminary studies have suggested that PACER is involved in the regulation of COX-2 expression in macrophagocyte and osteosarcoma cells. However, the role of this lncRNA in colorectal cancer (CRC) remains elusive. Here, we investigated the expression of PACER and its effect on cell proliferation and invasion to explore the role of PACER in CRC.p50-associated cyclooxygenase-2 extragenic RNA (PACER) is a recently identified antisense long non-coding RNA (lncRNA) located on the upstream of the promoter region of cyclooxygenase-2 (in situ hybridization (FISH) to establish the subcellular localization of PACER. COX-2 protein levels were quantified by Western blot analysis and grayscale scanning analysis following the knock-down of PACER. Luciferase assay was carried out to monitor the modulation of the COX-2 promoter region by PACER. Tumor xenografts models were used to investigate the impact of PACER on the tumorigenesis of CRC cells in vivo. Enzyme-linked immunosorbent assay (ELISA) was then used to quantify prostaglandin E2 (PGE2) production upon knock-down of PACER.Real-time quantitative PCR (RT-qPCR) analysis was used to evaluate the expression of PACER in CRC tissues and cells. Methyl thiazolyl tetrazolium (MTT) analysis was then used to investigate the inhibition effect of PACER knock-down in cell proliferation. The promoting role of this lncRNA on invasion by CRC cells was analysed by wound-healing assays, colony-formation assay, and transwell assays. We then used fluorescence in vitro. Analysis of lncRNA localization by FISH showed that it mainly resided in the nucleus. RT-qPCR showed that PACER increased mRNA levels of COX-2. Western blot analysis demonstrated, under normal circumstances, that knock-down of PACER decreased the COX-2 protein level. In the case of p50 absence, COX-2 protein increased rapidly and remained highly expressed after knocking down PACER. Luciferase assay revealed that PACER modulated the COX-2 promoter region. Mouse xenograft models of CRC revealed that PACER promoted colorectal tumorigenesis in vivo. ELISA revealed that PACER knock-down inhibited PGE2 production.RT-qPCR analysis revealed that PACER was highly expressed in CRC tissues and cells, and a high PACER-expression level was associated with poor prognosis. MTT assay, wound-healing assay, colony-formation assay, and transwell assay revealed that PACER enhanced CRC-cell proliferation, invasion, and metastasis COX-2 expression through the nuclear factor kappa B (NF-κB) pathway in CRC. An increased level of PACER enhances proliferation, migration, and invasion of tumor cells by increasing COX-2 and PGE2 synthesis.PACER modulates  Colorectal cancer (CRC) is one of the most prevalent malignant tumors globally . It is elncRNAs are nuclear or cytoplasmic RNA transcripts consisting of >200 nucleotides in length . With >2COX-2) is the key pro-inflammatory enzyme that catalyses arachidonic acid into prostaglandins, which is involved in inflammatory diseases and certain types of tumor , Beijing Science and Technology Plan [No.D171100002617004], and the Scientific Research Foundation of Graduate School of Harbin Medical University [YJSCX2017-63HYD].


The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulting in coronavirus disease 2019 (COVID-19) continues to cause a worldwide pandemic. Recognized clinical presentations of COVID-19 have evolved beyond solely respiratory symptoms. We report a 13-year-old girl with severe abdominal pain who was found to have chylous ascites, cardiac dysfunction, and multiple thrombi 10 weeks following a COVID-19 infection. Informed consent was obtained from the family before the submission of this article.A 13-year-old girl with a history of Ewing Sarcoma diagnosed in 2009, post left leg amputation and rotationplasty in remission since 2010 acutely developed nausea, nonbilious, nonbloody emesis, and severe cramping right lower quadrant abdominal pain, prompting admission for evaluation. Ten weeks before admission, she had tested positive for SARS-CoV-2 on real-time reverse transcription-polymerase chain reaction via nasopharyngeal swab when she had presented with fever, fatigue, and cough.Laboratory findings on admission were remarkable for leukocytosis, thrombocytosis, elevated inflammatory marker, low albumin, elevated aminotransferases, and prolonged prothrombin time Table . ElectroDue to the severity of abdominal pain, ascites, and history of Ewing sarcoma, she underwent diagnostic laparoscopy, which revealed a large amount of ascites and patchy inflamed and ischemic appearance of the liver Fig. A. The reAdditional tests for congestive hepatopathy revealed elevated B-type natriuretic peptide (1437 pg/mL) and an abnormal echocardiogram with severely depressed systolic function (ejection fraction [EF] 28%) and large thrombi in the right atrium and left ventricle . Liver enzymes and bilirubin had normalized. CT heart demonstrated resolution of the intracardiac and pulmonary thrombi.The COVID-19 pandemic continues to cause catastrophic disease in the USA. Increasing cases of COVID-19 have been documented in children and adolescents. The presence of gastrointestinal symptoms in children with COVID-19 has been well described . This isMultisystem inflammatory syndrome in children (MIS-C) has been described with associated fever, elevated inflammatory markers, and multi-organ involvement ,4. HowevThe rapid progression to decompensated heart failure following our patient’s COVID-19 infection raises suspicion for viral myocarditis as a possible etiology. Her initial presenting symptom of abdominal pain was ultimately attributed to ischemia caused by systolic heart failure. Congestive heart failure has been reported to lead to the development of chylous ascites and may have been the trigger in our patient’s case –10. HearThis is the first reported case of systolic heart failure leading to severe abdominal pain and chylous ascites in the setting of prior SARS-CoV-2 infection. As we continue to witness the spread of COVID-19, it is important to think broadly about our differential diagnosis for a patient presenting with primarily gastrointestinal symptoms. Our patient’s case emphasizes the need to consider multisystem involvement, especially in pediatric patients with a history of SARS-CoV-2 infection.


Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed in prostate cancer and correlates with the aggressiveness of the disease. PSMA is a promising target for imaging and therapeutics in prostate cancer patients validated in prospective trials. However, the role of PSMA in prostate cancer progression is poorly understood. In this review, we discuss the biology and scientific rationale behind the use of PSMA and other targets in the detection and theranostics of metastatic prostate cancer.Prostate cancer is the second most common cancer type in men globally. Although the prognosis for localized prostate cancer is good, no curative treatments are available for metastatic disease. Better diagnostic methods could help target therapies and improve the outcome. Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed on malignant prostate tumor cells and correlates with the aggressiveness of the disease. PSMA is a clinically validated target for positron emission tomography (PET) imaging-based diagnostics in prostate cancer, and during recent years several therapeutics have been developed based on PSMA expression and activity. The expression of PSMA in prostate cancer can be very heterogeneous and some metastases are negative for PSMA. Determinants that dictate clinical responses to PSMA-targeting therapeutics are not well known. Moreover, it is not clear how to manipulate PSMA expression for therapeutic purposes and develop rational treatment combinations. A deeper understanding of the biology behind the use of PSMA would help the development of theranostics with radiolabeled compounds and other PSMA-based therapeutic approaches. Along with PSMA several other targets have also been evaluated or are currently under investigation in preclinical or clinical settings in prostate cancer. Here we critically elaborate the biology and scientific rationale behind the use of PSMA and other targets in the detection and therapeutic targeting of metastatic prostate cancer. In particular, they are insensitive in the event of biochemical relapse with a rising prostate-specific antigen (PSA) after radical treatment, presenting an unmet need for better methods.Prostate cancer is the second most commonly diagnosed cancer in men and the sixth leading cause of cancer-related deaths among men worldwide although incidence and mortality of prostate cancer vary depending on the country . IncidenThe first-line treatment option for metastatic prostate cancer is androgen deprivation therapy (ADT) that can be combined with docetaxel chemotherapeutic agent or drugs interfering with androgen signaling in early castration naïve state, but eventually, the lethal castration-resistant disease develops ,3. The tFOLH1 (folate hydrolase 1) gene mapped to chromosome 11 short arm (11p11–11p12) and contains 19 exons, encoding a protein of 750 amino acids and a molecular weight of approximately 100 kDa [PSMA, also known as glutamate carboxypeptidase II (GCPII), N-acetylaspartylglutamate peptidase, and N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I), is a type II transmembrane glycoprotein encoded by  100 kDa .PSMA contains a catalytic domain responsible for both NAALADase and folate hydrolase activity and belongs to the M28 metalloprotease family that contains aminopeptidases and carboxypeptidases. PSMA protein has a large extracellular domain, a short transmembrane domain, and a short cytoplasmic tail ,7,8. TheFolh1 in mice to understand the physiological role of the mouse homolog of human PSMA [Folh1 gene using transcription activator-like effector nuclease (TALEN)-mediated mutagenesis. They confirmed that PSMA protein was not expressed and NAAG hydrolyzing activity was lowered, but the PSMA-deficient mice bred and developed normally. They reported that PSMA-deficient aged mice might have an increased propensity for enlarged seminal vesicles compared to WT, but no other obvious phenotype in the urogenital system. In contrast, Tsai et al. [In general, only very low levels of PSMA protein expression have been detected in healthy tissues such as the kidney, intestine, salivary glands, and brain, and it seems that prostatic epithelium is the only tissue to express a significant level of PSMA ,18. Despman PSMA ,20,21,22man PSMA . Bacich man PSMA  report tman PSMA . In accoman PSMA  producedγ-glutamate of the dietary folic-polyglutamates enabling absorption of monoglutamated folates into the enterocytes [In humans, the functional role of PSMA is context-dependent and tissue-specific. PSMA has an enzymatic activity to release glutamate from the substrate as a folate hydrolase and NAALADase ,27,28. Ierocytes ,30. In terocytes . Glutamaerocytes . In concPSMA was first characterized in 1986 by the murine monoclonal antibody 7E11, delivered from mice immunized with partially purified, cell membrane fractions isolated from the human prostate adenocarcinoma cell line LNCaP ,34,35,361 activation promotes activation of p21-activated kinase 1 (PAK) to interact with FLNa, disrupting PSMA-FLNa interaction and the enzymatic activity of PSMA. Disruption of PSMA-FLNa interaction causes a reduction in both integrin β1 signaling and PAK activation creating a negative feedback loop. Later, it was recognized that PSMA takes part in a pathway producing pro-angiogenic fragments from extracellular protein laminin, promoting angiogenesis by regulating integrin β1 signaling in endothelial cells [Interestingly, by using a PSMA targeting antibody (YPSMA-1), an inhibitor of the enzymatic activity (2-PMPA) or PSMA null mice as models, it was shown that PSMA regulates endothelial cell invasion into the extracellular matrix without significantly affecting viability, proliferation, or morphogenesis . This sual cells . In concAlthough PSMA was originally identified in a prostate cancer LNCaP cell line and early on linked to prostate cancer aggressiveness, PSMA is not expressed in many other commonly used commercially available prostate cancer cell lines and preclinical publications have been in part contradictory, demonstrating inhibition of PSMA to either promote or prevent invasion in vitro ,49. FirsFolic acid is a synthetic, fully oxidized, monoglutamated version of folate—found for example in vitamin supplements—that can directly be transported into cells while polyglutamated folates have to be hydrolyzed into monoglutamates before being absorbed in the digestive tract. It has been suggested that polyglutamated folate in turn could become available as a substrate for PSMA in particular if intracellular molecules were released by cancer cells undergoing necrotic cell death . Interes1, resulting in a switchlike change from activation of the proliferation-associated MAPK pathway to activation of a cell survival-associated PI3K-AKT pathway. This suggested one mechanism of how PSMA overexpression could drive prostate cancer growth and indicated that disrupting the interaction between PSMA and the scaffold might have therapeutic potential for patients with PSMA-positive prostate cancer. Mutations targeting phosphatase and tensin homolog (PTEN) or other components of the PI3K-AKT pathway are often found in prostate cancer and crosstalk between the PI3K-AKT pathway and AR signaling has been described [1-mediated mechanism linking PSMA to the PI3K-AKT pathway may thus result in a similar reciprocal feedback regulation towards AR signaling. Interestingly, RACK1 has also been shown to interact with AR and inhibit its function, putatively also connecting PSMA to AR signaling [Caromile et al.  crossed escribed ,65. Thisescribed ,65. The ignaling .In conclusion, recent studies using different model systems including transgenic mouse models with PSMA null background have elucidated several distinct mechanisms associating PSMA with survival-related signaling pathways with connections to the androgen receptor (AR) signaling in prostate cancer . The newPSMA expression is highly regulated in a prostate cell and prostate cancer cell-specific manner . A prostAndrogen signaling and subsequent AR activation is a hallmark of prostate cancer progression and surprisingly has long been known to downregulate PSMA ,71,72. AOverexpression of PSMA has been associated with DNA repair defects in tumors . However99mTc bone scintigraphy and CT are insensitive to detect in particular early metastases and there has been an unmet medical need for improved sensitive and specific imaging methods to guide treatment. Since the 1990s several PSMA based imaging methods have been developed. Currently, to detect PSMA, 68Ga-PSMA-11 is the most widely studied PET imaging ligand [99mTc bone scan in detecting bone metastases [18F-PSMA-1007 PET-CT despite showing non-metastatic bone lesions, similarly showed superior sensitivity when compared to conventional imaging with 14% of patients having metastases only visible by PSMA PET-CT [68Ga-PSMA-11 PET-MRI once before and three times after the administration of degarelix or firmagon. A heterogenous increase in the 68Ga-PSMA-11 uptake with a mean standardized uptake value (SUVmax) increase of 77% (range 8–238%) more evident in the bone metastases was observed 3–4 weeks post-ADT. The impact on performance was considered minor. One patient had more bone metastases visible due to the flare phenomenon without changing his management and ADT was determined not to interfere with imaging as no lesions disappeared within a month after initiation of ADT [99mTc-based SPECT (single-photon emission computed tomography)-compatible PSMA ligands have been developed and are currently under clinical assessment [99mTc-PSMA-SPECT-CT might have the potential to detect more aggressive prostate cancers, especially if PSMA PET-CT is not available.Conventional g ligand . Severalg ligand ,85. In ptastases . Longed tastases . Histopatastases . In a prA PET-CT . A smallA PET-CT . Nine pan of ADT . In para177Lu) have been evaluated as therapy ligands for metastatic prostate cancer patients. 177Lu is a β--emitting radionuclide , which by emitting a beta particle , induces cell death by breaking double-strand DNA [PSMA can be targeted by small-molecule ligands and antibodies (Ab) labeled with radionuclides  Figure B,C. The rand DNA ,94. The rand DNA ,96. The rand DNA . In salirand DNA . Althougrand DNA , PSMA tarand DNA .177Lu-PSMA-617 is a small molecule that binds with high affinity to the enzymatic site of PSMA enabling highly targeted delivery of β—radiation. 177Lu-PSMA-617 therapies seem promising to men with metastatic castration-resistant prostate cancer (mCRPC)  as a first-line therapy for hormonal naïve metastatic prostate cancer  A–D. A coPSMA-617 . The resin mCRPC . Fewer gin mCRPC . Many la225Ac), thorium-227 (227Th), and copper-64 (64Cu) are currently evaluated in phase I trials as alternative isotopes for radiotherapy. As opposed to 177Lu, 225Ac, and 227Th decay alpha particles with a shorter emission path of only a few cells and high local cell kill caused by higher energy compared to β-emitting 177Lu and 64Cu [225Ac-PSMA-617, resulting in a ≥90% decline in serum PSA in 82% of patients, including 41% of patients with undetectable serum PSA who remained in remission 12 months after therapy [225Ac-PSMA-617 and full-activity 177Lu-PSMA-617 was safe, generally well-tolerated, and showed efficacy in late-stage mCRPC patients after insufficient response to 177Lu-PSMA-617 monotherapy [131I-1095, for delivering iodine cytotoxicity selectively to the PSMA-expressing prostate cancer cells, in combination with enzalutamide in patients with mCRPC. Eligible criteria allow the inclusion of chemotherapy-naïve patients progressing under abiraterone. Another interesting setting is evaluating the efficacy of 177Lu-PSMA-I&T as a first-line treatment for oligometastatic prostate cancer relapse after prior surgery or external radical radiotherapy for local disease  is currently in phase I and contains a PSMA binding motif as well as an albumin-binding site that is thought to allow higher concentrations in the target tissue with reduced systemic side effects  shows typically only a low uptake in prostate cancer due to slow tumor growth especially in the early stages of the disease [18F-FDG-PET could be an efficient imaging method for these prostate cancers [18F-FDG for detecting some subtypes of prostate cancer. 18F-FDG might also have a role together with PSMA-imaging in selecting patients for PSMA targeted therapy. MCRPC patients with discordant imaging findings in metastases with high 18F-FDG uptake with low or non-existent PSMA-uptake are not considered candidates for molecular radiotherapy [Altered glucose metabolism, including increased uptake of glucose and a preference for aerobic glycolysis instead of oxidative phosphorylation even in the presence of oxygen, is considered one of the most extensively characterized metabolic hallmarks of many cancers . However disease . Interes cancers ,131,132.otherapy .18F-choline PET-CT showed a pooled sensitivity of 0.62, and specificity of 0.92 for detecting pelvic lymph node metastases, and more patients had positive findings in comparison to bone scintigraphy [68Ga-PSMA-PET-CT has overall better detection rates in prostate cancer patients compared to 18F-choline or 11C-choline PET-CT [Radiolabeled choline was until recently the most studied PET-CT tracers before PSMA became in Europe the predominant choice for molecular imaging of prostate cancer. Choline PET-CT imaging demonstrated its clinical value by showing a high accuracy for restaging patients with biochemical relapse after radical prostatectomy. Choline PET-CT imaging is based on detecting increased lipid biosynthesis and expression of choline in prostate cancer cells . Cholinetigraphy . The spetigraphy . Howevere PET-CT ,139,140.11C-acetate is a PET tracer that exploits the upregulation of fatty acid synthase in prostate cancer. Acetate is a naturally occurring substrate for fatty acid synthesis in acetyl-CoA form. Watt et al. [68Ga-PSMA-11 PET than 11C-acetate PET in detecting metastatic lesions [t et al.  have shot et al. . However lesions .11C-Glutamine and 18F-fluoroglutamine have shown potential for human use in cerebral gliomas [11C-Glutamine and 18F-FSPG (18F-(S)-4-(3-fluoropropyl)-L-glutamic acid) in four patients without toxicity or observed adverse events. Park et al. [18F-FSPG for PET imaging in 10 patients with newly diagnosed and 10 patients with recurrent prostate cancer demonstrating that 18F-FSPG is a promising tumor imaging agent for PET with high a detection rate and a favorable biodistribution. It has been suggested that targeting the glutamine metabolism might also be a potential treatment for numerous types of cancers, including prostate cancer [18F-fluorocyclobutane-1-carboxylic acid) which is a synthetic analog of the amino acid L-leucine transported into cells via amino acid transporters [18F-fluciclovine-PET for detecting biochemical recurrence in prostate cancer [Recent research suggests that alterations in and increased dependency on glutamine metabolisms might be an important hallmark of certain cancers . Glutami gliomas . Cohen e gliomas  demonstrk et al.  publishee cancer , but more cancer ,149,150.sporters . Howevere cancer .18F-NaF PET/CT has shown promise in detecting bone metastases and has been suggested to, e.g., have a role in the follow-up of therapy responses in bone predominant metastatic disease, but the obvious disadvantage is that its diagnostic power is limited to bone metastases only [18F-NaF PET/CT in clinical practice [18F-FDG-PET should be evaluated in some subtypes of prostate cancers and PSMA-low prostate tumors.ses only . Uptake practice . Some dipractice ,156. Curpractice  showed i68Ga-labeled bombesin  had high cancer-binding specificity and significantly higher uptake in prostate cancer than benign tissue. 68Ga-RM2 was also well-tolerated. 68Ga-RM2 was also promising in detecting biochemical recurrence [68Ga-PSMA-11 with 68Ga-RM2, no PSMA-negative patients showed RM2-accumulation [68Ga-PSMA-11 and 68Ga-RM2 identified the same cases of local recurrence, but 68Ga-RM2 scans were negative in some of the patients with PSMA-positive bone or lymph node metastases. 68Ga-RM2 scans did reveal some additional metastatic bone lesions but did not affect the line of treatment [177Lu-RM2 therapy was well tolerated in mCRPC patients with the pancreas being the critical organ [177Lu-radiopharmaceuticals simultaneously targeting PSMA and Bombesin (Lu-DOTA-iPSMA-Lys-BN) have been synthesized and shown to be taken up by human PC3 and LNCaP prostate cancer cells [Bombesin receptors  are G-protein coupled receptors that are highly overexpressed in several human tumors, such as prostate cancer, lung cancer , breast cancer, and renal cancer , in linecurrence . Howevercurrence . In a stmulation . Both 68reatment . Theranoal organ . Intereser cells . Dual ta68Ga-radiolabeled quinoline-based inhibitors of FAP (FAPI) [68Ga-FAPI has shown promise in detecting metastasis of various cancer types, including PSMA-negative prostate cancer metastases [68Ga-RM2 and 68Ga-FAPI in detecting PSMA-negative prostate cancer warrants further research.Cancer-associated fibroblasts (CAFs) are important non-mutated cellular components of the tumor microenvironment modulating angiogenesis, cancer metastasis, and therapy responses . CAFs exP (FAPI) ,170. 68Gtastases ,170. In 68Ga-PSMA-11 for this indication at the end of 2020. Future challenges with imaging approaches to optimize molecular therapies include uneven distribution and implementation of technologies, lack of proper validation, and inconsistent terminology in quantitative imaging biomarkers [Improved molecular imaging methods for prostate cancer have now emerged to guide treatment. First larger prospective clinical trials have been reported and support the use of PSMA-based PET imaging to detect prostate cancer metastases, resulting in FDA approval of omarkers . Tumor-s177Lu-PSMA-617 compared to the standard of care prove the efficacy of PSMA-targeting in metastatic prostate cancer and highlight the potential of PSMA as a target for molecular radiotherapy [Results of a recently reported randomized phase III trial of otherapy . A varieotherapy . CombiniDDR aberrations are associated with higher PSMA expression levels in prostate cancer . Poly (A177Lu-PSMA-617 for heavily pretreated mCRPC patients [ADT upregulates PSMA expression . The schpatients , but the