Since its licensing in 1971, the synthetic compound inosine pranobex has been effectively combating viral infections, including herpes zoster, varicella, measles, and infections caused by the herpes simplex virus, human papillomavirus, Epstein–Barr virus, cytomegalovirus, and respiratory viruses. With the emergence of SARS-CoV-2, new and existing drugs have been intensively evaluated for their potential as COVID-19 medication. Due to its potent immunomodulatory properties, inosine pranobex, an orally administered drug with pleiotropic effects, can, during early treatment, alter the course of the disease. We describe the action of inosine pranobex in the body and give an overview of existing evidence collected to support further efforts to study this drug in a rigorous clinical trial setup. Acute viral infections often have few, if any, treatment options apart from vaccination. The effort to create a sufficiently large portfolio of anti-viral drugs and treatments protocols is, therefore, as important as the effort to prevent individuals from contracting the virus. Although vaccination is the gold standard for preventing the spread of viral infections and their progression in those already infected, vaccinations have limitations. New virus variants can escape the vaccine, and hence a vaccine’s effectiveness can deteriorate over time. This risk is catalyzed by high viral incidence . NeverthUnfortunately, resistance to vaccination will remain in a certain percentage of the population ,4, and tThese rather general concerns proved applicable to the current unprecedented COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the outbreak in the late autumn of 2019, the pandemic has been imposing a tremendous global burden in terms of morbidity, mortality, and economic impact, and it is far from being successfully controlled ,6. COVIDAlong with the above-mentioned strategies, it is necessary also to evaluate the current guidelines and strategies to minimize the virus spread and ensure universal personal preventive and protective measures .The knowledge and understanding of the SARS-CoV-2 virus are evolving, in terms of its epidemiology, pathogenicity, and clinical manifestations, which ultimately map the strategic path, towards effective and safe treatment and production of reliable and potent vaccines .All aspects of SARS-CoV-2 virus and COVID-19 disease in adults and among children were already described in many publications ,15,16. CClinical manifestation among adults and the elderly is different from children clinical picture in terms of consequences. Eighty studies were included in the meta-analysis, including 61,742 patients with confirmed COVID-19 infection. The most common symptoms among COVID-19 infected patients were fever 87% and cough 68%. The laboratory analysis showed that thrombocytosis was present in 61%, CRP was elevated in 79%, and lymphopenia in 57.5%. The most common radiographic signs were bilateral involvement in 81%, consolidation in 73.5%, and ground-glass opacity in 73.5% of patients. Case fatality rate (CFR) in <15 year-olds was 0.6%, in >50 year-olds was 39.5%, and in all range groups it was 6% .Repurposing of existing anti-viral agents deserves attention since it may yield a fast and economical solution to both developed and undeveloped countries.Since 2020 there has been a substantial effort to repurpose anti-viral compounds with presumed anti-viral effects to treat COVID-19. Several review papers are available ,18,19,20Any successful control of a viral infection involves the complex interplay between diverse cell types associated with both innate and adaptive immunity. Natural killer (NK) cells are a type of innate lymphoid cell that plays an important role in the first line of immune defense against any viral infection, including COVID-19. They constitute the primary rapid, innate immune attack on virus-infected cells .Lymphopenia, a major immunological abnormality that in up to 96.1% occurs in severe COVID-19 patients, is strongly associated with mortality rate ,27. ZhenA small proportion of lymphocytes may express the main receptor for SARS-CoV-2, i.e., the angiotensin-converting enzyme 2 (ACE2). SARS-CoV-2 can also use ACE2-independent pathways to enter lymphocytes. Both SARS-CoV-2- and immune-mediated mechanisms may trigger lymphopenia by influencing lymphocyte production, survival, and tissue re-distribution. Metabolic and biochemical changes can also affect the production and survival of lymphocytes in COVID-19 patients. Lymphopenia can cause general immunosuppression and promote cytokine storms; both play important roles in viral persistence, viral replication, multi-organ failure, and death .In COVID-19 patients, the proportions of the NK- and CD8+ T cells expressing CD-107a, IFN-γ, and IL-2 are also reduced, confirming the exhaustion of cytotoxic lymphocytes . In one During the current pandemic of COVID-19, the health and safety of health care workers are of particular concern owing to their frequent exposure and high risks of infection. In March 2020, a clinical study on health care workers commenced in the Netherlands to examine the effects of stimulating innate immunity. Using a randomized controlled trial, the investigators aimed to stimulate innate immunity through Bacillus Calmette-Guérin vaccination to improve the clinical course of COVID-19 infections in health care workers and thereby reduce absenteeism, need for hospitalization and intensive care admission, and death rates during the current COVID-19 pandemic . Up to nThere are three typical complications of COVID-19. The most important is viral immunosuppression, which can cause sometimes leucopenia, but much more often it is lymphopenia which occurs in the majority of severe COVID-19 patients, and it is strongly associated with a high mortality rate. The second complication, which can also affect a significant number of patients is venous thromboembolism caused by viral replication in endothelium and by immunothrombosis . The lasAlthough antibiotics do not directly affect SARS-CoV-2, viral respiratory infections often result in bacterial pneumonia. Some patients may die from bacterial co-infection rather than the virus itself. Therefore, bacterial co-infection and secondary bacterial infection are considered critical risk factors for the severity and mortality rates of COVID-19 .All of these complications can be treated in the community at any general practitioner practice. Viral immunosuppression and its result lymphopenia can be treated by early applied immunomodulatory drugs, which can mitigate the effect of immunosuppression. The treatment of venous thromboembolism can start with acetylsalicylic acid or low–molecular-weight heparins . The secWhen a patient is hospitalized for COVID-19, also corticosteroids are in the focus of the treatment. Dexamethasone is the first known steroid medicine that can save the lives of seriously ill patients, and it is shown in a randomized clinical trial by the United Kingdom that it reduced the death rate in COVID-19 patients .https://pubmed.ncbi.nlm.nih.gov/ access date 15 August 2021), EBSCO (https://www.ebsco.com/ access date 15 August 2021), Scopus (https://www.scopus.com/ access date 15 August 2021), Cochrane Library (https://www.cochranelibrary.com/ access date 15 August 2021), WoS (https://www.webofscience.com/ access date 15 August 2021). The mesh words used during searching were: “inosine pranobex” or “isoprinosine” in combination with words “COVID-19” or “SARS-CoV-2” and “treatment” or “therapy” or “prevention” or “prophylaxis”. All retrieved studies are discussed in the present paper.The following databases were searched for clinical pharmacology and toxicology data: PubMed (Since 1971 the synthetic compound inosine pranobex (IP), also known as inosine acedoben dimepranol or methisoprinol, has been licensed under brand names such as Isoprinosine for the treatment of viral infections in several countries worldwide. It consists of a combination of the p-acetamidobenzoate salt of N, N-dimethylamino-2-propanol, and inosine in a 3:1 molar ratio. It is an orally administered drug with pleiotropic effects known for its in vitro and in vivo immunopotentiation. Various mechanisms of action have been reported on humoral as well as the cell-mediated immune response. IP has been shown to help restore depressed cell-mediated responses of diverse etiologies that accompany a variety of clinical conditions ,39,40,41A recent review paper provides a good overview of clinical trials conducted so far for the various indications such as treatment of HSV-1 and HSV-2, HPV, SSPV, Type B, and C viral hepatitis, Influenza and Rhinovirus infections, various immunodeficiency conditions, but also non-communicable diseases such as autoimmune diseases and chronic fatigue syndrome . There iAcute respiratory infections are globally the most frequent type of viral infection. Severe forms are responsible for approximately 3.9 million deaths per year and are one of the leading causes of morbidity and mortality worldwide . This nuBecause of the current COVID-19 pandemic, it is important to consider the results of a study using clinical subjects with laboratory-confirmed acute viral respiratory infections that were conducted to compare the efficacy and safety of IP and a placebo drug . In thisp = 0.324). A subgroup analysis in patients <50 years of age revealed a statistically shorter time to resolution of symptoms in those without related ongoing disease and those with BMI < 30 kg/m2. Safety was evaluated through analysis of adverse events, vital signs, and physical examinations. The study showed that IP is a generally safe drug for the treatment of patients with respiratory infections.In the study, 231 patients with influenza-like illness were treated with IP and compared with 232 patients receiving placebo in a clinical randomized, double-blind, multicenter study in the Czech Republic and Slovakia . The stuIP has been used due to its immunomodulatory and anti-viral properties for decades. Several mechanisms of action have been proposed. A review paper by Sliva et al. provides a comprehensive overview . Beyond Natural killer (NK) cells are effector cells of the innate immune system that control human infection in its early stage. They are a separate lymphocyte lineage, with cytotoxicity as well as cytokine-producing effector function ,76,77. TA clinical trial with 27 individuals followed the effect of IP administration (14 days) on multiple lymphocyte subsets–CD19 + B cells, CD3 + T cells, CD4 + T-helper cells, FoxP3hi/CD25hi/CD127lo regulatory T cells (Tregs), CD3 −/CD56 + NK cells, and CD3 +/CD56 + NKT cells, together with serum immunoglobulins and IgG subclasses. As early as within 1.5 h of receiving the drug, one-half of the cohort had a durable (>5 days) rise in NK cells. By the fifth day, all but one of the subjects had higher proportions of NK cells, and these elevations—effectively two-fold or higher—were maintained until the end of the study . The indActivated NK cells can recognize virus-infected cells and kill them using perforin and granzymes. Thus, from the beginning, natural immunity is significantly involved in the destruction of infected cells and fundamentally affects the prognosis of viral infections. NK cells are capable of eliminating virus-infected cells rapidly and directly, without antigen presentation or recognition. Stimulated by infections, cytokines, stress, or other cells of the immune system, NK cells release perforin and granzyme that kills infected cells . NK cellIP is a potent medication for treating or preventing viral infections under various conditions, including patients who are elderly but otherwise healthy. This is particularly important since, in these populations, NK performance is known to be compromised, and insufficient performance may be a key contributor to high rates of viral infections associated with immunosenescence ,87. ActiAnother proposed pharmacodynamic activity is based on the ability of IP to alter cellular immunity through the induction of NKG2D ligand expression on target cells, thereby enhancing immune cell activation through the NKG2D receptor. This mechanism seems to be additive to the above-described NK activation since it acts inside infected cells and makes them more visible to T lymphocytes. Using both targeted metabolic interventions and unbiased metabolomic studies, it was demonstrated that IP causes an increase in the intracellular concentrations of purine nucleotides and tricarboxylic acid (TCA) cycle intermediates and leads to NKG2D ligand induction. The degree of NKG2D ligand induction was functionally significant, leading to increased NKG2D-dependent target cell immunogenicity. These findings demonstrate that the immunomodulatory properties of IP are also due to metabolic activation with NKG2D ligand induction .In addition to venous thromboembolic disease or immunothrombosis and secondary pneumonia, the underlying problem of COVID-19 is initial immunosuppression caused by the virus. This manifests as selective lymphopenia, which, however, can be prevented by the use of IP. Due to the above-mentioned decrease of immune system activities by the SARS-CoV-2 virus, IP can not only prevent viral immunosuppression but also restore the immune system to its original state rather quickly.The results of these two studies indicate that IP can boost the levels of phenotypically competent NK cells in healthy individuals during conditions associated with acute viral respiratory infections, and it can be used to improve potentially compromised immune functions ,88.IP is not a causal drug but a drug that can help overcome the initial key complications of COVID-19 infections and can thus substantially alter the course of the disease.http://www.ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=46240&EncHid=&modid=&compid=%27,%2746240det%27 access date 4 November 2021). In this study sub-group analysis of patients showed that inosine pranobex, when added to standard of care containing (CSC) Azithromycin and Hydroxychloroquine with or without Ivermectin, produced significantly higher clinical response (CR) at Day-14 than the only standard of care . Overall, there was a trend of  higher CR, at Day 7, 14 and 21 in the IP + CSC group compared to the CSC group; however, statistical significance was not be reached. This may be because of the small sample size of the study variability in the current standard of care among the different sites. IP was well tolerated. The first study was followed by a phase 3, double-blind, placebo-controlled randomized trial studying the effects of adding IP to the standard of care in COVID-19 patients . So far, no randomized controlled clinical trial to study IP in patients with COVID-19 has been published.There have been two ongoing multicenter randomized clinical trials with IP in patients with moderate COVID-19 in India since the summer of 2020. The first was an open-label proof of concept study with 60 patients. It focused on the effect of IP in COVID-19 patients when used along with the standard of care vs. the standard of care. The study was registered on 14 August 2020  patients was made based on the above described previously published study indicating that IP could be effective and safe in treating acute viral respiratory infections .The most recent study from 2020 was conducted as a retrospective analysis of treatment without protocols, which reduces its scientific value; however, it still created an opportunity to study the real-world effects of IP in COVID-19 patients . The retThe study reported a notable difference in the COVID-19 case fatality rate between those treated with IP (12%) and those without IP treatment (28.6%). These figures were obtained from a rather heterogeneous set of patients and could hence be affected by a confounding effect, such as the underlying health condition or age, to some degree. In perhaps the most comparable set of patient data from only one of the homes , the case fatality rate observed among those treated with IP (NIP+ PCR+ = 19) compared with those untreated (NIP− PCR+ = 14) was 5.3% versus 28.6%, respectively. This study suggests that further clinical studies should be conducted to provide evidence of IP’s efficacy in COVID-19 patients.A randomized controlled study took place in Ecuador between March and April 2020 . In totaIP has long been known for its beneficial effect in the treatment of many viral infections, including influenza and other influenza-like states. There are plausible immunomodulatory mechanisms for its actions, which promise broad therapeutic effects across a variety of viral pathogen variants. IP alone will most likely not lead to a full recovery, but early immunomodulatory intervention could alter the course of the disease.Clinical and immunological studies and analyses conducted over the past six years have demonstrated the effect of IP, via natural killer cells and cytotoxicity, for treating the majority of investigated viral infections; this efficiency will hopefully be transferrable to the currently spreading acute viral respiratory infection COVID-19.It seems that early application of IP can mitigate initial viral immunosuppression and initial lymphopenia, which are strongly associated with COVID-19 progression, hospitalization, and mortality. We can conclude that to date limited clinical evidence supporting IP efficacy exists, but a retrospective study, as well as a small local study from Ecuador, or India have provided a distinct signal that IP could be beneficial in the treatment of COVID-19 patients.Since this drug was in use in the Czech Republic and potentially elsewhere, ananalysis of the health reimbursement data in those treated with IP combined with their subsequent health care utilization and mortality data could provide valuable insight into the real-world effectiveness of IP in COVID-19 patients and thus complement ongoing clinical studies.


Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance. ALK) gene creates potent oncogenic drivers in patients with non-small cell lung cancer (NSCLC) occurring in approximately 3-7% of all cases. The most common fusion partner is EML4 (echinoderm microtubule associated protein like 4)  . In addiistology . Tyrosinistology Table 1.de novo lack of treatment response and can be seen after treatment with a TKI  and its physiological receptor tyrosine kinase MET is associated with acquired resistance to various TKIs. reatment . Gab1 isreatment .in vitro and in vivo, accompanied by inactivation of the transcription-assisted regulator YAP. Cerivastatin can significantly induce YAP-targeted oncogenes  in drug-resistant cells, providing a theoretical basis using YAP as a potential therapeutic option in patients with acquired drug-resistant ALK-TKI  gene, also known as the ATP binding box subfamily B member 1(ABCB1) (P-glycoproteins (P-gp) are highly conserved ATP-dependent effluents encoded by the multidrug resistance 1(1(ABCB1) . The cen1(ABCB1) . In cont1(ABCB1) , 81.RB) genes is important for SCLC transformation, although the transformation mechanism is not fully understood  or squamous cell carcinoma (SCC) after targeted therapy against ALK-positive adenocarcinoma –86. Delederstood . Mutatioormation . In addiormation .In addition to the conversion of adenocarcinoma to SCC or SCLC, Koyama K. et al. reported a rare case of ALK-positive adenocarcinoma that converted to NSCLC with neuroendocrine differentiation. Histopathological examination of the tumor following alectinib resistance revealed a poorly differentiated carcinoma with insulinoma associated protein 1 (INSM1) expression. The expressions of CD133, Bcl-2, and SOX2 were positive when compared with the initial tumor. SOX2 expression was significantly increased compared to that before treatment. Immunohistochemical results of these markers associated with tumor stem-like cells and neuroendocrine differentiation suggest that tumor stem cells play a role in the histological transformation and acquired resistance mechanisms of ALK-reposition-positive tumors . HER2 plALK mutants L1196M and EMT were simultaneously detected in a patient with crizotinib resistance. ALK L1196M primarily existed within the epithelial tumor cells, suggesting that EMT and ALK mutations co-exist as independent mechanisms of drug resistance. EMT was associated with decreased expression of miR-200c and increased expression of ZEB1, leading to cross-resistance of the new generation of ALKi. The histone deacetylase (HDAC) inhibitor overcomes this resistance by reversing EMT in vitro and in vivo, suggesting that adding a new ALKi after pretreatment with an HDAC inhibitor may help overcome the co-occurrence of ALK resistance mutations and EMT  is a morphological change in which epithelial cells lose their polarity and intercellular connections becoming more mobile and invasive. Through EMT, tumor cells acquire mesenchymal morphology and the ability to migrate and invade. There are four pathways associated with EMT: proteoglycan in cancer, HIF-1 signaling, FoxO signaling, and extracellular matrix receptor interactions, related to the drug resistance mechanisms of crizotinib   on 42 crizotinib-resistant NSCLC patients. Two patients were found to have acquired mutations in the DNA mismatch repair gene izotinib . Lai, Y.sistance .The expression of the ATP-binding domain C-member 11 (ABCC11) in alectinib-resistant cell lines was significantly higher than that in alectinib-sensitive cell lines. This indicated that ABCC11 expression may be involved in the acquired drug resistance of alectinib . In addiProgression of ALK-TKI within 3 months is considered primary resistance. In theory, any of these mechanisms of acquired resistance that existed before the use of TKI could also lead to primary resistance .EML4-ALK rearrangement may also be a mechanism of primary resistance to crizotinib (BIM is a Bcl-2 (B lymphocytoma-2) -like protein 11 that activates programmed cell death in cells. The study found that patients with BIM with missing polymorphisms had shortened PFS and reduced objective response rate, which was an independent predictor of patients treated with crizotinib and was related to primary drug resistance . In addiizotinib .MYC amplification was a potentially new mechanism of primary ALK-TKI, resistance and proposed as a potential MYC-oriented inhibition strategy to overcome primary resistance of advanced ALK-rearrangement NSCLC  , 104. ALreported , 106.in vitro IC50 values for all available ALK TKIs regarding the different mutations. The findings illustrate that lorlatinib has the broadest activity against the G1202R mutation , variant 2 , variant 3 , variant 4 , and variant 5 . The two EML4-ALK variants that together account for up to 70-80% of all EML4-ALK variants are v1 and EML4-ALK v3a/b . In particular, the ALK G1202R mutation was more common in variant 3 than in variant 1 . Among the patients treated with the third-generation ALK TKI lorlatinib, variant 3 was associated with a significantly longer progression-free survival than variant 1   , 119. ThInterestingly, more patients are using second-generation TKIs. However, in this final J-ALEX OS analysis, prolongation of OS in the alectinib arm was not observed compared to the crizotinib arm. This indicates that longer PFS does not translate into longer OS, which gives clinicians something to think about when using ALKi’s. Therefore, there is much debate about whether PFS can be converted to OS, due to the following reasons. First, after the PFS benefit, disease progression may be faster than in the control group . Second,To expand PFS and OS, it is crucial to think about evidence-based treatment sequencing. Every ALK TKI has its own advantages and disadvantages . TherefoALK mutations or amplification. Therefore, the next generation of ALK-TKIs becomes sensitive to some mutations. However, nearly 40% of patients with second-generation TKI resistance are no longer dependent on ALK, so treatment opportunities for these patients are limited. Third-generation ALK-TKI or pemetrexed-based chemotherapy may be beneficial making loratinib more effective in patients with ALK kinase domain point mutation than those without ALK re-mutation  often occurs in ALK-positive NSCLC. EGFR bypass activation is known to be the drug resistance mechanism against ALK-TKI therapy. EGFR-TKI tant LMC . In addi cancers . Furtherutations , 140.ALK-dependent and non-dependent, the specific mechanisms have not been clarified, so there is urgency in developing strategies to overcome or prevent drug resistance. With a growing understanding of the mechanisms of drug resistance, a new generation of ALKi is expected to be more effective in overcoming and suppressing drug resistance. After drug resistance, it is recommended to biopsy again to identify the mutation site. Moreover, variants should also be of concern. In addition, combination therapy is also an option. However, there may be potential problems of increased toxicity or emergence of new toxicities, so these combinatorial treatment regimens still need to be explored. Furthermore, there is much debate about whether PFS can be converted to OS. In targeted therapy, it depends on the PFS1, 2, and 3. In patients with ALK fusion, the first generation may be followed by second generation therapy, or the second generation is followed by another second generation therapeutic. In short, these new approaches are promising at more effectively overcoming and suppressing drug resistance, translating into more profound and more prolonged responses in patients with ALK-driven cancers.Despite the significant efficacy of ALKi in ALK-positive NSCLC patients, drug resistance is inevitable in some patients. Although the mechanism of drug resistance can be divided into YP participated in the analysis, data interpretation, and wrote the manuscript. CD and ZQ polish the language and search the literature. CC analyzed the data and drew diagrams. FW designed the article ideas analyzed the data. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The coronavirus disease 2019 (COVID-19) pandemic brought about an unprecedented time. Multiple systemic complications have been recognized with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as it can do much more than affect the respiratory system. One of the intriguing neurological complications is Guillain-Barre syndrome (GBS). We reviewed three cases in which patients presented with GBS following COVID-19 infection. All three cases had positive lumbar puncture results with albumino-cytological dissociation. Each patient was treated with plasmapheresis and improved clinically. Although an exact causal relationship between COVID-19 and GBS cannot be drawn from this case series alone, it signifies the importance of this complication. It warrants further studies to establish the causal relationship. One should have a high suspicion for acute inflammatory demyelinating polyneuropathy (AIDP) in patients presenting with acute onset of ascending weakness following COVID-19 infection.  Since the pandemic began, much has been discovered about the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although primarily affecting the respiratory system, coronavirus disease 2019 (COVID-19) has been shown to cause several neurological complications and symptoms, including stroke, dizziness, headache, encephalopathy, hypogeusia, and hyposmia [In two-thirds of cases, Guillain-Barre syndrome (GBS) is an autoimmune inflammatory disease affecting the nerve roots and peripheral nerves, preceded by a recent infection . There hHerein we present three patients at a community hospital who presented with signs and symptoms consistent with GBS following COVID-19 infection.Patient 1A 55-year-old male with acute onset of bilateral hand and feet numbness and tingling sensations presented to the hospital. The patient stated he had new-onset difficulty with walking and fear of falling. His symptoms had started about two weeks back and progressed. Initially, it was paresthesia and then gradually developed weakness. He states his weakness was in both feet and then in the entire lower extremities. The patient has poorly controlled diabetes mellitus type 2 (hemoglobin A1C - 11.2%). On initial examination, the patient also had overlapping features of peripheral neuropathy, noted to have impaired crude touch, vibratory sense, proprioception, and pinprick sensation to bilateral feet. The patient was taking gabapentin at the time of presentation. His initial presentation was attributed to peripheral neuropathy secondary to diabetes mellitus, and he was discharged with a plan to follow up as an outpatient for further management. The patient had no symptoms suggesting COVID-19 infection. After a week, he was readmitted with a worsening bilateral lower extremity weakness and multiple falls. The patient's family -- wife and son had COVID-19 four weeks before admission. He admitted to intermittent subjective fevers over the past few weeks but was never tested for COVID-19. The patient was admitted with worsening bilateral lower extremity weakness and frequent falls. On examination, the patient had bilateral lower extremity weakness with distal weakness more significant than proximal weakness, absent deep tendon reflexes, and decreased lateral spinothalamic and proprioception sensory loss in bilateral lower extremities. MRI cervical and lumbar spine showed degenerative disc disease and neural foraminal narrowing at multiple levels; there were no spinal cord signal abnormalities and no other acute pathology to explain the patient's symptoms.Electromyography and nerve conduction studies showed severe motor neuropathy, predominantly axonal, with features of demyelinating neuropathy. These features were concerning for a variant of GBS-AMSAN . The cerebrospinal fluid (CSF) analysis showed elevated protein at 103 mg/dL with no cells. The patient's nerve conduction studies (NCS) were suggestive of AMSAN, and CSF findings were consistent with albumino-cytological dissociation; the patient was started on plasmapheresis. Anti-ganglioside antibody testing was negative. The patient received four sessions of plasmapheresis, and strength in bilateral lower extremities improved significantly. He was discharged home and subsequently seen in the Neurology clinic. He showed continued improvement in his motor strength in both lower extremities and could walk without support. Patient 2 A 67-year-old male presented to the hospital with generalized weakness and falls. The patient had been to a family gathering on “Thanksgiving,” and several of those family members tested positive for COVID-19 the next day. Three days later, the patient experienced a high fever with a maximum of 102 degrees Fahrenheit, headache, muscle aches, and generalized weakness. He opted not to get tested for COVID-19. Five to six days later, he started noticing bilateral lower extremity weakness and fell to the extent that he needed to borrow his girlfriend's walker to ambulate. On examination, the patient had a generalized weakness, worse in bilateral lower extremities, and absent deep tendon reflexes throughout. His weakness was more significant in distal lower extremities than in proximal lower extremities. On the second day of admission, the patient complained of difficulty swallowing and perioral numbness. He was subsequently transferred to the intensive care unit (ICU) for close monitoring of his respiratory status. The patient did not consent for electromyography (EMG)/NCS and lumbar puncture for CSF analysis. The patient was started on plasmapheresis due to great clinical concern for GBS. The patient agreed to have a lumbar puncture after a session of plasmapheresis. The CSF results showed elevated protein at 415 mg/dL with no cells. A total of five sessions of plasma exchange was completed, and his weakness improved. After a significant improvement in his strength, the patient was discharged from the hospital. Patient 3A 46-year-old female presented to the hospital with a chief complaint of subjective feeling of left-sided weakness. Her weakness was gradual in onset and progression. It had started about three to four days back and was progressive, which brought her to the emergency room (ER). The patient was diagnosed with COVID-19 two months before the onset of weakness, and she was asymptomatic. She had no other significant comorbidities. On examination, the patient was noted to have weakness in all four extremities, and lower extremities were more affected than upper extremities. The MRI of the brain and cervical spine did not show any acute pathology. The CSF analysis revealed elevated protein at 111 mg/dL with no cells, raising the concern for GBS. Plasmapheresis was done two days after hospitalization due to initial suspicion of stroke due to left side weakness and further work up-MRI of the brain was done to rule out stroke and CSF analysis was done for diagnosis of GBS. The patient underwent five sessions, and the patient's weakness improved.Much has been learned about the SARS-CoV-2 virus since the pandemic first began. Several neurological complications have been reported, studied, and thought to occur via two different pathways. The first proposed mechanism, hematogenous  or trans-neuronal route  of dissemination, causes complications such as hyposmia and hypogeusia in COVID-19 patients. The second proposed mechanism is an abnormal immune-mediated response induced by a cytokine storm that can lead to severe neurological complications such as GBS, encephalomyelitis, and encephalitis [The SARS-CoV-2 invades epithelial cells by binding with angiotensin-converting enzyme (ACE-2) receptors, localized inflammation, endothelial activation, tissue damage, and dysregulated cytokine release . CytokinAlthough primarily a clinical diagnosis, a high index of suspicion for GBS is necessary. Further confirmatory testing of lumbar puncture, electrodiagnostic studies, and antibody testing is essential. It is typical in GBS to have albumino-cytological dissociation in which there is elevated protein with normal cell count . ElectroGangliosides are found on the myelin of the peripheral nerves. In GBS, an immune-mediated response can be triggered that results in antibodies against the gangliosides . These aTreatment of GBS typically consists of immunomodulatory therapy with intravenous immune globulin (IVIG) or plasma exchange (PE) and supportive treatment. Both IVIG and PE are equally efficacious in aiding in recovery. The decision between these two options is dependent on individual circumstances such as cost and availability . During A study conducted in Northern Italy showed a significantly higher number of GBS patients during the COVID-19 outbreak and a high frequency of GBS patients with COVID-19, thus highlighting the possible role of SARS-CoV-2 in triggering GBS .There are certain limitations associated with Case 1. Firstly, he did not get tested for COVID-19; therefore, we cannot definitively state that he had the virus. However, given his high fever and close contact with individuals known to be infected, it is highly likely that the patient had COVID-19. Secondly, evaluation for weakness is compounded by his lumbar and cervical radiculopathy, which might have also contributed to his bilateral leg weakness. Moreover, his diminished deep tendon reflexes (DTRs) could also be an exam finding from his uncontrolled diabetic peripheral neuropathy and lumbar radiculopathy. However, lumbar puncture and EMG results support GBS diagnosis and could not be explained by the lumbar/cervical radiculopathy or peripheral neuropathy. Case 2 is also limited because the patient did not receive formal testing for COVID-19. Then again, as in Case 1, his clinical symptoms and close contact with the infected family raise high suspicion that he had the infection. This patient had a very classic case of GBS with the rapid onset of ascending weakness, including the development of respiratory distress, albumino-cytological dissociation in CSF studies, and rapid improvement following plasmapheresis. Case 3 initial presentation was not as typical for GBS as the other two cases. Her weakness was diffuse, and any acute onset of weakness was masked because she was pretty deconditioned following several months of unrelated illness and multiple hospital admissions before our evaluation. However, the CSF studies and improvement in weakness following plasmapheresis highly support the diagnosis of GBS. Anti-ganglioside antibody testing was negative in Case 1. Due to high clinical suspicion and CSF findings -- albumino-cytological dissociation, in cases 2 and 3, we did not do anti-ganglioside antibody testing. Though there were case reports of patients with COVID-19 and GBS, we found one reported case with positive GM1 ganglioside and COVID-19 in the literature, and the rest of them were either not tested or not positive for GM1. The pathophysiology of COVID-19 related GBS and MFS may be significantly different from cases in the pre-pandemic era though the clinical presentation is similar .Interestingly, a UK-based cohort study revealed no significant relationship between GBS and COVID-19 infection. No differences were seen in clinical and neurophysiological characteristics, the severity of GBS between COVID-19 and non-COVID-19 subjects. According to this study, no scientific data support the molecular mimicry association between SARS-CoV-2 to GBS at nucleic acid level . Although the strength of the relationship between COVID-19 and GBS is uncertain, with a mere association that cannot amount to etiology, these case studies presented here indicate that GBS can be a neurological complication following infection with the COVID-19 virus. All three cases were preceded by COVID-19 infection confirmed by electrodiagnostic evidence of demyelinating and axonal neuropathy, CSF with albumino-cytological dissociation, and clinical improvement following plasmapheresis. This case series suggests that differential diagnosis should include GBS if a patient presents with acute onset of weakness following COVID-19 infection. The observed alterations in the SARS-CoV-2 Delta variant due to variations in spike protein resulted in a novel Omicron variant; the transmission rate of the omicron variant is exponential . The ongCOVID-19 is a relatively new disease, its entire spectrum is unknown, and the virus, despite immunizations, is rapidly evolving. Therefore, in GBS cases in which no preceding infection or root cause is identified, it would also be prudent to perform COVID-19 polymerase chain reaction (PCR), COVID-19 antibody testing, and detailed clinical history. Additional research involving larger population studies needs to be conducted to determine the exact relationship between COVID-19 and GBS.


Background: The purpose of this study is to describe a single institution’s experience using Oncozene (OZ) microspheres for transarterial chemoembolization (OZ-TACE) of hepatocellular carcinoma (HCC), and to compare tolerability, safety, short-term radiographic tumor response, progression-free survival (PFS), and overall survival (OS) of these procedures to TACE (LC-TACE) performed with LC beads (LC). Methods: A retrospective, matched cohort study of patients undergoing DEB-TACE  with OZ or LC was performed. The cohort comprised 23 patients undergoing 29 TACE with 75 or 100 μm OZ and 24 patients undergoing 29 TACE with 100–300 μm LC. Outcome measures were changes in liver function tests, complications, treatment tolerability, short-term radiographic tumor response according to modified RECIST criteria for HCC, PFS, and 1-year OS. The Mann–Whitney U test, Fisher exact test, and log rank test were used to compare the groups. Results: The BCLC or Child–Pugh scores were similar between the OZ and LC group. However, the two groups differed with respect to the etiology of background cirrhosis (p = 0.02). All other initial demographic and tumor characteristics were similar between the two groups. OZ-TACE used less doxorubicin per treatment compared to LC-TACE . Rates of pain, nausea, and postembolization syndrome were similar, irrespective of the embolic agent used. OZ-TACE resulted in an overall complication rate comparable to LC-TACE . LC-TACE resulted in a higher percent increase in total bilirubin on post-procedure day 1 , but this difference resolved at 1 month. Both OZ-TACE and LC-TACE resulted in similar complete (31% vs. 24%) and objective (66% vs. 79%) target lesion response rates on 1-month post-TACE imaging. Both OZ-TACE and LC-TACE had similar median progression-free survival  and 1-year overall survival rates . Conclusion: With a significantly reduced dose of doxorubicin, TACE performed with Oncozene microspheres in a heterogeneous patient population is well-tolerated, safe, and produces a similar radiological response and survival rate when compared to LC Bead TACE. Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second most common cause of death from cancer worldwide . HCC-relOncozene microspheres  are among the most recent commercially available DEBs. Theoretical advantages include the availability in small diameters , which could allow for more distal occlusion and denser packing in intratumoral vessels, maximizing local delivery of the chemotherapeutic while sparing normal liver parenchyma . In vitrDespite these theoretical benefits, the clinical use of Oncozene microspheres described in the literature is limited ,10,11,12This single-center study was approved by the Institutional Review Board at our hospital (IRB#21-000278) and is compliant with the Health Insurance Portability and Accountability Act, with waiver of informed consent. A retrospective, matched cohort analysis was conducted on 29 OZ-TACE for 23 patients and 29 LC-TACE for 24 patients. TACE procedures performed with LC beads were selected as a matched cohort with respect to patient age and tumor characteristics. All patients had biopsy-proven HCC or Liver Imaging Reporting and Data System (LI-RADS) 5 liver masses. Patients were considered to be eligible for TACE if they were not candidates for percutaneous or surgical ablative therapies, had well-compensated cirrhosis with a Child–Pugh score up to B, and had a patent main portal vein.Catheter access to the hepatic vasculature was obtained in a standard fashion. Superselective catheterization of feeding vessels was performed with a coaxial microcatheter system. After distal positioning of the microcatheter, the DEB agent was delivered. The delivered Oncozene microspheres were 75 μm in size (except in 5 procedures with 100 μm). All procedures with LC Bead used 100–300 μm beads. Doxorubicin was the chemotherapeutic agent in all procedures. Embolic preparations were administered until near-stasis and absence of tumoral enhancement on angiography. Real-time fluoroscopy was utilized to minimize the reflux into nontarget vessels. All procedures were performed by interventionalists with 10–25 years of experience. Following the procedure, patients were admitted for overnight observation. Patients were discharged the next day in the absence of serious adverse events and control of pain and nausea with oral medications. Data were collected regarding narcotic use during the postprocedural hospitalization, and a standardized opioid equivalency table was used to account for differences in potency and routes of administration . Liver fComplications were noted in accordance with the quality improvement guidelines published by the Society of Interventional Radiology . Major cImaging with either contrast-enhanced multiphasic computed tomography or magnetic resonance imaging with Eovist was obtained within 1 month prior and after TACE. Serial images assessing progression were subsequently obtained at regular intervals as determined by the managing interventional radiologist and/or oncologist. Objective tumor response was evaluated using the modified Response Evaluation Criteria in Solid Tumors (mRECIST) assessment for HCC ,17,18. Tp < 0.05 was considered to be statistically significant.Significant differences between groups were analyzed with the Mann–Whitney U test and Fisher exact test, where appropriate. Kaplan–Meier analysis using the log-rank test was performed to assess survival differences. All statistical analyses were performed using SPSS Statistics 15 . A Our cohort consisted of 23 patients  who underwent 29 OZ-TACE and 24 patients  who underwent 29 LC-TACE. The mean age of the entire cohort was 67 years. The baseline clinical characteristics are summarized in p = 0.02). Patients who had OZ-TACE had higher albumin levels  and lower INR  at baseline compared to patients with LC-TACE. The range of doses prepared per treatment for both OZ-TACE and LC-TACE were similar at 75–100 mg. However, significantly less doxorubicin was delivered per treatment when Oncozene microspheres were used .The etiology of cirrhosis differed between the two groups, where patients who underwent OZ-TACE had a higher rate of nonalcoholic steatohepatitis and patients who had LC-TACE had a higher rate of hepatitis C and alcoholic cirrhosis , nausea , or postembolization syndrome  was also similar between the two groups (p = 0.10). During the postprocedural hospitalization, the observed rates of transient fever were not significantly different between the OZ-TACE and LC-TACE groups . All other changes in laboratory values were mild, transient, and were similar between the two groups , according to the Society of Interventional Radiology classification system. Complications in the Oncozene group were considered to be major: three patients required readmission or prolonged hospitalization for pain and nausea; two patients required readmission for fever and leukocytosis without an identified source of infection, which resolved with antibiotics; and one patient developed ischemic cholecystitis, requiring cholecystostomy tube placement. Of the three complications in the LC Bead group, two were major and one was minor: two patients required prolonged hospitalization for pain and nausea; and one patient was evaluated in the emergency department for pain and nausea, but did not require admission.There were six complications (21%) in the OZ-TACE group and three complications (10%) in the LC-TACE group . The 1-year overall survival rates were also similar (85% vs. 76%)  and objective (66% vs. 79%) target lesion response rates on imaging 1 month after TACE (The present study demonstrates that the choice between Oncozene microspheres and LC Bead during TACE did not significantly impact the complication rates or treatment tolerability. When the short-term radiographic response was assessed, the two groups demonstrated comparable rates of complete and objective target lesion response.Although the distribution of cirrhosis etiology differed between the two groups, we would not expect this to affect our outcomes of safety, tolerability, and short-term radiographic response. Furthermore, Trevisani et al. demonstrated that the etiology of cirrhosis did not impact the survival of patients with HCC, with factors such as oncologic features and treatment found to be more important . The difIn our series, the choice of DEB did not impact the short-term radiographic response, progression-free survival, or overall survival. We hypothesized that Oncozene microspheres would perform better than 100–300 μm LC Bead on the basis of a few studies. First, Lee et al. demonstrated that upon histopathologic analysis of a rabbit tumor model, 100–300 μm particles were distributed intratumorally and at the periphery, while 300–500 μm particles were mainly distributed at the tumor periphery and within the hepatic artery at a distance from the tumor . The cli2, which is a significant consideration for patients with HCC, who often require multiple TACE procedures for disease control and bridging to transplant [Although Oncozene microspheres and LC Bead appeared to impact tumor radiographic response similarly in our study, it is worth noting that less doxorubicin was used per treatment when Oncozene microspheres were used. Of note, the average amount of doxorubicin prepared for each treatment was similar in both groups. This is likely due to in vivo pharmacokinetic data demonstrating a longer release time of chemotherapeutic and greater area under the concentration–time curve with Oncozene microspheres as compared to LC Bead . Future ansplant .The literature describing the use of Oncozene microspheres for HCC is limited, but our findings are consistent with those of previous studies. In comparison to our study, previous reports consisted of single cohort designs, and examined smaller particle sizes with higher doses of doxorubicin. Malagari et al. prospectively studied a group of 52 patients treated with 40/75/100 μm particles, depending on tumor size, loaded with either 100 or 150 mg of doxorubicin . AccordiLimitations of this study are due to the small number of patients and retrospective design, which affects the interpretability of the survival data as stated above. There is expected risk of misclassification bias due to its retrospective nature. However, this was minimized as the data collection process was primarily performed by two investigators. Another limitation due to the retrospective nature of the study is that follow-up echocardiograms were not obtained to assess for anthracycline-related toxicity. As for the medication usage, although an attempt was made to quantify the amount of narcotics used by each patient, we cannot account for narcotics used by a patient after discharge. Many patients in this study received treatment for HCC prior to undergoing OZ-TACE or LC-TACE. These treatments could potentially affect hepatic arterial integrity and affect tumor vascularity, although this is difficult to quantify and control for. Future directions may include a prospective, comparison study to focus on a mid-term and long-term clinical, complications and safety outcomes, including post-embolization syndromes, true narcotic usage in both in-patient and out-patient settings, tumor response with and without other treatments, and potential combinational use of transarterial chemoembolization with and without systemic treatment. As clinical experience with OZ-TACE grows, outcomes among larger patient cohorts may also be assessed with more rigorous analysis, such as propensity score matching. It would also be interesting to see if clinical or radiographic outcomes varied with Oncozene microsphere size, as almost all the patients in the OZ-TACE cohort were treated with 75 μm particles.In conclusion, the results of this study suggest that with significantly reduced doses of doxorubicin, TACE performed with Oncozene microspheres in a heterogeneous patient population is well-tolerated, safe, and produces a similar radiographic response and survival rate when compared to TACE performed with LC Bead.


Solar elastosis is associated with a diffuse yellow hue of the skin. Photoaging is related to lipid peroxidation leading to the formation of carbonyl groups. Protein carbonylation can occur by addition of reactive aldehydes, such as malondialdehyde (MDA), 4-hydroxy-nonenal (4-HNE), and acrolein. All the proteins concerned with this modification, and the biological consequences of adduct formation, are not completely identified. The link between yellowish skin and dermal carbonylated proteins induced by aldehyde adducts was investigated. The study was carried out on ex vivo skin samples from sun-exposed or sun-protected areas and on in vitro dermal equivalent models incubated with 5 mM MDA, 4-HNE, or acrolein. The yellow color and the level of MDA, 4-HNE, and acrolein adducts were evaluated. Yellowish color differences were detected in the dermis of sun-exposed skin compared to sun-protected skin and in in vitro models following addition of MDA, 4-HNE, or acrolein. The yellowing was correlated with the carbonyl adducts increasing in the dermis and in in vitro models incubated with aldehydes. The stronger yellowing seemed to be mediated more by MDA than 4-HNE and acrolein. These observations suggest that dermal carbonylation especially induced by MDA result in the yellow hue of dermis and is involved, in part, in the yellowing observed during skin photoaging. Skin photoaging is an accelerated aging mechanism that results from exposure to ultraviolet (UV) radiation leading to hypertrophic skin, deep wrinkles, loss of skin elasticity, a leathery skin, and a yellow discoloration . This skIn this study, we aim to understand the role of MDA in skin yellowing occurring with photoaging by analyzing the dermis of sun-exposed skin and sun-protected skin, through colorimetric parameters, protein carbonyl detection, and by testing in vitro the effect of MDA in dermis skin yellowing.n = 6, age range 53 to 68 years old). Sun-exposed skin samples were obtained from face-lift (cheek) surgery tissue .Twenty-three skin samples from adult women with Caucasian skin type (phototype I–III) were collected. Skin explants, collected from healthy subjects undergoing reconstructive or aesthetical surgery, were obtained from Icelltis  and Alphenyx  under the authorizations delivered by the French Ministry of Research with the approval of the French Ethical Committee. Written informed consent was obtained from all donors. Sun-protected skin samples were obtained from breast surgery tissue  and fibroblasts, as previously described . After dHuman skin samples were fixed in neutral formalin then embedded in paraffin. We stained 5 µm paraffin sections with orcein for elastic fiber detection and with sirius red for collagen fiber visualization. Using Histolab software , the percentage of dermal elastin (including elastotic tissue) and collagen surface were quantified.TM Gold mounting medium with Dapi . Immunostainings were analyzed with a Leica microscope coupled with a camera Retiga 2000R . Histolab software  was used for quantitative image evaluation. The level of labeled protein expression was quantified in the dermis as fluorescent integrated emission (surface * intensity). Results were expressed as percentages of areas of the measured dermis.Immunofluorescence was performed on 5 µm thick paraffin sections using specific antibodies: rabbit anti-human MDA , rabbit anti-human 4-HNE , and mouse anti-human acrolein clone 5F6 . Briefly, after a heat-mediated antigen retrieval step, using citrate buffer pH 6, samples were blocked using 10% goat serum  for 30 min at room temperature. Then, sections were incubated with the primary antibody’s solutions at 1:200 overnight at 4 °C. Primary antibodies were detected by a goat anti-mouse  or a goat anti-rabbit  conjugated to Alexa fluor 488 at 1:500. Stained tissue sections were mounted using the ProlongColor was measured by a spectro-colorimeter  to obtain the color coordinates L*, a*, b* which characterize colors: lightness L* derives from the luminance of the surface and the two parameters a* and b* express the difference in color compared to a gray surface of the same lightness. For the ex vivo human skin sample, the individual typology angle (ITA) reflecting the skin color for each skin sample was calculated based on these spectrophotometric measurements. ITA allowed us to classify skin type color and to select skin samples with a similar skin type A 11]. T. T11]. TAfter dermal-epidermal separation, the overall content of carbonyl proteins (Oxi-Proteome) in the dermal protein extracts was obtained from ex vivo sun-protected versus sun-exposed aged samples. These analyses and quantification were performed by OxiProteomics .p-values and effect sizes estimated. p-values < 0.05 were considered significant.The Wilcoxon signed-rank test was used to compare the distinct groups and the p < 0.05) than sun-protected skin  reflecting the skin color for each skin sample was calculated , and no ted skin C.p < 0.05) (p < 0.05)  F. The ob < 0.05) G–I.p < 0.05)  in tissue extracts from dermis showed that chronic UV exposure in sun-exposed skin induced the accumulation of protein oxidation in human skin ( < 0.05) A,B.p < 0.05), but not a significant accumulation of 4-HNE and acrolein adducts in sun-exposed dermis when compared to sun-protected dermis  in cutaneous tissues, which are considered the main contributors to photoaging ,19. ROS The present work attempted to characterize sun-exposed skin compared to sun-protected skin from old Caucasian women, considering the skin yellowing as a perceptible feature of photoaging. We focused on the dermis and analyzed their colorimetric parameters and protein carbonyl expressions. The first results showed that the dermis from sun-exposed skin presented a more yellowish appearance, as compared to sun-protected skin. This result agreed with previous results from Oshima et al.  that desCarbonyl groups may be introduced into proteins by addiction of reactive aldehydes derived from the oxidation of polyunsaturated fatty acids (PUFAs) . AldehydIn this study, we observed a higher accumulation of MDA adducts in sun-exposed skin. To highlight the role of MDA in the formation of yellowing skin, we carried out in vitro experiments using dermis equivalents, composed of type I collagen, treated with aldehydes derived from lipid peroxidation. We observed a clear yellowish color modification of acellular equivalent dermis incubated with a non-physiological concentration of MDA, 4-HNE, or acrolein to accelerate the process of carbonylation. At the same concentration, MDA is the most efficient agent to produce yellow aggregates when compared to 4-HNE and acrolein. These results support our in vivo observations suggesting that collagen is an important target of the MDA as summarized in It would be interesting in future work to study the evolution of the b* parameter in photo-exposed versus non-photo-exposed skin, from the same donor and/or from a younger donor. Furthermore, we could consider studying the synergistic in vitro effect of the various adducts in the phenomenon of photoaging in our models to mimic the photoaging phenomenon occurring in the skin.This study highlights the significant role of MDA in the development of the yellowish color change in sun-exposed skin, contributing to the skin damage observed during photoaging. This is of particular importance for elderly people, particularly of Asian skin type, that tend to show a significant yellowish skin color change with photoaging. The use of suitable sunscreen with or without treatment with compounds that can reduce the formation of or trap carbonyl proteins such as MDA, e.g., carnosine ,31, coul


The coronavirus disease 2019 (COVID-19) pandemic poses new challenges for caregivers of adults with chronic or disabling conditions. This study uses nationally representative data to examine the prevalence of pandemic care challenges and supports and their associations with caregiver mental health and interpersonal well-being.Participants include 311 caregivers aged 50–80 in the United States who were providing care for an adult with a chronic or disabling condition from the June 2020 National Poll on Healthy Aging. Five care challenges  and 2 supports  are treated as predictors of caregiver mental health  and interpersonal well-being .Each care challenge/support was endorsed by 13%–23% of caregivers. In adjusted models, difficulty getting needed medical care was associated with greater caregiver stress, depressive symptoms, and lower interpersonal well-being. All care challenges universally predicted greater caregiver stress. Caregiving supports were not independently associated with caregiver’ mental health and interpersonal well-being.Care challenges were associated with caregivers’ mental health and interpersonal well-being during the early months of the pandemic. Some of these challenges may be attributed to changing public health guidelines and practices as the pandemic unfolded, whereas others are relevant to all care contexts . Tools and supports for caregivers must consider both changing policies and care needs. Translational Significance: Using national data, caregivers of adults with chronic or disabling conditions reported on care challenges and supports they experienced during COVID-19. Each challenge and support were reported by less than ¼ of the sample. Yet challenges, particularly difficulty getting needed medical care for the care recipient, were related to negative mental health outcomes for caregivers. Pandemic policies and clinical efforts toward maintaining medical care and social supports for vulnerable older adults may improve patient health, caregiver well-being, and have a great public health benefit. Furthermore, tools and supports for caregivers must consider both changing policies and care needs for maximum impact.The emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has placed unprecedented strain on interpersonal, health care, and economic systems worldwide. Research on natural disasters suggests that older adults, and especially those with preexisting medical conditions, are particularly vulnerable to global crises . CorrespFamily caregivers remain underrecognized in their role as “frontline” providers helping those with chronic or disabling conditions to age in place and follow public health guidelines. There is pressure on family caregivers to protect their own well-being so they can continue to provide care. Yet a number of social and service-related barriers, due to public health efforts to curb the spread of the virus, may increase care-related stress and reduce well-being for caregivers. Specific policies may lead to restrictions on typical daily activities, reduced physical activity, less social support and instrumental care-related support, loss of outlets , increased difficulty in or discouragement from accessing formal care supports and health care services , or reliance on these services in new modalities . The U-M Institutional Review Board determined the study to be exempt due to deidentified participants.The National Poll on Healthy Aging, a recurring nationally representative online cross-sectional survey conducted on various topics, is supported by the University of Michigan (U-M) and the American Association for Retired Persons (AARP). Ipsos conducts the poll by sampling households from its KnowledgePanel, a probability-based web panel designed to be representative of the U.S. population. The data were drawn from the survey conducted between June 3 and 18, 2020 among 2,074 noninstitutionalized adults aged 50–80 years . Our study selects for those adults who identified as an unpaid caregiver for a relative or friend aged 18 or older with a chronic or disabling condition : Challenges: Difficulty getting needed in-home and out-of-home services , difficulty getting needed medical care for your care recipient, confusion on recommended public health guidelines, providing less care to reduce risk/spread of COVID-19, and decrease in support from family and friends; Supports: Increase in support from family and friends and received information from health care professionals about caring for someone with COVID-19. As challenges were formatted as dichotomous items for brevity of the poll, we ask about both an increase and decrease in support in separate items noting that the pandemic may lead to changes in both directions .Participants were surveyed about whether they ever experienced any of the following caregiving stress during the COVID-19 pandemic were assessed on a 4-point scale from less stressful to much more stressful. Caregiver self-reported mental health was assessed with a self-rating on a 5-point scale from poor to excellent. Depressive symptoms over the last 2 weeks were measured with the Patient Health Questionnaire-2 (PHQ-2) that includes little interest or pleasure in doing things and feeling down, depressed, or hopeless measured on a 4-point scale from not at all to nearly every day  to 3 (often).Having Participants provided demographic information including age, gender, race/ethnicity, education, and income.The first aim was to utilize national data on older adults to identify the frequency of various health and informal care challenges and supports caregivers faced during the COVID-19 pandemic. Descriptive statistics were used to examine sample characteristics and rates of pandemic-related challenges and supports. The total number of challenges participants reported is also described.t-tests were used to examine mean differences in mental and interpersonal well-being of the caregivers between those who did and did not endorse each care challenge or support. Next, each COVID-19 care challenge or support that exhibited a significant difference between means in three or more mental health and interpersonal well-being outcomes was included as a predictor in an ordinary least squares regression model to estimate unique associations between each care challenge and the mental health and interpersonal well-being outcomes. We used a criterion of at least three significant effects to reduce the number of care challenge and support predictors in the subsequent multiple regressions and evaluated the impact of this criterion through a sensitivity analysis where different criteria were used. If we used a more liberal approach of accepting a predictor with two significant associations, we would have included one additional predictor “difficulty getting needed in-home and out-of-home services.” Whereas, if we were stricter and included a criterion of four significant bivariate associations, we would lose two predictors, “confusion on recommended public health guidelines” and “providing less care to reduce risk/spread of COVID-19.” All regression analyses accounted for controls listed above as main effects to control for intercept differences of these variables and used survey weights to generate nationally representative estimates. Standardized estimates are reported.Our second aim was to explore how the pandemic challenges and supports were associated with the mental health and interpersonal well-being of caregivers and this was examined in two ways. First, t-tests and included in subsequent regression models. These were difficulty getting needed medical care for the care recipient, confusion on recommended public health guidelines, providing less care to reduce risk of COVID-19 spread, and decrease in support from family and friends. Among the challenges not included in the regression models, caregivers reporting difficulty getting needed services had greater caregiver stress  and worse self-rated health  on average. On the other hand, the two supports were largely unrelated to caregiver mental health and interpersonal well-being, with the exception being that those reporting an increase in support had greater feelings of a lack of companionship . Full results are given in The majority of caregivers were aged 50–64 (65.0%), female (58.7%), and White (69.3%), with 8.1% of the sample being Black, 15.4% Hispanic, and 7.2% another/multiple racial groups. The majority of caregivers found caregiving to be more stressful during the first 3 months of the pandemic compared to before the pandemic . Feelings of loneliness were common with 48.7% feeling a lack of companionship and 64.6% feeling isolated at least some of the time. On the other hand, only 6.1% reported interpersonal conflicts over half of the days. Depressive symptoms were relatively high, with 12.5% feeling anhedonia and 8.1% feeling depressed for over half the days. Full sample characteristics are given in SE = 0.09, p < .001), confusion on public health guidelines , providing less care to reduce spread , and experiencing a decrease in support from family and friends  all were independently associated with more caregiving stress during the pandemic. On the other hand, the caregiving challenges differentially predicted mental health symptoms and interpersonal well-being. Caregiver’s self-rated mental health was only significantly associated with providing less care to reduce the risk/spread of COVID-19 . Depressive symptoms, on the other hand, were significantly associated with medical and public health challenges, with having difficulty getting needed medical care consistently associated with both depressive symptoms and the overall PHQ-2 score. However, feeling depressed, alone, was significantly associated with confusion on public health guidelines .Ordinary least squares regression  results SE = 0.10, p < .05; companionship: β = 0.13, SE = 0.10, p < .05; isolation: β = 0.21, SE = 0.11, p < .01) and experiencing a decrease in support  were consistently associated with reporting all interpersonal stressors. Providing less care to reduce spread of COVID-19 was also independently associated with caregiver’ isolation . Confusion on public health guidelines was unrelated to interpersonal well-being.Both difficulty getting needed medical care  and supports  to be reported by 13%–24% of caregivers and that these challenges and supports were associated with self-reported caregiver stress, depressive symptoms, and interpersonal difficulties. These findings align with emerging research on the increased burden and stress for caregivers during the pandemic , yet alsWhile each specific pandemic-related care challenge was experienced by less than a quarter of caregivers, challenges strongly related to caregiver’s mental health and interpersonal well-being during the COVID-19 pandemic. Individual care challenges had relatively low frequency, yet so did potential care supports, with only 14% of caregivers reporting receipt of information from health care professionals about caring for someone with COVID-19. While it is possible that this information was only being disseminated to those actively caring for someone with COVID-19, older caregivers and their care recipients with chronic illness are at higher risk of COVID-19 complications  endorsing the care challenge often fell below 15. Future research in larger samples may explore whether factors like gender, age, race, and education moderate associations between pandemic care challenges and caregiver well-being. Additionally, as the primary focus of the National Poll on Healthy Aging was not on caregiving, items on the care recipient such as age, relation to the caregiver, and health condition were not ascertained and thus could not be accounted for within analyses. Of note, as outcome measures were Likert scales, we also ran models as ordinal logistic regressions and identified comparable statistical results.Care challenges, many evident prior to COVID-19 yet accentuated by pandemic circumstances, illuminate how disparities in care supports can affect a caregiver’s stress and interpersonal well-being. Stress Process Models of caregiving emphasize how such factors as program availability and support received relate to how a caregiver appraises their care situation and whether a caregiver experiences negative mental health repercussions . Even st


RUNX1-RUNX1T1 who underwent preemptive treatment with the combined application of tislelizumab (an anti-PD-1 antibody) and azacitidine to avoid HR following allo-HSCT. On day +81, molecular relapse with MRD depicted by RUNX1-RUN1T1-positivity as well as mixed donor chimerism occurred in the patient. On day +95, with no signs of GVHD and an excellent eastern cooperative oncology group performance status (ECOG PS), the patient thus was administered with 100 mg of tislelizumab on day 1 and 100 mg of azacitidine on days 1-7. After the combination therapy, complete remission was successfully achieved with significant improvement in hematologic response, and the MRD marker RUNX1-RUNX1T1 turned negative, along with a complete donor chimerism in bone marrow. Meanwhile, the patient experienced moderate GVHD and immune-related adverse events (irAEs), successively involving the lung, liver, lower digestive tract and urinary system, which were well controlled by immunosuppressive therapies. As far as we know, this case is the first one to report the use of tislelizumab in combination with azacitidine to prevent post-transplant relapse in AML. In summary, the application of ICIs in MRD positive patients might be an attractive strategy for immune modulation in the future to reduce the incidence of HR in the post-transplant setting, but safer clinical application schedules need to be explored.Acute myeloid leukemia (AML) patients who develop hematological relapse (HR) after allogeneic hematopoietic stem cell transplantation  generally have dismal clinical outcomes. Measurable residual disease (MRD)-directed preemptive interventions are effective approaches to prevent disease progression and improve prognosis for molecular relapsed patients with warning signs of impending HR. In this situation, boosting the graft-vs-leukemia (GVL) effect with immune checkpoint inhibitors (ICIs) might be a promising prevention strategy, despite the potential for causing severe graft-vs-host disease (GVHD). In the present study, we reported for the first time an AML patient with  RUNX1-RUNX1T1, are approachable for MRD monitoring , allogeneic hematopoietic stem cell transplantation  represents a major curative approach principally through the induction of the graft-vs-leukemia (GVL) effect –3. Howevnitoring –17. It hPatients with MRD persistence after allo-HSCT may respond to treatments aiming to restore or augment the GVL effect. Besides pharmacological anti-leukemic approaches, cellular immunotherapy strategies stand for the second backbone for the prevention and treatment of AML recurrence after allo-HSCT by interfering with the immune microenvironment and optimizing the GVL effect , 18. ImmRUNX1-RUNX1T1 who underwent preemptive treatment with tislelizumab , an antihuman PD-1 monoclonal IgG4 antibody, together with azacitidine to avoid HR after allo-HSCT.Additionally, recent studies have shown that the detection of severely depleted PD-1-expressing T-cells shortly following allo-HSCT is predictive of disease recurrence and is associated with worse survival –32. ThesRUNX1-RUNX1T1 . In addition, next-generation sequencing did not detect any gene mutation. RUNX1/RUNX1T1 mRNA levels were monitored throughout the course of disease using RT-PCR . Then, the patient received three cycles of consolidation chemotherapy with high dose cytarabine contributing to continuous CR. However, molecular remission was not obtained with an MRD determined by the positive RUNX1/RUNX1T1 . Therefore, allo-HSCT was carried out as a potential curative approach for this high-risk patient. In December 2019, the patient received granulocyte-colony stimulating factor-mobilized peripheral blood stem cell (CD34+ 7.01×106 cells/kg) from his human leukocyte antigen (HLA) identical brother, with fludarabine , busulfan  and cytarabine  as conditioning regimen and short-term methotrexate and cyclosporine as prophylactic agents of GVHD. His platelets and neutrophils were implanted on day +14 and +12, respectively. One month after allo-HSCT, the patient successfully obtained CR with negative MRD  as well as mixed donor chimerism (94%) detected by multiplex short tandem repeat polymerase chain reaction (STR-PCR) in his bone marrow   generating a leukemia-specific fusion gene product, g RT-PCR Figure 1However, despite dose reduction, tislelizumab still induced immune related adverse events (irAEs) or/and GVHD in this patient. The patient successively developed fever, cough, liver dysfunction, diarrhea and hematuria. Firstly, the patient occurred high fever on the first day of treatment, with the onset of cough and dyspnea in the next 2 days, accompanied by a significant increase of C-reactive protein (CRP) (102 mg/L). The effect of multiple antibiotic treatments was limited. Then the chest computed tomography (CT) scan revealed bilateral new ground glass opacities , 34.Finally, response was ongoing 60 days after tislelizumab therapy with negative MRD Figure 1Loss of GVL effect is generally accountable to the relapse after allo-HSCT, which leads to tumor cells escaping from allogeneic immune response , 35. WitIn the post-HSCT relapse management, a preemptive therapy approach to prevent disease progression is more attractive and effective. Preemptive treatment with DLI is one of the most effective strategies to restore the GVL effect after allo-HSCT, whereas it is not actually available for all patients because of donor decline and severe GVHD , 37. NewIt is understandable that ICIs may potentially trigger uncontrollable immune breakthrough events, in particular severe GVHD, in the post-transplant setting , 35, 40.Moreover, the time to ICIs initiation is controversial and remains to be explored. A recent study has showed that a shorter interval between allo-HSCT and initial PD-1 blockade administration was related to an increased risk of attendant GVHD, although there was no statistically significant difference . SimilarFurthermore, alternative approaches to safely promote the GVL effect in post-transplant setting could take advantage of the beneficial effects of HMAs. One such method combines DLI with HMAs, and has revealed efficacy especially in patients with molecular and/or late relapses in myeloid malignancies , 47. RecWe are just beginning to touch the tip of the iceberg in the understanding of whether ICIs therapy should be used after allo-HSCT, when they should be given, which drugs to choose, and what doses to apply. Nonetheless, monitoring and close clinical assessment of treatment-related adverse events are extremely important for patients receiving ICIs therapy after allo-HSCT . AlthougAlthough DLI has been the principal strategy to address post-HSCT recurrence by augmenting the GVL effect for many years, anti-PD1 antibodies can be modulated more easily than donor-derived cellular products to selectively induce the GVL effect without triggering severe GVHD. Therefore, we believe that anti-PD-1 antibodies in combination with HMAs such as azacitidine is a suitable option for preventing and treating AML relapsing after allo-HSCT. Furthermore, on the premise of safety, we would prefer to apply ICIs therapy in a prophylactic or preemptive manner instead of waiting for complete disease recurrence, thus improve the prognosis of transplant recipients.To the best of our knowledge, this case is the first one to report an objective response with some durability to PD-1 inhibition in combination with azacitidine, complicated by the moderate GVHD and irAEs of the lung, lower digestive tract, liver, and urinary system in the setting of a molecular relapsed AML patient after allo-HSCT. The application of ICIs in MRD-positive patients might also be a promising approach for cellular immunotherapy in the future to overcome the risk of HR in the context of post-transplant, but safer clinical application principles need to be established.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by the ethical committee of Tongji Medical College, Huazhong University of Science and Technology. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.HY and YY obtained and analyzed the clinical data. YT and ZZ made the figures. The authors all contributed to caring for the patient, editing the figures, and writing and editing the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Natural Science Foundation of China (grant number 81500168).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Rapid introduction and spread of SARS-CoV-2 have posed unique challenges in understanding the disease, role in vertical transmission, and in developing management. We present a case of a patient with COVID-19 infection and fetus with new-onset fetal SVT.  A 26-year-old gravida 4 para 2012 with third trimester COVID-19 infection was diagnosed with new onset fetal SVT. Successful cardioversion was achieved with flecainide. The patient was followed outpatient until induction of labor at 39 and 3/7 weeks of gestational age resulting in an uncomplicated vaginal delivery. Postpartum course was uncomplicated.  Fetal SVT is a potential complication of maternal COVID-19 infection. The use of transplacental therapy with flecainide is an appropriate alternative to digoxin in these cases. Coronavirus disease 2019 (COVID-19), first identified in December 2019 in Wuhan, China, is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, COVID-19 cases in the world surpassed 200 million with over 5 million deaths , 4. LateVertical transmission of COVID-19 appears to be rare, but possible. In pregnant women with positive COVID-19 test or clinical diagnosis of COVID-19, the majority of cases were negative for COVID-19 in samples including breastmilk, amniotic fluid, umbilical cord blood, and neonatal throat swabs. In the rare cases with positive results, variations in collection times and other factors could not rule out postnatal infection , 4, 6. OIn this report, we present a case of a 26-year-old COVID-19-positive patient in a fetus with new onset supraventricular tachycardia (SVT) treated with flecainide. While intermittent SVT poses a low risk of hemodynamic complications, sustained SVT  can result in congestive heart failure leading to nonimmune fetal hydrops, premature delivery, and fetal demise , 9. AfteA 26-year-old G4P2012 female was transferred from an outside hospital at 31 and 5/7 weeks of gestation for fetal tachycardia. Her pregnancy was complicated by a positive COVID-19 test one day prior to transfer, tobacco use, and GBS positive status. Three days prior to transfer, she reported anosmia and ageusia. She was otherwise healthy. On admission, vitals were stable and baseline CMP and CBC were appropriate for pregnancy. Fetal nonstress test (NST) was significant for fetal intermittent SVT to 170-200 s bpm over 50% of the time. Bedside ultrasound demonstrated a 1 : 1 ratio with fetal heart rate of 340 bpm. Growth was appropriate for gestational age with normal Doppler studies and AFI . PediatrThe patient in our case report is a unique instance of fetal SVT in the presence of maternal COVID-19 infection. It is possible that vertical transmission has the ability to affect cardiac conduction in the fetus. Much of the initial information in understanding COVID-19 relied on comparisons with similar betacoronaviruses, including SARS and MERS, which did not show evidence of vertical transmission in pregnancy and demonstrated variable effects on pregnancy complications , 10. RecThis case may be a new and rare association between betacoronaviruses and fetal arrhythmias in general. Fetal SVT is one of the most common fetal arrhythmias resulting in fetal heart rates over 200 bpm . SVT is Transplacental treatment of fetal SVT has some variability. When fetal heart rate is over 180 bpm, treatment is warranted to avoid the complications of heart failure, hydrops, and subsequent morbidity and mortality . While fManagement of COVID-19 and SVT during pregnancy depends on the stability of the mother and fetus and the complications present. An interdisciplinary coordination and assessment of risks and benefits is crucial. Further studies are necessary to explore the extent fetal complications of COVID-19, including the potential association of fetal arrhythmias.


Thyroid cancer (TC) is rare relative to cancers of many other organs . The majority of TCs are differentiated tumors that are relatively easy to treat and have a good prognosis. However, for anaplastic TC, a rapidly growing and aggressive tumor, treatment is suboptimal because the effective drugs cause severe adverse effects. Drug delivery by nanocarriers can improve treatment by reducing side effects. This can either be mediated through better retention in the tumor tissue due to size (passive targeting) or through the attachment of specific molecules that zero in on the cancer cells (active targeting). Nanoparticles are already used for diagnosis and imaging of TC. For unresectable anaplastic TC, nanoparticle-based treatments, less suitable for deeply located cancers, could be useful, based on low-intensity focused ultrasound and near-infrared irradiation. All potential applications of nanoparticles in TC are still in the preclinical phase.Cancers of the endocrine system are rare. The majority are not highly malignant tumors. Thyroid cancer (TC) is the most common endocrine cancer, with differentiated papillary and follicular tumors occurring more frequently than the more aggressive poorly differentiated and anaplastic TC. Nanoparticles (NP)  have been developed to improve the detection of biomarkers and routine laboratory parameters , tumor imaging, and drug delivery in TC. The majority of drug-loaded nanocarriers to be used for treatment was developed for anaplastic tumors because current treatments are suboptimal. Further, doxorubicin, sorafenib, and gemcitabine treatment can be improved by nanotherapy due to decreased adverse effects. Selective delivery of retinoic acid to TC cells might improve the re-differentiation of de-differentiated TC. The use of carbon NPs for the prevention of parathyroid damage during TC surgery does not show a clear benefit. Certain technologies less suitable for the treatment of deeply located cancers may have some potential for unresectable anaplastic carcinomas, namely those based on low-intensity focused ultrasound and near-infrared irradiation. Although some of these approaches yielded promising results in animal studies, results from clinical trials are currently lacking.  These estimations are in line with data of the Global Cancer Statistics 2020 for 36 Cancers in 185 Countries that reported 19.3 million new cases and almost 10 million cancer death in 2020 fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) can also be used. In the case of a suboptimal response, administration of lenvatinib and sorafenib is recommended (Monitoring after radioiodine treatment includes thyroglobulin (Tg) and anti-Tg antibody levels, in addition to TSH levels. Tg measurement is the most sensitive parameter for persistent and/or recurrent disease. Tg antibodies can interfere with the measurement and yield evidence of functional thyroid cells. Elevated levels may indicate recurrent/metastatic disease. Neck ultrasound should also be included in routine monitoring. Whole-body scans (WBC) with a radioactive iodine tracer as well as . Bi. Bi20]. TKIs have been approved for treating differentiated TC, MTC, and ATC. Their use should be considered after careful weighing of the potential risks and benefits of this therapy. Lenvatinib has serious adverse effects on the cardiovascular system, liver, and renal function. Sorafenib use is associated with severe skin adverse events, hemorrhage, and cardiovascular effects. A systematic review by Fleeman et al. found that improvements in progression-free survival and objective tumor response rate were accompanied by increased risk of adverse effects . The effFor poorly differentiated tumors and ATC, total thyroidectomy + neck dissection followed by external beam radiotherapy (EBRT) ± chemotherapy is performed . In caseThe TKIs playing an established role in the treatment of TC act on RET, FGFR, cKIT, PDGFR, VEGFR (lenvantinib), BRAF, RET, c-KIT, PDGFR, VEGFR (sorafenib), BRAF (dabrafenib), MEK (trametinib), RET, VEGFR (cabozantinib), and RET, EGFR, and VEGFR (vandetanib) ,27. The term “nanomedicine” has been coined by Dr. Robert Freitas in 1994 and was defined in 2004 by the European Science Foundation (ESF) and in 2006 by the United States’ National Institutes of Health (NIH). Both reports emphasize that nanomedicine emerged from nanotechnology, which is generally defined by the creation and use of materials at the level of molecules and atoms  . VanishiCommonly used NPs in cancer are organic , inorganic , and hybrid  particles . They deA literature search for original articles in the PubMed data base using “nano*” AND “cancer” AND “gold” or “quantum dots” or “mesoporous silica” or “iron oxide” or “carbon” or “liposomes” or “polymeric” showed that most studies used gold NPs (6200), followed by carbon-based materials (3700), polymeric (3000), liposomes (2600), and iron oxide NPs (2200). It appears not surprising that most studies focused on gold NPs because this material is suitable for drug delivery and sensor technology . The biological effects of NPs are determined by a panel of interacting parameters, namely, their composition, physical properties, surface properties, and targeting molecules, and it is difficult to predict the influence of variation in one particular parameter on the overall effect . Informa64Cu-liposomes in PET is suitable for the screening and could serve for patient selection. Drug delivery by NPs does not appear to be high in absolute terms. A meta-analysis based on 117 publications reported that on average 0.7% of the administered nanoparticle dose reached the tumor cells of solid tumors  FDOPA and [68Ga]DOTATOC are the preferred tracers for MTC  CuS) NPs [64Cu] CuS NPs were injected into tumors derived from 5 × 105 luminescent Hth83 cells (ATC cells transfected with luciferase) and the mice underwent a PET scan to localize the tumor -1H,2H-benzo[h] 1,6-naphthyridin-2-one) target the VEGFR2, which plays a critical role in transforming precancerous lesions to malignant tumors. The NPs inhibited growth of human anaplastic carcinoma FRO cells more effectively compared with each single agent and did not affect Nthy-ori3–1 normal human cells . The parerations . EncapsuMesoporous organic silica is a type of silica-containing organic group that gives rise to mesoporosity. Such MSNs loaded with doxorubicin were more successful than the melanin-linked NPs produced from dopamine hydrochloride. While the melanin-linked NPs had a doxorubicin loading capacity of 20%, the mesoporous organic silica particles reached 47.02% ,76. CoatLiposomes are one of the most established nanocarriers. They allow delivery of various drugs with good encapsulation capacity and prolonged circulation, such as in daunorubicin and pegylated liposomal doxorubicin. Further, they enable functionalization with different targeting molecules and are biocompatible. The nucleoside analog gemcitabine has various limitations. It is quickly metabolized and excreted, and causes various side effects and resistance in tumor cells. The hydrophilic gemcitabine molecule is difficult to incorporate into most nanocarriers. Gemcitabine-loaded liposomes were markedly more cytotoxic to ARO cells, derived from an ATC, than the free drug, but in the absence of comparison to other cells, the advantage of encapsulation was not clear . In the Increased antiproliferative efficacy was shown for liposomes loaded with all-trans retinoic acid in comparison with the free drug on three different human thyroid carcinoma cell lines  but its action on normal cells was not studied . Lipid pmicroRNA-34b-5p-loaded pegylated lipid particles were tested in human ATC cells (8505C and BHT-101) and in immortalized follicular epithelial cNthy-ori 3-1 cells as controls . miR-34b4k) particles coated with nonapeptide PEP-1 to target the IL-13 receptor alpha 2, over-expressed on tumor cells, e.g., the ATC cell line THJ-16T, resveratrol-treated tumors were similar in size to docetaxel- and doxorubicin-treated tumors ).Despite the various proposed uses of NPs in diagnosis and treatment of TC, data from clinical trials are limited. CALAA-01 is a transferrin-targeted nanocomplex consisting of siRNA to reduce expression of the M2 subunit of ribonucleotide reductase and cyclodextrin-containing polymer. The trial was terminated due to dose-limiting toxicities .Future and ongoing trials will evaluate the use of several nanoparticles as a tracer for lymph node mapping to improve the surgical treatment of thyroid cancer. These particles include carbon nanoparticles alone, carbon nanoparticles in combination with indocyanine green dye, and anti-Tg antibody functionalized fluorescent polystyrene particles .®) is being evaluated in combination with the anti-PDL-1 antibody Atezolizumab  and in combination with the glycogen synthase kinase 3 beta (GSK-3β) inhibitor, 9-ING-41 .For multidrug chemotherapy of TC, the efficacy of the approved albumin-bound particle form of paclitaxel (nab-paclitaxel, AbraxaneCompared to other tumors, a relatively low number of NPs has been studied for diagnosis and treatment of TC. Reasons for that may be that TC is not a common cancer and TC, with the exception of de-differentiated tumors and ATC, is not highly aggressive. Tumor accumulation of NPs can either use passive targeting by the EPR effect or use tumor-specific targeting molecules. NPs could improve diagnosis and monitoring of TC by more sensitive sensor technologies, e.g., BRAF V600 mutation and for imaging. Encapsulation into nanocarriers increased the efficacy of doxorubicin, sorafenib, and gemcitabine treatment, and decreased their adverse effects. Improved delivery of retinoic acid to TC cells could improve the re-differentiation therapy of de-differentiated TC.All NPs, except carbon NPs during TC surgery, are in the pre-clinical phase of drug development and, quite frequently, only in vitro cellular studies, often without comparison to normal cells, are available. Although encouraging results from animal studies have been reported, their value for predicting efficacy in humans is subject to the inherent limitations of the models. These include the clonal origin of the xenografts, leading to lower heterogeneity, the larger relative size of the xenografts compared to human tumors but smaller size at treatment, immunodeficient status of the athymic mice, inoculation at a young age, subcutaneous versus orthotopic localization, and often the absence of metastases in the mouse models . These d