Treatment of spinal cord injury with biomaterials and stem cell therapy in non-human primates and humans

Spinal cord injury results in the loss of sensory,motor,and autonomic functions,which almost always produces permanent physical disability.Thus,in the search for more effective treatments than those already applied for years,which are not entirely efficient,researches have been able to demonstrate the potential of biological strategies using biomaterials to tissue manufacturing through bioengineering and stem cell therapy as a neuroregenerative approach,seeking to promote neuronal recovery after spinal cord injury.Each of these strategies has been developed and meticulously evaluated in several animal models with the aim of analyzing the potential of interventions for neuronal repair and,consequently,boosting functional recovery.Although the majority of experimental research has been conducted in rodents,there is increasing recognition of the importance,and need,of evaluating the safety and efficacy of these interventions in non-human primates before moving to clinical trials involving therapies potentially promising in humans.This article is a literature review from databases(PubMed,Science Direct,Elsevier,Scielo,Redalyc,Cochrane,and NCBI)from 10 years ago to date,using keywords(spinal cord injury,cell therapy,non-human primates,humans,and bioengineering in spinal cord injury).From 110 retrieved articles,after two selection rounds based on inclusion and exclusion criteria,21 articles were analyzed.Thus,this review arises from the need to recognize the experimental therapeutic advances applied in non-human primates and even humans,aimed at deepening these strategies and identifying the advantages and influence of the results on extrapolation for clinical applicability in humans.

Optimizing care for gastric cancer with overt bleeding:Is systemic therapy a valid option?

Gastric cancer(GC)and gastroesophageal junction cancer(GEJC)represent a significant burden globally,with complications such as overt bleeding(OB)further exacerbating patient outcomes.A recent study by Yao et al evaluated the effectiveness and safety of systematic treatment in GC/GEJC patients presenting with OB.Using propensity score matching,the study balanced the comparison groups to investigate overall survival and treatment-related adverse events.The study's findings emphasize that systematic therapy can be safe and effective and contribute to the ongoing debate about the management of advanced GC/GEJC with OB,highlighting the complexities of treatment decisions in these high-risk patients.

Human induced pluripotent stem cell-derived therapies for regeneration after central nervous system injury

In recent years,the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine.Considering the non-regenerative nature of the mature central nervous system,the concept that“blank”cells could be reprogrammed and functionally integrated into host neural networks remained intriguing.Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells,such as neurons.While embryonic stem cells demonstrated great potential in treating central nervous system pathologies,ethical and technical concerns remained.These barriers,along with the clear necessity for this type of treatment,ultimately prompted the advent of induced pluripotent stem cells.The advantage of pluripotent cells in central nervous system regeneration is multifaceted,permitting differentiation into neural stem cells,neural progenitor cells,glia,and various neuronal subpopulations.The precise spatiotemporal application of extrinsic growth factors in vitro,in addition to microenvironmental signaling in vivo,influences the efficiency of this directed differentiation.While the pluri-or multipotency of these cells is appealing,it also poses the risk of unregulated differentiation and teratoma formation.Cells of the neuroectodermal lineage,such as neuronal subpopulations and glia,have been explored with varying degrees of success.Although the risk of cancer or teratoma formation is greatly reduced,each subpopulation varies in effectiveness and is influenced by a myriad of factors,such as the timing of the transplant,pathology type,and the ratio of accompanying progenitor cells.Furthermore,successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration.Lastly,host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression.Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes.This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.

Neoadjuvant therapy for pancreas cancer: Past lessons and future therapies

Pancreatic adenocarcinoma remains a most deadly malignancy, with an overall 5-year survival of 5%. A subset of patients will be diagnosed with potentially resectable disease, and while complete surgical resection provides the only chance at cure, data from trials of postoperative chemoradiation and/or chemotherapy demonstrate a modest survival advantage over those patients who undergo resection alone. As such, most practitioners believe that completion of multimodality therapy is the optimal treatment. However, the sequence of surgery, chemotherapy and radiation therapy is frequently debated, as patients may benefit from a neoadjuvant approach by initiating chemotherapy and/or chemoradiation prior to resection. Here we review the rationale for neoadjuvant therapy, which includes a higher rate of completion of multimodality therapy, minimizing the risk of unnecessary surgical resection for patients who develop early metastatic disease, improved surgical outcomes and the potential for longer overall survival. However, there are no prospective, randomized studies of the neoadjuvant approach compared to a surgeryfirst strategy; the established and ongoing investigations of neoadjuvant therapy for pancreatic cancer are discussed in detail. Lastly, as the future of therapeutic regimens is likely to entail patient-specific genetic and molecular analyses, and the treatment that is best applied based on those data, a review of clinically relevant biomarkers in pancreatic cancer is also presented.

Crimean-Congo hemorrhagic fever: etiology, diagnosis, management and potential alternative therapy

Crimean-Congo hemorrhagic fever(CCHF)virus belongs to the genus Nairovirus and family Bunyaviridae.CCHF is a tickborne disease that has mostly been reported from Asia,Africa and Europe.Early diagnosis of CCHF is essential for patient care and preventing its spread to normal individuals.Treatment of CCHF is mostly limited to the use of ribavirin and palliative care.The practice of using interferon and vaccines has also been proved to be ineffective and unsafe.A search for an effective alternative treatment of the CCHF still continues.Therefore,the current review focusses on the cause,prevalence,mode of transmission,pathophysiology,signs,symptoms,diagnostic features and treatment options of CCHF.This review also highlights the possible alternative therapy in the form of antiviral medicinal plants which are effective against viral hemorrhagic fever.These medicinal plants have shown convincing evidence for their activities against different viral hemorrhagic fevers and may be used alone or in combination with existing therapies to achieve an optimum therapeutic response.

When combination therapy isn't working: Emerging therapies for the management of inflammatory bowel disease

Although antagonists of tumor necrosis factor have resulted in major therapeutic benefits in inflammatory bowel disease, the magnitude and durability of response are variable. Similar to previously available drugs such as 5-aminosalicylates and immunomodulators, the therapeutic effect is not universal leaving many people searching for options. The development of newer agents has benefited from advances in the understanding of the pathophysiology of the disease. Uncontrolled activation of the acquired immune system has an important role, and lymphocytes, cytokines, and adhesion molecules are broadly targeted for therapeutic intervention. There is increasing evidence of an important role of the innate immune system and the intestinal epithelium, and the therapeutic paradigm is also shifting from immunosuppression to the reinforcement of the intestinal barrier, and modification of the disease process. In this review, we explore the limitation of current therapy as well as mechanisms of actions of new drugs and the efficacy and adverse events from data from clinical trials.

Characteristics of fever and response to antipyretic therapy in military personnel with adenovirus-positive community acquired pneumonia

Background:In 2014,an outbreak of adenoviral pneumonia occurred in the Korean military training center.However,there are limited data on the characteristics of the fever and its response to antipyretic therapy in immunocompetent adults with adenovirus-positive community-acquired pneumonia(CAP).Methods:The medical records of the patients who were admitted to the Armed Forces Chuncheon Hospital for the treatment of CAP between January 2014 and December 2016 were retrospectively analyzed.The patients were divided into three groups,namely,the adenovirus-positive(Adv)group,the adenovirus-negative(Non-Adv)group and the unknown pathogen group,according to the results of a polymerase chain reaction(PCR)test and sputum culture used to measure adenovirus and other bacteria or viruses in respiratory specimens.We evaluated and compared the demographics,clinicolaboratory findings and radiological findings upon admission between the two groups.Results:Out of the 251 military personnel with CAP during the study periods,67 were classified into the Adv group,while 134 were classified into the Non-Adv group and 50 were classified into the unknown pathogen group.The patients in the Adv group had a longer duration of fever after admission((3.2±1.6)d vs.(1.9±1.2)d vs.(2.2±1.5)d,P=0.018)and symptom onset((5.8±2.2)d vs.(3.9±2.5)d vs.(3.7±2.0)d,P=0.006)than patients in the Non-Adv and unknown pathogen groups,respectively.The patients in the Adv group had a higher mean temperature at admission(37.8±0.3 vs.37.3±0.3 vs.37.3±0.3,P=0.005),and more patients were observed over 40 and 39 to 40(14.9%vs.2.2%vs.4.0%,35.8%vs.3.7%vs.6.0%,P<0.001)than those in the Non-Adv and unknown pathogen groups,respectively.The Adv group more commonly had no response or exhibited adverse events after antipyretic treatment compared to the Non-Adv group(17.9%vs.1.5%,35.0%vs.4.3%,P<0.001,P=0.05,respectively).In addition,the time from admission to overall clinical stabilization was significantly longer in the patients in the Adv group than in those in the Non-Adv group((4.3±2.8)d vs.(2.9±1.8)d,P=0.034,respectively).Furthermore,no significant difference in the length of hospital stay was observed between the two groups,and no patient died in either group.Conclusions:In this study,Adv-positive CAP in immunocompetent military personnel patients had distinct fever characteristics and responses to antipyretic treatment.

A Retrospective Study of Continuous Renal Therapy and Anticoagulation in Patients with Hemorrhagic Fever with Renal Syndrome

Objective To observe the application of continuous renal replacement therapy(CRRT) and heparin anticoagulation in patients with HFRS, and to explore a more suitable anticoagulant strategy. Methods Eighty-five severe-type patients(severe group) and 71 critical-type patients(critical group) were enrolled in this study. The frequency of CRRT was compared between the two groups; the frequency of CRRT treated with and without heparin anticoagulation and the frequency of hemorrhage and channel blood clotting induced by the two anticoagulant strategies were observed. Results The frequency of CRRT in the critical group was higher than that in the severe group(P < 0.001). The frequency of CRRT initiated during the overlapping phases in the critical group was significantly higher than that of the severe group(P = 0.032). The total times of CRRT was 103, and 70 of them were treated with heparin anticoagulation. The frequencies of hemorrhage induced by heparin anticoagulation and no heparinization were 16 and 0, respectively, and the frequencies of channel blood clotting were 2 and 4, respectively. Conclusions CRRT has been used extensively in the critical-type patients with HFRS. The heparin anticoagulation and no anticoagulant strategies should be used more rationally in patients treated with CRRT, according to the clinical characteristics of the disease.

Loco-regional therapies for patients with hepatocellular carcinoma awaiting liver transplantation: Selecting an optimal therapy

Hepatocellular carcinoma(HCC) is a common, increasingly prevalent malignancy. For all but the smallest lesions, surgical removal of cancer via resection or liver transplantation(LT) is considered the most feasible pathway to cure. Resection- even with favorable survival- is associated with a fairly high rate of recurrence, perhaps since most HCCs occur in the setting of cirrhosis. LT offers the advantage of removing not only the cancer but the diseased liver from which the cancer has arisen, and LT outperforms resection for survival with selected patients. Since time waiting for LT is time during which HCC can progress, locoregional therapy(LRT) is widely employed by transplant centers. The purpose of LRT is either to bridge patients to LT by preventing progression and waitlist dropout, or to downstage patients who slightly exceed standard eligibility criteria initially but can fall within it after treatment. Transarterial chemoembolization and radiofrequency ablation have been the most widely utilized LRTs to date, with favorable efficacy and safety as a bridge to LT(and for the former, as a downstaging modality). The list of potentially effective LRTs has expanded in recent years, and includes transarterial chemoembolization with drug-eluting beads, radioembolization and novel forms of extracorporal therapy. Herein we appraise the various LRT modalities for HCC, and their potential roles in specific clinical scenarios in patients awaiting LT.

Cupping Therapy for 103 Cases of High Fever due to Infection of the Upper Respiratory Tract

The cupping therapy has remarkable antipyretic effect in the treatment of fever. In recent years, the author has treated 103 cases of high fever caused by infection of the upper respiratory tract and obtained quite satisfactory therapeutic results. A report follows.

Advances in radiotherapy and targeted therapies for rectal cancer

The last decade witnessed a significant progress in understanding the biology and immunology of colorectal cancer alongside with the technical innovations in radiotherapy.The stepwise implementation of intensitymodulated and image-guided radiation therapy by means of megavolt computed tomography and helical tomotherapy enabled us to anatomically sculpt dose delivery,reducing treatment related toxicity.In addition,the administration of a simultaneous integrated boost offers excellent local control rates.The novel challenge is the development of treatment strategies for medically inoperable patient and organ preserving approaches.However,distant control remains unsatisfactory and indicates an urgent need for biomarkers that predict the risk of tumor spread.The expected benefit of target?ed therapies that exploit the tumor genome alone is so far hindered by high cost techniques and pharmaceuticals,hence hardly justifying rather modest improvements in patient outcomes.On the other hand,the immune landscape of colorectal cancer is now better clarified with regard to the immunosuppressive network that promotes immune escape.Both N2 neutrophils and myeloid-derived suppressor cells(MDSC)emerge as useful clinical biomarkers of poor prognosis,while the growing list of anti-MDSC agents shows promising ability to boost antitumor T-cell immunity in preclinical settings.Therefore,integration of genetic and immune biomarkers is the next logical step towards effective targeted therapies in the context of personalized cancer treatment.

Combining chemotherapy and targeted therapies in metastatic colorectal cancer

Colorectal cancer remains one of the major causes of cancer death worldwide. During the past years, the development of new effective treatment options has led to a considerable improvement in the outcome of this disease. The advent of agents such as capecitabine, irinotecan, oxaliplatin, cetuximab and bevacizumab has translated into median survival times in the range of 2 years. Intense efforts have focused on identifying novel agents targeting specific growth factor receptors, critical signal transduction pathways or mediators of angiogenesis. In addition, several clinical trials have suggested that some of these molecularly targeted drugs can be safely and effectively used in combination with conventional chemotherapy. In this article we review various treatment options combining cytotoxic and targeted therapies currently available for patients with metastatic colorectal cancer.

Revolutionizing gastric cancer treatment:The potential of immunotherapy

Gastric cancer,a prevalent malignancy worldwide,ranks sixth in terms of frequency and third in fatality,causing over a million new cases and 769000 annual deaths.Predominant in Eastern Europe and Eastern Asia,risk factors include family medical history,dietary habits,tobacco use,Helicobacter pylori,and Epstein-Barr virus infections.Unfortunately,gastric cancer is often diagnosed at an advanced stage,leading to a grim prognosis,with a 5-year overall survival rate below 5%.Surgical intervention,particularly with D2 Lymphadenectomy,is the mainstay for early-stage cases but offers limited success.For advanced cases,the National Comprehensive Cancer Network recommends chemotherapy,radiation,and targeted therapy.Emerging immunotherapy presents promise,especially for unresectable or metastatic cases,with strategies like immune checkpoint inhibitors,tumor vaccines,adoptive immunotherapy,and nonspecific immunomodulators.In this Editorial,with regards to the article“Advances and key focus areas in gastric cancer immunotherapy:A comprehensive scientometric and clinical trial review”,we address the advances in the field of immunotherapy in gastric cancer and its future prospects.

Pathologically successful conversion hepatectomy for advanced giant hepatocellular carcinoma after multidisciplinary therapy:A case report and review of literature

BACKGROUND Hepatocellular carcinoma(HCC)is one of the leading causes of death due to its complexity,heterogeneity,rapid metastasis and easy recurrence after surgical resection.We demonstrated that combination therapy with transcatheter arterial chemoembolization(TACE),hepatic arterial infusion chemotherapy(HAIC),Epclusa,Lenvatinib and Sintilimab is useful for patients with advanced HCC.CASE SUMMARY A 69-year-old man who was infected with hepatitis C virus(HCV)30 years previously was admitted to the hospital with abdominal pain.Enhanced computed tomography(CT)revealed a low-density mass in the right lobe of the liver,with a volume of 12.9 cm×9.4 cm×15 cm,and the mass exhibited a“fast-in/fast-out”pattern,with extensive filling defect areas in the right branch of the portal vein and an alpha-fetoprotein level as high as 657 ng/mL.Therefore,he was judged to have advanced HCC.During treatment,the patient received three months of Epclusa,three TACE treatments,two HAIC treatments,three courses of sintilimab,and twenty-one months of lenvatinib.In the third month of treatment,the patient developed severe side effects and had to stop immunotherapy,and the Lenvatinib dose had to be halved.Postoperative pathological diagnosis indicated a complete response.The patient recovered well after the operation,and no tumor recurrence was found.CONCLUSION Multidisciplinary conversion therapy for advanced enormous HCC caused by HCV infection has a significant effect.Individualized drug adjustments should be made during any treatment according to the patient's tolerance to treatment.

Immunotherapy for esophageal cancer:Where are we now and where can we go

Immune checkpoint inhibitor therapy has dramatically improved patient prognosis,and thereby transformed the treatment in various cancer types including esophageal squamous cell carcinoma(ESCC)in the past decade.Monoclonal antibodies that selectively inhibit programmed cell death-1(PD-1)activity has now become standard of care in the treatment of ESCC in metastatic settings,and has a high expectation to provide clinical benefit during perioperative period.Further,anti-cytotoxic T-lymphocyte–associated protein 4(CTLA-4)monoclonal antibody has also been approved in the treatment of recurrent/metastatic ESCC in combination with anti-PD-1 antibody.Well understanding of the existing evidence of immune-based treatments for ESCC,as well as recent clinical trials on various combinations with chemotherapy for different clinical settings including neoadjuvant,adjuvant,and metastatic diseases,may provide future prospects of ESCC treatment for better patient outcomes.

Helical tomotherapy and systemic targeted therapies in solitary plasmacytoma: Pilot study

AIM: To assess the feasibility of the combination of helical tomotherapy(HT) and a concurrent systemic targeted therapy in patients with solitary plasmacytoma (SP) with the aim to decrease toxicity while improving therapeutic efficacy. METHODS: Six patients with biologically, histologically, and radiologically confirmed SP were treated using HT and a systemic targeted treatment concomitantly. Total dose was 40 Gy/20 fractions. Four patients received 4 cycles of concurrent lenalidomide-dexamethasone combination and two patients were treated with concomitant bortezomib-dexamethasone. All toxicities were described using the Common Terminology Criteria for Adverse Effects v3.0.RESULTS: Five patients had a bone tumor and one patient had an isolated pancreatic mass. Five patients presented with pain, one had neurologic symptoms related to medullary compression, which was treated by an emergency surgery. Median age was 59.5 years (range, 50-74 years). All patients had initial positron emission tomography-computed tomographys, three patients had total body bone magnetic resonance imaging examination, and three patients had computed tomodensitometry scans. The toxicity profile was excellent with no higher than grade 1 toxicity. Four of the six patients experienced a partial radiological response, four had complete response on positions emission tomography and 5/6 patients experienced a complete relief of their symptoms 4 mo after treatment. At a median follow-up of 18 mo, 5/6 patients were controlled clinically, radiologically, and biologically. CONCLUSION: Using HT, we could deliver a highly conformal irradiation concurrently with a molecularly targeted therapy. This association yielded in a high response rate and a low toxicity. A prospective study with longer follow-up will help determining the true benefit of such strategy.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

The Risk of Severe Acute Kidney Injury Requiring Renal Replacement Therapy in Viral Hemorrhagic Fevers. A Review of Literature

Objective: It demonstrates the correlation of the viral hemorrhagic fever with kidney failure and the treatment as well as the outcome. Method: A PubMed search of the English literature from 1999 to 2019 was performed using “viral hemorrhagic fever, Case Report, Renal Failure” as the subject. The inclusion criteria were the following: 1) case report and case series of two or more patients;2) the report detailed the clinical presentation and reported the status of the renal system;3) the report described the management of renal failure if any;and 4) the etiology of the infection is known and is one of the known agents of viral hemorrhagic fever, listed on the centers of disease control website. We excluded infections related to vaccination related to viral hemorrhagic fever. Result: We found the mean age of these patients was 41.5. The male to female ratio was about 3.5:1. Dengue and Hantaviruses constituted 70.5% of patients. The overall mortality of the study cohort was 32.2%. Half of the patients had acute kidney injury and required renal replacement therapy. The chi-square statistic is 0.41;The p-value is 0.51;The chi-square statistic is 6.4254. Overall mortality was 32.3% in one cohort of 78 patients. The illness goes through several stages [1] [2] of clinical features and some viruses in the group have a high case fatality rate. Conclusions: Early diagnosis with aggressive supportive care is critical for improving clinical outcomes. Renal involvement is common. Amongst the cohort reviewed, of patients who had acute kidney injury, half of the patients required renal replacement support. However, some viruses cause greater kidney injury than others, for instance, kidney injury is more severe in Dengue hemorrhagic fevers when compared to Hantaviruses. Simultaneous management of public health by prevention and control of outbreaks is particularly important.

Present and future of new systemic therapies for early and intermediate stages of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is a high mortality neoplasm which usually appears on a cirrhotic liver.The therapeutic arsenal and subsequent prognostic outlook are intrinsically linked to the HCC stage at diagnosis.Notwithstanding the current deployment of treatments with curative intent(liver resection/local ablation and liver transplantation)in early and intermediate stages,a high rate of HCC recurrence persists,underscoring a pivotal clinical challenge.Emergent systemic therapies(ST),particularly immunotherapy,have demonstrate promising outcomes in terms of increase overall survival,but they are currently bound to the advanced stage of HCC.This review provides a comprehensive analysis of the literature,encompassing studies up to March 10,2024,evaluating the impact of novel ST in the early and intermediate HCC stages,specially focusing on the findings of neoadjuvant and adjuvant regimens,aimed at increasing significantly overall survival and recurrence-free survival after a treatment with curative intent.We also investigate the potential role of ST in enhancing the downstaging rate for the intermediate-stage HCC initially deemed ineligible for treatment with curative intent.Finally,we critically discuss about the current relevance of the results of these studies and the encouraging future implications of ST in the treatment schedules of early and intermediate HCC stages.

Back to the drawing board:Overview of the next generation of combination therapy for inflammatory bowel disease

Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this approach.The importance of controlled trials should be stressed in establishing new treatment paradigms.Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.