Cardiomyopathies:Evolution of pathogenesis concepts and potential for new therapies

Cardiomyopathies are defined as diseases of the myocardium with associated structural and functional abnormalities. Knowledge of these pathologies for a long period was not clear in clinical practice due to uncertainties regarding definition,classification and clinical diagnosis. In recent decades,major advances have been made in the understanding of the molecular and genetic issues,pathophysiology,and clinical and radiological assessment of the diseases. Progress has been made also in management of several types of cardiomyopathy. Advances in the understanding of these diseases show that cardiomyopathies represent complex entities. Here,special attention is given to evolution of classification of cardiomyopathies,with the aim of assisting clinicians to look beyond schematic diagnostic labels in order to achieve more specific diagnosis. Knowledge of the genotype of cardiomyopathies has changed the pathophysiological understanding of their etiology and clinical course,and has become more important in clinical practice for diagnosis and prevention of cardiomyopathies. New approaches for clinical and prognostic assessment are provided based on contemporary molecular mechanisms of contribution in the pathogenesis of cardiomyopathies. The genotype-phe-notype complex approach for assessment improves the clinical evaluation and management strategies of these pathologies. The review covers also the important role of imaging methods,particularly echocardiography,and cardiac magnetic resonance imaging in the evaluation of different types of cardiomyopathies. In summary,this review provides complex presentation of current state of cardiomyopathies from genetics to management aspects for cardiovascular specialists.

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.

Role of left ventricular twist mechanics in cardiomyopathies, dance of the helices

Left ventricular twist is an essential part of left ventricular function. Nevertheless, knowledge is limited in "the cardiology community" as it comes to twist mechanics. Fortunately the development of speckle tracking echocardiography, allowing accurate, reproducible and rapid bedside assessment of left ventricular twist, has boosted the interest in this important mechanical aspect of left ventricular deformation. Although the fundamental physiological role of left ventricular twist is undisputable, the clinical relevance of assessment of left ventricular twist in cardiomyopathies still needs to be established. The fact remains; analysis of left ventricular twist mechanics has already provided substantial pathophysiological understanding on a comprehensive variety of cardiomyopathies. It has become clear that increased left ventricular twist in for example hypertrophic cardiomyopathy may be an early sign of subendocardial(microvascular) dysfunction. Furthermore, decreased left ventricular twist may be caused by left ventricular dilatation or an extensive myocardial scar. Finally, the detection of left ventricular rigid body rotation in noncompaction cardiomyopathy may provide an indispensible method to objectively confirm this difficult diagnosis. All this endorses the value of left ventricular twist in the field of cardiomyopathies and may further encourage the implementation of left ventricular twist parameters in the "diagnostic toolbox" for cardiomyopathies.

Distribution of late gadolinium enhancement in various types of cardiomyopathies:Significance in differential diagnosis, clinical features and prognosis

The recent development of cardiac magnetic resonance(CMR)techniques has allowed detailed analyses of cardiac function and tissue characterization with high spatial resolution.We review characteristic CMR features in ischemic and non-ischemic cardiomyopathies(ICM and NICM),especially in terms of the location and distribution of late gadolinium enhancement(LGE).CMR in ICM shows segmental wall motion abnormalities or wall thinning in a particular coronary arterial territory,and the subendocardial or transmural LGE.LGE in NICM generally does not correspond to any particular coronary artery distribution and is located mostly in the mid-wall to subepicardial layer.The analysis of LGE distribution is valuable to differentiate NICM with diffusely impaired systolic function,including dilated cardiomyopathy,end-stage hypertrophic cardiomyopathy(HCM),cardiac sarcoidosis,and myocarditis,and those with diffuse left ventricular(LV)hypertrophy including HCM,cardiac amyloidosis and Anderson-Fabry disease.A transient low signal intensity LGE in regions of severe LV dysfunction is a particular feature of stress cardiomyopathy.In arrhythmogenic right ventricular cardiomyopathy/dysplasia,an enhancement of right ventricular(RV)wall with functional and morphological changes of RV becomes apparent.Finally,the analyses of LGE distribution have potentials to predict cardiac outcomes and response to treatments.

Benefit of stem cells and skeletal myoblast cells in dilated cardiomyopathies

Although some authors suggest that there is mitotic division in the heart,most cardiomyocytes do not have the capacity to regenerate after myocardial infarction and when this occurs there is a deterioration of contractile function,and if the area of infarction is extensive ventricular remodeling may occur,leading to the development of heart failure.Cell transplantation into the myocardium with the goal of recovery of cardiac function has been extensively studied in recent years. The effects of cell therapy are based directly on the cell type used and the type of cardiac pathology.For myocardial ischemia in the hibernating myocardium, bone marrow cells have functional benefits,however these results in transmural fibrosis are not evident. In these cases there is a benefit of implantation with skeletal myoblasts,for treating the underlying cause of disease,the loss of cell contractility.

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.

Role of hepatitis C virus in myocarditis and cardiomyopathies

Recent nationwide clinico-epidemiological surveys in Japan showed that the occurrence of cardiomyopathies was most frequently seen in the age of sixties, and that cardiomyopathies are important causes of heart failure in the elderly. Viral infection was conventionally considered to cause myocarditis, which resulted in the development of dilated cardiomyopathy. Recent studies suggest that hepatitis C virus (HCV) is involved in the development of dilated cardiomyopathy, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy in addition to myocarditis. Furthermore, left ventricular aneurysm represents the same morbid state not only after myocardial infarction but also after myocarditis. There were wide variations in the frequency of detection of HCV genomes in cardiomyopathy in different regions and in different populations. Major histocompatibility complex class Ⅱ genes may play a role in the susceptibility to HCV infection, and may influence the development of different phenotypes of cardiomyopathy. If in fact the myocardial damage is caused by HCV, it might be expected that interferon (IFN) administration would be useful for its treatment. Hepatitis patients receiving IFN treatment for hepatitis were screened by thallium myocardial scintigraphy, and an abnormality was discovered in half of the patients. Treatment with IFN resulted in a disappearance of the image abnormality. It has thus been suggested that mild myocarditis and myocardial damage may be cured with IFN. We have recently found that high concentrations of circulating cardiac troponin T are a specific marker of cardiac involvement in HCV infection. By measuring cardiac troponin T in patients with HCV infection, the prevalence of cardiac involvement in HCV infection will be clarified. We are proposing a collaborative work on a global network on myocarditis/cardiomyopathies due to HCV infection. (J Geriatr Cardiol 2004;1(2):83-89. )

Impact of cardiac magnetic resonance imaging in nonischemic cardiomyopathies

Non-ischemic cardiomyopathies include a wide spectrum of disease states afflicting the heart, whether a primary process or secondary to a systemic condition. Cardiac magnetic resonance imaging(CMR) has established itself as an important imaging modality in the evaluation of non-ischemic cardiomyopathies. CMR is useful in the diagnosis of cardiomyopathy, quantification of ventricular function, establishing etiology, determining prognosis and risk stratification. Technical advances and extensive research over the last decade have resulted in the accumulation of a tremendous amount of data with regards to the utility of CMR in these cardiomyopathies. In this article, we review CMR findings of various non-ischemic cardiomyopathies and focus on current literature investigating the clinical impact of CMR on risk stratification, treatment, and prognosis.

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.

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.

Transient stress cardiomyopathies in the elderly： Clinical ＆ Pathophysiologic considerations

Transient stress-induced cardiomyopathies have been increasingly recognized and while rare,they tend to affect elderly women more than other demographic groups.One type,often called tako-tsubo cardiomyopathy （TTC）,is typically triggered by significant emotional or physical stress and is associated with chest pain,electrocardiogram （ECG） changes and abnormal cardiac enzymes.Significant left ventricular regional wall motion abnormalities usually include an akinetic ＂ballooning＂ apex with normal or hyperdynamic function of the base.A second type,often called neurogenic stunned myocardium,typically associated with subarachnoid hemorrhage,also usually presents with ECG changes and positive enzymes,but the typical wall motion abnormalities seen include normal basal and apical left ventricular contraction with akinesis of the mid-cavity in a circumferential fashion.The pathophysiology,clinical care and typical courses,are reviewed.

Weighted gene co-expression network analysis reveals similarities and differences of molecular features between dilated and ischemic cardiomyopathies

Cardiomyopathies represent the most common clinical and genetic heterogeneous group of diseases that affect the heart function.Though progress has been made to elucidate the process,molecular mechanisms of different classes of cardiomyopathies remain elusive.This paper aims to describe the similarities and differences in molecular features of dilated cardiomyopathy(DCM)and ischemic cardiomyopathy(ICM).We firstly detected the co-expressed modules using the weighted gene co-expression network analysis(WGCNA).Significant modules associated with DCM/ICM were identified by the Pearson correlation coefficient(PCC)between the modules and the phenotype of DCM/ICM.The differentially expressed genes in the modules were selected to perform functional enrichment.The potential transcription factors(TFs)prediction was conducted for transcription regulation of hub genes.Apoptosis and cardiac conduction were perturbed in DCM and ICM,respectively.TFs demonstrated that the biomarkers and the transcription regulations in DCM and ICM were different,which helps make more accurate discrimination between them at molecular levels.In conclusion,comprehensive analyses of the molecular features may advance our understanding of DCM and ICM causes and progression.Thus,this understanding may promote the development of innovative diagnoses and treatments.

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.

Value of cardiac magnetic resonance on the risk stratification of cardiomyopathies

Cardiomyopathies represent a diverse group of heart muscle diseases with varying etiologies,presenting a diagnostic challenge due to their heterogeneous manifestations.Regular evaluation using cardiac imaging techniques is impera-tive as symptoms can evolve over time.These imaging approaches are pivotal for accurate diagnosis,treatment planning,and optimizing prognostic outcomes.Among these,cardiovascular magnetic resonance(CMR)stands out for its ability to provide precise anatomical and functional assessments.This manuscript ex-plores the significant contributions of CMR in the diagnosis and management of patients with cardiomyopathies,with special attention to risk stratification.CMR’s high spatial resolution and tissue characterization capabilities enable early detec-tion and differentiation of various cardiomyopathy subtypes.Additionally,it offers valuable insights into myocardial fibrosis,tissue viability,and left ven-tricular function,crucial parameters for risk stratification and predicting adverse cardiac events.By integrating CMR into clinical practice,clinicians can tailor patient-specific treatment plans,implement timely interventions,and optimize long-term prognosis.The non-invasive nature of CMR reduces the need for invasive procedures,minimizing patient discomfort.This review highlights the vital role of CMR in monitoring disease progression,guiding treatment decisions,and identifying potential complications in patients with cardiomyopathies.The utilization of CMR has significantly advanced our understanding and management of these complex cardiac conditions,leading to improved patient outcomes and a more personalized approach to care.