Current Advances In Treatment Research Articles

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case-Control Study.

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients' blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

BRAFV600E Metastatic Melanoma Journey: A Perspective from a Patient and his Oncologist.

This article is co-authored by a patient with BRAFV600E metastatic melanoma and his treating oncologist. The patient describes how he coped with his diagnosis and treatment. He details the pathway of his melanoma treatment, which has spanned over 10 years, including surgical interventions, medical treatment, and participation in clinical trials. He relates his experience of living with the disease-and the adverse effects of treatment-in the long term. The clinical perspective of his treating oncologist reviews the diagnostic process and explains how the therapeutic options were selected for and with the patient. The oncologist also addresses the integration of the patient into clinical trials involving programmed death-1 (PD-1) inhibitors and BRAF/MEK inhibitors. Challenges related to the adverse effects that occurred and the personalised treatment of the patient are also discussed. Finally, the article evaluates current advances in treatment and future therapeutic approaches. This case highlights the challenges of identifying which therapeutic options are most appropriate for individual patients with BRAFV600E metastatic melanoma.

Neurological, Extracardiac, and Cardiac Manifestations of Ebstein's Anomaly Along With its Genetics, Diagnostic Techniques, Treatment Updates, and the Future Ahead.

Ebstein's anomaly is a congenital heart defect characterized by the displacement of the tricuspid valve, and its leaflets to be malformed. Due to the defect involving the tricuspid valve, there is a reverse flow of blood into the right-sided atrium, which may lead to cardiac hypertrophy and edema of the lower extremities. There is a decreased flow of blood out of the right heart due to reduced right ventricular contractility and tricuspid regurgitation. Children afflicted with thisanomaly usually suffer from atrial septal defect and this is usually diagnosed before birth on a routine ultrasound scan. In neonates, cyanosis can be seen due to right-to-left atrial shunting or as a result of severe congestive heart failure. If the infant has pulmonary hypertension, cyanosis is markedly increased as there will be a limitation in pulmonary blood flow. In adults, arrhythmias, cyanosis, and heart failure are seen. The bundle of Kent leads to the formation of an electrical conduction abnormality between the right ventricle and atrium. This leads to a condition commonly known as Wolff- Parkinson-White syndrome in patients. An enlarged spherical heart is usually present on a chest X-ray. ECG changes of Ebstein's anomaly show taller than usual P waves, PR prolongation, and right bundle branch block. There can be certain neurological and extracardiac manifestations too such as hemiplegia, stroke, dysarthria, etc. During fetal life, specifically at 16 and 20 weeks of gestation, the anomaly can be diagnosed via echocardiography. Prostaglandin infusion (PGE1) is given to maintain pulmonary circulation in neonates if cyanosis is seen. In children and adults with congestive cardiac failure due to this anomaly, medical management includes digoxin, beta-blockers, diuretics, and angiotensin converting enzyme (ACE) inhibitors to improve heart failure. Surgical treatment includes valve reconstruction. In this article, we review the pathophysiology, genetics, diagnosis, management, and prognosis of Ebstein's Anomaly along with a comprehensive discussion on its genetics, neurological manifestations, extracardiac features, and current advancements in treatment.

Systemic Sclerosis: A Case Report and Review of Current Advances in Treatment

Systemic sclerosis (SSc) is a chronic multisystem disease characterized by excess deposition of connective tissue in skin and internal organs, associated with microvasculature changes and immunologic abnormalities.
 We hereby report a case of scleroderma in a 52 year old female with classical clinical and histopathological findings. The latter part of this article discusses and reviews existing and novel emerging therapies for the treatment of SSc, with an emphasis on recent trials targeting the cutaneous and pulmonary manifestations of this disease.

The diagnostic and prognostic potential of the EGFR/MUC4/MMP9 axis in glioma patients

Glioblastoma is the most aggressive form of brain cancer, presenting poor prognosis despite current advances in treatment. There is therefore an urgent need for novel biomarkers and therapeutic targets. Interactions between mucin 4 (MUC4) and the epidermal growth factor receptor (EGFR) are involved in carcinogenesis, and may lead to matrix metalloproteinase-9 (MMP9) overexpression, exacerbating cancer cell invasiveness. In this study, the role of MUC4, MMP9, and EGFR in the progression and clinical outcome of glioma patients was investigated. Immunohistochemistry (IHC) and immunofluorescence (IF) in fixed tissue samples of glioma patients were used to evaluate the expression and localization of EGFR, MMP9, and MUC4. Kaplan–Meier survival analysis was also performed to test the prognostic utility of the proteins for glioma patients. The protein levels were assessed with enzyme-linked immunosorbent assay (ELISA) in serum of glioma patients, to further investigate their potential as non-invasive serum biomarkers. We demonstrated that MUC4 and MMP9 are both significantly upregulated during glioma progression. Moreover, MUC4 is co-expressed with MMP9 and EGFR in the proliferative microvasculature of glioblastoma, suggesting a potential role for MUC4 in microvascular proliferation and angiogenesis. The combined high expression of MUC4/MMP9, and MUC4/MMP9/EGFR was associated with poor overall survival (OS). Finally, MMP9 mean protein level was significantly higher in the serum of glioblastoma compared with grade III glioma patients, whereas MUC4 mean protein level was minimally elevated in higher glioma grades (III and IV) compared with control. Our results suggest that MUC4, along with MMP9, might account for glioblastoma progression, representing potential therapeutic targets, and suggesting the ‘MUC4/MMP9/EGFR axis’ may play a vital role in glioblastoma diagnostics.

Role of ncRNA in multiple myeloma.

Multiple myeloma (MM) remains incurable despite advances in current treatment. Patients with MM exhibit significant variations in their prognosis and survival. Recently, genetic abnormalities, such as chromosomal variations and gene mutations, have been increasingly recognized in MM. Therefore, better prognostic indicators of MM are required for the diagnosis and treatment of patients with MM. ncRNAs are non-protein-coding transcripts that regulate gene expression at the post-transcriptional level. Deregulation of ncRNAs affects cell cycle progression, cancer cell invasionand metastasis. The abnormal expression of these ncRNAs is also critical for the pathogenesis of several cancers, including MM. Hence, this review aims to discuss the recent findings on the role of regulatory ncRNAs and evaluate their potential value in MM.

A Multiscale View of the Mechanisms Underlying Ketamine's Antidepressant Effects: An Update on Neuronal Calcium Signaling.

Major depressive disorder (MDD) is a debilitating disease characterized by depressed mood, loss of interest or pleasure, suicidal ideation, and reduced motivation or hopelessness. Despite considerable research, mechanisms underlying MDD remain poorly understood, and current advances in treatment are far from satisfactory. The antidepressant effect of ketamine is among the most important discoveries in psychiatric research over the last half-century. Neurobiological insights into the ketamine’s effects have shed light on the mechanisms underlying antidepressant efficacy. However, mechanisms underlying the rapid and sustained antidepressant effects of ketamine remain controversial. Elucidating such mechanisms is key to identifying new therapeutic targets and developing therapeutic strategies. Accumulating evidence demonstrates the contribution of the glutamatergic pathway, the major excitatory neurotransmitter system in the central nervous system, in MDD pathophysiology and antidepressant effects. The hypothesis of a connection among the calcium signaling cascade stimulated by the glutamatergic system, neural plasticity, and epigenetic regulation of gene transcription is further supported by its associations with ketamine’s antidepressant effects. This review briefly summarizes the potential mechanisms of ketamine’s effects with a specific focus on glutamatergic signaling from a multiscale perspective, including behavioral, cellular, molecular, and epigenetic aspects, to provide a valuable overview of ketamine’s antidepressant effects.

Treatment outcomes in refractory lupus nephritis: Data from an observational study.

Despite current advances in treatment, refractory lupus nephritis (RLN) continues to pose a challenge. The present paper studies the clinical profile and treatment outcomes in patients with RLN. This observational, bidirectional study enrolled consecutive lupus nephritis (LN) patients from August 2018 to January 2019, who either failed to improve within three months, did not achieve partial renal response (PR) at six months, or did not achieve complete renal response (CR) after two years of treatment. Patients were followed every three months; treatment details and outcomes [CR, PR, no renal response (NR)], doubling serum creatinine, and death were recorded. Group comparisons were made using ANOVA and chi-square test. Factors affecting renal response were studied using linear regression. Forty-five of forty-eight enrolled patients completed at least nine months of follow-up and were included in outcome analysis. The median (IQR) SLE duration was three years (2-6 years). The majority of patients (n = 25) had proliferative LN (ISN/RPS class III/IV), with nine patients having pure membranous LN (class V). The mean activity and chronicity indices were 8 and 0. Over a median (IQR) follow-up period of 15 (12-27) months, 28 had CR, 9 had PR, and 8 showed no response to a switch in an immunosuppressive (IS) agent. Repeat renal biopsy (n = 8) with a mean (±SD) biopsy interval of 2 (±1) years showed histological class transformation in more than half of the patients. There was no significant difference in treatment outcome and time to attain response based on individual IS agent or sequence of IS agents used. None of the variables (duration of SLE or nephritis, baseline SLEDAI, leukopenia, hypertension, elevated anti-dsDNA, low complements, serum albumin, 24-hour urinary protein, biopsy class) predicted renal response on univariate analysis. No patient had a doubling of serum creatinine or progression to end-stage renal disease. There were three deaths, all related to infection. A change in immunosuppression produces response in most RLN patients while a fifth of them showed no response to therapy. No predictor of renal response was identified. Histologic class switch was frequent. Renal function did not decline over a year of follow-up.

Correlation between Serum Uric Acid Level and Severity of Coronary Artery Stenosis in Patients with Acute Coronary Syndrome

Acute coronary syndrome (ACS) is a life-threatening disease which remains one of the causes of high morbidity and mortality despite the current advances in treatment. The relationship between the serum uric acid (SUA) level and ischemic heart disease continues to be controversial and still has not been established as a cardiovascular risk factor. The cooperative interaction between the two factors has not yet fully understood. Prior epidemiological evidence of the causal relationship between the too is still argumentative. Various studies have been done using the same methods; yet, the outcomes were different. This study aimeds to conduct a meta-analysis to synthesize the results of recent studies in order to obtain accurate quantitative data. This systematic study followed the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guideline and studies published in the period of January 2010 to May 2020 were screened using the Cochrane Library, Ebsco, Medline/PubMed, ProQuest and Science Direct as the sources. Meta-analysis was conducted to synthesize the association between the SUA level and severity of coronary artery stenosis using random effect model to account for possible study heterogeneity. Heterogeneity was assessed using I2 and the meta-analysis was performed using Comprehensive Meta Analysis Version 3 (CMA3) software. Five studies (n = 601 subjects) identified a correlation between serum uric acid level and Gensini score (r = 0.548; p <0.001) in ACS patients. Heterogeneity bias was found in the analysis, whereas publication bias was not found. Thus, the severity of coronary artery stenosis in patients with ACS is positively correlated with serum uric acid level.

MicroRNA-487a-3p inhibits the growth and invasiveness of oral squamous cell carcinoma by targeting PPM1A

ABSTRACT Oral squamous cell carcinoma (OSCC) forms the majority of the entire cancerous tumors which occur in the mouth. Current treatment advances, such as surgical resection, chemotherapy, and radiotherapy, have significantly helped reduce OSCC. However, the overall patient survival rate remains relatively low. MiRNAs, a non-coding RNA group, are essential for multiple biological functions, which are essential for the progression of cancer, including survival of the cell, migration, multiplication, differentiation, and apoptosis. The study aimed to explore the existing association between miR-487a-3p and PPM1A and elucidating their role in modulation of proliferation in OSCC cell lines. In this study, we used CAL-27 and TCA-8113 OSCC cell lines and human samples to validate our results. The manifestation of miR-487a-3p and PPM1A was checked using quantitative real-time PCR. The miR-487a-3p and PPM1A binding was investigated through western blot assay and dual-luciferase reporter gene. Functional experiments, including colony formation, CCK-8, and transwell experimentations, were undertaken to validate cells’ growth and invasion activities. According to the results, the expression of miR-487a-3p is regulated in the OSCC cell lines compared to normal cells. Moreover, the mimicking of miR-487a-3p significantly reduces the OSCC cell growth and invasion, and PPM1A overexpression exerts oncogenic effects and hinders the anti-oncogenic effects of miR-487a-3p. In conclusion, the study demonstrated that miR-487a-3p might act as a tumor suppressor by inhibiting the growth and invasion of OSCC via regulating PPM1A expression.

Conclusion: advances in current treatment for patients with newly diagnosed multiple myeloma.

Conclusion: advances in current treatment for patients with newly diagnosed multiple myeloma

Abstract 250: Economic Burden of Mortality and Cardiovascular Events among Patients with Acute Coronary Syndromes in a Commercial Health Plan

Introduction: Despite current advances in treatment, acute coronary syndromes (ACS), continues to result in high morbidity and mortality. Annually, an estimated 1.5 million hospital discharges involve patients with ACS. As such, ACS is associated with a substantial economic burden to the US healthcare system, with current estimates ranging from $75-$150 billion annually in aggregate direct medical costs. Adding anticoagulant to standard of care (SOC) may reduce the number of cardiovascular (CV) events in ACS patients. This study estimates the economic burden of mortality and CV events among ACS patients within a commercial health plan. Methods: We developed an Excel-based decision-analytic model to estimate the annual economic burden of mortality and CV events (myocardial infarction (MI), ischemic stroke (IS), stent thrombosis (ST), intracranial hemorrhage (ICH), and major bleeds) in a hypothetical commercial plan with a population of ACS patients who were candidates for rivaroxaban anticoagulation therapy. The baseline ACS population of 6,650 patients was calculated from literature estimates and included 100% on standard of care, and 0% on dual SOC and rivaroxaban anticoagulation therapy. ACS prevalence was adjusted for age and anticoagulation status. Estimates for the two-year rates for mortality and CV events were obtained from the two-year randomized double-blind, placebo-controlled rivaroxaban ATLAS clinical trial. Healthcare costs were drawn from the published literature and adjusted to 2011 USD. Results: The baseline model projected a total of 299 deaths from any cause, resulting in an estimated $9.52 million in two-year mortality-related healthcare costs to a commercial health plan. In addition, the baseline model estimated 439 MI, 67 IS, 193 ST, 13 ICH, and 27 major bleeding events that were not associated with CABG, resulting in a total of $41.3 million in two-year healthcare costs to a commercial health plan. All other factors being equal, a 10% increase in the dual SOC and rivaroxaban anticoagulation therapy from the SOC population would reduce the number of mortalities by 11, ST events by 5, and MI events by 3, while the number of ischemic stroke events would remain the same. Conversely, there would be an increase of 1 ICH event and 7 major bleeding events not associated with CABG. Two-year ACS-related mortality and CV event costs to the commercial health plan would be reduced by $48,437 for every 1,000 patients with ACS. Conclusion: Our findings suggest that a modest 10% increase in anticoagulant use among patients with ACS would reduce mortality, MI, ST and related healthcare costs by 4%, 0.7%, and 3%, respectively. Addition of anticoagulation therapy potentially reduces the incidence of ACS-related mortality, MI, ST and associated healthcare costs to a commercial health plan, and benefits from anticoagulation use should be balanced against the risk of bleeding.

Advances in current treatment for patients with newly diagnosed multiple myeloma

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of monoclonal plasma cells at multiple sites in the bone marrow, with accompanying alterations in the bone marrow microenvironment, and suppression of the host antitumor immune response, resulting in the uncontrolled accumulation of malignant plasma cells and excess secretion of immunoglobulins (paraproteins). MM, in almost all cases, is preceded by a premalignant phase, monoclonal gammopathy of undetermined significance (MGUS).1 MGUS is present in ∼3% of the population aged >50 years and progresses through asymptomatic smoldering myeloma to symptomatic MM at a rate of 1% annually.2 MM is usually diagnosed when the disease becomes symptomatic, classically presenting with bone pain, anemia, renal insufficiency, hypercalcemia and recurrent infections due to immune deficiency. MM has an annual age-adjusted incidence of 5.8 cases per 100 000 of the population and predominantly affects older individuals; the median age at diagnosis is 69 years.3, 4 MM is an incurable disease and the survival prognosis for patients diagnosed with MM has historically been poor. The introduction of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) in the 1980s improved response rates and progression-free survival (PFS), but median overall survival (OS) remained at 65 years for whom OS is only 26 months.8 The treatment of MM in elderly patients remains a clinical challenge—they are usually ineligible for stem cell transplantation and are unable to tolerate the toxicity of intense chemotherapy. Besides age at diagnosis and disease stage, prognosis is also adversely affected by the presence of several ‘high-risk' genetic markers, including deletions of chromosome 13, hypodiploidy and deletions of chromosome 17p, t(4;14) or t(14;16).2 Significant improvements in response rates, PFS and OS have been seen in patients with NDMM treated with combination regimens based on immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib).9, 10, 11, 12, 13, 14, 15, 16 These advances, coupled with an improved understanding of the disease, have shifted the treatment paradigm in MM. The current aim of this therapy for patients with NDMM is to achieve deep and long-term clinical remissions with early and continued use of regimens that are effective and safe to maintain disease control and extend OS. The purpose of this supplement is to review current approaches to the treatment of NDMM, providing an update on the most recent developments and treatment regimens involving the novel therapies, and highlighting the key issues that clinicians face when devising a long-term management strategy for NDMM patients. In the first article, Drs Munshi and Girnius provide an overview of the current approaches related to the diagnosis and management of MGUS, smoldering MM and MM, highlighting the need for a long-term approach to optimize disease control and the importance of a risk-stratified approach to treatment. In the second article, Drs Giralt and Bensinger discuss the role of ASCT and the role of novel therapies in induction treatment. The question of how to optimize the response to ASCT using consolidation therapy with novel agents is then addressed by Drs Moreau and Touzeau, including a review of recent clinical evidence showing the benefit of post-transplantation maintenance treatment with novel agents to extend PFS. Finally, Professor San Miguel and Dr Mateos provide an overview of the treatment options available for NDMM patients ineligible for HDT–ASCT because of either advanced age or comorbid conditions. Again, the focus is on the way in which the novel therapies have transformed the treatment options available to this population, who represent the majority of NDMM patients. In this setting, early and continued treatment with novel agents appears to have the potential to extend survival times for elderly and frail patients for whom outcomes have remained poor. Collectively, these articles illustrate how the introduction of novel agents, such as lenalidomide and bortezomib, has transformed the approach to treatment of NDMM and has provided a valuable clinical update for those working in this field.

Poster 18: Squamous Cell Carcinoma of the Oral Tongue: Histopathologic Markers Associated With Outcome

Cancer of the head and neck is among the top 10 malignancies in the United States and worldwide, with squamous cell carcinoma (SCC) of the oral cavity/oropharynx representing the vast majority. Despite current advances in treatment, the 5-year disease free survival remains largely unchanged over the last several decades. Advanced stage tumors (III/IV) are treated with multi-modality therapy while early tumors (stages I/II) are treated for the most part with single modality treatment. Treatment based on the TNM staging system unfortunately carries a 25-37% rate of recurrence in this latter group of patients, further emphasizing the need for additional information on tumor characteristics that may be critical in treatment decision making.

Nerve Injury With Reflex Sympathy Dystrophy (RSD)

Reflex sympathetic dystrophy (RSD) and Causalgia are rare complications of dentoalveolar surgery that can cause debilitating, life-altering morbidity. This presentation will provide clarification of terminology and modern ISP taxonomic classification of these pain syndromes, current understanding of pathophysiology, signs and symptoms that will aid in early diagnosis, current advances in treatment, and referral recommendations.

Growing Pains

With advances in the management of patients with congenital heart disease (CHD), the number of adults with CHD has grown substantially. In the decade after the first intracardiac repair of a congenital heart defect in 1952, congenital heart surgery was associated with short-term mortality rates of 60% to 70%. 1 In the current era, mortality for even the most complex defects is 10% or less in high-volume congenital heart centers. 2 As a result of both improved surgical care and advances in medical management, more than 80% of patients born with CHD can expect to live into adulthood.3 By 2020, it is projected that the majority of patients with CHD will be 18 years of age. 4 Article p 2345 In this context, it is important to consider where and by whom these patients should be treated. Historically, CHD has been the domain of children’s hospitals with specialized resources for managing these conditions. At such centers, pediatric cardiologists, congenital heart surgeons, and anesthesiologists are arguably most familiar with the complex anatomy and physiology associated with CHD, as well as the most current treatment advances. Specialized intensive care units, nursing staffs, and radiology services are additional advantages of pediatric congenital heart centers. On the other hand, as patients with CHD move into adulthood, they acquire other medical conditions less familiar to physicians and staff at children’s hospitals, including obesity, hypertension, diabetes mellitus, and chronic lung disease. Effective management of such comorbidities may be equally important to enhancing patient longevity and quality of life and may be better entrusted to physicians and systems used to treating adults. In this issue of Circulation, Karamlou et al5 help inform one crucial component of this broader debate: which types of surgeons should be operating on adults with CHD. The

Clinical Aspects of Congenital Diaphragmatic Hernia in the Central Counties of Taiwan

SUMMARY Congenital diaphragmatic hernia (CDH) occurs approximately 1 in 3000 live births. Eighty-five percent were left sided and commonly occurred as classic posteriolateral or Bochdalek hernia. Pulmonary hypoplasia and pulmonary hypertension were frequently associated. A reported incidence of 40-50% of CDH patients were associated with other malformations, the most common of which are those involving the central nervous system. Mortality rates are around 40% but some studies reported 16-25% with current advances in treatment. From July 1995 through May 2003, 11 infants of CDH were treated at Changhua Christian Hospital (CCH). Of the infants, 2 were prenatally diagnosed, 7 (64%) were left sided, 3 (27%) were right sided and one (9%) was paraesophageally located. 8 (73%) of the infants expired either days or months after birth. Barotrauma occurred in 4(36%) infants. Three (27%) infants had pulmonary dysplasia and pulmonary hypertension. Four (3 6%) infants associated with intestinal malformation. One infant had major cardiac defects and chromosome anomaly. The mortality rate of CDH was 73%. It was higher than other studies. However, the survival rates in recent 6 years had reached 50%. It is probably related to the improvement of care. INTRODUCTION Congenital diaphragmatic hernia (CDH) is an anomaly occurs in approximately 1/3000 live births 1. The etiology of the disease was not well known. It was postulated that the defect may be related to the failure of the pleuroperitoneal canal to close during the 8th week of gestation. This may only be the explanation for patients with small diaphragmatic defect.

Beta-blocker use in decompensated heart failure

Despite the current advances in treatment, acute decompensated heart failure accounts for more than 1 million hospital admissions annually. Many of the patients hospitalized are already receiving long-term treatment with beta-blockers. For patients who receive full dose beta-blocker therapy and suffer acute decompensated heart failure, clinicians face two key questions: what to do, if anything, with the dosage of beta-blocker and what is the best way to integrate inotropic and beta-blocker therapies for patients who require inotropes. This article discusses these issues and reviews the available literature. Because these topics have received little systematic evaluation, we also present our clinical approaches to these problems.

Therapeutic choices in the current millennium: Hemophilia workshop highlights

Many issues affect hemophilia care providers when managing bleeding episodes in individuals with hemophilia. A diverse group of hemophilia providers from the United States met at two workshops to discuss the issues influencing treatment choices in the current millennium and to learn about current advances in treatment of hemophilia. This paper provides a summary of the discussions at these workshops. Despite the progress made in the management of patients with hemophilia, the workshop highlighted the fact that there were still many unanswered questions.

Development of cell markers for the identification and expansion of islet progenitor cells.

Diabetes mellitus results from the anatomical or functional loss of insulin-producing beta cells of the pancreas. Despite significant advances in current treatment, patients with diabetes still do not maintain optimal glucose levels and therefore face debilitating complications such as hypoglycemia, retinopathy or cardiovascular diseases later in life. Islet transplantation therefore holds great promise as an ultimate cure for diabetes. However, the shortage of availability of donor sources of islets for transplantation has largely hampered this therapy. In this respect, the use of alternative sources of islets such as the ex vivo culture and expansion and differentiation of functional endocrine cells for treating diabetes has been a major focus of diabetes research. The identity of the islet stem/progenitor cells has remained either elusive or at least equivocal because of the lack of cell markers for identification of these cells. Recent successes in studying the organogenesis of pancreas as well as in vitro islet progenitor cell identification studies have provided tremendous insight for the cell markers that are essential in the isolation and characterization of these cells prospectively both in vivo and in vitro. If we can identify the markers that will aid the isolation and purification of islet progenitor cells, or factors that determine pancreatic cell fate, we might be able to coerce them from turning into specific endocrine cells or pancreas in vitro. This article will focus on this subject and will review the latest achievements in the study of cell markers for islet progenitor cells.