First‐line treatment selection and early monitoring patterns in chronic phase‐chronic myeloid leukemia in routine clinical practice: SIMPLICITY

Achieving successful outcomes in chronic phase‐chronic myeloid leukemia (CP‐CML) requires careful monitoring of cytogenetic/molecular responses (CyR/MR). SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor use and management patterns in patients with CP‐CML receiving first‐line imatinib (n = 416), dasatinib (n = 418) or nilotinib (n = 408) in the US and 6 European countries in routine clinical practice. Twelve‐month follow‐up data of 1242 prospective patients (enrolled October 01 2010‐September 02 2015) are reported. 81% of patients had baseline comorbidities. Treatment selection was based on perceived efficacy over patient comorbidity profile. There was a predominance of imatinib‐treated patients enrolled earlier in the study, with subsequent shift toward dasatinib‐ and nilotinib‐treated patients by 2013/2014. Monitoring for either CyR/MR improved over time and was documented for 36%, 82%, and 95% of patients by 3, 6, and 12 months, respectively; 5% had no documentation of CyR/MR monitoring during the first year of therapy. Documentation of MR/CyR testing was higher in Europe than the US (P < .001) and at academic versus community practices (P = .001). Age <65 years, patients being followed at sites within Europe, those followed at academic centers and patients no longer on first‐line therapy were more likely to be monitored by 12 months. SIMPLICITY demonstrates that the NCCN and ELN recommendations on response monitoring have not been consistently translated into routine clinical practice. In the absence of appropriate monitoring practices, clinical response to TKI therapy cannot be established, any needed changes to treatment strategy will thus not be implemented, and long‐term patient outcomes are likely to be impacted.     

Drug‐resistant tuberculosis: Past,present, future

In a population of Mycobacterium tuberculosis, random chromosomal mutation that results in genetic resistance to anti‐tuberculosis (TB) drugs occurs at a relatively low frequency. Anti‐TB drugs impose selection pressure so that mycobacterial mutants gradually outnumber susceptible bacilli and emerge as the dominant strains. Resistance to two or more anti‐TB drugs represents cumulative results of sequential mutation. The fourth report on global anti‐TB drug resistance provides the latest data on the extent of such problem in the world. The median prevalence of multi‐drug‐resistant TB (MDR‐TB) in new TB cases was 1.6%, and in previously treated TB cases 11.7%. Of the half a million MDR‐TB cases estimated to have emerged in 2006, 50% were in China and India. The optimal duration of any given combination of anti‐TB drugs for treatment of MDR‐ and extensively drug‐resistant TB (XDR‐TB) has not been defined in controlled clinical trials. Standardized treatment may be feasible for MDR‐TB patients not previously treated with second‐line drugs, but a different strategy needs to be applied in the treatment of MDR‐TB patients who have received second‐line drugs before. Unfortunately, the reliability of drug susceptibility testing of most second‐line anti‐TB drugs is still questionable. Drug‐resistant TB is not necessarily less virulent. Findings from modelling exercise warned that if MDR‐TB case detection and treatment rates increase to the World Health Organization target of 70%, without simultaneously increasing MDR‐TB cure rates, XDR‐TB prevalence could increase exponentially. Prevention of development of drug resistance must be accorded the top priority in the era of MDR‐/XDR‐TB.     

Introduction: Antihypertensive therapy: Past, present, and future

Adapted from Messerli FH, Laragh JH: Antihypertensive therapy: Past, present and future. In Messerli FH (ed): The ABC's of Antihypertensive Therapy(English language ed.) New York: Raven Press. (Used with permission.)     

Point‐of‐care diagnosis of tuberculosis: Past,present and future

Diagnosis represents only one aspect of tuberculosis (TB) control but is perhaps one of the most challenging. The drawbacks of current tools highlight several unmet needs in TB diagnosis, that is, necessity for accuracy, rapidity of diagnosis, affordability, simplicity and the ability to generate same‐day results at point‐of‐care (POC). When a return visit is required to access test results, time to treatment is prolonged, and default rates are significant. However, a good diagnostic tool is also critically dependent on obtaining an adequate biological sample. Here, we review the accuracy and potential impact of established and newer potential POC diagnostic tests for TB, including smear microscopy, the Xpert MTB/RIF assay (Cepheid) and the Determine TB lipoarabinomannan antigen test (Alere). Novel experimental approaches and detection technologies for POC diagnosis of active TB, including nucleic acid amplification tests, detection of volatile organic compounds or metabolites, mass spectroscopy, microfluidics, surface‐enhanced Raman spectroscopy, electrochemical approaches, and aptamers among others, are discussed. We also discuss future applications, including the potential POC diagnosis of drug‐resistant TB and presumed latent TB infection. Challenges to the development and roll‐out of POC tests for TB are also reviewed.     

呼吸介入治疗的元宇宙：前生、今世与未来

<正>元宇宙(Metaverse)一词,诞生于1992年尼尔·斯蒂芬森(Neal Stephenson)的科幻小说《雪崩》(Snow Crash),小说描绘了一个庞大的虚拟现实世界,人们用数字化身来控制,并相互竞争以提高自己的地位。实际上,它就是一个虚拟的新世界,生活在那个时代的人类将会拥有两个身份,一个是虚拟身份,一个是现实身份。元宇宙类似一个完全虚拟的多人社交世界,它可以是单纯的社交娱乐,也可以是一个游戏的服务器,每一个玩家在其中都有属于自己的虚拟身份,并且可以完全沉浸其中,与其它玩家进行社交、对战、娱乐等行为。     

Rotation of nilotinib and imatinib for first‐line treatment of chronic phase chronic myeloid leukemia

The introduction of second‐generation tyrosine‐kinase inhibitors (TKIs) has generated a lively debate on the choice of first‐line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR‐ABL1 positive, chronic phase, CML patients. One hundred twenty‐three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5‐year overall survival and progression‐free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use. Am. J. Hematol. 91:617–622, 2016. © 2016 Wiley Periodicals, Inc.     

Ribavirin:Past,present and future

Before the advent of direct acting antiviral agents(DAAs) ribavirin, associated to pegylated-interferon played a crucial role in the treatment of chronic hepatitis C, preventing relapses and breakthroughs. In the present era of new potent DAAs, a place is still devoted to the drug. Ribavirin associated with sofosbuvir alone is efficient in the treatment of most cases of G2 infected patients. All options currently available for the last difficult-to-treat cirrhotic G3 patients contain ribavirin. Reducing treatment duration to 12 wk in G1 or G4 cirrhotic compensated patients is feasible thanks to ribavirin. Retreating patients with acquired anti NS5 A resistance-associated variants using ribavirin-based strategies could be useful. The addition of ribavirin with DAAs combinations however, leads to more frequent but mild adverse events especially in cirrhotic patients. Preliminary data with interferon-free second generation DAAs combinations without ribavirin suggest that future of the drug is jeopardized even in difficult-totreat patients: The optimization of ribavirin dosage according to an early monitoring of blood levels has been suggested to be relevant in double therapy with peginterferon or sofosbuvir but not with very potent combinations of more than two DAAs.     

Antiviral therapy for chronic hepatitis C: past, present, and future

Antiviral therapy for chronic hepatitis C has dramatically advanced since the discovery of the hepatitis C virus (HCV) in 1989 and the introduction of interferon (IFN) monotherapy in the early 1990s. The current standard therapy uses a combination of pegylated IFN and ribavirin. The duration of therapy and response to therapy are HCV genotype-specific. Genotype 1 patients require 48 weeks of the combination therapy for 50% successful viral elimination, while genotype 2 patients require 24 weeks of therapy for 80% or 90% viral elimination. Early viral kinetics after the initiation of therapy is a useful predictor of the sustained virologic response (SVR), which is formally determined at 24 weeks after completion of the treatment. For example, an early virologic response, which is determined by a 2-log reduction of HCV RNA or viral elimination at 12 weeks after the initiation of therapy, is a strong negative predictor of SVR in genotype 1 patients. In contrast, a rapid virologic response of HCV RNA-negative at 4 weeks after the initiation of therapy identifies genotype 2 “super-responders,” who may require a shorter period of therapy. Adherence to therapy is one of the most important factors for successful viral clearance. Hematopoietic growth factors such as epoetin and granulocyte-colony stimulating factor help reduce therapy-mediated cytopenia and improve patient compliance, thereby leading to better viral clearance. New types of anti-HCV agents such as HCV protease and polymerase inhibitors are needed for those patients that do not respond to combination therapy.     

Helicobacter pylori: Past, present and future

Abstract Much has been achieved in Helicobacter pylori research, to the point that the growth of new knowledge is bound to slow down. However, expectations for further developments remain high. Knowledge about the characteristic organism and behaviour is already extensive. Particularly intriguing are the differences in genetic make-up in the various geographical regions. Sadly, detailed knowledge on how the organism spreads is still lacking. The spectrum of clinical presentation in humans is largely known. Helicobacter pylori is disappearing worldwide, allowing the relative frequency of H. pylori n-egative ulcer disease to increase. The extent to which H. pylori disappearance and eradication is responsible for decreasing prevalence of gastric cancer remains speculative. Antimicrobial therapy is dominated by proton pump inhibitor triple therapy as first line therapy, with quadruple therapy as second rescue line therapy. The long-term consequences of the rising resistance to the 'key' antimicrobials are so far unknown, because few data are available on therapeutic outcomes in routine practice outside pharmaceutical trials.     

Heart regeneration: Past, present and future

The heart has been considered a post-mitotic organ without regenerative capacity for most of the last century. We review the evidence that led to this hypothesis in the early 1900s and how it was progressively modified, culminating with the report that we renew 50% of our cardiomyocytes during our lifetime. The future of cardiac regenerative therapies is discussed, presenting the difficulties to overcome before repair of the diseased heart can come into clinical practice.     

Stents for colorectal obstruction:Past,present,and future

Since the development of uncovered self-expanding metal stents(SEMS) in the 1990 s, endoscopic stents have evolved dramatically. Application of new materialsand new designs has expanded the indications for enteral SEMS. At present, enteral stents are considered the first-line modality for palliative care, and numerous types of enteral stents are under development for extended clinical usage, beyond a merely palliative purpose. Herein, we will discuss the current status and the future development of lower enteral stents.