2019 INTERNATIONAL MEDIA KIT · 2019-02-22 · 2019 INTERNATIONAL MEDIA KIT | nejmadsales.org 3...

2019 INTERNATIONAL MEDIA KIT Print

Effective January 1, 2019 Revised September 10, 2018

The New England Journal of Medicine

NEJM Journal Watch

Results In Newsletter Series

http://www.nejmgroup.org

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A Quarterly Publication of

Volume 8, issue 2

RESULTS IN

Arthritis/Rheumatology

The Most-Viewed Articles about Arthritis/Rheumatology from February to April 2017

DISTRIBUTION PROVIDED THROUGH A GRANT FROM« Overexpression of the Cytokine BAFF and Autoimmunity Risk. See article on page 7.

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ORIGINAL ARTICLE

Adalimumab plus Methotrexate for Uveitis in Juvenile Idiopathic ArthritisAthimalaipet V. Ramanan, F.R.C.P.C.H., F.R.C.P., and others

Juvenile idiopathic arthritis (JIA) is the most com-mon rheumatic disease in children. Children with JIA are at risk for inflammation of the uvea (uveitis). Uveitis develops in approximately 12 to 38% of pa-tients with JIA within 7 years after the onset of ar-thritis.1,2 Despite current screening and therapeutic options, visual impairment in both eyes may devel-op in up to 15% of children with JIA-associated uve-itis, and they may be certified as legally blind.3,4

Experimental models of autoimmune uveitis have shown that tumor necrosis factor α (TNF-α) plays a pivotal role in the pathogenesis,5 findings that have been borne out in the treatment of uve-itis in adults6-8 and in pediatric case series.9-17 Adalimumab is a fully humanized anti–TNF-α monoclonal antibody. A multicenter, randomized, double-blind, parallel-group trial showed a sig-nificant benefit of adalimumab in children with active rheumatoid arthritis.18 We carried out the SYCAMORE trial to assess the role of adalimu mab in the treatment of methotrexate-refractory JIA-associated uveitis.

M E T HODS

Protocol and Trial PopulationIn this multicenter, double-blind, randomized, placebo-controlled trial, the primary end point

was the efficacy of adalimumab in children with active JIA-associated uveitis, as measured by var-ious scoring systems. All the patients had been receiving a stable weekly dose of methotrexate for at least 12 weeks.

An independent ethics committee and the Medi-cines for Healthcare Products Regulatory Agency approved the trial protocol (available with the full text of this article at NEJM.org). Each parent or guardian provided written informed consent, and each child gave assent when appropriate. The au-thors vouch for the fidelity of this report and the trial to the protocol. AbbVie provided the active drug and placebo that were used in the trial. AbbVie had no part in the trial design, the collec-tion or analysis of the data, or the preparation of the manuscript. AbbVie representatives reviewed the final draft of the manuscript. All the authors assume responsibility for the accuracy and com-pleteness of the data and analyses. University Hos-pitals Bristol NHS Foundation Trust, as the sponsor of this trial, has a data-sharing agreement with AbbVie in support of regulatory purposes.

Children and adolescents 2 years of age or older who had active JIA-associated uveitis were eligible to undergo randomization. Stable metho-trexate treatment meant that the dose (10 to 20 mg

EDITORIAL

Adalimumab in the Treatment of Uveitis in Juvenile Idiopathic ArthritisJennifer E. Thorne, M.D., Ph.D.

Uveitis encompasses a collection of ocular diseases that are characterized by intraocular inflammation and categorized according to the anatomical loca-tion of the inflammation in the eye. In the United States, uveitis is estimated to be the fifth or sixth leading cause of blindness and affects a broad range of age groups, including children. As such, there is the potential for more years lost because of visual disability than from age-related ocular diseases that affect people much later in life.1,2 Juvenile idiopathic arthritis (JIA)–associated uveitis is typically a chronic bilateral anterior uveitis and is among the most common forms of uveitis in children. JIA- associated uveitis often manifests with ocular com-plications resulting in visual loss, and it therefore necessitates aggressive therapy, typically in the form of immunosuppressive drugs.3

There has been an upward trend in the frequen-cy of published descriptions of clinical trials inves-tigating treatments for uveitis. These have included government-sponsored and industry-sponsored trials, as well as placebo-controlled and compara-tive trials, which have involved the regional and systemic administration of glucocorticoids and immunosuppressive agents, including biologic agents. Most of these studies, including ones showing the ability of adalimu mab to reduce the risk of visual impairment and uveitis recurrence,4,5 have enrolled adult patients who had received a diagnosis of a heterogeneous group of intermedi-ate or posterior uveitides or panuveitides.

In this [April 27] issue of the Journal [N Eng J Med 2017;376], Ramanan and colleagues report the results of a randomized, controlled clinical trial

INSIDE

ORIGINAL ARTICLE

Inhibiting Plasma Kallikrein for Hereditary Angioedema Prophylaxis p. 2

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ORIGINAL ARTICLE

Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis p. 3

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

REVIEW ARTICLE

Psoriatic Arthritis p. 6

abstractBACKGROUNDAdalimumab, a fully human anti–tumor necrosis factor α monoclonal antibody, is effective in the treatment of juvenile idiopathic arthritis (JIA). We tested the efficacy of adalimumab in the treatment of JIA-associated uveitis.

METHODSIn this multicenter, double-blind, randomized, placebo-controlled trial, we assessed the efficacy and safety of adalimumab in children and adolescents 2 years of age or older who had active JIA-associated uveitis. Patients who were taking a stable dose of methotrexate were ran-domly assigned in a 2:1 ratio to receive either adalimu-mab (at a dose of 20 mg or 40 mg, according to body weight) or placebo, administered subcutaneously every 2 weeks. Patients continued the trial regimen until treat-ment failure or until 18 months had elapsed. They were followed for up to 2 years after randomization. The pri-mary end point was the time to treatment failure, de-fined according to a multicomponent intraocular in-flammation score that was based on the Standardization of Uveitis Nomenclature criteria.

RESULTSThe prespecified stopping criteria were met after the enrollment of 90 of 114 patients. We observed

16 treatment failures in 60 patients (27%) in the adalim-umab group versus 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P<0.0001 [the prespecified stopping boundary]). Adverse events were reported more frequently in patients receiving adalim-umab than in those receiving placebo (10.07 events per patient-year [95% CI, 9.26 to 10.89] vs. 6.51 events per patient-year [95% CI, 5.26 to 7.77]), as were serious ad-verse events (0.29 events per patient-year [95% CI, 0.15 to 0.43] vs. 0.19 events per patient-year [95% CI, 0.00 to 0.40]).

CONCLUSIONSAdalimumab therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis who were taking a stable dose of methotrexate. Patients who received adalimumab had a much higher incidence of adverse events and serious ad-verse events than those who received placebo. (Funded by the NIHR Health Technology Assessment Programme and Arthritis Research UK; SYCAMORE EudraCT num-ber, 2010-021141-41.)

continued on page 7

continued on page 4


Volume 10, issue 1

DISTRIBUTION PROVIDED THROUGH A GRANT FROM

The Most-Viewed Articles about Asthma/Lung Disease from September 2017 to January 2018

« Mepolizumab for Eosinophilic COPD See article on page 3.

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PERSPECTIVE

Where There’s Wildfire, There’s SmokeJohn R. Balmes, M.D.

With the undeniable march of climate change, the danger of catastrophic wildfires is increasing around the globe, with such fires occurring in Australia, Canada, Chile, Indonesia, Portugal, and Russia, as well as the United States, over the past decade. Large forest fires in the western United States have been nearly five times as frequent on an annual basis as they were 50 years ago. These fires are burning more land area and lasting much longer. The wildfire season has also become much longer, as exemplified by the Thomas fire near Santa Barbara, which became California’s largest wildfire in modern history on December 22, 2017; the wildfire season in California typically ends in October, when autumn rains begin.

When catastrophic wildfires either come near or hit populated urban areas, as has recently oc-curred in both northern and southern California, large numbers of people are exposed to relatively high levels of smoke (see images on page 5). Wildfire smoke contains carbon dioxide, water vapor, carbon monoxide, particulate matter, complex hydrocarbons, nitrogen oxides, trace minerals, and several thousand other compounds. The actual composition of smoke depends on the fuel type (e.g., deciduous vs. coniferous trees), the temperature of the fire, and the wind condi-tions. Wood smoke contains many of the same toxic and carcinogenic substances as cigarette smoke, including benzene, benzo[a]pyrene, and dibenz[a,h]anthracene.

Particulate matter (PM) — typically a mixture of solid particles and liquid droplets — is the prin-cipal pollutant of health concern from wildfire smoke for the relatively short-term exposures (hours to weeks) typically experienced by the pub-lic. Most PM in wood smoke is very small (0.4 to 0.7 μm), and particles of this size can be inhaled into the alveoli. The 24-hour air-quality standard set by the U.S. Environmental Protection Agency (EPA) for fine particles (PM2.5, particles smaller than 2.5 μm in mass median aerodynamic

INSIDE

EDITORIAL

Eosinophil Biology in COPD p. 2

ORIGINAL ARTICLE

Mepolizumab for Eosinophilic COPD p. 3

Long-Term Effects of Inhaled Budesonide p. 4

ORIGINAL ARTICLE

Airway Mucin Concentration as a Marker of Chronic BronchitisMehmet Kesimer, Ph.D., and others

Human airway surfaces are protected from the nox-ious effects of inhaled substances by a mucus clear-ance system that traps deposited materials and clears them from the lung.1 A failure of mucus transport, with pulmonary mucus accumulation, contributes to sputum production, airflow obstruc-tion, and exacerbations in muco-obstructive pulmo-nary diseases.2-6 One such muco-obstructive disease is chronic bronchitis, also known as chronic mucus hypersecretion. Chronic bronchitis is a syndrome that is associated with cigarette smoking; it is de-fined by patient-reported chronic cough and spu-tum production and, when associated with airflow obstruction, is a component of chronic obstructive pulmonary disease (COPD). Despite the importance of mucus accumulation in the pathogenesis of chronic bronchitis, a unifying hypothesis that de-scribes the failure of mucus flow with consequent mucus accumulation in chronic bronchitis has been lacking, and there have been no laboratory methods to confirm a diagnosis of chronic bronchitis.

The mucus that forms the protective barrier on airway surfaces is composed of water (approxi-mately 98%), ions, globular proteins, and polymeric mucin macromolecules.1,7 The high-molecular-weight (>107 Da) mucin polymers, predominantly MUC5B and MUC5AC, provide the biophysical properties required for airway mucus transport and

generate the perception of mucus as a “gel.”8 In one biophysical model (the “two-gel hypothesis”), it is posited that respiratory mucin concentrations gov-ern the rates of mucus transport in the lung.9 In this model, it is predicted that as mucin concentra-tions rise, a threshold concentration is exceeded, after which mucus transport ceases and adherent mucus plaques form on airway surfaces.9 Ultimate-ly, some accumulated mucus may be expectorated as sputum. Accumulated mucus that cannot be ex-pectorated serves as the nidus for airflow obstruc-tion, inflammation, and intermittent infection.6,10,11 Thus, this model predicts that an increased mucin concentration will be associated with sputum pro-duction and disease severity in chronic bronchitis.

The hypothesis that total mucin concentration is a biochemical hallmark of the pathogenesis of chronic bronchitis was tested in an extensively phenotyped cohort of the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). Associations between total mucin concentrations12 and sputum production, sputum characteristics, and disease severity, as indexed by means of spirometry and according to exacerbation frequency, were tested. Potential etiologic pathways for high mucin concentrations, including cigarette smoking and asthma, were also explored. Because

abstractBackgroundChronic obstructive pulmonary disease (COPD) is char-acterized by chronic bronchitic and emphysematous components. In one biophysical model, the concentra-tion of mucin on the airway surfaces is hypothesized to be a key variable that controls mucus transport in healthy persons versus cessation of transport in per-sons with muco-obstructive lung diseases. Under this model, it is postulated that a high mucin concentration produces the sputum and disease progression that are characteristic of chronic bronchitis.

METHODSWe characterized the COPD status of 917 participants from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) using ques-tionnaires administered to participants, chest tomogra-phy, spirometry, and examination of induced sputum. Total mucin concentrations in sputum were measured with the use of size-exclusion chromatography and re-fractometry. In 148 of these participants, the respiratory secreted mucins MUC5AC and MUC5B were quantitat-ed by means of mass spectrometry. Data from chronic-bronchitis questionnaires and data on total mucin concentrations in sputum were also analyzed in an in-dependent 94-participant cohort.

RESULTSMean (±SE) total mucin concentrations were higher in current or former smokers with severe COPD than in controls who had never smoked (3166±402 vs. 1515±152 μg per milliliter) and were higher in partici-pants with two or more respiratory exacerbations per year than in those with zero exacerbations (4194±878 vs. 2458±113 μg per milliliter). The absolute concentrations of MUC5B and MUC5AC in current or former smokers with severe COPD were approximately 3 times as high and 10 times as high, respectively, as in controls who had never smoked. Receiver-operating-characteristic curve analysis of the association between total mucin concen-tration and a diagnosis of chronic bronchitis yielded ar-eas under the curve of 0.72 (95% confidence interval [CI], 0.65 to 0.79) for the SPIROMICS cohort and 0.82 (95% CI, 0.73 to 0.92) for the independent cohort.

CONCLUSIONSAirway mucin concentrations may quantitate a key com-ponent of the chronic bronchitis pathophysiologic cas-cade that produces sputum and mediates disease severity. Studies designed to explore total mucin con-centrations in sputum as a diagnostic biomarker and therapeutic target for chronic bronchitis appear to be warranted. (Funded by the National Heart, Lung, and Blood Institute and others.)

continued on page 3

continued on page 5



Volume 1, issue 1

The Most-Viewed Articles about Cardiovascular Disease from November 2017 to January 2018

EDITORIAL

Back to the Future in Cardiogenic Shock — Initial PCI of the Culprit Lesion OnlyJudith S. Hochman, M.D., and Stuart Katz, M.D.

Approximately 5 to 10% of cases of acute myocar-dial infarction are complicated by cardiogenic shock, which is associated with early mortality of 40 to 50%.1 Nearly two decades ago, the SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial established that mortality was lower with emergency revascu-larization than with initial medical stabilization and selective delayed revascularization in patients with ST-segment elevation myocardial infarction (STEMI).2,3 In the SHOCK trial, percutaneous coro-nary intervention (PCI) of the culprit lesion only was the most common therapy for initial revasculariza-tion. Although more complete revascularization might have been expected to have an increased ben-efit, the small subgroup that underwent initial mul-tivessel PCI had higher mortality than the subgroup that underwent culprit-lesion-only PCI (adjusted hazard ratio, 2.75; 95% confidence interval [CI], 1.05 to 7.25; P = 0.04).4 A meta-analysis of 10 cohort studies, which included a total of 6051 patients with cardiogenic shock, also showed higher early mor-tality with multivessel PCI than with culprit-lesion-only PCI (37.5% vs. 28.8%, P = 0.001).5

Although these results were highly confound-ed, they led to reevaluation of the recommendation to consider initial multivessel PCI in patients with cardiogenic shock. Thiele and colleagues report the results of the CULPRIT-SHOCK (Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock) trial, which was a randomized trial that compared culprit-lesion-only PCI with immediate PCI of all obstructive lesions (i.e., those with >70% stenosis of the diameter) in patients who had STEMI or non–ST-segment elevation myocardial infarction (NSTEMI) with cardiogenic shock.6 In the multivessel PCI group, recanalization of chronic total occlusions was performed when pos-sible, and complete revascularization was achieved

ORIGINAL ARTICLE

PCI Strategies in Patients with Cardiogenic ShockHolger Thiele, M.D., and others

The mortality associated with cardiogenic shock in acute myocardial infarction can be reduced with the use of early revascularization, predominantly per-cutaneous coronary intervention (PCI), to restore blood flow to the culprit coronary artery.1-3 Up to 80% of patients who have cardiogenic shock pres-ent with multivessel coronary artery disease,4 and mortality is higher with multivessel disease than with single-vessel disease.5-7 The value of perform-ing immediate PCI for clinically important steno-ses of major nonculprit coronary arteries is contro-versial, and to our knowledge, randomized trials that have addressed this issue have not included patients with cardiogenic shock.8-11

Several theoretical arguments support immedi-ate revascularization of all coronary arteries with clinically important stenoses or chronic total occlu-sions in addition to the culprit lesion, particularly in patients with cardiogenic shock. The most no-table argument is the potential to improve overall myocardial perfusion and function. However, im-mediate multivessel PCI might pose additional risks, such as induction of further is che mia, vol-ume overload, and renal impairment due to the use of an increased dose of contrast material. Current evidence from nonrandomized studies involving patients with cardiogenic shock suggests that mortality at short-term follow-up is higher after immediate multivessel PCI than after PCI of the culprit lesion only.12 Guideline recommendations

differentiate between stable and unstable hemody-namic status.13,14 European guidelines recommend the consideration of immediate PCI of nonculprit lesions in patients with cardiogenic shock. U.S. guidelines give no specific recommendation. How-ever, recent U.S. appropriate-use criteria indicate that it is appropriate to perform immediate revas-cularization of a nonculprit artery if cardiogenic shock persists after revascularization of the cul-prit artery.13-15 The Culprit Lesion Only PCI versus Multivessel PCI in Cardiogenic Shock (CULPRIT-SHOCK) trial was designed to test the hypothesis that PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, would result in better clinical outcomes than imme-diate multivessel PCI among patients who have multivessel coronary artery disease and acute myo-cardial infarction with cardiogenic shock.

M E T HODS

Trial Design and OversightThe trial design has been published previously.4 This investigator-initiated, randomized, open- label, European multicenter trial involved pa-tients who had acute ST-segment elevation or non–ST-segment elevation myocardial infarction that was complicated by cardiogenic shock, with planned early revascularization by means of PCI

A

B

« Case 39-2017: A 41-Year-Old Woman with Recurrent Chest Pain. See article on page 5.

INSIDE

PERSPECTIVE

Redefining Hypertension — Assessing the New Blood-Pressure Guidelines p. 5

ORIGINAL ARTICLE

Safety of MRI in Patients with Cardiac Devices p. 7

abstractBACKGROUNDIn patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of pa-tients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial.

METHODSIn this multicenter trial, we randomly assigned 706 pa-tients who had multivessel disease, acute myocardial in-farction, and cardiogenic shock to one of two initial re-vascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of non-culprit lesions, or immediate multivessel PCI. The pri-mary end point was a composite of death or severe renal failure leading to renal-replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke.

RESULTSAt 30 days, the composite primary end point of death or renal-replacement therapy had occurred in 158 of the 344

patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P = 0.01). The relative risk of death in the culprit-lesion-only PCI group as compared with the mul-tivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P = 0.03), and the relative risk of renal-replacement thera-py was 0.71 (95% CI, 0.49 to 1.03; P = 0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups.

CONCLUSIONSAmong patients who had multivessel coronary artery dis-ease and acute myocardial infarction with cardiogenic shock, the 30-day risk of a composite of death or severe renal failure leading to renal-replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent im-mediate multivessel PCI. (Funded by the European Union 7th Framework Program and others; CULPRIT-SHOCK ClinicalTrials.gov number, NCT01927549.)

continued on page 2

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Volume 1, issue 1

The Most-Viewed Articles about Cancer Therapeutics from December 2017 to February 2018

EDITORIAL

Developing Anticancer Drugs in Orphan Molecular Entities — A Paradigm under ConstructionFabrice André, M.D., Ph.D.

Genomic characterization of cancers has shown that some oncogenic alterations occur at very low frequency and are shared across tumor types. For example, NTRK translocations mediate malignant transformation and are observed in less than 1% of cancers and in more than 20 cancer types.1 The genes NTRK1, NTRK2, and NTRK3 encode for the tropomyosin receptor kinase (TRK) proteins TRKA, TRKB, and TRKC, respectively. In this [Febru-ary 22] issue of the Journal [N Eng J Med 2018;378], Drilon et al.2 report a pooled analysis of three pro-spective clinical trials testing larotrectinib, a TRK inhibitor, in 55 patients. The overall response rate was 80%, and 71% of the responses were still ongo-ing at 1 year. The authors used a noncomparative, genomic-driven, single-group trial across tumor types to change practice. This study is an illustra-tion of what is likely to be the future of drug devel-opment in rare genomic entities (see figure on page 3).

Although not specific to rare genomic seg-ments, drug development that is based on single-group trials is particularly adapted to rare clinical scenarios with well-established natural histories. Indeed, because rare genomic segments are de-fined by a genomic alteration that drives cancer progression, they usually have high sensitivity to targeted therapies. In addition, the low incidence of these genomic segments makes randomized trials challenging. For example, a single-group trial led

ORIGINAL ARTICLE

Larotrectinib in TRK Fusion–Positive CancersAlexander Drilon, M.D., and others

BACKGROUNDFusions involving one of three tropomyosin recep-tor kinases (TRK) occur in diverse cancers in chil-dren and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK in-hibitor, in adults and children who had tumors with these fusions.

METHODSWe enrolled patients with consecutively and prospec-tively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each

site, into one of three protocols: a phase 1 study in-volving adults, a phase 1–2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety.

RESULTSA total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had

A B

C D

« Ecthyma Gangrenosum. See article on page 7.

INSIDE

REVIEW ARTICLE

Adverse Events with Immune Checkpoint Blockade p. 2

ORIGINAL ARTICLE

Hyperthermic Intraperitoneal Chemotherapy p. 3

Osimertinib in Untreated EGFR-Mutated Advanced NSCLC p. 4

EDITORIAL

Osimertinib as First-Line Treatment in EGFR-Mutated Non–Small-Cell Lung Cancer p. 5

IMAGES IN CLINICAL MEDICINE

Ecthyma Gangrenosum p. 7

Efficacy.

Panel A shows a waterfall plot of the maximum change in tumor size, according to tumor type. One patient (asterisk) had a tropomyosin receptor kinase (TRK) solvent front resistance mutation (NTRK3 G623R) at baseline owing to previous therapy. One patient (dagger) had a pathological complete response. Data for 1 patient are not shown; the patient had clinical deterioration and no tumor measurements after baseline were recorded. GIST denotes gastro intestinal stromal tumor, and IFS infantile fibrosarcoma. Panel B shows a swimmer plot of outcomes in all 55 patients. One patient (double dagger) had a missing restaging scan after the confirmed response was established, and progression-free survival was censored at 3.7 months.

Max

imum

Cha

nge

in T

umor

Siz

e (%

)

50

40

20

30

10

0

−20

−30

−90

−10

−40

−50

−60

−70

−80

−100

B Outcomes

A Maximum Change in Tumor Size, According to Tumor Type

Soft-tissue sarcoma

Lung tumor

GIST

Thyroid tumor

Colon tumor

Melanoma Breast tumor

Appendix tumor

IFS

Salivary-gland tumor

Cholangiocarcinoma

Pancreatic tumor

0 3 6 9 12 15 18 21 24 27

93.2

*

†

Median timeto response,

1.8 mo

Treatment after progressionTreatment after surgery

Partial responseComplete response

Treatment ongoing

SurgeryPathological complete response

‡

Overall Treatment Duration (mo)

continued on page 2

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Volume 9, issue 2

RESULTS IN

DiabetesThe Most-Viewed Articles about Diabetes from January to March 2017


ORIGINAL ARTICLE

Bariatric Surgery vs. Medical Therapy for DiabetesPhilip R. Schauer, M.D., and others

Observational studies1-6 and randomized, con-trolled trials, which have generally been short-term studies,7-19 have shown that bariatric sur-gery, when used specifically to treat diabetes, significantly improves glycemic control and re-duces cardiovascular risk factors. In the Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial, we report-ed that, at 1 year and 3 years after randomization, both gastric bypass and sleeve gastrectomy were superior to intensive medical therapy alone in achieving excellent glycemic control (i.e., glycated hemoglobin ≤6.0%), reducing cardiovascular risk, improving quality of life, and decreasing medica-tion use.8-10 The current article provides results of the final, 5-year follow-up analyses from that trial and attempts to address questions regarding the relative long-term efficacy and safety of bariatric surgery and its effects on diabetes-related end-organ disease.

M E T HODS

Trial DesignThe rationale, design, and methods of the trial have been reported previously.8,20 The complete protocol was approved by the institutional review board at the Cleveland Clinic and is available with the full text of this article at NEJM.org. Briefly, the trial was a three-group, randomized, controlled, nonblinded, single-center study involving 150 obese patients who had type 2 diabetes, in which the effects of intensive medical therapy alone were compared with those of intensive medical therapy plus either gastric bypass or sleeve gastrectomy. Patients were randomly assigned in a 1:1:1 ratio to one of the three study groups, with stratification according to baseline use of insulin. Eligibility criteria included an age of 20 to 60 years, a glycated hemoglobin level of more than 7.0%, and a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 27 to 43. All the patients provided written informed consent.

INSIDE


Glucagonoma-Associated Rash p. 5

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

REVIEW ARTICLE

Mechanisms, Pathophysiology, and Management of Obesity p. 6

↑ Adiposity

↑ Lipid production↑ Adipokine synthesis

↑ Adipose tissuemacrophages and other

inflammatory cells

↑ Activity of the sympathetic nervous system

Mechanical stress

Renal compression

Obstructivesleep apnea

Osteoarthritis Gastroesophagealreflux disease

Barrett’s esophagus

Esophagealadenocarcinoma

↑ Pharyngealsoft tissue

↑ Mechanicalload on joints

↑ Intraabdominalpressure

Systemic andpulmonary

hypertension

Congestive heart failure

Stroke

Chronic kidney disease

↑ Proinflammatory cytokines

Hydrolysis of triglycerides

Release offree fatty acids

Dyslipidemia

Impaired insulinsignaling and

↑ insulin resistance

↑ Insulin

Type 2 diabetes

Lipotoxicity

Coronaryartery disease

Nonalcoholicfatty liver disease

Steatohepatitis

Cirrhosis

↑ Activity of therenin–angiotensin–aldosterone system

« Mechanisms, Pathophysiology, and Management of Obesity. See article on page 6.

abstractBACKGROUNDLongterm results from randomized, controlled trials that compare medical therapy with surgical therapy in patients with type 2 diabetes are limited.

METHODSWe assessed outcomes 5 years after 150 patients who had type 2 diabetes and a bodymass index (BMI; the weight in kilograms divided by the square of the height in meters) of 27 to 43 were randomly assigned to receive intensive medical therapy alone or intensive medical therapy plus RouxenY gastric bypass or sleeve gastrectomy. The primary outcome was a glycated hemoglobin level of 6.0% or less with or without the use of diabetes medications.

RESULTSOf the 150 patients who underwent randomization, 1 patient died during the 5year followup period; 134 of the remaining 149 patients (90%) completed 5 years of followup. At baseline, the mean (±SD) age of the 134 patients was 49±8 years, 66% were women, the mean glycated hemoglobin level was 9.2±1.5%, and the mean BMI was 37±3.5. At 5 years, the criterion for the primary end point was met by 2 of 38 patients (5%) who received medical therapy alone, as compared with 14 of 49 patients (29%) who underwent gastric bypass (unadjusted P = 0.01, adjusted P = 0.03, P = 0.08 in the intention totreat analysis) and 11 of 47 patients (23%) who

underwent sleeve gastrectomy (unadjusted P = 0.03, adjusted P = 0.07, P = 0.17 in the intentiontotreat analysis). Patients who underwent surgical procedures had a greater mean percentage reduction from baseline in glycated hemoglobin level than did patients who received medical therapy alone (2.1% vs. 0.3%, P = 0.003). At 5 years, changes from baseline observed in the gastricbypass and sleevegastrectomy groups were superior to the changes seen in the medicaltherapy group with respect to body weight (−23%, −19%, and −5% in the gastric bypass, sleevegastrectomy, and medicaltherapy groups, respectively), triglyceride level (−40%, −29%, and −8%), highdensity lipoprotein cholesterol level (32%, 30%, and 7%), use of insulin (−35%, −34%, and −13%), and qualityoflife measures (general health score increases of 17, 16, and 0.3; scores on the RAND 36Item Health Survey ranged from 0 to 100, with higher scores indicating better health) (P<0.05 for all comparisons). No major late surgical complications were reported except for one reoperation.

CONCLUSIONSFiveyear outcome data showed that, among patients with type 2 diabetes and a BMI of 27 to 43, bariatric surgery plus intensive medical therapy was more effective than intensive medical therapy alone in decreasing, or in some cases resolving, hyperglycemia. (Funded by Ethicon EndoSurgery and others; STAMPEDE ClinicalTrials .gov number, NCT00432809.)

continued on page 3

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CORRESPONDENCE

Intralymphatic Injection of Autoantigen in Type 1 DiabetesTO THE EDITOR: Residual insulin secretion de-creases complications and improves quality of life in patients with type 1 diabetes. However, ef-fective interventions to preserve residual beta-cell function are lacking. Antigen-based therapy re-quires adequate presentation to T cells. Treatment with antigen-based therapy with the use of glu-tamic acid decarboxylase (GAD65) has been en-couraging but not sufficiently effective.1

To render the presentation of GAD65 antigen to T cells in the lymph nodes more efficient than has previously been described,2,3 we now report the administration of GAD65 autoantigen directly into an inguinal lymph node rather than subcuta-neously. We also added oral vitamin D therapy as a potential immune modulator, although one trial showed that beta-cell function was not preserved in patients who received vitamin D alone.4

DIAGNODE-1 (GAD-Alum [Diamyd] Adminis-tered into Lymph Nodes in Combination with Vitamin D in Type 1 Diabetes; ClinicalTrials.gov number, NCT02352974), a pilot open-label clinical trial, involved six adult patients who were 20 to 22 years of age and had had incident diabetes for less than 6 months. All the patients were GAD65 antibody–positive and had fasting C-peptide levels greater than 0.12 nmol per liter (0.36 ng per milli-liter). They received an injection of 4 μg of alum-formulated GAD65 (GAD-alum) into an inguinal lymph gland under direct ultrasonographic guid-ance, followed by two intranodal booster injec-tions at 1-month intervals. Each patient also re-ceived vitamin D (calciferol) in an oral solution (2000 U per day) over 4 months, starting 1 month before the first GAD-alum injection. All patients provided written informed consent. The trial was approved by the research ethics committee at Linköping University, Linköping, Sweden, and by the Medical Products Agency, Uppsala, Sweden.

Beta-cell function was estimated with mixed-meal tolerance tests. Immune function was as-sessed by means of cell-proliferation assays, flow


Volume 9, issue 1

RESULTS IN

Heart FailureThe Most-Viewed Articles about Heart Failure from December 2016 to February 2017


ORIGINAL ARTICLE

A Fully Magnetically Levitated Circulatory PumpMandeep R. Mehra, M.D., and others

INSIDE

ORIGINAL ARTICLE

Intrapericardial Left Ventricular Assist Device p. 5

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


Gas in the Left Atrium and Ventricle p. 7

A

Right ventricle

Right ventricle

Aorta

Esophagus

Atrial–esophagealfistula

Right atrium

Left atrium

Left atrium

Left ventricle

Air

B

« Gas in the Left Atrium and Ventricle. See article on page 7.

abstractBACKGROUNDContinuous-flow left ventricular assist systems increase the rate of survival among patients with advanced heart failure but are associated with the development of pump thrombosis. We investigated the effects of a new magnetically levitated centrifugal continuous-flow pump that was engineered to avert thrombosis.

METHODSWe randomly assigned patients with advanced heart fail-ure to receive either the new centrifugal continuous-flow pump or a commercially available axial continuous-flow pump. Patients could be enrolled irrespective of the in-tended goal of pump support (bridge to transplantation or destination therapy). The primary end point was a com-posite of survival free of disabling stroke (with disabling stroke indicated by a modified Rankin score >3; scores range from 0 to 6, with higher scores indicating more se-vere disability) or survival free of reoperation to replace or remove the device at 6 months after implantation. The trial was powered for noninferiority testing of the primary end point (noninferiority margin, −10 percentage points).

RESULTSOf 294 patients, 152 were assigned to the centrifugal-flow pump group and 142 to the axial-flow pump group.

In the intention-to-treat population, the primary end point occurred in 131 patients (86.2%) in the centrifugal-flow pump group and in 109 (76.8%) in the axial-flow pump group (absolute difference, 9.4 percentage points; 95% lower confidence boundary, −2.1 [P<0.001 for non-inferiority]; hazard ratio, 0.55; 95% confidence interval [CI], 0.32 to 0.95 [two-tailed P = 0.04 for superiority]). There were no significant between-group differences in the rates of death or disabling stroke, but reoperation for pump malfunction was less frequent in the centrifugal-flow pump group than in the axial-flow pump group (1 [0.7%] vs. 11 [7.7%]; hazard ratio, 0.08; 95% CI, 0.01 to 0.60; P = 0.002). Suspected or confirmed pump thrombo-sis occurred in no patients in the centrifugal-flow pump group and in 14 patients (10.1%) in the axial-flow pump group.

CONCLUSIONSAmong patients with advanced heart failure, implanta-tion of a fully magnetically levitated centrifugal-flow pump was associated with better outcomes at 6 months than was implantation of an axial-flow pump, primarily because of the lower rate of reoperation for pump mal-function. (Funded by St. Jude Medical; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.)

A scarcity of effective therapeutic options for ad-vanced heart failure has led to the development of durable mechanical circulatory support devices. Left ventricular assist devices, more accurately known as left ventricular assist systems, increase the rate of survival and improve quality of life among patients with advanced heart failure. How-ever, these clinical benefits are balanced by an in-creased risk of infection, bleeding, neurologic events, and pump malfunction that is due princi-pally to pump thrombosis.1,2

As adoption of circulatory pumps has expand-ed, concerns about pump thrombosis have height-ened. In 2013, two reports suggested that there has been an increase in the risk of pump throm-bosis, beginning in 2011, associated with a cur-rently approved axial continuous-flow pump, HeartMate II.3,4 Pump thrombosis has also been associated with an approved centrifugal continuous-flow pump, HeartWare.5,6 The need for surgical pump exchange due to pump thrombosis results in substantial complications and increased cost of care.7 These concerns have lowered enthusiasm for expansion of this therapy to patients who are less severely ill and have even led to the premature dis-continuation of a clinical trial.7,8

A new fully magnetically levitated centrifugal continuous-flow circulatory pump, HeartMate 3, has been engineered to reduce shear stress on

blood elements and avert pump thrombosis.9,10 This pump has wide blood-flow passages and no mechanical bearings, is frictionless, and is pro-grammed to facilitate rapid changes in rotor speed to create an intrinsic artificial pulse. This fixed pulse, which is asynchronous with the native heartbeat, reduces stasis in the pump.

We conducted a trial to compare clinical out-comes with the centrifugal-flow pump HeartMate 3 with outcomes with the axial-f low pump HeartMate II in patients with advanced heart failure that is refractory to standard medical therapy. In this report, we present the results of the first pre-specified analysis of the trial.

M E T HODS

Trial Design and OversightThe Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Sup-port Therapy with HeartMate 3 (MOMENTUM 3) was a nonblinded randomized trial that compared the centrifugal-flow pump HeartMate 3 with the axial-flow pump HeartMate II in patients with ad-vanced heart failure.10 The trial was sponsored by St. Jude Medical, which provided the trial devices. The trial protocol, which is available with the full text of this article at NEJM.org, was designed by

continued on page 2

continued on page 2

EDITORIAL

Mechanical Circulatory Support Devices — In ProgressRoland Hetzer, M.D., Ph.D., and Eva M. Delmo Walter, M.D., Ph.D.

Clinical research into mechanical circulatory sup-port systems dates back to the 1960s, with the first reported successful human implantation of a left ventricular assist device (LVAD) for postoper-ative heart failure, in a 37-year-old woman with aortic insufficiency and mitral stenosis.1 Early ventricular assist devices were typically extracor-poreal pumps. In general, only short-term use was clinically feasible; the duration of support was limited by the high risk of thrombosis, bleed-ing, infection, and device malfunction.

Investigators during the 1970s and 1980s fo-cused their efforts on the development of implant-able pulsatile pumps to reduce some of the risks associated with the external machines.2 In 2001, one of these devices, the HeartMate VE, although it was large and noisy, was shown to be associated with a rate of survival at 1 year that was higher than that with medical management alone among patients with end-stage heart failure.3

The risk of adverse events remained high with these early LVADs. Although the risk of infection was decreased with implantable devices, it was not fully resolved, since each such pump required an external drive line for its operation, which cre-ated a point of entry for bacterial migration. Thromboembolism remained an issue, and the anticoagulation to reduce the risk of thromboem-bolism increased the risk of bleeding. These pul-satile pumps required considerable mechanical energy and incorporated inflow and outflow valves, resulting in a substantial risk of device failure over time.

Implantable small rotary (continuous-flow) blood pumps have revolutionized mechanical cir-culatory support since the first human implanta-tion in 1998.4 They are noiseless, which is an im-portant feature for patients’ quality of life. The subsequent evolution of magnetic levitation in

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