Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 9th June 2016 (#46)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
Please do not feel restricted by my recommendations. In
the perspective section there are two very interesting articles I can recommend
on Paediatric and Childhood in the United States (http://www.nejm.org/doi/full/10.1056/NEJMp1603516)
and The Hell of Syria’s Field Hospitals (http://www.nejm.org/doi/full/10.1056/NEJMp1603673)
Must Read Articles
None
Articles Recommended for Medical Students
ORIGINAL ARTICLE
Indacaterol–Glycopyrronium
versus Salmeterol–Fluticasone for COPD
This
randomized trial compared a long-acting beta-agonist (LABA) plus a glucocorticoid
with a LABA plus a long-acting muscarinic antagonist for preventing
exacerbations of chronic obstructive pulmonary disease. The exacerbation rate
was lower with the latter treatment.
EDITORIAL
Another
Choice for Prevention of COPD Exacerbations
This article with the accompanying editorial compares
two fixed dosage drug combinations, of both a long-acting beta-agonist (LABA)
and an inhaled glucocorticoid (IC) or a LABA and a long-acting muscarinic antagonist
(LAMA), in preventing COPD exacerbations of all severities.
The LABA+ IC combination was salmeterol + fluticasone
(Advair, Galactosmithkline). The LABA+LAMA was a combination of indacaterol+
glycopyrronium (Ultibro Breezhaler, Novartis). This was a 52 weeks,
randomized, double-blind, double-dummy, non-inferiority trial with 1680
patients in the LABA + LAMA and 1682 in the LABA + IC. See Figure 1 to compare
the completion rate. The primary outcome was the annual rate of all COPD
exacerbations.
The overall results of the FLAME study are as follows:
1. LABA
+ LAMA was superior to the LABA + IC in reducing the overall rate of COPD
exacerbations (11% lower).
2. The
incidence of pneumonia was slightly higher in the LABA + IC group (4.8% versus
3.2%, p = 0.02).
3. The
incidence of adverse events and death (Table 2) was similar in both groups.
4. The
annual rate of moderate to severe exacerbations was higher in the LABA + IC
group (p <0.001)
5. The
time to the first exacerbation overall was longer for the LABA + LAMA group.
6. The
baseline eosinophil count did not influence outcome in either group
Subgroup analysis is presented in Figure 3. A detailed
discussion of the study and COPD in general is presented in the editorial.
Several problems I have with this type of study is that the fixed doses used
are determined by the Pharmaceutical preparation and the assumption that all
LABAs (indacaterol, salmeterol and formoterol) are similar in efficacy and side
effects.
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case
17-2016 — A 60-Year-Old Woman with Increasing Dyspnea
A 60-year-old
woman was seen in a pulmonary clinic because of increasing dyspnea. Chest
imaging revealed bronchiectasis and mild, diffuse bronchial-wall thickening. A
diagnostic procedure was performed.
This 60 year-old female presents with a non-productive
cough and increasing dyspnoea. Her symptoms become progressively more severe,
eventually requiring a bilateral lung transplant. There is an excellent review
of her clinical data, pulmonary function tests and high resolution pulmonary CTs. There is a detailed differential diagnosis
focusing on asthma, COPD, ACOS, bronchiectasis and bronchiolitis. The DD discussion is well worth reading.
IMAGES IN CLINICAL MEDICINE
Hyperkalemia
after Missed Hemodialysis
A
48-year-old man with a history of end-stage renal disease who had undergone
parathyroidectomy owing to tertiary hyperparathyroidism 1 month earlier
presented to the ED with weakness and diffuse muscle aches after missing a
hemodialysis session.
This is an interesting ECG showing features of
hyperkalaemia with peaked T waves. It also shows a prolonged QT segment which
is usually seen in hypokalaemia and other electrolyte abnormities. In this
patient the prolonged QT segment was due to hypocalcaemia and hypomagnesaemia associated
with the “hungry bone syndrome” which was only normalized by replacing calcium
with vitamin D.
Recommended
learning:
1. Review
the ECG changes related to high or low potassium and calcium and relate these
to events occurring in the cardiac myocyte action potential (http://www.pathophys.org/physiology-of-cardiac-conduction-and-contractility/)
2. Review
the “hungry bone syndrome.”
IMAGES IN CLINICAL MEDICINE
Ventricular
Septal Defect after Acute Myocardial Infarction
A
76-year-old man with a 1-week history of continuous chest pain presented to the
ED with rapidly progressive dyspnea on exertion. Transthoracic echocardiography
revealed a large, sharply demarcated interventricular septal defect with a
turbulent left-to-right transseptal flow, shown in videos.
This is a great case with a typical ECG and TEE that even
I could interpret. As I had not reviewed
this topic in depth for many years, I had assumed that all ruptures of the
interventricular septum occurred 3-5 days after septal infarction. I was pleased to be re-educated on this topic.
If you are interested in exploring this topic further, I recommend this well written
review which was published in the Eur. Heart J. in 2014 by the Cleveland Clinic
Cardiothoracic Group. (https://eurheartj.oxfordjournals.org/content/ehj/35/31/2060.full.pdf)
Recommended
learning: Review the complications of myocardial infarction.
ORIGINAL ARTICLE
Cryoballoon
or Radiofrequency Ablation for Paroxysmal Atrial Fibrillation
Over 700 patients with drug-refractory paroxysmal
atrial fibrillation were randomly assigned to cryoballoon or radiofrequency
ablation. Cryoballoon ablation was noninferior to radiofrequency for the
composite of recurrent atrial arrhythmia, use of antiarrhythmic drugs, or
repeat ablation.
The students appeared particularly interested in this
article, as students in MED300 and MED400 during cardiology rotations are
exposed to the radiofrequency ablation (RFA) technique. I understood for the
first time (see excellent Figure 1) the basis of the technique I had heard so
much about. These techniques contrast selectively frying the conduction system
at the pulmonary vein antra (RFA) with freezing the conduction system
(cryoballoon ablation).
The study compares the newer cryoballoon technique with
RFA in a randomized trial involving 762 patients with drug-resistant atrial
fibrillation. There is no obvious difference between the results of either
technique with respect to efficacy of treatment or overall safety.
Cryoballoon treatment is faster, requires less formal
training, and as such, is not limited to only specialized centres. However it
requires the need for significant fluoroscopy. With RFA, the technique takes
longer, requires detailed training in cardiac electrophysiology, is limited to
specific centres, requires minimal fluoroscopy and the target for ablation is
more specific. How will the costs
compare?
Recommended
learning:
1. Review
the causes, clinical presentations and management of atrial fibrillation.
2. Review
the cardiac conduction system
Important Articles Related to Mechanisms of Disease and
Translational Research
CLINICAL IMPLICATIONS OF BASIC RESEARCH
Targeting
a Long Noncoding RNA in Breast Cancer
A
study of a specific long noncoding RNA in a mouse model of breast cancer shows
that knockdown of its expression suppresses metastasis.
I found this to be a stimulating discussion of the
research study (Arun et al Genes Dev 2016) which examines the function of a long
noncoding RNA (defined as a RNA with greater than 200 nucleotides, lncRNA). As only 1.5% of the 3 billion base pairs in
humans represent protein-coding sequences, many lncRNAs are produced, although
the functions of most of those currently identified are unknown.
High levels of a lncRNA designated MALAT1 (metastasis-associated
lung adenocarcinoma transcript 1) are found in mice with breast cancer with a
high metastatic potential. In the reviewed study, high MALT1 level mice with
breast cancer who receive an antisense oligonucleotide MALT1 inhibitor develop
a cystic breast cancer that does not metastasize (see Fig. 1).
The following are known about MALAT1:
1. MALAT1
is elevated in multiple human tumour types that metastasise.
2. If
MALAT1 is inhibited in human cancer cells grown in tissue culture, the cells
stop proliferating and are no longer able to metastasize when implanted into
immunocompromised mice.
3. MALAT1
knockout (ko) mice (i.e. they do not harbour the gene for MALAT1) reach a
normal age, indicating that MALAT1 is not essential for normal mouse
development.
4. When
MALAT1 ko mice are bred with mice who have a strong oncogene in mammary tissue,
those mice that have the oncogene + MALAT1 die early from metastatic breast
cancer. Those with the oncogene without MALAT1 develop a poorly metastatic
cancer, suggesting that MALAT1 is responsible for the metastatic potential of
the tumour.
5. MALAT1
is highly conserved over evolution which suggests a biologically importance not
yet appreciated.
The possible role of lncRNAs opens an entirely new potential
area in biological approaches to oncology. Will inhibitors of MALAT1 in humans,
or other oncogenic lncRNAs yet to be identified, play a role in cancer therapy
in the future? The future of this therapy appears very interesting and full of
potential, particularly in the clinical sciences and translational research.
Other Articles which should interest medical students
EDITORIAL
Roads
Diverge — A Robert Frost View of Leukemia Development
This
is a major advance in mutations found in patients with acute myeloid leukaemia and
in particular their use in defining clinical features and in particular the
clinical outcomes.
The paper (http://www.nejm.org/doi/full/10.1056/NEJMoa1516192)
describes a study of mutated genes in 1540 patients, aged 18 to 65 years, with
acute myeloid leukaemia. 5234 oncogenic driver mutations were found in
76 genes or genomic areas (of 111 studied) and 2 or more of these driver
mutations were found in 86% of patients.
Based on identification of these
mutations, the cohort could be divided into 11 groups containing
co-compartmentalised mutations, each group with distinct features and clinical
outcomes. Furthermore, three heterogeneous genomic categories were defined
based on gene mutations affecting specific DNA e.g. chromatin, p53,
RNA-splicing regulators. This article is well reviewed in the editorial (http://www.nejm.org/doi/full/10.1056/NEJMe1603420) which
describes an excellent model for leukaemogenesis.
REVIEW ARTICLE
Renal
Complications of Hematopoietic-Cell Transplantation
Despite
overall improvement in the outcomes of hematopoietic-cell transplantation,
kidney injury is a frequent complication. The author reviews the causes,
diagnosis, and management of renal complications and disorders after
hematopoietic-cell transplantation.
This is an article to be read by interns and physicians
in training (particularly those involved in haematopoietic-cell transplantation
and renal physicians) but may be of interest to some students with a particular
interest in these areas. It is clearly a review article that should be stored
for the future.
I found some interesting points:
1. The
commonest cause of acute and chronic renal impairment is GVHD.
2. Hepatic
sinusoidal obstruction syndrome (formerly Budd Chiari syndrome) can contribute
to acute kidney injury and can be significantly reduced by modifying high-dose
conditioning regimens (pre-transplant therapy consisting of anti-T cell
antibodies, radiation therapy, immunosuppressive and anti-malignancy
chemotherapy). This entity results from injury to sinusoidal endothelium and
activation of stellate cells in the liver.
3. While
calcineurin inhibitors can cause renal arteriolar vasoconstriction, they are
not felt to contribute significantly to acute kidney injury overall.
4. Elafin
is an endogenous serine protease inhibitor produced by epithelial cells and
macrophages and is a surrogate marker for inflammation. Increased levels of
elafin in urine may indicate glomerular inflammation or if demonstrated by
immunohistochemistry in distal and collecting duct lining cells may indicate
distal tubular injury.
Recommended
learning:
1. Review
the cells present within the liver and their function.
2. Consider
the clinical scenarios associated with significant activation of serine
proteases and their inhibitors.
