Professional Documents
Culture Documents
Key Advances in Medicine 2015
Key Advances in Medicine 2015
IN MEDICINE
January 2016
ENDOCRINOLOGY
NEPHROLOGY
RHEUMATOLOGY
CARDIOLOGY
GASTROENTEROLOGY
& HEPATOLOGY
UROLOGY
NEUROLOGY
CLINICAL
ONCOLOGY
Neurology
Oncology
Rheumatology
Urology
www.nature.com/libraries/medical
January 2016
The articles included in Nature Reviews Key Advances in Medicine were originally
published online and appear in the February 2016 issues of the eight clinical
Nature Reviews journals. Thejournals editors commissioned international experts
to write a short essay highlighting key papers that made the biggest contribution
to their field in 2015. Between them, the clinical Nature Reviews journals published
44 articles, which are collated in this eBook; if you choose to cite an article, please
use the original journal citation rather than citing the eBook.
1
3
4
6
C A R D I O LO G Y
ARRHYTHMIAS IN 2015 Advances in drug, ablation,
anddevice therapy forcardiac arrhythmias
Laurent Macle and Stanley Nattel
CORONARY INTERVENTION IN 2015 Improvement
12
14
16
18
20
22
of dyslipidaemia
Scott M. Grundy
E N D O C R I N O LO G Y
24
26
27
29
31
33
C L I N I C A L O N C O LO G Y
BREAST CANCER IN 2015 Academic research sheds light
on issues that matter to patients
Martine J. Piccart and Isabelle Gingras
COLORECTAL AND GASTRIC CANCER IN 2015 The
development of new agents andmolecular classifications
Eric Van Cutsem and Michel Ducreux
OVARIAN CANCER IN 2015 Insights into strategies for
optimizing ovarian cancer care
Robert L. Coleman
35
37
39
40
42
44
John B. Dixon
transgenerational inheritance
Michael K. Skinner
hormone-sensing-dependent regulation
Tony K.T. Lam
G A S T R O E N T E R O LO G Y
& H E PATO LO G Y
REGENERATIVE MEDICINE IN 2015 Generating and
aneffective treatment
Klaas Poelstra
choose carefully
Ruth E.Ley
andtreatment
Barbara Rehermann
in endoscopicimaging
Bishnu P. Joshi and Thomas D. Wang
46
N E P H R O LO G Y
48
50
51
53
56
58
60
N E U R O LO G Y
68
69
71
73
76
78
80
R H E U M ATO LO G Y
GLUCOCORTICOIDS IN 2015 New answers to old
problems
Sarah A.Jones and Eric F.Morand
SYSTEMIC LUPUS ERYTHEMATOSUS IN 2015 Cellular and
U R O LO G Y
SEXUAL DYSFUNCTION IN 2015 Recovering sex drive
81
63
83
65
61
of multiplesclerosis
Olga Ciccarelli and Alan Thompson
Copyright 2016 Macmillan Publishers Limited. All rights reserved. Printed in the
Disclaimer: Although every effort is made by the publishers to see that no inaccurate
or misleading data, opinions or statements appear in this collection, they wish to make it
clear that the data and opinions appearing in articles and advertisements herein are the
responsibility of the contributor or advertiser concerned. The journal does include the
personal opinions of the authors; therefore, it is not intended to be relied on solely as a
guide to good practice or safe treatment. Accordingly, the publishers, employees, offices
and agents accept no liability whatsoever for the consequences of any such inaccurate or
misleading data, opinion or statement. Although every effort is made to ensure that drug
doses and other quantities are presented accurately, readers are advised that the new
methods and techniques involving drug usage and described within this journal should only
be followed in conjunction with the drug manufacturers own published literature.
CARDIOLOGY
ARRHYTHMIAS IN 2015
Ablation
Devices
JANUARY 2016 | 1
C A R D I O LO G Y
Key advances
Pulmonary-vein isolation alone is as
effective as several more complex
procedures for the suppression of persistent
atrial fibrillation (AF)1
Identification and further ablation of
pulmonary veins with dormant conduction
at risk of subsequent reconnection can
improve the effectiveness of pulmonary-vein
isolation procedures for paroxysmal AF2
Digoxin use for rate control in AF might be
associated with increased incidence of
adverse cardiovascular events, so the drug
should be used cautiously and with careful
dose selection4
Defibrillation testing is not needed at the
time of cardiovertordefibrillator
implantation for most patients7
Novel implantable devices, such as
subcutaneous implantable cardiovertor
defibrillators and leadless pacemakers, are
effective and are likely to gain wide clinical
use in the near future10
2 | JANUARY 2016
Acknowledgements
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
C A R D I O LO G Y
C O R O N A RY I N T E R V E N T I O N I N 2 0 1 5
Improvement of long-term
outcomes after PCI
Uwe Zeymer
Third-generation drug-eluting stents (DES) have emerged as first-line
devices for percutaneous coronary intervention, even in patients with high
bleeding risk. Studies published in 2015 report that bioabsorbable vascular
scaffolds are equally effective and safe as DES in low-risk populations and,
with the addition of extended dual antiplatelet therapy, might improve
long-term outcomes.
Percutaneous coronary intervention (PCI) has
emerged as the revascularization therapy of
choice in the majority of patients with stable
coronary artery disease and acute coronary syn
dromes1. With the development of new inter
ventional techniques and devices, even complex
lesions such as chronic total occlusions, left
main stenosis, and bifurcation lesions can be
treated with high acute procedural success rates.
However, two major issues related to outcomes
after PCI still remain. The introduction of baremetal stents and drug-eluting stents (DES) has
diminished, but not completely eliminated, the
problem of early and late restenosis2. Whether
the need for long-term target-lesion revascu
larization owing to restenosis and acute ischae
mic events can be further reduced is unknown.
Inaddition, although prolonged dual antiplate
let therapy (DAPT) for >12months results in
a further decrease in very late stent thrombo
sis and ischaemic events, it is also associated
with an increase in bleeding complications3.
Therefore, the optimal duration of DAPT
remains to be determined.
Bioabsorbable vascular scaffolds (BVS)
were developed to improve long-term out
comes after PCI. The occurrence of late adverse
events (restenosis and stent thrombosis) with
permanent metallic stents might be related to
persistent inflammation, loss of normal vessel
curvature, impaired vasomotion, strut frac
ture, ongoing tissue growth within the stent
frame, and neoatherosclerosis. To overcome
these problems, BVS were developed to pro
vide mechanical support and optimal drug
delivery associated with excellent mid-term
results, followed by complete bioresorption
over severalyears.
In the ABSORB3 multicentre, random
ized trial4, the Absorb BVS (Abbott Vascular,
USA) the first BVS approved for commercial
Patient profile
1 month
3 months
6 months
12 months
>12 months
JANUARY 2016 | 3
C A R D I O LO G Y
1.
Key advances
The bioabsorbable vascular scaffold
Absorbwas as safe and effective as a
third-generation drug-eluting stent in a
low-risk percutaneous coronary intervention
(PCI) population during 1year followup4
A polymer-free and carrier-free drug-coated
stent with a reduced duration of dual
antiplatelet therapy of 4weeks was as safe
and more effective than a bare-metal stent
in patients with high bleeding risk7
In patients treated with PCI for acute
coronary syndromes, longer term dual
antiplatelet therapy beyond 12months
further reduces ischaemic events and
stentthrombosis9
2.
3.
4.
5.
6.
7.
8.
9.
C A R D I A C R E S U S C I TAT I O N I N 2 0 1 5
4 | JANUARY 2016
C A R D I O LO G Y
Recognition
and activation
of emergency
response
system
Immediate
high-quality
CPR
Rapid
debrillation
Layperson responders
Basic and
advanced
emergency
medical
services
Advanced life
support and
post-arrest
care
Population-based training35
Telephone-assisted CPR3,5
Notication of nearby volunteer
responders by mobile phone6
Expected outcomes
Increase rate of CPR initiated before ambulance arrival
10% immediately with rapid interventions
Achieve >50% rates over time
Reliable delivery of eective post-CPR care
JANUARY 2016 | 5
C A R D I O LO G Y
interventions that treated 40 cases of OHCA
per year (n=54). In total, 24% of patients in
the study had good functional recovery, but
no clear association existed between the num
ber of patients with OHCA admitted to each
hospital and outcome. Treatment at a cardiac
centre that treated 40 cases of OHCA year
(OR1.32, 95%CI 1.061.64) and <40 cases
of OHCA per year (OR1.63, 95%CI 1.35
1.97) were both associated with good neuro
logical recovery, compared with treatment at
noncardiac intervention centres.
After decades of research into therapies
to mitigate ischaemiareperfusion injury
in each organ after cardiac arrest, a single
intervention to treat whole body ischaemia
reperfusion injury remains elusive. In the
absence of such a breakthrough, the greatest
opportunities to increase survival after OHCA
involve reducing delays to intervention and
ensuring reliable delivery of specialized care
to all patients (FIG.1). Current evidence sug
gests that system-level changes might result in
national or state rates of layperson CPR >50%,
and that cheap, readytoimplement interven
tions such as SMS and telephone-assisted CPR
can immediately increase layperson response.
With improved layperson response, survival
might be possible for >10% of patients. Finally,
admission of patients after OHCA to hospi
tals that provide high-intensity care after
CPR is associated with increased survival.
Policiesand incentives to promote layperson
response andencourage accountable hospital
care will lead to more lives being saved.
Clifton W. Callaway is at the Department of Emergency
Medicine and Department of Pharmacology and
Chemical Biology, University of Pittsburgh,
Iroquois400A, 3600 Forbes Avenue,
Pittsburgh,Pennsylvania15260, USA.
callawaycw@upmc.edu
doi:10.1038/nrcardio.2015.201
Published online 14 Jan 2016
1.
2.
3.
4.
5.
6.
7.
Acknowledgements
6 | JANUARY 2016
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
C A R D I O LO G Y
confirmed 47 of 48 previously reported genes
at a nominal significance level. The majority
(98.3%) of the significant loci were common
variants. However, owing to the increased
precision of imputation afforded by the 1000
Genomes Project, rare frequency SNPs in
APOE and PCSK9 showed strong associations
that were overlooked in the HapMap-based
GWAS2,3. The CARDIoGRAMplusC4D con
sortium identified eight new loci from their
additive models. These loci were biologi
cally relevant and valid candidate genes with
well-documented roles in vessel wall biology,
including cell adhesion, leukocyte and vascular
smooth muscle cell migration, vascular smooth
muscle cell phenotypic switching, transforming
growth factor signalling, angiogenesis, and
nitric oxide signalling. These candidate genes
are also known to have anti-inflammatory and
infarct-sparing effects.
The large sample size in this study also
allowed exploration of recessive and dominant
modes of inheritance. Using a recessive inherit
ance model to determine susceptibility to CAD
from homozygosity for the less frequent allele,
two new recessive loci were identified, n
either
of which were significant using an additive
model. The dominant inheritance model
identified variants that had been detected with
the additive analysis. Together, these results
suggest that CAD is largely determined by
common SNPs with small effectsizes.
Inherited genetic factors are thought to
contribute to MI that occurs early in life5.
Common variants in approximately 45 genes
and rarevariants in LDL-related genes have
previously been associated with early MI6. Do
and colleagues used a range of approaches to
evaluate how low-frequency and rare vari
ants across the genome contribute to risk of
early MI6. Using whole-exome sequencing,
the investigators sequenced all protein-coding
genes in 1,027 patients with early MI (men aged
50years, women aged 60years) and 946 older
MIfree controls (men aged 60years, women
aged 70years). On average, each person had
43nonsense, 7,828 missense, 92 splice-site, 189
indel frameshift, 366 indel nonframeshift, and
103 nonsynonymous singleton variants. None
of the approximately 20,000 genes analysed in
the discovery set wassignificant.
The discovery sequencing results were
followed up using four different approaches6.
The first (statistical imputation in 64,132
patients and controls) and second (analysing
the Illumina Exome chip in 15,936 patients
and controls) approaches did not produce
significant findings for low-frequency vari
ants. In their third approach, the investigators
conducted targeted resequencing of APOA5 in
6,721 patients and 6,711 controls. Using burden
Disease
MI6
DCM8
Conrmed 47 of 48 previously
A burden of rare alleles in
reported genomic loci and
two genes, LDLR and APOA5,
identied 10 new loci containing contributes to MI risk
candidate causal genes with
roles in vessel wall biology
CAD4
Objectives
To conrm existing and identify
additional CAD-associated loci
Techniques
GWAS meta-analysis of
~185,000 cases and controls,
interrogating 6.7 million
common and 2.7 million
low-frequency variants
Findings
Figure 1 | The use of genomic techniques to identify new CVD-causing variants and
toevaluate how they contribute to disease pathogenesis. CAD, coronary
disease;
Nature artery
Reviews
| Cardiology
CVD,cardiovascular disease; DCM, dilated cardiomyopathy; GWAS, genome-wide association
studies; iPS, induced pluripotent stem cells; MI, myocardial infarction; TTN, titin.
C A R D I O LO G Y
Bygrowing CMTs on flexible and rigid canti
levers (tomimic levels of biomechanical stress)
and treating with isoproterenol (to mimic
adrenergic stimulation), the investigators
suggested that TTNtvs can cause decreased
response to mechanicalload.
Together, these studies indicate that in
iPS-CMTs, missense mutations, and TTNtvs
can result in forms of sarcomere insufficiency
that can lead to deficits in baseline and stress-
response contractile function, factors critical in
the pathogenesis of DCM. The importance of
this study lies not only in its functional insights
with potentially profound therapeutic value,
but in its model integration and scaffolding of
complementary microbiological and molecular
biological experimental approaches.
The studies discussed in this article con
tribute to the advancement of cardiovascular
genomics in two ways. First, each study adds
to the body of knowledge within its respective
disease domain by identifying novel risk vari
ants or confirming suspected variants (FIG.1).
Furthermore, these studies illustrate that
although molecular genomic data might serve
as the basis of all future research, adequately
powered studies combining analytical, func
tional, and bioinformatic techniques need to be
integrated before even the most rudimentary
translational steps can be undertaken.
Donna K. Arnett is at the UAB School of Public Health,
Department of Epidemiology, University of Alabama at
Birmingham, 220E 1530 3rd Avenue South,
Birmingham, Alabama 35294, USA.
arnett@uab.edu
doi:10.1038/nrcardio.2015.202
Published online 14 Jan 2016
Kessler,T., Erdmann,J. & Schunkert,H. Genetics
ofcoronary artery disease and myocardial infarction
2013. Curr. Cardiol. Rep. 15, 368 (2013).
2. Deloukas,P. etal. Large-scale association analysis
identifies new risk loci for coronary artery disease.
Nat.Genet. 45, 2533 (2013).
3. The CoronaryArteryDisease(C4D)Genetics Consortium.
A genome-wide association study in Europeans and
South Asians identifies five new loci forcoronary artery
disease. Nat. Genet. 43, 339344 (2011).
4. Nikpay,M. etal.A comprehensive 1000 Genomesbased genome-wide association meta-analysis of
coronary artery disease. Nat. Genet. 47, 11211130
(2015).
5. Lloyd-Jones,D.M. etal. Parental cardiovascular
disease as a risk factor for cardiovascular disease
inmiddle-aged adults: a prospective study of parents
and offspring. JAMA 291, 22042211 (2004).
6. Do,R. etal. Exome sequencing identifies rare LDLR
andAPOA5 alleles conferring risk for myocardial
infarction. Nature 518, 102106 (2015).
7. Teslovich,T.M. etal. Biological, clinical and population
relevance of 95 loci for blood lipids. Nature 466,
707713 (2010).
8. Hinson,J.T. etal. Titin mutations in iPS cells define
sarcomere insufficiency as a cause of dilated
cardiomyopathy. Science 349, 982986 (2015).
9. Hershberger,R.E., Hedges,D.J. & Morales,A. Dilated
cardiomyopathy: the complexity of a diverse genetic
architecture. Nat. Rev. Cardiol. 10, 531547 (2013).
10. Herman,D.S. etal. Truncations of titin causing dilated
cardiomyopathy. N.Engl. J.Med. 366, 619628
(2012).
1.
DY S L I P I DA E M I A I N 2 0 1 5
Advances in treatment
ofdyslipidaemia
Scott M. Grundy
Statins remain the first-line therapy for dyslipidaemia. In 2015, however,
effectiveness in reducing serum cholesterol levels and decreasing rates of
cardiovascular disease in combination with statins has been demonstrated
for two new classes of drugs: cholesterol-absorption inhibitors and PCSK9
inhibitors. The latter rival statins in their capacity to lower cholesterol levels.
Findings from a meta-analysis and three sem
inal, randomized, controlled trials (RCTs) pub
lished in 2015 have far-reaching implications
for the management of cholesterol levels. Inthe
past 3decades, cholesterol-lowering therapy
has been dominated by statins. These drugs
reduce LDL-cholesterol (LDLC) levels with
few adverse effects. RCTs document their effi
cacy in reducing atherosclerotic cardiovascular
disease (ASCVD). Several statins are now avail
able as inexpensive, generic drugs. Statins are
the standard of care for secondary prevention
of ASCVD, and are being used increasingly
in primary prevention. They inhibit choles
terol synthesis and reduce hepatic cholesterol
content, which increases expression of LDL
receptors and lowers serum LDLC level. Highintensity statins can reduce LDLC levelsby
up to 60%. Two other drugs, ezetimibe and
inhibitors of proprotein convertase subtilisin/
kexin type9 (PCSK9), also lower LDLC levels
through their actions on LDL receptors (FIG.1).
A meta-analysis by the Cholesterol
Treatment Trialists (CTT) Collaboration
showed that statin therapy is equally efficacious
in reducing major cardiovascular events in
men as in women1. In this analysis, relative risk
of vascular events was reduced by 22% in men
and by 16% in women for every 1.0mmol/l
(38.6mg/dl) decrease in LDLC level. No
adverse effects on cancer or noncardiovascular
mortality were found in either men or women.
This meta-analysis confirms that for every
1% reduction in the LDLC level, the risk of
events related to ASCVD is reduced by ~1%.
Consequently, a 50% decrease in LDLC level
with high-intensity statins should reduce the
risk of ASCVD by ~50%, a benefit that applies
equally to men and women. However, the
findings sparked another question, namely
whether further reduction in LDLC levels,
beyond those achieved by treatment with high-
intensity statins, would yield an additional
reduction in risk.
8 | JANUARY 2016
Acetate
PCSK9
inhibitors
(4060%)
Endosomal
degradation
Cholesterol
Dietary
cholesterol
Ezetimibe
(1520%)
Nature Reviews | Cardiology
Figure 1 | Statins, ezetimibe,
and PCSK9
inhibitors all increase the expression of LDL
receptors and reduce LDLcholesterol
levels (by percentages shown). Statins inhibit
cholesterol synthesis in the liver, ezetimibe
blocks cholesterol absorption in the intestine,
and proprotein convertase subtilisin/kexin
type9 (PCSK9) inhibitors block the
PCSK9mediated degradation of LDL receptors.
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
C A R D I O LO G Y
Key advances
Statin therapy reduces the risk of
atherosclerotic cardiovascular disease
toanequal extent in both men and women1
Addition of ezetimibe to statins given at
maximum dose further reduces the risk
ofcardiovascular disease compared
withstatins alone2
Proprotein convertase subtilisin/kexin
type9 inhibitors greatly enhance the
reduction of LDLcholesterol levels, even
when combined with statins, and seem
incrementally to reduce the risk of
atherosclerotic disease4,5
Acknowledgements
H E A RT FA I L U R E I N 2 0 1 5
C A R D I O LO G Y
Key advances
Adaptive servo-ventilation for central sleep
apnoea in systolic heart failure seems to be
harmful, and the use of this therapy should
be discouraged in these patients2
Oral treatment for type2 diabetes mellitus
with empagliflozin (an inhibitor of sodium/
glucose cotransporter2) convincingly
reduced the development of heart failure3
Glycaemic control with the dipeptidyl
peptidase4 inhibitor sitagliptin did not
increase the risk of major adverse
cardiovascular events in patients with
type2 diabetes4
The SPRINT trial showed the benefits of more
intensive control of systolic blood pressure
compared with the current standard target6
Still no effective therapy available for
Chagas cardiomyopathy after a long-term
study of benznidazole8
SGLT2 inhibitors
SGLT2
Glucose
Collecting
duct
SGLT1
No glucose
S1 segment of
proximal tubule
Distal S2/S3 segment
of proximal tubule
Glycosuria
Nature Reviews | Cardiology
10 | JANUARY 2016
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
C A R D I O LO G Y
6,068 patients with type2 diabetes and a recent
coronary event in the ELIXA study5. The pri
mary composite end point of cardiovascular
mortality, nonfatal myocardial infarction,
stroke, or hospitalization for unstable angina
was similar in the two groups (HR1.02, 95%CI
0.891.17) and demonstrated noninferiority
(P<0.001) to placebo. Hospitalizations for
heart failure did not differ between the two
groups (HR0.96, 95%CI 0.781.13).
Antihypertensive treatment reduces the
risk of stroke, myocardial infarction, and heart
failure, but the target for blood-pressure lower
ing is unknown. Researchers in the SPRINT
trial6 investigated whether reduction of systolic
blood pressure to <120mmHg was superior to
the standard target of <140mmHg. The study,
which included a total of 9,361 patients, was
stopped prematurely because of a significant
reduction in the primary composite end point
of cardiovascular mortality, nonfatal myo
cardial infarction, stroke, acute coronary event,
or hospitalization for heart failure in the group
with the lower blood-pressure target. In this
group, all-cause mortality was significantly
reduced (HR0.73, 95%CI 0.600.90, P=0.003)
compared with the standard-treatment
group, as was hospitalization for heart failure
(HR0.62, 95%CI 0.450.84, P=0.002). The
SPRINT trial substantially adds to the evidence
for benefits associated with more aggressive
lowering of systolic blood pressure compared
with current standard targets and, importantly,
the results were obtained by using a variety of
antihypertensive drugs.
In Latin America, the most common
form of nonischaemic cardiomyopathy is
Chagas disease, which develops 2030years
after the initial infection by the parasite
JANUARY 2016 | 11
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A Decade in Medicine
The past 10 years has seen great advances in the understanding and treatment of human disease. For expert
perspectives on the most important breakthroughs, dont miss the A Decade in Medicine eBook.
In this special collection of 47 articles commissioned to celebrate the 10th anniversary of the launch of the
clinical Nature Reviews journals leading experts highlight the most important advances in eight medical
specialties between 2004 and 2015, and comment on future developments in their fields.
Download the eBook free here: http://www.nature.com/reviews/collection/adecadeinmedicine/index.html
CLINICAL ONCOLOGY
BREAST CANCER IN 2015
S.Bradbrook/NPG
JANUARY 2016 | 12
C L I N I C A L O N C O LO G Y
The winner in terms of progression-free survival (PFS) and timetotreatment failure was
the relatively cheap drug paclitaxel6.
Similarly, our colleagues in the UK can be
proud of their practice-changing trial7 of up
front carboplatin (AUCx6 once every 3weeks)
versus docetaxel (100mg/m2 every 3weeks) in
women with metastatic triple-negative breast
cancer (TNBC): a superior response rate for the
alkylating agent over the taxane was demonstrated in 43 patients with BRCA-mutated
tumours, representing around 8% of the trial
population. When receiving carboplatin,
patients with BRCA-mutated tumours had
a median PFS of 6.8months compared with
3.1months in BRCA-wild-type patients7. Full
publication of this important trial is pending.
Following over two decades of intensive
basic research effort to dissect the molecular
mechanisms of endocrine resistance in breast
cancer, we can celebrate the rewards of the successful registration of new targeted compounds
that delayed the onset of treatment resistance in
patients with mBC. Letrozole combined with
the CDK4/6 inhibitor palbociclib received
conditional accelerated approval by the FDA
as the first-line endocrine-based therapy for
mBC, on the basis of extended PFS results in
a randomized phaseII trial8; palbociclib also
improved PFS by 5months in combination
with fulvestrant in a phaseIII trial involving 521
patients with relapsed or progressive disease
during prior endocrine therapy9. Palbociclib
is associated with a manageable toxicity profile
(neutropenia and fatigue), and maintenance of
global quality of life9. Whether palbociclib will
provide better survival outcomes than evero
limus remains unknown. Of note, no biomarkers for either of these compounds have
been validated, beyond the oestrogen receptor,
which is a serious problem in view of the steep
rises in drug prescription costs.
A huge unmet medical need remains for
women with metastatic TNBC, as this disease
usually progresses rapidly following three to
7.
8.
9.
10.
11.
12.
Key advances
The excellent disease-free survival observed with adjuvant paclitaxel and trastuzumab without
anthracyclines have set a new standard of care for the adjuvant treatment of small (T1T2),
node-negative, HER2positive breast cancer, and highlighted the possibility to deescalate
treatment for low-risk, early stage, HER2positive disease1.
The very low incidence of breast-cancer recurrence observed in node-negative patients
withalow risk Oncotype DX score confirms that these patients should be spared
adjuvantchemotherapy3.
New data suggest that carboplatin can improve progression-free survival in patients with
BRCA-mutated tumours when used as first-line therapy for metastatic disease7.
In 2015, two studies demonstrated that palbocilib can improve progression-free survival
of patients with metastatic disease in both the first-line8 and second-line9 settings, and
palbociclib in combination with letrozole received conditional FDA approval for the first-line
treatment of oestrogen-receptor-positive, HER2negative metastatic breast cancer.
13 | JANUARY 2016
13.
14.
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2016 Macmillan Publishers Limited. All rights reserved
C L I N I C A L O N C O LO G Y
C O L O R E C TA L A N D G A S T R I C C A N C E R I N 2 0 1 5
The median survival of patients with metastatic colorectal cancer (mCRC) has improved
over the past 15years: in contemporary trials
median survival durations of approximately
30months have been reported1. Several new
drugs have contributed to this advance; however, an unmet need for new agents with a
greater clinical effect, which can break this
wall of 30months, remains. By contrast, the
median survival of patients with metastatic
gastric cancer (mGC) remains poor and,
generally, does not exceed 12months. Over
the past year, encouraging data on three new
treatments for mCRC and a new targeted
therapy for mGC have been presented. In
addition, new genetic classifications have
been proposed that might help to further
advance p
ersonalized molecular medicine
for thesediseases.
C L I N I C A L O N C O LO G Y
tumours that demonstrate microsatellite
instability (MSI)are more responsive to
PD1 blockade than MMR-proficientor
microsatellite-stabletumours7. In particular, immune-related objective responses and
20week immune-related progression-free survival (PFS) were achieved in four of 10 patients
(40%) and seven of nine patients (78%) with
MMR-deficient mCRC, respectively, compared
with none of 18 patients (0%) and two of 18
patients (11%) with MMR-proficient mCRC7.
Furthermore, excellent survival outcomes
were observed in patients with MMR-deficient
mCRC: both median PFS and overall survival
were not reached after a median followup
duration of 36months in this group, but were
only 2.2monthsand 5months, respectively,
in patients with MMR-proficient mCRC7.
MMR-deficiency occurs in many cancers,
and in patients with CRC, it can arise from an
inherited germ-line genetic defect, in the context of Lynch syndrome (hereditary nonpolyposis colorectal cancer),or it can be sporadic.
In either case, the resulting neoplasms harbour
hundreds or thousands of mutations, and are
considered as hypermutated and, therefore,
highly immunogeniclesions7.
With regard to mGC, active first-line and
second-line treatment optionsremain a major
unmet clinical need. Until now, trastuzumab
was the only targeted agent with clinically-
relevant activity in patients with gastric cancer.
Early results with antiVEGFR2 monoclonal
antibody ramucirumab indicated that monotherapy with this agent significantly prolongs
the survival of previously treated patients with
mGC, although the magnitude of the benefit
remains limited (median overall survival of
5.2months versus 3.8months with placebo)8.
More-recent data indicate, however, that the
combination of ramucirumab with paclitaxel
improves overall survival and could, therefore,
be regarded as a new standard second-line
Key advances
On the basis of an overall survival improvement demonstrated in the RECOURSE study2
published in 2015, TAS102 joins regorafenib as an FDA-approved treatment for chemorefractory
metastatic colorectal cancer (mCRC)
A 2015 study did not identify circulating biomarkers that predict response to regorafenib in
patients with mCRC, but nevertheless demonstrated the potential of liquid biopsies to improve
personalized medicine4
New data suggest that the novel anti-EGFR antibody mixture Sym0045, and the
immune-checkpoint inhibitor pembrolizumab7 hold considerable promise to further advance
mCRC outcomes
Recent data for ramucirumab support the use of this agent with paclitaxel as standard
second-line therapy for chemorefractory metastatic gastric cancer9
In the past year, classifications were proposed for both gastric cancer10 and colorectal cancer11,
which might facilitate patient stratification and further improve the outcomes of patients with
these diseases
15 | JANUARY 2016
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C L I N I C A L O N C O LO G Y
100
90
80
70
60
50
40
30
20
10
SD
PD
er
th
O
at
e
Pr
os
t
cr
ea
Pa
n
st
ORR
Br
ea
ria
va
Robert L.Coleman
since been conducted, demonstrating clinical efficacy in patients with tumours carrying
germline or somatic BRCA1 and/or BRCA2
mutations. Considerable focus has been
placed on patients with ovarian and breast
cancers, although these mutations also occur
in other tumour types. In 2015, Kaufman
and colleagues4 published a nonrandomized
phaseII trial of olaparib (at least one dose)
in 298 patients carrying a known deleterious germline mutation in BRCA1 or BRCA2.
The largest cohort comprised patients with
ovarian cancer (n=193), but the study also
recruited patients with breast, pancreatic,
prostate, and other solid tumours. The ratio
of BRCA1 to BRCA2 mutations was variable
among the cohorts, with BRCA1 mutations
being dominant for ovarian cancer. The
overall objective response rate (ORR) varied significantly by disease type (FIG.1). For
patients with ovarian cancer, the median
progression-free survival was 7.0months
and the overall survival was 16.6months4.
The olaparib regimen was well tolerated. No
differences in the ORR related to the BRCA
gene mutation status or to prior platinum
exposure were observed, although patients
with ovarian cancer were excluded from the
latter analysis because they had all received
previous platinum-b ased chemotherapy 4.
After a drought of new drug approvals for
ovarian cancer in the USA, the results from
this trial, combined with a large efficacy and
safety database of patients treated with olaparib in a variety of clinical settings proved
to be sufficient to warrant accelerated regu
latory approval of olaparib by the FDA in
December 2014. The evidence was convin
cing because the expectations for a response
O VA R I A N C A N C E R I N 2 0 1 5
NE
JANUARY 2016 | 16
C L I N I C A L O N C O LO G Y
to chemotherapy alone after exposure to
three or more lines of therapy is around
10%5. The reference metric was based on
patients that had developed resistance to
platinum regardless of their BRCA mutation
status, but this level of activity for a novel
non-chemotherapeutic agent is notable. The
conditional approval by the FDA in this setting has had a notable ripple effect on drug
development, opening a new domain for
evaluating promising pharmaceutical assets6.
Ovarian cancer is paradigmatic of an
immunos uppressive tumour, and there
are many reasons to believe that this disease would be amenable to treatment with
immunotherapy : ovarian-cancer cells
express cancer-specific antigens, elicit spontaneous antitumour immune response after
immunot herapy, and are associated with
variable tumour-infiltrating lymphocytes
(TILs)the presence and character of which
is a significant prognostic factor7. Several
immune-targeted strategies have shown
modest efficacy over the past four decades,
but the recent discovery of the immune-
checkpoint inhibitors have ushered in a new
era in immune-oncology. In a phaseII trial
published in the past year, Hamanishi etal.8
evaluated one of these agents, the antiPD1
(programmed cell-death protein 1) antibody nivolumab, in patients with recurrent,
platinum-resistant ovarian cancer; 12months
of therapy at two dose levels was evaluated,
with a primary end point of best overall
RECIST response. In general, both dosages
were well tolerated. Eight out of 20 patients
experienced grade 3 or 4 adverse events,
but only two of them required treatment
discontinuation. The adverse event profile
was consistent with that of this class of agent
across multiple tumour types. Objective
responses were observed in three patients
(15%)8. Two complete responses (CR) were
observed, including one in a patient with disseminated ovarian clear-cell cancer, a notori
ously chemorefractory histologic subtype.
PD1 ligand 1 (PDL1) expression was not
correlated with ORR, as has been reported
for other tumour types 9. A response rate
of 15% might appear modest compared to
Key advances
Adherence to guideline-directed care improves outcomes in ovarian cancer2; moreover, access
to guideline-compliant comprehensive cancer care centres might offer added benefits
The initial clinical efficacy of novel therapeutics, such as poly(ADP-ribose) polymerase (PARP)
inhibitors4 and immune-checkpoint inhibitors8, has ushered in a new wave of drug development
in ovarian cancer
Ovarian cancer is characterized by genomic chaos; the selective pressure ofchemotherapy
induces a number ofmolecular events that are being characterized by deep genomic sequencing10
17 | JANUARY 2016
Acknowledgements
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C L I N I C A L O N C O LO G Y
M E TA S TAT I C P R O S TAT E C A N C E R I N 2 0 1 5
JANUARY 2016 | 18
C L I N I C A L O N C O LO G Y
Key advances
Early administration of docetaxel to patients
with metastatic prostate cancer significantly
benefits the outcomes of those patients2
The majority of castration-resistant
prostatecancer contains potentially
actionable mutations9
Prostate cancer with certain aberrations in
DNA repair respond to poly(ADP-ribose)
polymerase (PARP) inhibition10
19 | JANUARY 2016
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C L I N I C A L O N C O LO G Y
therapy, whereas the CheckMate017 investigators2 found no such correlation in patients
with squamous NSCLC. Indeed, 45.2% of
patients with predetermined cutoff of PDL1
expression included in KEYNOTE001
responded to pembrolizumab, with a median
PFS of 6.3months (comparedwith a response
rate of 19.4% and PFS of 3.7months in the
Egbert F.Smit and Paul Baas
trial cohort overall)3. Assuch, pembrolizumab
was approved together with a companion
Lung-cancer treatment paradigms continue to advance as we exploit our
diagnostic PDL1 assay. Nonetheless, treatgrowing understanding of the genetic basis of both tumorigenesis and
ment decisions are complicated by the use
therapy resistance. Moreover, ongoing developments with targeted
of different assay platforms and cutoff points
therapies are improving patient outcomes, with two new drugs approved in for PDL1 expression in clinical trials1,3. On
the basis of the data presented in 2015, one
2015 for non-small-cell lung cancer and many others showing promise.
might conclude that higher tumour PDL1
expression correlates with response rate and
survival. Conflicting data have emerged, howIn 2015, the therapeutic landscape for patients by the FDA as second-line treatments for ever, regarding the negative predictive value
with lung cancer has expanded through the NSCLC. Moreover, studies of immune- of this putative marker. Indeed, 1119% of
development of agents directed at both estab- checkpoint inhibition in the first-line, adju- patients with no tumour PD-L1 expreslished and novel targets. Immune-checkpoint vant, and m aintenance s ettings are now sion can nevertheless achieve a long-lasting
inhibition is one of the new and most-exciting underway(TABLE1).
response to agents targeting the PD1PDL1
The lack of a biomarker with suffi- axis4. Notably, such response rates among only
breakthroughs in the treatment of advancedstage non-small-cell lung cancer (NSCLC). cient sensitivity and specificity to predict the biomarker-negative subgroups are compaThe immune-checkpoint inhibitors under response to therapy is a major issue in the rable to those achieved in the overall populaclinical evaluation in NSCLC can be divided selection of patients for treatment with tion of patients with advanced-stage NSCLC
into two major classes: inhibitory antibodies immune-checkpoint inhibitors. Of note, the with the second-line treatments used in the
that target cytotoxic Tlymphocyte-associated CheckMate057 and KEYNOTE001 data1,3 past decadeand that are still used today.
antigen 4 (CTLA4), namely, ipilimumab showed that tumour-cell PDL1 expression Tumour heterogeneity, sampling issues, and
and tremelimumab; or those that block the was correlated with the efficacy of antiPD1 the use of archived material might represent
interaction between programmed cell-death
protein 1 (PD1) and its ligand PDL1
(TABLE 1) . Most progress has been made,
Table 1 | Agents targeting the PD1PDL1 axis in phaseIII NSCLC trials
however, with the antiPD1 antib odies
Remarks (ClinicalTrials.gov ID)
Drug
Type
Target Status
nivolumab and pembrolizumab, which have
Nivolumab
Human
PD1
PhaseIII
Registered
for second-line treatment of
been associated with unprecedented results
(BMS936558)
IgG4
(completed/
advanced-stage
NSCLC (NCT01642004
and minimal toxicities compared with
ongoing)
and NCT01673867). Trials ongoing
conventionalchemotherapy.
in other settings and in combination
In 2015, nivolumab was demonstrated to
with other therapies (NCT02041533;
NCT02477826)
have consistent antitumour activity against
both nonsquamous and squamous advancedPembrolizumab
Humanized PD1
PhaseIII
Registered for second-line treatment of
(MK3475)
IgG4
(completed/ PDL1positive advanced-stage NSCLC
stage NSCLC in the CheckMate057 and
ongoing)
(phase completed but not reported:
CheckMate017 phaseIII trials1,2, respectively,
NCT01905657). Trials ongoing in other
when used as a single agent in the second-
settings and in combination with other
line setting. Approximately 20% of patients
therapies (NCT02220894; NCT02142738;
responded to this agent, compared with 912%
NCT02578680; NCT02504372)
of those who received standard second-line
Atezolizumab
Humanized PDL1 PhaseIII
In various settings and with various
docetaxel, and a higher proportion were
(MPDL3280A)
IgG1
(ongoing)
therapies (NCT02367794; NCT02367781;
NCT02409342; NCT02366143;
alive at 1year (51% and 42% in the nonsquaNCT02409355; NCT02486718)
mous and squamous disease settings, respectively, versus 39% and 24% with docetaxel)1,2.
Durvalumab
Human
PDL1 PhaseIII
+/ tremelimumab (NCT02453282;
(MEDI4736)
IgG1
(ongoing)
NCT02542293; NCT02352948),
Compared with docetaxel, nivolumab also
as a maintenance therapy after
improved the median overall survival of
chemoradiation for stage III disease
patients with either nonsquamous NSCLC
(NCT02125461), and in the adjuvant
1
(9.4months versus 12.2months; P=0.002) ,
setting (NCT02273375)
or squamous-cell disease (6.0months verAvelumab
Human
PDL1 PhaseIII
Versus platinum-based doublet
sus 9.2months; P<0.001)2. In 2015, similar
(MSB0010718C) IgG1
(ongoing)
chemotherapy in the first-line
efficacy was observed for pembrolizumab in
(NCT02576574), and docetaxel in the
second-line (NCT02395172)
the large, phaseI, KEYNOTE001 trial3, and
NSCLC, non-small-cell lung cancer; PD1, programmed cell-death protein 1; PDL1, PD-1 ligand 1.
both this agent and nivolumab were approved
LUNG CANCER IN 2015
JANUARY 2016 | 20
C L I N I C A L O N C O LO G Y
important challenges in expression profiling
of PDL1; the ideal t iming, sampling method,
and quantitation of this marker need to be
clarified. Other potential biomarkers are also
under investigation, such as mutational load
and tumour-infiltrating lymphocyteprofiles.
Just over 10years after the value of activa
ting EGFR mutations for predicting the bene
fit of gefitinib treatment in patients with lung
adenocarcinoma was established, the efficacy
of two third-generation EGFR inhibitors has
now been reported5,6. These novel inhibitors,
which are selective for EGFR harbouring
activating and T790M gatekeeper resistance
mutations, will undoubtedly serve as the next
landmark therapy in this disease. The T790M
mutation accounts for approximately 60%
of resistance to first-generation (erlotinib,
gefitinib) and second-generation(afatinib)
EGFR inhibitors. In two phaseI/II trials5,6,
published in 2015, the third-generation
EGFR inhibitors rociletinib (CO1686) and
osimertinib (mereletinib, AZD9291) were
associated with objective response rates of
59% and 61%, respectively, in patients with
metastatic NSCLC that had progressed on
prior EGFR-inhibitor therapy and subsequently tested positive for the T790M mutation. This efficacy was achieved at the expense
of predictable minor toxicity events5,6. One
exception was rociletinib-associated hyperglycaemia5, which seems to be attributable
to inhibition of IGFR1 by a drug metabolite;
however, this interaction could, in fact, be
advantageous, as resistance to EGFR inhibi
tors might be mediated partially by IGFR1
bypass signalling. In late 2015, on the basis
of these findings, osimertinib was approved
by the FDA for the treatment of EGFRT790Mpositive metastatic NSCLC that is resistant to
first/second-generation EGFRinhibitors.
Unfortunately, secondary resistance to
these third-generation agents has also been
described in 2015. In a total of 27 patients
studied7,8, the EGFRT790M allele disappeared
Key advances
Immunotherapies are showing continued promise in the treatment of non-small-cell lung
cancer (NSCLC)13, with nivolumab and pembrolizumab approved for the second-line
treatment of metastatic squamous and nonsquamous disease in 2015
Third-generation EGFR inhibitors have been associated with impressive response rates in
patients with NSCLC and EGFRT790Mmediated resistance to earlier-generation inhibitors5,6;
osimertinib is now approved for this indication
Intrinsic tumour heterogeneity underlies eventual resistance to these new EGFR inhibitors;
liquid biopsies might be useful in monitoring disease evolution and informing treatment
decisions7,8
Other molecular targeted therapies are showing potential as lung-cancer treatments,
including MET inhibitors9, and RovaTthe first potential targeted treatment for small-cell
lung cancer10
21 | JANUARY 2016
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C L I N I C A L O N C O LO G Y
MELANOMA IN 2015
Immune-checkpoint blockade
durable cancer control
Elizabeth I.Buchbinder and F.Stephen Hodi
In 2015, advances in immunotherapy for metastatic melanoma have come to
fruition, with phaseIII data supporting the combination of ipilimumab and
nivolumab as first-line therapy. Understanding the mechanisms involved in
aneffective antitumour immune response are now key to further advances.
Several studies published in 2015 have increased our understanding of the
complex relationships that exist between our immune system and malignancy.
S.Bradbrook/NPG
JANUARY 2016 | 22
C L I N I C A L O N C O LO G Y
highlighted by pre-existing CD8+ Tcell infiltration. This finding emphasizes the importance of understanding why some tumours
have a more-robust adaptive recognition by
the host immune system6. A profound leap
forward in this understanding came from the
findings of Spranger etal.9, who investigated
the gene-expression profiles of 266 cutaneous
melanomas and divided them into inflamed
and non-inflamed cohorts. They found that
catenin signalling was active in the non-
inflamed cohort and an increased CTNNB1
(catenin) score was predictive for a lack of
Tcell infiltration, with an odds ratio of 4.9
(REF.9). Inthis study, genetically engineered
Braf V600E/Pten/mutantmice and Braf V600E/
Pten //Ctnnbmutant mice were used to
evaluate this association further9. Melanoma
tumours that developed in Braf V600E/Pten//
Ctnnb-mutant mice demonstrated failure of
Tcell priming, which was suggested to be
related to defective recruitment and activation of CD103+ dendritic cells (DCs)9. Failed
recruitment of CD103+ DCs was partially due
to defective production of the chemokine
CCL4, owing to induction ofATF3which
suppresses CCL4by mutant -catenin9.
Thus the WNT/catenin pathway might
contribute to immune evasion in melanoma,
with potential therapeutic implications. This
work identified important signalling pathways related to adaptive immune responses,
and indicated a potential targetable mechanism by which tumour cells can exclude
Tcellinfiltration9.
Genomic analyses have added tremendous
insight into what drives the host immune system to mount an adaptive response against
tumours. This year, Rizvi etal.5 examined
Key advances
The combination of CTLA4 blockade and PD1 blockade in the treatment of patients with
metastatic melanoma result in an improved response rate and progression-free survival
compared with treatment with either agent individually, leading to its approval by the FDA as
afront-line therapy4
Toxicity from immune-checkpoint blockade can be severe and the combination of CTLA4
blockade with PD1 blockade led to 55% of patients experiencing grade 34 treatment-related
adverse events4
The baseline inflammatory status of the melanoma tumour is predictive of patient response to
immune-checkpoint blockade6, and one mechanism of Tcell exclusion from tumours seems to be
through catenin signalling9
Mutational burden of tumours has been associated with response to immune-checkpoint
blockade in both melanoma and non-small-cell lung cancer5,6
23 | JANUARY 2016
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ENDOCRINOLOGY
OBESITY IN 2015
Advances in managing
obesity
John B. Dixon
Successful management of obesity requires integration of pharmaceutical
agents and bariatric surgeries with traditional lifestyle modifications.
Notable developments for managing obesity in 2015 included the
demonstration of weight-beneficial outcomes for liraglutide and
empagliflozin, and the first 5year followup of patients with type2 diabetes
mellitus and obesity randomly assigned to receive bariatric surgery or
conventional medical therapy.
Obesity is a serious relapsing chronic dis
ease that requires a long-term chronicdisease model of care. Behavioural and/
or lifestyle interventions that include a
high-quality diet, caloric restriction, reduced
sedentary behaviour and increased physical
activity form the cornerstones of traditional
care. However, by themselves, these inter
ventions produce only limited sustained
weight loss in the majority of adults. The
central control of energy balance and vig
orous defence of an individuals maximal
weight underlies the difficulties in relying
on lifestyle interventions alone to success
fully manage either of these conditions. In
addition to lifestyle changes, a broad range of
safe and effective interventions are needed to
manage obesity and the effects of the disease
on physical and mental function, quality of
life, end-organ damage and mortality, along
with the capacity to deliver interventions to
those most in need. Applying the principles
of chronic disease management to obesity
would see treatments to promote weight loss
combined when needed (FIG.1). Sustained
weight loss of >5% of a patients body weight
provides measurable clinical benefit, but the
association between the degree of weight loss
and the extent of the benefit is not linear for
many complications; any additional benefit
beyond that afforded by 10% weight loss is
often attenuated1. An important emerging
Traditional lifestyle
modication
Pharmacological
agents
Bariatric surgery
Weight loss
24 | JANUARY 2016
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E N D O C R I N O LO G Y
Key advances
Liraglutide, a drug primarily used for
glycaemic control, is an effective weight
loss treatment and reduces the risk of
patients with obesity developing
prediabetes mellitus or type2 diabetes
mellitus (T2DM)2
The sodiumglucose cotransporter2
inhibitor, empagliflozin, reduces the risk of
cardiovascular events in patients with
T2DM and leads to sustained weight loss3
Patients with T2DM who underwent
bariatric surgery had sustained weight loss
5years after surgery, even though 3350%
of those in remission for T2DM relapsed6
JANUARY 2016 | 25
E N D O C R I N O LO G Y
THYROID CANCER IN 2015
Key advances
ALK
EIF1AX
HABP2
Tumour
NPG
Thyroid
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E N D O C R I N O LO G Y
the HABP2 mutation associated with the
Gly534Glu substitution as a susceptibility
variant for familial, nonsyndromic, non
medullary thyroid cancer. The mechanisms
by which this variant might promote the
development of PTC are not clear. However,
when understanding of these mechanisms
improves, light could be shed on alternative
pathways that lead to thyroidcarcinogenesis.
The studies discussed so far (together with
the existing body of literature) improve our
understanding of the molecular mechanisms
of sporadic and familial forms of thyroid can
cer, provide new potential targets for thera
peutic inhibition and expand the arsenal of
biomarkers that can be used for cancer diag
nosis. The third point is of particular impor
tance for thyroid nodules that cannot be
diagnosed definitively as benign or malignant
on the basis of routine cytological evaluation
of cells collected from nodules using fineneedle aspiration. In the USA alone, every
year >100,000 patients are diagnosed with
nodules that have indeterminate cytology6.
The unclear diagnosis prevents optimal
management of these patients and frequently
results in avoidable diagnostic surgeries.
Extensive characterization of the mutational
landscape of thyroid cancer, which has accel
erated over the past few years after the intro
duction of powerful new technologies such as
next-generation sequencing, has provided a
basis for creating multigene mutational pan
els for the detection of cancer in thyroid nod
ules. As driver mutations in thyroid cancer
are known to include point mutations, such
as those of BRAF and RAS, and gene fusions,
such as those affecting RET, NTRK1/3 and
ALK, both mutation types are included in
these panels.
A study published in 2015 reported the
results of the validation of a gene panel
in a common category of indeterminate
cytology known as atypia of undetermined
s ignificance/follicular lesion of undeter
mined significance (AUS/FLUS) 7 . The
panel that was evaluated included 14 genes
that were studied for point mutations and
42 types of gene fusion, together with the
expression levels of certain cell lineage mark
ers. The mutational panel, called ThyroSeq
(University of Pittsburgh Medical Center,
USA), was tested in a large series of patients
with nodules who had received a diagnosis
of AUS/FLUS. The panel had 91% sensitiv
ity and 92% specificity for cancer detection
in these nodules, which resulted in a 97%
negative predictive value and a 77% positive
predictive value in the studied cohort. The
results of the study provide a rationale for
offering diagnostic genetic testing in clinical
E N D O C R I N E D I S R U P TO R S I N 2 0 1 5
Epigenetic transgenerational
inheritance
Michael K. Skinner
Endocrine disruptors are critical environmental exposures that influence
health and can promote epigenetic transgenerational inheritance of
disease and abnormal physiology. Advances in 2015 included analyses of
the effects of endocrine disruptors on human disease, further examples
ofendocrine disruptors promoting transgenerational behavioural effects,
insights into effects of endocrine disruptors on epigenetic programming
ofprimordial germ cells and the finding that endocrine disruptors can
transgenerationally promote genetic mutations.
Environmental compounds that alter and/or
disrupt normal endocrine hormone signal
ling at the receptor or signal transduction
level are termed endocrine disruptors. The
first endocrine disruptors studied and shown
to promote abnormal physiology and disease
were diethylstilbestrol (DES) and dichloro
diphenyltrichloroethane (DDT)1. The num
ber of known endocrine disruptors has since
expanded dramatically to include compounds
such as bisphenolA (BPA) and phthalates;
natural compounds, such as genistein from
plants, can also act as endocrine disruptors1.
Over the past several decades, research on
endocrine disruptors has improved our
E N D O C R I N O LO G Y
Endocrine disrupter exposure
Female/male
F2
Germline F1
F1
F0
F0
Multigenerational
exposures
28 | JANUARY 2016
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E N D O C R I N O LO G Y
modifications. These epigenetic processes
are so interlinked that they must be viewed
as integrated rather than disconnected. The
observation that PGCs and the developing
germ line undergo major epigenetic pro
gramming, which can be transgenerationally
altered by endocrine disruptors 7, was a
significant advance in2015.
Endocrine-disruptor-induced epigenetic
transgenerational inheritance of germ line
epimutations has a critical role in this form
of nongenetic inheritance1. Previous stud
ies have shown that susceptibility to genetic
mutations is increased by epigenetic altera
tions such as CpG methylation that promotes
C to T conversions (point mutations), DNA
methylation that influences repeat element
copy number variation (CNV) and transpos
able element movement, and histone mod
ifications and DNA methylation that alter
chromosome translocation breakpoints. The
role of genetics in epigenetic transgenera
tional inheritance is, thus, important. In 2015,
my colleagues and I showed that vinclozo
lin promotes epigenetic transgenerational
inheritance of genetic mutations in sperm
(that is, CNV)9. In the directly exposed F1
generation, no change in CNV was seen, but
in the F3 generation a significant increase in
CNV was observed9. Transgenerational alter
ations in the epigenome, therefore, increase
genetic instability and promote genetic muta
tion and variation. Transgenerational mech
anisms and phenotypes will probably involve
a combination of epigenetics and genetics,
as genetics and epigenetics cannot be sep
arated9. Further studies are now needed to
elucidate this process, which might have a
critical role in environmentally influenced
disease aetiology and evolution.
The effects of endocrine disruptors on
epigenetic programming during develop
ment provides a molecular mechanism for
the development of disease later in life 1.
In the event that germ line epigenetic pro
gramming is altered, this change can lead to
environmentally induced epigenetic trans
generational inheritance of disease and phe
notypic variation. Although the majority of
environmental exposures are not endocrine
disruptors, in todays society, endocrine dis
ruptors are an important source of contami
nation. The advances in 2015 discussed here
support critical effects of endocrine disrup
tors on human health and in inducing epi
genetic transgenerational inheritance, and
increase our understanding of the molec
ular processes involved. This form of non
genetic inheritance that is environmentally
responsive affects all of biology from disease
aetiology to evolution.
3.
4.
5.
6.
7.
8.
9.
Acknowledgements
H E PAT I C G L U C O S E M E TA B O L I S M I N 2 0 1 5
E N D O C R I N O LO G Y
Food intake
Blood insulin
Nutrients
Bile acids
FXR
Brain
S-nitrosylation
ER stress
Glucose
production
Insulin resistance
Figure 1 | Regulation of hepatic glucose metabolism by the gut, brain and liver.
Nature Reviews | Endocrinology
Targetingfarnesoid Xactivated receptor (FXR) in the gut, the insulin receptor in the brain and
Snitrosylation in the liver in a nutrient-dependent manner alters hepatic glucose production
invivo. ER, endoplasmic reticulum.
signalling mediated by
thehepatic insulin receptor is
not required to inhibit hepatic
glucose production
Although an increase in circulating lev
els of the gut-derived hormone fibroblast
growth factor 15 (FGF15) in rodents (or
FGF19 in humans) occurs in parallel with
reduced hepatic glucose production, this
relationship remains correlative in nature
and raises the question of whether alterna
tive mechanisms such as a gutbrainliver
neuronal network could be responsible
for fexaramine reduc ing hepatic glucose
production. Consistent with this hypothe
sis, metformin activates 5-AMP-activated
protein kinase in the small intestine of dia
betic rodents, which results in lowering of
hepatic glucose production and plasma
levels of glucose via a neuronal network 2,
Key advances
Oral administration of the gut-restricted farnesoid Xactivated receptor agonist fexaramine
lowers hepatic glucose production1
Hepatic insulin receptor-mediated signalling is not required for glucose homeostasis in
postprandial states6,7
Snitrosylation of proteins in the liver mediates obesity-induced inflammation that impairs
endoplasmic reticulum function, prolongs endoplasmic reticulum stress in the liver and disrupts
whole-body glucose homeostasis9
30 | JANUARY 2016
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2016 Macmillan Publishers Limited. All rights reserved
E N D O C R I N O LO G Y
and colleagues9 published in 2015 reported
that Snitrosylation of proteins in the liver
mediates obesity-induced inflammation that
impairs endoplasmic reticulum function, pro
longs endoplasmic reticulumstress in the liver
and disrupts whole-body glucose homeostasis
(FIG.1). Specifically, obesity causes inducible
nitric oxide synthase expression in the liver
of rodents and disrupts glucose homeostasis
in parallel with an increase in Snitrosylation
of hepatic proteins as a consequence of
inflammation-dependent production ofnitric
oxide. The increase in Snitrosylation of pro
teins in the liver targets inositol-requiring
protein 1 (IRE1) and inhibits its ribo
nuclease activity, which leads to a reduction
in Xbox-binding protein1 (XBP1) splicing
activity and an increase in endoplasmic retic
ulum stress, eventually leading to disruption
of hepatic insulin action and whole-body glu
cose tolerance. Although Yang and colleagues
did not directly address whether the hepatic
Snitrosylation-dependent pathway alters
hepatic glucose metabolism, disruption of
glucose homeostasis by hepatic Snitrosylation
is probably due to dysregulation of hepatic
glucose metabolism, particularly as inflam
matory pathways in the liver are capable of
negating insulins ability to inhibit hepatic
glucoseproduction.
Although Yang etal.9 demonstrated that
obesity induces hepatic inflammation and
Snitrosylation-dependent pathways that dis
rupt hepatic endoplasmic reticulum function
and glucose homeostasis, a direct influx of
nutrients into hepatocytes might not be the
only mechanism that triggers such a hepatic
response, as the release of hepatic inflammatory
molecules is triggered by the brain10. Future
investigations are necessary to address whether
extrahepatic tissues, acting via a neuronal net
work, can regulate hepatic inflammation and
endoplasmic reticulumstress.
In summary, four notable studies published
in 2015 indicate that hepatic glucose metabo
lism is regulated by nutrient-dependent and
hormone-sensing-dependent signalling path
ways in the gut, brain and liver1,6,7,9. Targeting
these molecular pathways in the gut, brain
and/or liver might serve as an integrative
strategy to lower hepatic glucose production
and restore glucose homeostasis in patients
with diabetes mellitus and obesity.
Tony K. T. Lam is at the Toronto General Research
Institute and Department of Medicine, University
Health Network, MaRS Centre, Toronto Medical
Discovery Tower, Room 10705, 101 College Street,
Toronto, Ontario M5G 1L7, Canada.
tony.lam@uhnres.utoronto.ca
doi:10.1038/nrendo.2015.204
Published online 27 November 2015
1.
2.
3.
4.
5.
6.
7.
Acknowledgments
I S L E T- C E L L B I O L O G Y I N 2 0 1 5
Understanding
secretion, ageing and
death in cells
Gordon C.Weir
The pancreatic islets of Langerhans have been intensively investigated for
many years, largely because of their central role in the pathogenesis of
type1 and type2 diabetes mellitus. Notable advances in 2015 related to
glucose-stimulated insulin secretion in cells, cell death and the role of
epigenetics in cell heterogeneity.
Pancreatic cells are remarkable for their
precisely controlled secretion of insulin in
response to glucose and a variety of other
secretagogues. The mechanisms responsi
ble for glucose-stimulated insulin secretion
(GSIS) are truly elegant. Glucose metabo
lism is tightly linked to insulin secretion, and
major control is exerted by glucokinase, the
rate-limiting enzyme in glycolysis. The link
between glucose metabolism and exocytosis
of insulin has been examined in detail and
an important unanswered question in cell
biology concerns the mechanism responsible
for GSIS that is independent of ATP-sensitive
potassium (K ATP ) channels. The K ATP channel-dependent mechanisms of GSIS are
much better understood; under the influ
ence of glucose metabolism, KATP channels
are closed and the resultant depolarization
epigenetic modifications
can account for differences in
the function and proliferative
capacity of cells
cell deficiency is an important part of
the pathogenesis of type1 diabetes melli
tus (T1DM) and type2 diabetes mellitus
(T2DM), but it has not been possible to
quantitate cell mass in living people. In
T1DM, the presence of antibodies against
cell antigens has been associated with
autoimmune destruction of cells that is
thought to take place years before the diag
nosis of disease. Our understanding would
be greatly enhanced if cell mass and the
rates of cell death could be measured invivo.
However, whereas progress has been made
with imaging of inflammation in T1DM2,
attempts to image cell mass have not yet
provided sufficient specificity or precision.
In the quest to measure cell death,
Herold and colleagues3 used an exciting new
PCR-based technique for the measurement
of unmethylated DNA in the circulation.
Epigenetic methylation of DNA determines
whether a gene will be expressed in a particu
lar cell type. The CpG sites associated with the
insulin gene in cells have much less methyl
ation than those in other cell types, such that
unique, identifiable epigenetic markers in the
circulation can be measured by PCR to obtain
the ratio of unmethylated to methylated DNA,
as an indicator of cell death. The half-life
of methylated DNA is thought to be <2h, but
PCR provides the necessary specificity and
sensitivity to enable reliable measurement.
The PCR assay was used to examine sam
ples obtained from 50 individuals at risk of
developing T1DM, and from four patients
who had received islet autotransplants. The
results suggest that during the years prior
to diagnosis of T1DM the process of auto
immune killing of cells is sporadic, and
it intensifies in the months leading up to
symptomatic presentation, along with the
appearance of antibody markers. In patients
NP
G
E N D O C R I N O LO G Y
32 | JANUARY 2016
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E N D O C R I N O LO G Y
An ongoing, rapid increase in data gen
eration is occurring, resulting from increas
ing use of genome-wide characterization of
DNA, epigenetic markers, mRNA and non
coding RNA, as well as proteomics, metab
olomics and other omics technologies. The
bioinformatics field is keeping up remarkably
well with this glut of information. The appli
cation of these advances in the field of isletcell biology should lead to progress in our
understanding of the causes of cell inade
quacy in diabetes mellitus, which should in
turn open new therapeutic opportunities.
Gordon C.Weir is at the Section on Islet Cell and
Regenerative Biology, Joslin Diabetes Center,
OneJoslin Place, Boston, Massachusetts 02215, USA.
gordon.weir@joslin.harvard.edu
doi:10.1038/nrendo.2015.236
Published online 4 Jan2016
1. Ferdaoussi,M. etal. Isocitrate-toSENP1
signalingamplifies insulin secretion and rescues
dysfunctional cells. J.Clin. Invest. 125, 38473860
(2015).
2. Gaglia,J.L. etal. Noninvasive imaging of pancreatic
islet inflammation in type1A diabetes patients. J.Clin.
Invest. 121, 442445 (2011).
3. Herold,K.C. etal. cell death and dysfunction
duringtype1 diabetes development in atrisk
individuals. J.Clin. Invest. 125, 11631173
(2015).
4. Avrahami,D. etal. Aging-dependent demethylation
ofregulatory elements correlates with chromatin
stateand improved cell function. Cell Metab. 22,
619632 (2015).
5. Meier,J.J. etal. cell replication is the primary
mechanism subserving the postnatal expansion of
cell mass in humans. Diabetes 57, 15841594
(2008).
PCOS IN 2015
E N D O C R I N O LO G Y
Ricardo Azziz is at the Medical College of Georgia,
Georgia Regents University, 1120 15th Street,
Augusta, Georgia 30912, USA.
razziz@gru.edu
Key advances
As a highly prevalent
disorder that is associated
withreduced fertility, PCOS
seems to represent an
evolutionary paradox
As a highly prevalent disorder that is
associated with reduced fertility, PCOS
seems to represent an evolutionary paradox.
The similarity of PCOS globally, and the
presence of common loci in Chinese and
European cohorts, suggests that PCOS has a
long history, and that these loci could harbour
doi:10.1038/nrendo.2015.230
Published online 4 Jan2016;
corrected online 29 Jan 2016
Zawadski,J.K. & Dunaif,A. in Polycystic Ovay
Syndrome (eds Dunaif,A. etal.) 377384
(BlackwellScientific, 1992).
2.
Hayes,M.G. etal. Genome-wide association
ofpolycystic ovary syndrome implicates
alterationsingonadotropin secretion in
Europeanancestry populations. Nat. Commun. 6,
7502 (2015).
3.
Chen,Z.J. etal. Genome-wide association study
identifies susceptibility loci for polycystic ovary
syndrome on chromosome 2p16.3, 2p21 and
9q33.3. Nat. Genet. 43, 5559 (2011).
Shi,Y. etal. Genome-wide association study identifies
4.
eight new risk loci for polycystic ovary syndrome.
Nat.Genet. 44, 10201025 (2012).
5.
Day,F.R. etal. Causal mechanisms and balancing
selection inferred from genetic associations with
polycystic ovary syndrome. Nat. Commun. 6, 8464
(2015).
6.
Jones,M.R. etal. Systems genetics reveals the
functional context of PCOS loci and identifies
geneticand molecular mechanisms of disease
heterogeneity. PLoS Genet. 11, e1005455
(2015).
7.
McAllister,J.M. etal. Overexpression of a
DENND1Aisoform produces a polycystic ovary
syndrome theca phenotype. Proc. Natl Acad. Sci.
USA 111, E1519E1527 (2014).
8.
Goodarzi,M.O. etal. Replication of association of
DENND1A and THADA variants with polycystic ovary
syndrome in European cohorts. J.Med. Genet. 49,
9095 (2012).
9.
Hardy,J. & Singleton,A. Genomewide association
studies and human disease. N.Engl. J.Med. 360,
17591768 (2009).
10. Vink,J.M., Sadrzadeh,S., Lambalk,C.B.
&Boomsma,D.I. Heritability of polycystic
ovarysyndrome in a Dutch twin-family study.
J.Clin.Endocrinol. Metab. 91, 21002104
(2006).
1.
TGACACATC
TGCGATCGC ATCGCTT
CG
GCGCTACAT TCCGATC
GA
C
T
CGCCGTA
GCATCGATC
GATCCGPTC TTTCGTA
TC
GATAATCAG CTACGAC
AT
CGCAATOCG CAATGCG
CG
A
GTACTGSG
GTACTGCGA
ATCTACGAC CTAGCTG
AT
GCCGTATCG CCTCAGT
AC
G
T
AAGTCCT
TTACTCTTA
G
TCAGGTCA
NPG
34 | JANUARY 2016
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A Decade in Medicine
The past 10 years has seen great advances in the understanding and treatment of human disease. For expert
perspectives on the most important breakthroughs, dont miss the A Decade in Medicine eBook.
In this special collection of 47 articles commissioned to celebrate the 10th anniversary of the launch of the
clinical Nature Reviews journals leading experts highlight the most important advances in eight medical
specialties between 2004 and 2015, and comment on future developments in their fields.
Download the eBook free here: http://www.nature.com/reviews/collection/adecadeinmedicine/index.html
Central
vein
Dierentiation,
morphogenesis
Wnts
Stromal
mesenchyme
Pluripotent
stem cells
H. pylori
pathogenesis
Bile
duct
Hepatocyte
regeneration,
during chronic
injury
Hepatocyte
regeneration,
during acute injury
and senescence
Gastric
organoid
Gastric
epithelium
Surgical
biopsy
Pancreatic
organoid
Pancreatic
cancer
Figure 1 | Regeneration and generation of the gastrointestinal tract. The boxed panel on the left
Nature
Reviews | in
Gastroenterology
& Hepatology
highlights liver regeneration under normal homeostatic
conditions,
response to chronic
injury or in
response to acute injury. Stomach organoids derived from pluripotent stem cells were used to study
Helicobacterpylori infection (top right). Moreover, pancreatic organoids derived from the pancreas
were used to model pancreatic cancer (bottom right)10. HNF4, hepatocyte nuclear factor4.
35 | JANUARY 2016
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2016 Macmillan Publishers Limited. All rights reserved
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
Key advances
Wnt-responsive, pericentral hepatoctyes
located around the central vein contribute
to normal liver tissue homeostasis4
Cells adjacent to the portal vein have
molecular characteristics of duct cells and
hepatocytes, and give rise to hepatocytes in
response to chronic injury3
Biliary ductal cells form hepatocytes
in the context of hepatic injury and
hepatocyte senescence2
Human and mouse pancreatic ductal cells
can give rise to pancreatic organoids8;
pancreatic cancer organoids can give rise
tometastatic pancreatic cancer
Gastric organoids can be generated from
mouse pluripotent stem cells7
Acknowledgements
JANUARY 2016 | 36
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
LIVER FIBROSIS IN 2015
Macrophage
miR-142-5p
miR-130a-3p
VEGF-A
Extracellular
matrix
Sinusoidal
endothelial cell
TGF
Hepatic
stellate cell
Hepatocyte
Probrotic
TGF
NR4A1
Antibrotic
37 | JANUARY 2016
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2016 Macmillan Publishers Limited. All rights reserved
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
polarize into a proinflammatory cell type
with matrix-degrading activities (M1 pheno
type) upon stimulation by IFN or bacterial
components such as lipopolys accharide.
Alternatively, macrophages can polarize into
an M2 phenotype, associated with tissue
repair and fibrosis, after stimulation by IL4
and/or IL13. Moreover IL10 can induce an
anti-inflammatory profile in macrophages
that produces profibrotic cytokines such as
TGF3. Although the factors that modulate
macrophage polarity are known, modu
lation of macrophage plasticity invivo to
induce regression of fibrosis has been diffi
cult to achieve. In 2015, a study by Su etal.4
characterized microRNA (miR)-1425p and
miR130a3p levels in lung and liver fibrotic
tissue in mice and humans. IL4 and IL13
caused an upregulation of miR1425p and
a downregulation of miR130a3p levels in
macrophages, which was associated with
the induction of profibrotic activities in
these cells. Subsequent administration of
miR1425p antisense oligonucleotides and
agents that mimic miR130a3p led to a
strong reduction in matrix deposition within
lungs of bleomycin-treated mice and livers
of carbon-tetrachloride-treated mice. This
study opens up a valuable option for the
resolution of liver fibrosis by modification of
macrophage polarization. We have not fully
gained the fruits of the discovery of small
interfering RNAs (siRNAs) and miRNAs yet,
mainly due to delivery problems. However,
Calvente et al. 5 delivered siRNA against
procollagen using nanoparticles and they
Key advances
The nuclear receptor nucelar receptor4A1
has a key role in terminating the profibrotic
feedback loop induced by transforming
growth factor in fibroblasts, offering new
targets for antifibrotic therapies1
Scar-infiltrating myeloid cells produce
vascular endothelial growth factor A, which
is essential for the resolution of fibrosis2
The clinical testing of experimental
antifibrotic compounds requires definition
of clear end-points in clinical trials, patient
stratification and, most of all, noninvasive
tests to monitor liver fibrosis at an
earlystage6
microRNAs 1425p and 130a3p are found
to regulate macrophage profibrogenic
activities which opens up options for the
resolution of liver fibrosis through
modification of macrophage polarization4
Microbiome analysis in stool or saliva might
provide innovative tools in the
prognostication of the cirrhotic process7
JANUARY 2016 | 38
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
Key advances
G U T M I C R O B I O TA I N 2 0 1 5
Ruth E.Ley
OTELLLAA
V
RE
TER OI
AC
IDD
ES
Laura Marshall/NPG
39 | JANUARY 2016
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
Of these, P.copri had the highest number of
accessory genes within its genome (an acces
sory gene was defined as a species-specific
gene seen in some samples). The vastly differ
ent genome gene repertoires of strains within
and between Prevotella spp., and across hosts,
probably underlies some of the differences
observed in responses at the genus level to diet
and health conditions acrossindividuals.
Prevotella in the gut has previously been
positively associated with HIV5,10 and addition
of P.copri DSM 18025 to mice treated with
antibiotics has been shown to increase their
susceptibility to colitis induced by dextran
sulfate sodium4. In 2015, Dillon etal.5 showed
that P.copri levels were markedly elevated in
the mucosa and stool of patients infected with
HIV. Furthermore, exposure of key dendritic
cells to P.copri DSM 18205 boosted cytokine
production. The authors suggested that
increased levels of P.copri might contribute to
driving chronic inflammation in individuals
infected with HIV.
Notably, all three studies querying the
effects of P.copri on the host 1,4 or host cells5
used the same strain. P. copri CB7 (JCM
13464; DSM 18205), an isolate obtained from
the faeces of a healthy 52year-old Japanese
man, is currently the only cultured represent
ative of its species available from public cul
ture collections. Thanks to this constraint, it
is clear that a single strain of P.copri can act
in what has been interpreted as a beneficial or
detrimental manner, depending on the con
text. Adding strain variability to the system
compounds itscomplexity.
Prevotella is a large genus with high
species diversity; species can have high levels
of genomic diversity between strains. In the
human population, strain variation adds
another layer of uncertainty for predicting
how Prevotella will function in any given gut
ecosystem. To predict its function will require
a finer-grained understanding of these spe
cies genetic potential, their ecology, their
interactions with other microbes present and
with their host. A stronger grasp of strainlevel genome content on a per-individual
basis, obtained through metagenomic tech
niques, will inform attempts to modulate
levels of these bacteria therapeutically either
for improving metabolism or reducing risk of
inflammation in susceptiblehosts.
Ruth Ley is at Department of Molecular Biology and
Genetics, 467 Biotech, Cornell University, Ithaca,
NewYork 14853, USA and Department of Microbiome
Science, Max Planck Institute for Developmental Biology,
Spemannstrasse 35, Tbingen 72076, Germany.
rel222@cornell.edu
doi:10.1038/nrgastro.2016.4
Published online 1 Feb 2016
1.
2.
3.
4.
5.
6.
HCV IN 2015
Advances in hepatitisC
research andtreatment
Barbara Rehermann
In 2015, new treatment regimens were revealed that achieve >95% cure rates
for all HCV genotypes. The HCV polymerase structure was solved in
catalytically relevant HCV replication steps and in the context of nucleotide
analogue inhibition. Moreover, HCV research taught us new links between
innate antiviral responses, lipid metabolism and intracellular
membraneformation.
HCV is an enveloped, positive-stranded RNA
virus representing the Hepacivirus genus in
the Flaviviridae family. More than 185million
people worldwide are chronically infected with
HCV and at risk of developing liver cirrhosis
and hepatocellular carcinoma1. HCV exists in
six major genotypes and >100subtypes and,
in each patient, creates an astounding num
ber of quasispecies. This sequence diversity is
facilitated by the high virus production rate
of more than 1012 virions per patient per day
and the lack of a proofreading ability of the
RNAdependent HCV polymerase (RdRp).
The year 2015 provided insights into struc
tural changes of RdRp during HCV genome
replication and into the structural basis for
the antiviral effect of the nucleotide analogue
inhibitor (the active form of sofosbuvir) that
has revolutionized HCV treatment. The RdRp
(encoded by NS5B) catalyzes the synthesis of
a negative-stranded RNA intermediate that
then serves as template for the synthesis of
multiple positive RNA strands. The latter
are translated into HCV proteins, used as
templates for further minus-strand RNA
synthesis or are packaged into virions that
are released from cells. In an elegant study,
Appleby and coauthors2 stalled the RdRp in
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
Key advances
The structure of the RNA-dependent RNA
polymerase is solved in two catalytically
relevant formations during HCV replication,
revealing the structural basis for the antiviral
effect of sofosbuvir2
The all-oral, interferon-free combination
treatment of nucleotide analogue inhibitor
sofosbuvir and the NS5A inhibitor
velpatasvir achieves 99% sustained virologic
response rates in patients with chronic HCV
genotype 1, 2, 4, 5, or 6 infection3
Successful HCV treatment is associated with
a rapid normalization of intrahepatic
inflammation and innate immune
cellactivation7
The cytosolic lipid-binding protein
SEC14like protein2 is required for
replication of clinical isolates of HCV of
diverse genotypes in cell culture9
Increased 25hydroxysterol levels during
HCV infection induce microRNA185 to
regulate lipid metabolism, revealing a new
immunemetabolomic host response axis
with antiviral function10
a 100
50
25
200
b 4
75
150
100
50
id
W
or
ld
w
(1 IFN
98
9)
IF
N
+
(1 RB
99 V
pe
8)
gIF
N
pe
+
g( R
IF
N 200 BV
+ R 1)
BV
+
(2 DA
01 A
1)
IF
Nfre
e
(2 DA
01 A
4)
U
St nite
at d
es
Cured
Infected
Figure 1 | Patients cured of HCV infection. a | Graph shows cured patients as percentage of patients
Nature
Reviews
& Hepatology
treated with the indicated regimens. Year in brackets
indicates
when| Gastroenterology
the treatment was introduced.
|
b Absolute number of patients in the USA and worldwide who were cured by 2013 (REF. 6). About
600,000 patients worldwide were treated with sofosbuvir-containing regimens by the end of 2015.
Ofthe 185 million people worldwide infected with HCV, only a minority have been diagnosed. Green
bars represent patients infected with HCV and orange bars represent cured patients. Cure is defined
as achieving sustained virologic response. DAA, direct acting antivirals; RBV, ribavirin.
41 | JANUARY 2016
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
membranous web formation and decreasing
HCV replication. Using mice with chimeric
human livers as a model for HCV infection,
the authors showed that HCV tries to counter
act this effect by decreasing intracellular levels
of miR185 and miR130 (the latter is not
induced by 25hydroxysterol, but stimulates
the expression of miR185).
Collectively, these findings exemplify that
HCV continues to teach us new insights into
intracellular immune responses. Despite being
a master teacher of cell biology, HCV also
revealed its achilles heel because it can now
be eradicated in >95% of treated patients with
pan-genotype all-oral treatment regimens.
These unprecedented response rates extend
to patients with HCV genotype3 infections
and/or decompensated cirrhosis, which were
formerly termed difficult-totreat. Global
eradication efforts should now focus on redu
cing the number of undiagnosed persons and
advancing treatment regimens to allow shorter
treatment duration, reduce treatment costs and
make it more accessible. Finally, a focus on
public health measures and vaccine develop
ment to reduce HCV spread among popula
tions with high infection and reinfection risk
is needed.
Barbara Rehermann is at the Immunology Section,
Liver Diseases Branch, National Institute of
Diabetesand Digestive and Kidney Diseases,
NationalInstitutesof Health, DHHS, 10 Center Drive,
Bethesda,Maryland20892, USA.
rehermann@nih.gov
doi:10.1038/nrgastro.2015.227
Published online 21 Jan 2016
Cox,A.L.Global control of hepatitis C virus. Science
349, 790791 (2015).
2.
Appleby,T.C. etal. Structural basis for RNA
replication by the hepatitis C virus polymerase.
Science 347, 771775 (2015).
3.
Feld,J.J. etal. Sofosbuvir and velpatasvir for HCV
genotype 1, 2, 4, 5, and 6 infection. N.Engl. J.Med.
http://dx.doi.org/10.1056/NEJMoa1512610.
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Foster,G.R. etal. Sofosbuvir and velpatasvir for HCV
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Curry,M.P. etal. Sofosbuvir and velpatasvir for HCV
in patients with decompensated cirrhosis. N.Engl.
J.Med. http://dx.doi.org/10.1056/NEJMoa1512614.
6. Holmberg S. D. et al. Hepatitis C in the United States.
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Serti,E. etal. Successful interferon-free therapy of
chronic hepatitis C virus infection normalizes natural
killer cell function. Gastroenterology 149,
190200.e2 (2015).
Yamane,D. etal. Regulation of the hepatitis C virus
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RNA replicase by endogenous lipid peroxidation.
Nat.Med. 20, 927935 (2014).
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Saeed,M. etal. SEC14L2 enables pan-genotype HCV
replication in cell culture. Nature 524, 471475
(2015).
10. Singaravelu,R. etal. MicroRNAs regulate the
immunometabolic response to viral infection
in the liver. Nat. Chem. Biol. 11, 988993 (2015).
1.
Acknowledgements
G A S T R O I N T E S T I N A L I M AG I N G I N 2 0 1 5
JANUARY 2016 | 42
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
a
SCC
OAC
Biliary
tract
Gastric
PDAC
Crohns
disease
Ulcerative
colitis
Squamous
Squamous
BE
BE
HGD
HGD
43 | JANUARY 2016
Acknowledgements
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
PA N C R E AT I C C A N C E R I N 2 0 1 5
An association between
cancer survival and 22 distinct
leukocyte subsets has been
revealed...
Pancreatic cancer has a very poor progno
sis, with a 5year survival rate of only 6% and
8085% of patients with pancreatic cancer diag
nosed at a stage when the tumour is unresect
able. Early detection is projected to increase
survival by 3040%1. Serum levels of carbo
hydrate antigen 199 (CA199) above 37U/ml
is the best established blood test for the detec
tion of pancreatic cancer. CA199 can discrim
inate between patients with pancreatic cancer
and healthy individuals with a sensitivityof
80.3% (95% CI 77.782.6) andaspecificity
of 80.2% (95% CI 78.082.3)2, and between
malignant and benign pancreatic disease
with a sensitivity of 78.2% (95% CI 72.380.4)
anda specificity of 82.8%3. However, to reduce
health-care expenditure and prolong patients
survival, an assay for early diagnosis would
have to perform with a minimum sensitivity of
88% at a specificity of 85%4. Aiming to iden
tify a marker with a higher diagnostic accuracy
than CA199, Melo and co-workers established
Tumour models
Monolayer
Organoids
cell-culture
Genetically
Xenografts
engineered
mouse models
2D co-culture
Targets of analysis
Exosomes
Cell-free DNA
Proteome
Metabolome
Transcriptome
Genome
Analysis tools
PRECOG
Virtual
microdissection
CIBERSORT
Next-generation
sequencing
Systems biology
Figure 1 |Nature
Complementary
experimental & Hepatology
Reviews | Gastroenterology
systems can elucidate diagnostic and
prognostic biomarkers for pancreatic cancer.
Pancreatic cancer research is multi-layered, with
many different approaches possible to
understand the disease. An integrated approach,
incorporating data from across multiple complex
experimental systems, each burdened with
limitations if used as a standalone system, will
speed up the identification of biomarkers for
pancreatic cancer. CIBERSORT, Cell type
Identification By Estimating Relative Subsets Of
known RNA Transcripts; PRECOG, PREdiction
ofClinical Outcomes from Genomic Profiles.
G A S T R O E N T E R O L O G Y & H E PAT O L O G Y
approach known as CIBERSORT. CIBERSORT
estimates the abundances of cell types from
gene expression data to detect and character
ize leukocyte contamination in bulk tumour
transcriptomes7. The prognostic potential of
leukocyte signatures has been demonstrated
by numerous studies, including the work
published this year by Gentles and colleagues.
However, concerns remain that heterogeneity
of the extent of stromal involvement and the
scarcity of tumour cells reduces the value of
prognostic biomarkers from whole tumour
tissue samples.
To overcome these limitations, Moffitt
etal.8 developed a computer-based algor
ithm to perform virtual microdissection on
microarray data from local and metastasized
pancreatic cancer tissue, cell lines and normal
pancreatic tissue. In line with previous find
ings, two tumour subtypes were identified,
validated and defined as classic and basallike, with the basal-like subtype associated
with poorer clinical outcomes. Furthermore,
they delineated two stromal types: nor
malstroma and activated stroma. The acti
vated stromatype, which was associated with
reduced median survival time, was character
ized by increased macrophage expression of
genes such as ITGAM, CCL13 and CCL18, and
members of the SPARC, WNTand MMP fam
ilies. Findings from this study are interesting
Key advances
Exosomal glypican1 is a highly specific and
sensitive biomarker of pancreatic cancer
diagnosis, and holds promise for early cancer
detection, at least in high-risk cohorts5
Next-generation sequencing of cell-free
DNA allows identification of tumour-derived
mutations without directly sampling
thetumour6
Pooling large data sets that include data on
tumour gene expression and clinical
outcomes aids the identification of
cancer-specific signatures that are
predictive of disease7
Virtual microdissection of RNA microarray
data is feasible and can classify tumour
andstroma subtypes8
Organoid models of human and mouse
pancreatic cancer recapitulate the key
features of the disease more accurately
thanmonolayer cell cultures or
patient-derived xenografts9
45 | JANUARY 2016
Acknowledgements
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2016 Macmillan Publishers Limited. All rights reserved
Connect to...
Follow us on Twitter
For the latest news from the journal and beyond: @NatRevGastroHep
For regular updates on new content across all the Nature Reviews journals https://www.facebook.com/NatureReviews
Get monthly e-mail alerts to the content of this journal sent FREE to your inbox by registering online
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Web feeds
We operate an advance online publication (AOP) service for authors and readers to view the latest articles published online
ahead of print http://www.nature.com/nrgastro/journal/vaop/ncurrent
A selection of articles on a related theme, with content ranging from Research Highlights through to Reviews and Perspectives
http://www.nature.com/nrgastro/focus/index.html & http://www.nature.com/nrgastro/collection/index.html
Article series
A special series of articles that explores a specific theme and comprises Reviews and Perspectives that are published
consecutively over a period of time http://www.nature.com/nrgastro/series
Posters
Conferences
You can meet the editors of Nature Reviews Gastroenterology & Hepatology at some of the meetings listed on our conferences
page http://www.nature.com/nrgastro/info/info_conf.html
A Decade in Medicine
The past 10 years has seen great advances in the understanding and treatment of human disease. For expert
perspectives on the most important breakthroughs, dont miss the A Decade in Medicine eBook.
In this special collection of 47 articles commissioned to celebrate the 10th anniversary of the launch of the
clinical Nature Reviews journals leading experts highlight the most important advances in eight medical
specialties between 2004 and 2015, and comment on future developments in their fields.
Download the eBook free here: http://www.nature.com/reviews/collection/adecadeinmedicine/index.html
NEPHROLOGY
PODOCYTE BIOLOGY IN 2015
46 | JANUARY 2016
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
N E P H R O LO G Y
Mitochondrion
Podocyte
KLF6
SCO2
PHB2
TRPC6
Ca2+
NFAT
Calcineurin
Injury
Adriamycin
WT1
Actn4
Arhgap24
Cd2ap
Col4a3/4/5
Foxc1
Igta3
Lama5/b2
Lmx1b
Mafb
Magi2
Myo1e
Nphs1
Nphs2
Plce1
Ptpro
Tcf21
GBM
Endothelial cell
Figure 1 | Studies over the past year have provided key insights into
transcriptional
Nature
Reviews | Nephrology
programming, susceptibility to injury and mitochondrial health in the podocyte.
GBM,glomerular basement membrane.
Acknowledgements
JANUARY 2016 | 47
N E P H R O LO G Y
I M M U N E R E G U L AT I O N O F K I D N E Y D I S E A S E I N 2 0 1 5
Updates on immunosuppression in
kidney disease
Hans-Joachim Anders
Numerous studies in 2015 focused on therapeutic immune modulation and
immunosuppression. Trials of budenoside in patients with IgA nephropathy
who are unresponsive to supportive therapy, and of low-dose IL2 to
enforce regulatory Tcell-mediated immunosuppression in autoimmune
disease all produced promising results.
The use of immunosuppressive drugs for
chronic primary IgA nephropathy (IgAN)
other than rapidly progressive, crescentic
IgAN, is a matter of debate among physicians. To date, many trials have been underpowered, single centre, and have lacked
a rigorous runin phase with optimized
conventional therapy, and thus have been
insufficient to guide clinical practice1. The
STOP IgAN trial addressed the use of conventional immunosuppressive drugs in
patients with persistent proteinuria >0.75g
per 24h after 6months of an escalating conventional supportive therapy protocol that
included angiotensin-converting-enzyme
(ACE) inhibitors, blood pressure control
<125/75mmHg, statins, dietary counselling
with regard to sodium and protein intake,
and smoking cessation2. A first, and important result was that 106 of 309 (34%) of the
patients who completed the runin phase
achieved a reduction in proteinuria <0.75g
per 24h. These patients were considered
to have responded to conventional therapy and were at low-risk of chronic kidney
disease (CKD) progression. Those who did
not respond to the 6months of aggressive
supportive care (162 patients) were randomized to either continue with supportive
treatment or to receive additional steroid or
cyclophosphamide treatment (depending on
CKD stage) for 3years. At 3years, a greater
number of patients had reached full clinical
remission in the immunosuppressive therapy group than in the matched supportive
care group, but there was no effect on annual
loss ofestimated glomerular filtration rate
(eGFR)of >15 ml/min/1.73m2 during the
3year duration of the study and a considerable number of patients experienced adverse
events such as diabetes mellitus, weight
gain, and infections. Immunosuppression
markedly reduced the disappearance of
optimized supportive
therapy is the first choice for
most patients with IgAN
Considerable evidence has accrued to
implicate intestinal mucosal immunity in
the pathogenesis of IgAN 3, forming the
rationale to test a modified release formulation of budenoside (Nefecon; Pharmalink,
Stockholm, Sweden)-an orally administered glucocorticosteroid that can reach the
mucosa of the lower ileum and ascending
colon and suppress mucosal immunity. The
phaseIIb NEFIGAN trial randomly allocated
patients who exhibited persistent proteinuria
>0.75g per 24h after a 6month runin period
with angiotensin blockade using ACE inhibitors, angiotensin-receptor blockers,or both
to a 9month course of either 8mg or16mg
budenoside or placebo4. Amarked reduction
Key advances
Optimized supportive therapy for 6months can suppress proteinuria to <0.75g per 24h in
~34%patients with IgA nephropathy (IgAN)2
Steroids, cyclophosphamide, or azathioprine show little benefit in those with IgAN who do not
sufficiently respond to supportive therapy, when considering the effects of drug toxicity2
Budenoside elicits minimal drug toxicity but has effects on proteinuria and estimated glomerular
filtration rate beyond renin-angiotensinsystem blockade in IgAN, thus supporting a pathogenic
role of mucosal immunity4
Low-dose injection of IL2 can control progression of autoimmune diseases, probably by activating
regulatory Tcells to suppress innate and adaptiveimmunity6
Debate on the utility of mouse models in human inflammation research is ongoing, but a
reanalysis of comparative transcriptome data suggests strong similarities between these species9
48 | JANUARY 2016
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
N E P H R O LO G Y
Atherosclerosis
By boosting TREG cells, IL-2
could help control local
inammation to reduce
plaque formation
Mild to moderate
constitutional
symptoms such as
asthenia, myalgia, fever
and arthralgia
Systemic lupus
erythematosus
By blocking TFH cells and
stimulating TFR cell
dierentiation, IL-2 could
reduce autoantibody
formation and immune
complex deposition
Type 1 diabetes
By boosting TREGcells,
IL-2 could suppress
eector T cellmediated killing of
insulin-producing cells
Kidney diseases?
Local reaction
at injection site
Rheumatoid arthritis
By boosting TREG cells,
blocking TH17 cells and
favouring pTREG cells, IL-2
could help to control
inammation-dependent
joint destruction
Figure 1 | Low-dose IL2 therapy for autoimmune diseases. The capacity of low-dose IL2 to
Nature Reviews | Nephrology
activate and expand TREG cells via the high affinity IL2 receptor will not only suppress nonrenal forms
of autoimmunity but also renal manifestations of autoimmune diseases and intra-renal inflammation.
The forms of renal inflammation that might benefit from low-dose IL2 therapy requires exploration.
pT , peripherally induced regulatory T; T , T follicular helper cell; T , T follicular regulatory; T , T helper.
Image adapted from Nat. Rev. Immunol. 15, 283294 (2015), Macmillan Publishers Limited.
REG
FH
FR
doi:10.1038/nrneph.2015.202
Published online 14 Dec 2015
Acknowledgements
JANUARY 2016 | 49
N E P H R O LO G Y
STEM CELLS AND RENAL DEVELOPMENT IN 2015
ES/iPS cells
Nephron
progenitors
Progenitor
propagation
Collecting duct
Dierentiation
S-shaped
body
Eerent arteriole
Glomerular capillaries
Podocytes
Parietal epithelium
(Bowmans capsule)
Progenitor
ageing
Ureteric
bud
Renal
vesicle
Loop of
Henle
Figure 1 | Strategies towards the generation, propagation and differentiation of nephron progenitors. Nephron progenitors have been shown
Naturestem
Reviews
Nephrology
to age invivo, and interact with the ureteric bud to form the nephron. Nephron progenitors can now be induced from pluripotent
cells,| and
propagated invitro with at least partial differentiation potential. ES, embryonic stem; iPS, induced pluripotent stem.
50 | JANUARY 2016
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
N E P H R O LO G Y
Key advances
Nephron progenitors age during
development invivo, but old progenitors
can be rejuvenated when surrounded by
younger progenitors1
Nephron progenitors can be expanded
invitro beyond their physiological lifespan2.
Kidney organoids containing multiple
lineages can be induced from human
induced pluripotent stem cells invitro6
Understanding the
mechanisms of kidney fibrosis
Dong Zhou and Youhua Liu
The year 2015 has seen great progress in the renal fibrosis field, as key
studies began to build a consensus on the importance of epithelial-to
mesenchymal transition, cell cycle arrest, and defective metabolism in the
pathogenesis of kidney fibrosis. New findings also point to a role of
developmental signalling in renal fibrogenesis.
Renal fibrosis is an important topic that
attracts broad interest in nephrology owing to
its status as a hallmark and common outcome
across all kinds of progressive chronic kidney
disease (CKD). The year 2015 saw much progress in the renal fibrosis field, with major
breakthroughs and new findings markedly
advancing our understanding of the fibrogenic process. These studies have laid strong
foundations for the future development of
novel treatments for fibrotic CKD. For the
first time in more than a decade, scientists
in the field have begun to build a consensus
on several key issues such as the importance
of partial epithelial-tomesenchymal transition (EMT), cell cycle arrest, and defective
cellular metabolism in the development and
progression of kidneyfibrosis.
N E P H R O LO G Y
markers and gain of mesenchymal features.
Such a notion, however, has been intensely
contested as studies using genetic cell lineage
tracing could not find evidence of a direct
contribution of epithelial cells to the myo
fibroblast population in the fibrotic kidney1,
instigating a controversy over the relative contribution of EMT to fibroblast activation that
has lasted several years.
In 2015, two backtoback studies
addressed this dispute and offered new
insights into the potential role of tubular
EMT in the development and progression
of renal fibrosis2,3. Thesestudies tackled the
issue by generating genetically modified
mice, in which Snail or Twist, two key transcription factors that regulate the EMT programme, were ablated specifically in tubules.
As a result, the EMT programme is specifically inhibited in the renal tubular epithelium
invivo. Both studies demonstrated that inhibition of the EMT programme by conditional
deletion of Snai1 or Twist1 in tubular epithelial cells reduced interstitial fibrosis in numerous CKD models, including unilateral ureteral
obstruction, nephrotoxic serum-induced
nephritis, and folic acid-induced nephro
pathy. Not surprisingly, inhibition of an EMT
programme in the kidney also led to preservation of tubular cell integrity and function,
restoration of tubular repair and regeneration,
and a reduction in myofibroblast accumu
lation, suggesting that the EMT programme
is crucial and required for initiating tubular
dysfunction and driving fibrosis development
after various insults.
The mechanism of EMT involvement in
renal fibrosis revealed by these studies is particularly intriguing. Both studies found that
tubular epithelial cells only undergo a partial
EMT during renal fibrosisthe cells express
markers of both epithelial and mesenchymal
cells and remain associated with their basement membrane. In this respect, these observations are in harmony with earlier genetic cell
linage tracing studies1, and demonstrate that
a complete phenotypic conversion of tubular
epithelial cells to a myofibroblast phenotype is
extremely rare, if occurring at all. Nevertheless,
this partial EMT is sufficient to induce tubular function impairment, triggering cell cycle
arrest and promoting the release of critical
fibrogenic cytokines. Lovisaetal. further
demonstrated that one of the functional consequences of partial EMT is the induction of
arrest in the G2 phase of the cell cycle, which
compromises the potential of tubular epithelial cells to repair and regenerate3. As cell cycle
arrest has been postulated as a mechanistic
pathway that leads to kidney fibrosis, the linkage of EMT to cell cycle arrest is especially
PGC-1
CPT-1
PPAR
Secretory
phenotype
Shh
TGF-
Wnts
+ RAS
Snail
or Twist
Partial EMT
FAO
Dysregulated
FA metabolism
ATP depletion
Dedierentiation
Lipid deposition
TEC
Basement membrane
Fibroblast
+ Proliferation
+ Activation
+ ECM production
ECM
52 | JANUARY 2016
Key advances
Renal tubular epithelial cells undergo a
partial epithelial-tomesenchymal transition
after injury, which impairs tubular repairand
regeneration, induces cell cycle arrest,
anddrives interstitial fibroblast activation2,3
Kidney fibrosis is associated with defective
cellular metabolism and mitochondrial
dysfunction in renal tubular epithelial cells;
approaches to restore fatty acid metabolism
or stimulate metabolic pathways might
represent new therapeutic strategies to
combat fibrotic kidney disease4,5
Activation of key developmental pathways
such as Wnt and hedgehog signalling after
injury has a critical role in triggering
fibroblast proliferation, as well as in
activating the intrarenal reninangiotensin
system810
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
N E P H R O LO G Y
One common outcome of partial EMT, cell
cycle arrest, and depressed metabolism following kidney injury is the conversion of tubular
cells to a pathologic secretory phenotype. Our
understanding of the secretome by injured
tubular epithelial cells continued to advance in
2015. Emerging evidence suggests that injured
tubular cells produce and secrete the ligands of
key developmental signalling pathways, such
as Wnts and sonic hedgehog (Shh)6. Tubulederived Shh mediates epithelialmesenchymal
communication by selectively targeting interstitial fibroblasts in a paracrine manner, and
induces fibroblast proliferation and myo
fibroblastic activation, leading to kidney fibro
genesis6. An interesting study in 2015 showed
that hedgehog-responding Gli1+ cells possess
features of mesenchymal stem cells invitro,
and proliferate and expand following kidney
injury7. Genetic ablation of these cells substantially ameliorates kidney fibrosis. Consistent
with these findings, pharmacologic inhibition
of Shh/Gli signalling reduces the size of the
myofibroblast population and inhibits fibrosis
after injury6,8.
Wnt ligands are induced in many cell types
of the injured kidney and can target both interstitial fibroblasts and tubular epithelial cells via
autocrine or paracrine mechanisms. Similar to
Shh, Wnts induce fibroblast proliferation and
myofibroblastic activation, leading to matrix
overproduction and the development of fibrosis9. In 2015, we showed that multiple genes of
the reninangiotensin system are direct targets
of Wnt/catenin signalling in tubular epithelial cells10. These studies provide a novel mechanistic link between Wnt upregulation and
activation of the intrarenal reninangiotensin
system, hypertension, and kidney fibrosis.
In summary, important studies published
in 2015 highlight a central role for varying
tubular responses such as partial EMT, cell
cycle arrest, and defective metabolism in driving renal fibrosis (FIG.1). Intriguingly, these
tubular responses eventually converge on the
acquisition of a secretory phenotype in tubular epithelial cells, leading to the release of
pathological mediators that sustain fibroblast
activation and inflammation. In our opinion,
advances in understanding the pathogenesis
of renal fibrosis in 2015 will be memorable,
and should inspire more intensive studies for
many years to come.
Dong Zhou and Youhua Liu are at the Department
ofPathology, University of Pittsburgh School of
Medicine, 200 Lothrop Street, Pittsburgh,
Pennsylvania 15261, USA.
Youhua Liu is also at the State Key Laboratory of
Organ Failure Research, Nanfang Hospital, Southern
Medical University, 1838 North Guangzhou Avenue,
Guangzhou 510515, China.
Correspondence to Y.L.
liuy@upmc.edu
doi:10.1038/nrneph.2015.215
Published online 30 Dec 2015
1.
2.
3.
4.
5.
Acknowledgements
H Y P E RT E N S I O N I N 2 0 1 5
Lara Crow/NPG
N E P H R O LO G Y
Key advances
Uncontrolled resistant hypertension (RH) increases the risks of renal, cardiac and cerebrovascular
complications; blood pressure (BP) control reduces these risks2
In a real-world population of patients with RH, renal denervation provided fairly safe BP
reduction beyond that achieved using intensive pharmacological therapies6
The diuretic spironolactone is an effective fourth-line antihypertensive drug for patients with RH,
suggesting that sodium retention might be the predominant pathophysiological mechanism in
these patients7
In patients with RH, poor medication adherence prevents effective BP control and regression of
target organ damage and has differential effects on the efficacy of antihypertensive regimens8
54 | JANUARY 2016
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
N E P H R O LO G Y
Lilach O. Lerman and Stephen C. Textor are at
theDivision of Nephrology & Hypertension,
MayoClinic, 200 First Street SW, Rochester,
Minnesota55905, USA.
Correspondence to L.O.L.
lerman.lilach@mayo.edu
doi:10.1038/nrneph.2015.199
Published online 14 Dec 2015
1.
2.
3.
4.
5.
6.
7.
8.
9.
Acknowledgements
JANUARY 2016 | 55
Connect to...
Follow us on Twitter
For the latest news from the journal and beyond: @NatRevNeph
For regular updates on new content across all the Nature Reviews journals https://www.facebook.com/NatureReviews
Get monthly e-mail alerts to the content of this journal sent FREE to your inbox by registering online
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Web feeds
We operate an advance online publication (AOP) service for authors and readers to view the latest articles published online
ahead of print http://www.nature.com/nrneph/journal/vaop/ncurrent
A selection of articles on a related theme, with content ranging from Research Highlights through to Reviews and Perspectives
http://www.nature.com/nrneph/focus/index.html & http://www.nature.com/nrneph/collections/index.html
Posters
Conferences
You can meet the editors of Nature Reviews Nephrology at some of the meetings listed on our conferences page
http://www.nature.com/nrneph/info/info_conf.html
A Decade in Medicine
The past 10 years has seen great advances in the understanding and treatment of human disease. For expert
perspectives on the most important breakthroughs, dont miss the A Decade in Medicine eBook.
In this special collection of 47 articles commissioned to celebrate the 10th anniversary of the launch of the
clinical Nature Reviews journals leading experts highlight the most important advances in eight medical
specialties between 2004 and 2015, and comment on future developments in their fields.
Download the eBook free here: http://www.nature.com/reviews/collection/adecadeinmedicine/index.html
NEUROLOGY
PA R K I N S O N D I S E A S E I N 2 0 1 5
STEP 1
Is parkinsonism (bradykinesia plus rest tremor
and/or lead-pipe rigidity) present?
STEP 2
Not clinical PD
or
Consider prodromal PD
Yes
STEP 3
No
No
Not clinical PD
Yes
0 red ags + 2
supportive criteria
1 red ag + 1
supportive criteria
or
2 red ags + 2
supportive criteria
Clinically established PD
Clinically probable PD
Not clinical PD
JANUARY 2016 | 56
N E U R O LO G Y
Key advances
A task force established by the International Parkinson and Movement Disorder Society (MDS)
proposed new clinical diagnostic criteria for Parkinson disease (PD), which incorporate nonmotor
features, ancillary tests and absolute exclusion criteria3
The MDS task force also proposed research criteria for prodromal PD, which are primarily intended
to identify candidates for enrolment into clinical trials of putative neuroprotective therapies2
Animal studies demonstrated distinct functional effects of small aggregates of synthetic
synuclein with differing structural characteristics, supporting the hypothesis that
differentsynuclein strains underlie development of PD versus multiple system atrophy8
Direct detection of synuclein oligomers in post-mortem brain tissue from patients with PD
wasachieved by a novel approach based on the proximity ligation assay, revealing previously
undetected synuclein pathology in PD9
57 | JANUARY 2016
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
N E U R O LO G Y
STROKE IN 2015
CT perfusion
imaging
Endovascular
thrombectomy
IV rtPA
CT scan
CT angiography
Preoperative DSA
Postoperative DSA
JANUARY 2016 | 58
N E U R O LO G Y
Key advances
MR CLEAN led the way to a series of randomized controlled trials that have conclusively
demonstrated that endovascular thrombectomy improves functional outcomes in patients with
disabling ischaemic stroke1
Endovascular thrombectomy benefits patients with stroke resulting from persistent proximal
occlusion of an intracranial vessel in the anterior circulation, if the intervention can be started
within 6h of stroke onset1
Very early and intensive mobilization is not beneficial and can be detrimental after a stroke,
andshould probably be avoided in patients with severe infarcts or intracerebral haemorrhage; 8
A conservative mobilization strategy during the first 2448h is more advisable than early
intensive mobilization
Cognitive decline can be accelerated after a clinical stroke, not only acutely but also over the
ensuing years10; the mechanisms underlying cognitive deterioration after stroke need to be
better elucidated
New learning and verbal memory tend to be more affected in the acute phase after stroke,
whereas executive dysfunction predominates in the later phase10
59 | JANUARY 2016
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
N E U R O LO G Y
NEURO-ONCOLOGY IN 2015
Lower-grade gliomas
(WHO grades II and III)
No IDH mutations
20%
IDH1/2 mutations
80%
Histological
classication
Additional
mutated genes
Clinical prognosis
1p/19q codeletion
30%
Intact 1p/19q
50%
Oligodendroglioma
Astrocytoma
TP53, ATRX
TERT, EGFR,
CDKN2A, MDM4,
PTEN, NF1
Good
Intermediate
Poor (similar
to glioblastoma)
Type I
Type II
Type III
JANUARY 2016 | 60
N E U R O LO G Y
Key advances
Recent genome-wide analyses allowed the
precise classification of lower-grade
gliomas into three subtypes (typeIIII),
according to their genomic alterations57
Combining radiotherapy with procarbazine,
lomustine and vincristine chemotherapy to
treat high-risk grade II gliomas significantly
improved patient survival8,9
In October 2015, the FDA approved the use
of tumour treating fields in conjunction with
standard chemotherapy to treat patients
with glioblastoma
The combination of chemotherapy
andtumour treating fields to treat patients
with glioblastoma improved their survival
while preserving life quality10
M U LT I P L E S C L E R O S I S I N 2 0 1 5
61 | JANUARY 2016
N E U R O LO G Y
The mechanisms that underlie the patho
genesis of MS are yet to be fully elucidated, but
they are known to include a cascade of events
that induce physical and cognitive deficits. A
reduction in neuronal integrity and function
that affects the grey matter compartment is
thought to be the key pathological process
that leads to cognitive impairment in MS.
Findings of a study published by Freeman
etal.1 in 2015 suggest that synaptic and/or
dendritic damage occurs prior to quantifiable
grey matter volume loss, and might reflect
neuronal and axonal loss that contributes to
clinical deficits. In this study, Freeman and
colleagues1 used [11C]flumazenil ([11C]FMZ)
PET, which quantifies aminobutyric acid
typeA (GABAA) receptor density invivo, to
identify grey matter damage beyond cortical
lesions2. FMZ is an antagonist of the central
benzodiazepine receptor, a component of
the GABAA receptor complex that is present
on axosomatic and axodendritic synapses
throughout the cortical and subcortical grey
matter. The number of [11C]FMZ binding sites
per grey matter region was lower in several
cortical areas (the parietal, cingulate andinsu
lar cortices and the left frontal cortex) and
subcortical regions (the thalamus, hippocam
pus and amygdala) in patients with MS than
in healthy controls. Greater amounts of neu
ronal damage were seen in patients with sec
ondary progressive MS than in patients with
relapsingremitting MS (RRMS), but the most
striking result was that [11C]FMZ binding was
lower in patients with RRMS than in healthy
controls even in the absence of notable grey
matter atrophy. A significant relationship was
found between the level of cortical [11C]FMZ
binding and performance on several cognitive
tests. A goal of future research is to provide
neuroprotective and reparative therapies that
could be applied at such early stages of MS
to stop or at least slow down neurodegener
ation and reduce cognitive impairment in
progressive MS3.
Clinically isolated syndrome (CIS) rep
resents a patients first neurological episode
that is suggestive of MS. Most patients with
CIS develop RRMS within 5years of onset,
and most patients with RRMS develop pro
gressive MS 1015years after onset of MS.
Although challenging, formulating a prog
nosis that accurately predicts the development
of MS and the accumulation of neurological
disability is crucial for designing successful
treatment plans for individual patients. A key
step towards such individualized treatment
of patients with CIS is to stratify them into
groups according to demographic, clinical,
radiological and biological characteristics.
Patients in such groups are likely to have a
Maximizing
physical and
cognitive
ability in MS
Identifying therapies
for progressive MS
different risk of developing MS and longterm disability, so will benefit from different
treatments at different time points.
A study published by Tintore etal.4 in 2015
illustrates the importance of this stratifica
tion step. This study included a single-centre
cohort of 1,015 patients with CIS who were
clinically and radiologically followed up for
a mean of 6.8years4. The results showed that
10 brain lesions visible with MRI at the onset
of CIS was highly predictive (classified in the
study as a high-impact prognostic factor) of
development of MS and disability. The pres
ence of oligoclonal bands in the cerebrospinal
fluid was also predictive, but to a lesser extent
(classified as a medium-impact prognostic
factor). Presentation of CIS with optic neuritis
and the use of a disease-modifying treatment
had a (probably marginal) protective effect
against the development of MS and disability.
Other demographic factors, such as gender
and age at onset, were low-impact prognos
tic factors. The study had some methodologi
cal limitations, such as the number of patients
who dropped out during followup (unavoid
able in this type of longitudinal study) and
the fact that the latest 2010 McDonald diag
nostic criteria were not used. Nevertheless,
Key advances
Synaptic and/or dendritic loss might be an early pathological abnormality in multiple sclerosis
(MS) and precede MRI-detectable volume loss1
In clinically isolated syndrome, oligoclonal bands and the lesions detected with brain MRI are
prognostic factors for the development of MS and early disability4
The relapse rate was 50% lower when patients switched from injectable disease-modifying
treatment to natalizumab than when they switched to fingolimod, but no difference was
observed in disability progression6
Although MS patients live longer than before, their life expectancy remains ~7years shorter than
that of a matched healthy population; treatment of comorbidities might improve survival8
The Progressive MS alliance is driving an initiative to identify new treatments to slow or stop
progression of MS3
JANUARY 2016 | 62
N E U R O LO G Y
of relapse-free patients on natalizumab.
Importantly, however, 6month sustained dis
ability progression rates did not differ between
the two treatments. This finding highlights the
need to identify new treatments that can slow
or stop progression of MS, a major initiative
being driven by the Progressive MS Alliance,
who, in 2015, published an appraisal of current
knowledge in this area and suggested future
steps3. One other important consideration is
that drug efficacy is only one factor that is
considered by doctors and patients when dis
cussing treatment escalation; treatment safety
and tolerability, together with risk assessment7,
are additional important elements, particularly
from the patients perspective.
In addition to specific treatment
approaches, a holistic approach to manage
ment, including a focus on well-being, is
paramount, and identifying and managing
comorbidities is an important element of
this approach. The impact of comorbidities
on clinical symptoms and disability progres
sion in MS is becoming clear, and knowledge
of how physical and mental comorbidities
affect MS will improve management of the
complexity of the disease.
In 2015, Marrie etal.8 addressed the ques
tion of whether comorbidities are responsible
for the reduced survival associated with MS.
They used population-based administrative
data to study 5,797 people with MS and 28,807
healthy controls who were matched for sex,
year of birth and geographical region. Median
survival from birth was 75.9years in the MS
population, and 83.4years in the control popu
lation, which corresponded to a twofold unad
justed increase in the hazard of death in the
MS population. Comorbidities (depression,
diabetes and ischaemic heart disease) were
associated with increased mortality in MS,
but did not confer a greater risk of mortality
in the MS population than in the control pop
ulation. Mortality from infectious diseases and
diseases of the respiratory system was higher
in the MS population than in thecontrol
population. These findings extendthe results
ofprevious studies that reported an effect of
comorbidity on the diagnosis of and disability
in MS9, suggesting that treatment and preven
tion of comorbidities improves survival in MS.
Future research will fill important gaps in our
knowledge about the worldwide epidemiology
of comorbidity in MS10.
These recent advances in MS research and
clinical trials will help clinicians to manage the
complexity of MS in clinical practice and will
inform future research in the field. We antici
pate that 2016 will bring major advances in the
treatment of progressive MS, which remains a
substantial unmet need3.
2.
3.
4.
5.
6.
Acknowledgements
The NMR Unit and its staff are supported by the UK Multiple
Sclerosis Society, National Institute for Health Research
University College London HospitalsUniversity College
London Biomedical Research Centre, the Engineering and
Physical Sciences Research Council, and University College
London internal funding schemes.
A.T. has received honoraria and support for travel for consultancy from Biogen Idec, Eisai, Genzyme, Novartis and
Medday, and for speaking from EXCEMED, Novartis,
Remedica and Teva. He receives an honorarium from Sage
Publications as Editor-in-Chief of Multiple Sclerosis Journal.
O.C. serves as a consultant for Biogen, GE Healthcare and
Novartis, and payments are made to the institution; she
receives an honorarium as Associate Editor of Neurology.
EPILEPSY IN 2015
63 | JANUARY 2016
N E U R O LO G Y
with tonicclonic convulsions, for example,
valproate is often the most effective AED3.
However, other factors influence the choice of
AED, including pregnancya factor that has
caused controversy over the past 12months.
At the end of 2014, the European Medicines
Agency (EMA) published a report advising
that valproate should not be administered to
women who can become pregnant or girls
unless other treatments are ineffective or not
tolerated (see the EMA website). The rec
ommendation was based on studies showing
that valproate can cause fetal malformations
and affect fetal brain development if taken at
a considerable range of doses during preg
nancy4,5. Nevertheless, a large number of
girls and women have idiopathic general
ized epilepsy with tonicclonic seizures and
would, therefore, benefit from treatment
with the cheap and effective valproate. The
fact that valproate is the most effective option
for controlling tonicclonic convulsions in
certain types of epilepsy means that use of
alternative AEDs increases the risk of inju
ries and sudden unexpected death in epilepsy
(SUDEP). The EMA recommendation, there
fore, makes thecounselling of women with
epilepsydifficult.
undiagnosed seizures
can have socioeconomic
consequences
Two important papers published in 2015
addressed the problem of the teratogenic
risks of valproate use during pregnancy. The
first was a prospective observational study
of IQ in children whose mothers had epi
lepsy and received different AEDs during
pregnancy6. 408 children aged 6years were
included. Requirements for educational
interventions were assessed in addition to IQ
so as to provide a real-world measure of the
effects of IQ differences. Children of moth
ers who received >800mg of valproate daily
had significantly lower IQs than did children
of mothers who received carbamazepine or
lamotrigine. In children who were exposed
to <800mg of valproate daily during preg
nancy, IQ was not affected, although four
of 17 children in this group had impaired
verbal abilities that necessitated educational
support. In contrast to an earlier study by
the NEAD (Neurodevelopmental Effects
of Antiepileptic Drugs) group7, this study
revealed no influence of periconceptional
folate on the cognitive development of the
offspring, so the relevance of this intervention
is still undetermined. The authors concluded
Key advances
In almost 50% of patients with epilepsy, theindex seizure that leads to the first consultation is not
the first seizure experienced2
Valproate, a widely used drug for tonicclonic seizures in idiopathic generalized epilepsy, affects
the IQ of children only when used by their mother at a dose of >800mg daily during pregnancy6
The risk of major congenital malformations is relatively low if the daily dose of valproate during
pregnancy does not exceed 700mg8
Perampanel is a powerful new drug for thetreatment of tonicclonic seizures in idiopathic
generalized epilepsy9
The zinc-dependent metal-regulatory transcription factor1 has been identified asa target for
preventing epileptogenesis inexperimental epilepsy10
N E U R O LO G Y
In combination, the most prominent
epilepsy studies published in 2015 high
lightedthe socioeconomic consequences of
epilepsy, the importance of diagnosing epi
lepsy at its onset, and managing the condi
tion in this context. In particular, studies that
examined epilepsy management in women
who are of child-bearing age or who wish
to become pregnant have provided reassur
ance that valproate is effective with limited
risks when administered at low doses, despite
use of the drug becoming increasingly con
troversial. Parampanel could offer new pos
sibilities for seizure management, but time
will be needed to gather data about its use in
pregnancy. The ideal solution for managing
epilepsy and minimizing its socioeconomic
consequences would be to prevent epilepto
genesis; experimental data published in this
field of research in 2015 are promising, but
translational aspects remain problematic and
pose a challenge for the future.
Christian E. Elger is in the Department of Epileptology,
University of Bonn, Sigmund-Freud-Strasse 25,
53127Bonn, Germany.
christian.elger@ukb.uni-bonn.de
doi:10.1038/nrneurol.2016.1
Published online 22 Jan 2016
1.
FURTHER INFORMATION
European Medicines Agency, Valproate and related
substances: http://www.ema.europa.eu/ema/index.
jsp?curl=pages/medicines/human/referrals/Valproate_and_
related_substances/human_referral_prac_000032.
jsp&mid=WC0b01ac05805c516f
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
N E U R O D E G E N E R AT I V E D I S E A S E I N 2 0 1 5
65 | JANUARY 2016
N E U R O LO G Y
ofpatients with AD or FTLD5, providing sup
port for links between the molecular mech
anisms of tau-dependent neurodegeneration
in PSP, AD and FTLD.
Another molecule that regulates tau
structure and function is the peptidyl-prolyl
cistrans isomerase NIMA-interacting 1
(Pin1). PIN1 mutations have previously
been implicated as a genetic risk factor for
AD. Pin1 exerts a neuroprotective effect by
modulating the chirality of tau phosphory
lated at residue 231 (p231 tau), maintaining
it in a trans conformation and preventing the
formation of toxic cis p231 tau (cis ptau), a
process that Kondo etal. termed cistauosis
(REF.7). Kondo and coworkers discovered that
cis ptau was prominent in autopsy specimens
from humans with CTE7, in line with the pre
vious reports that have described fulminant
tau pathology in CTE. The researchers were
also able to induce cistauosis in mouse models
of single or repetitive traumatic brain injury
(TBI), and in cultured neurons by inducing
neuronal stress7. In these models, cistauosis
led to disruption of microtubule assembly,
impaired axonal transport, and spread of cis
ptau to contiguous neurons via a prion-like
mechanism with resulting induction of apop
tosis. Remarkably, this pathogenic cascade
was prevented by monoclonal antibodies to cis
ptau, which decreased cellular neurotoxicity,
histopathological changes and behavioural
deficits in rodent models of TBI7. Similar to
appoptosin-induced tau cleavage, cistauosis
occurred before insoluble tau deposition, and
within days of the induction of of TBI7. The
findings suggest that monoclonal antibodies
that neutralize toxic forms of tau, such as cis
ptau, might be effective therapies.
An intriguing study by Olivera etal.8 sug
gests that tau could spread into the periphery
in individuals with TBI. In military personnel
Genetic
risk factor
rs1768208
T-allele
Protein
Conformational Amplication
change
and spread
Phenotype Biomarker
Appoptosin
PSP
No biomarker
available
AD
Tau PET
Caspase-3
Tau
MAPT H1/H1
haplotype
?
Tau fragments
Tau
?
FTLD-tau Volumetric
MRI
Cis-p-tau
Pin1
PIN1
Trans-p-tau
Nuclear
membrane
Microtubule
CTE
No biomarker
available
TBI
Plasma tau
Neuronal
membrane
Normal tau
Toxic cis-phospha-tau
Phosphate
Key advances
Cistauosis is a conformational change in phosphorylated tau, observed in chronic traumatic
encephalopathy and Alzheimer disease, that contributes to microtubule dysfunction, prion-like
spread of abnormal tau and apoptosis7
In cell culture and animal models, the neuropathological effects of cistauosis can be blocked
byatherapeutic monoclonal antibody against the cis-phospho-tau epitope7
Overexpression of the mitochondrial carrier protein appoptosin, associated with a strong
genetic risk factor for progressive supranuclear palsy (PSP), promotes caspase-mediated tau
cleavage, motor dysfunction and tau neuropathology5
In asymptomatic carriers of mutations linked with frontotemporal dementia, cognitive and
structural MRI changes are detected years before expected disease onset, suggesting the
possibility of clinical prevention trials in MAPT mutation carriers9
Elevated tau levels are measurable in the peripheral blood of individuals with a history
ofrepetitive traumatic brain injury, and correlate with the severity of clinical symptoms8
Pure tauopathies, such as PSP, constitute ideal human patient models for translational studies
oftau, including clinical trials
N E U R O LO G Y
America, the ARTFL and LEFFTDS projects,
which are similar to GENFI, will further
enable such studies.
Advances in understanding the patho
physiology of tau-dependent neurodegen
eration have sharpened the rationale for
new therapies aimed at the tau protein itself.
Insights from PSP and CTE have suggested
mechanisms that initiate tau pathology, new
targets for tau directed therapeutics and
potential biomarkers to assess therapeutic
effects in humans.
Julio C. Rojas and Adam L. Boxer are at the Clinical
Trials Program, Memory and Aging Center, Department
of Neurology, University of California, San Francisco,
675 Nelson Rising Lane, Suite 190, MC 1207,
SanFrancisco, California 94143, USA.
Correspondence to A.L.B.
adam.boxer@memory.ucsf.edu
doi:10/1038/nrneurol.2016.5
Published online 22 Jan 2016
1.
2.
3.
4.
5.
6.
7.
8.
67 | JANUARY 2016
Acknowledgements
J . C . R . a n d A . L . B. a re s u p p o r t e d by N I H ( g ra n t s
U 5 4 N S 0 9 2 0 8 9 a n d R 01 AG 0 3 8 7 91 ) a n d t h e Ta u
Consortium.
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The past 10 years has seen great advances in the understanding and treatment of human disease. For expert
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In this special collection of 47 articles commissioned to celebrate the 10th anniversary of the launch of the
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RHEUMATOLOGY
G L U C O C O RT I C O I D S I N 2 0 1 5
patients, >50,000 patients with SLE were monitored for 1year and categorized according to
glucocorticoid use. Importantly, this analysis
included patients from all care settings covered
by the database and not just tertiary centres.
The study showed that glucocorticoid use was
pervasive, with more than half of all patients
exposed to glucocorticoids, and the majorityexposed to high doses. Glucocorticoid use
was associated with severe SLE phenotypes,
including renal disease, and was associated
with greater need for healthcare resources,
including hospitalization and coprescription,
which ultimately result in high costs a relationship that was dependent on glucocorticoid
dose. Although the patients included in this
study were diagnosed with SLE via diagnostic
codes only, and despite the fact that this study
could not discriminate between costly medical
events associated with disease activity versus
those directly attributable to glucocorticoid
use perse4, the relationship between glucocorticoid use and healthcare costs remained
after adjustment for known patient-related
variables. Total costs over 1year for patients
treated with high-dose glucocorticoids were,
at USD45,000 per year, threefold those of
patients not treated with glucocorticoids. An
urgent need to better understand the link
between glucocorticoid use in the context
of SLE and healthcare costs has thus been
identified (FIG.1).
Given the known problems of gluco
corticoid use, the search for metabolically
inert glucocorticoid mimetics with a reduced
health and economic burden has been
described as the holy grail of inflammation
68 | JANUARY 2016
CsA
Glucocorticoids
GILZ
Financial
burden
Healthcare
costs
Morbidity
Inammatory
disease remission
Figure 1 | Beneficial
anti-inflammatory
effects
Nature
Reviews | Rheumatology
versus harmful metabolic consequences of
glucocorticoids. New data has made clear that
considerable economic cost ensues from the
use of glucocorticoids in diseases such as
systemic lupus erythematosus (SLE), even
though the cost-per-pill of this treatment is
low. The endogenous protein glucocorticoidinduced leucine zipper (GILZ) exerts important
inhibitory effects on Bcell activation and T
helper (TH)17 pathways, suggesting that
GILZisa potential glucocorticoid mimetic.
Ciclosporin (CsA) has been shown to selectively
regulate TH17 pathways even in situations
where glucocorticoids do not, suggesting
theexistence of immune-pathway selective
mechanisms of glucocorticoid resistance
thatmight be targeted directly.
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
R H E U M AT O L O G Y
Key advances
The healthcare costs associated with
resorting to glucocorticoid use to control
autoimmunity in patients with systemic
lupus erythematosus (SLE) has been defined
as USD45,000 per year three times the
cost for patients with SLE not treated
withglucocorticoids4
In the quest for safe and effective
glucocorticoid alternatives,
glucocorticoid-induced leucin zipper
(GILZ)stands out as a strong contender,
particularly as GILZ has now been shown
tocontrol Bcell survival and activation
inthe context ofSLE7,8
A pathway responsible for glucocorticoid
insensitivity has been identified in T helper
type17 (TH17) cells which could be targeted
in novel therapeutic approaches10
Acknowledgements
S Y S T E M I C L U P U S E RY T H E M AT O S U S I N 2 0 1 5
R H E U M AT O L O G Y
Key advances
Myeloid cells contribute to aberrant
follicular helper T (TFH) cell activity in SLE
viathe OX40LOX40 axis2
Expression of ICOSL in myeloid cells
promotes local inflammation by sustaining
effector Tcells in inflamed tissues4
Aberrant mitochondrial oxidative
phosphorylation in lupus Tcells can be
pharmacologically inhibited to suppress
autoimmunity and nephritis10
OX40
Immune
complexes
B cell
Autoantibody
production
OX40L
Myeloid APC
Other
stimuli
TFH
ICOSL
ICOS
TEFF
TMEM
Tissue
inammation
Inamed tissue:
Kidney
Skin
Figure 1 | Cellular and metabolic requirements for the generation of effector Tcells in patients
with SLE. Immune complexes and other stimuli lead to increased expression
of OX40
ligand
Nature Reviews
| Rheumatology
(OX40L) on myeloid antigen-presenting cells (APCs), which engage OX40 on CD4+ cells to
propagate the generation of follicular helper T (TFH) cells.Myeloid APCs express inducible Tcell
costimulator (ICOS) ligand (ICOSL), which facilitates the maintenance of effector and memory
Tcells at sites of inflammation.These activated cells use both aerobic glycolysis and oxidative
phosphorylation to meet their energy requirements. SLE, systemic lupus erythematosus;
TEFF,effector T cell; TMEM, memory T cell.
70 | JANUARY 2016
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
R H E U M AT O L O G Y
clinical research has shown that the magnitude
of the cell infiltrate dictates future kidney function. Teichmann etal.4 show that the mainten
ance of T effector cells in the inflamed kidney
depends on the presence of ICOL-expressing
myeloid cells. The ICOSLICOS axis leads to
the activation of AKT, which, in turn, stimulates the rapamycin-sensitive mechanistic
target of rapamycin (mTOR) complex 1, a
pathway of considerable interest as a target for
the treatment ofSLE8.
Tcells, like all active cells, need energy to
execute their tasks. Stimulation of naive Tcells
introduces a metabolic remodelling process
(aerobic glycolysis), which endows the cells with
the energy required to accomplish their effector
functions. Although glycolysis yields considerably less energy (stored in ATP) than oxidative phosphorylation, the former is preferred
because it generates metabolic intermediates
(precursors for nucleotides and amino acids)
necessary for cell growth and proliferation9.
Yin etal.10 present data demonstrating that
both aerobic glycolysis and mitochondrial oxidative phosphorylation are elevated in Tcells
from lupus-prone mice and from patients with
SLE, as compared with nonautoimmune mice
and healthy controls, respectively. The activation of SLE Tcells (and many of them are
already activated) might have been expected
to promote only aerobic glycolysis, as happens in normal cells. The observed increase in
mitochondrial metabolism is consistent with
previously reported mitochondrial abnormalities in patients with SLE8, which contribute
to aberrant Tcell function. The reason for
this partial diversion to oxidative phosphoryl
ation in SLE Tcells is unclear. In preclinical
studies, Yin etal.10 found that treatment with
2deoxyDglucose (an aerobic glycolysis
inhibitor) and metformin (a mitochondrial
metabolism inhibitor) resulted in suppression
of autoimmunity and nephritis in two different strains of lupus-prone mice (B6.Sle1.Sle2.
Sle3 and NZB/W). Although neither of these
drugs would be used as monotherapy in the
treatment of active SLE, they would probably
serve as valuable adjuvants to minimize the use
of immunosuppressive agents. Metabolomics is
a new field within the study of autoimmunity,
and it is certain that this report will be followed
by manyothers.
From the clinical point of view, the three
reports discussed here present a number of
novel targets for the treatment of SLE: the
OX40LOX40 and ICOSLICOS axes, myeloid
CD11c+ APCs, and two metabolic pathways
active in lupus Tcells (FIG.1). As mentioned in
this commentary, however, the contribution of
these pathways to the expression of disease in
individual patients couldvary.
2.
3.
4.
P S O R I AT I C A RT H R I T I S I N 2 0 1 5
Advancement continues
in imaging, tight control
and newdrugs
Ignazio Olivieri and Salvatore DAngelo
In 2015, a EULAR task force released evidence-based recommendations
onthe use of imaging in the clinical management of spondyloarthritis,
including psoriatic arthritis. These recommendations, together with
articles dealing with tight control strategies and use of the IL17A inhibitor
secukinumab, have consolidated progress in the management of
psoriaticarthritis.
The progressive improvement in the management of psoriatic arthritis (PsA)1 that began in
earnest at the onset of the new millennium has
continued apace during 2015 (FIG.1). The main
areas of progress include improvements in
treatment strategies, the evolution of outcome
assessment due to the use of validated instruments for several manifestations of psoriatic
disease and composite disease activity indices, and advances in pharmacologic therapy
forPsA1.
The clinical spectrum of PsA is broad, and
the course of the disease is variable. In addition to the skin and nails, PsA affects the joints,
entheses, synovial sheaths of tendons, and axial
skeleton. Currently, PsA is classified as a form
of spondyloarthritis (SpA) alongside ankylosing spondylitis, arthritis related to inflammatory bowel disease, reactive arthritis and
R H E U M AT O L O G Y
Key advances
The EULAR recommendations for the use of
imaging in the diagnosis and treatment
ofspondyloarthritis including psoriatic
arthritis (PsA) are practical and valuable in
daily clinical practice2
Tight control of disease activity using a
treattotarget approach substantially
improves joint outcomes for patients with
early PsA4
Secukinumab was superior to placebo
forpatients with PsA in two studies, and
canbe seen as an additional option to
anti-TNFtreatment9,10
Diagnosis
EULAR imaging
recommendations
Treatment
strategies
Tight
control
Advances
in psoriatic
arthritis
in 2015
versus Standard
care
TICOPA study
New drugs
TH17
IL-17A
Secukinumab
Figure 1 | Recent advances in management of psoriatic arthritis. Key publications in 2015 highlight progress in imaging2, treatment strategies4 and drug development9,10 for psoriatic arthritis.
Nature Reviews | Rheumatology
72 | JANUARY 2016
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2016 Macmillan Publishers Limited. All rights reserved
R H E U M AT O L O G Y
secukinumab (10mg/kg) at weeks 0, 2 and 4
followed by monthly subcutaneous doses of
75mg or 150mg 9. By contrast, FUTURE 2
compared placebo with subcutaneous secukinumab doses of 75mg, 150mg or 300mg,
administered weekly for 4 weeks during
loading then monthly 10. A combined total
of 1,003 patients were enrolled in the two
studies. Both studies met their primary endpoint (the proportion of patients achieving
an ACR20 response) at week 24. In FUTURE
1, secondary endpoints also included ACR50
and ACR70 responses, PASI75 and PASI90
responses, the change from baseline in
DAS28CRP (28joint disease activity score
calculated with Creactive protein level),
the physical component summary score
of the Medical Outcomes Study 36Item
Short-Form Health Survey (SF36), and
Health Assessment Questionnaire Disability
Index (HAQDI) scores. The percentage
of patients with resolution of dactylitis and
enthesitis was higher in the secukinumab
groups than the placebo groups, and progression of joint structural damage was lessened
with secukinumab treatment. Secukinumab
efficacy was sustained through 52weeks and
was seen both in patients who had received
previous anti-TNF treatment and in those had
not, although to a lesser extent in the former
group. Secukinumab treatment was well tolerated, and the safety profile was consistent
with that observed in previous clinical trials in PsA and psoriasis, including a higher
rate of infections (including candidiasis) and
cardiov ascular events with secukinumab
groups than with placebo. In summary, the
FUTURE studies suggest that secukinumab
can be an option for the treatment of patients
with PsA in whom anti-TNF agents are
inappropriate, ineffective or not tolerated.
In conclusion, developments in 2015 in
diagnosis, treatment strategies and new drugs
promise to continue to improve the management of PsA. Prompt dissemination of the
imaging recommendations and tight-control
strategies, together with the forthcoming
commercialization of new drugs, will considerably improve PsA management within the
next fewyears.
Ignazio Olivieri and Salvatore DAngelo are at the
Rheumatology Department of Lucania, San Carlo
Hospital of Potenza and Madonna delle Grazie Hospital
of Matera, Contrada Macchia Romana, Via Potito
Petrone Snc, Potenza 85100, Italy.
Correspondence to I.O.
ignazioolivieri@tiscali.it
doi:10.1038/nrrheum.2015.184
Published online 22 Jan 2016
1.
2.
3.
4.
5.
6.
7.
Acknowledgements
I N F L A M M AT I O N I N R H E U M AT O L O G Y I N 2 0 1 5
R H E U M AT O L O G Y
angiopoietin-related protein 41. In a mouse
model of gouty arthritis 2 , human AAT
reduced joint inflammation and synovial
levels of IL13. As plasma-derived AAT has
been successfully used in AAT-sufficient
humans to treat acute STsegment elevation
myocardial infarction4 and in children with
type1 diabetes, AAT could be used today to
treat acute flares of gout. A drawback of this
approach is that AAT needs to be administered intravenously. Therefore, a novel form
of recombinant AAT was generated by fusing
AAT to the Fc domain of IgG13. The AAT
Fc molecule was 4050 times more effective
than plasma-derived AAT in reducing uratecrystal-induced joint inflammation in this
mouse model 3. Given its higher potency,
AATFc can be administered subcutaneously
an important advantage over plasmaderived AAT when treating patients. Addi
tionally, the risk of viral transmission associated with treating humans with blood-derived
products from other humans is not a concern with recombinant AATFc. The cost
of recombinant AATFc is also considerably lower than that of plasma-derived AAT,
and production is not limited to the pool of
human plasma. For all these reasons, AATFc
seems to be a promising new agent for the
treatment of inflammatory diseases.
Most studies on gout have focused on
inflammation, owing to the involvement
of monosodium urate (MSU) crystals in
the pathogenesis of the disease. However,
whether uric acid itself can have direct
proinflammatory effects remains mostly
unknown. In addition to gout, several other
diseases are associated with elevated serum
uric acid levels, including type2 diabetes,
atherosclerosis, metabolic syndrome and
chronic kidney disease. In a study published
in 2015, Crisan and colleagues revealed
that uric acid primes human blood monocytes to increase production of IL1 5 .
Monocytes from patients with hyperuricaemia and gout release more IL1 when
exposed to MSU crystals or Toll-like receptor 2 (TLR2) agonists, and monocytes from
healthy individuals without elevated serum
uric acid levels also released more IL1
when primed exvivo with clinically relevant
uric acid concentrations. The unexpected
mechanism explaining these observations
involves uric-acid-mediated reduction of
transcription and production of IL1Ra;
as IL1Ra is highly effective at reducing
gout-related inflammation, uric-acidmediated suppression of endogenous IL1Ra
production shifts the balance towards
IL1induced inflammation. In some ways,
this imbalance mediated by uric acid mimics
74 | JANUARY 2016
Key advances
Naturally occurring 1antitrypsin (AAT)
and a synthetic AATIgG fusion protein are
novel therapies for acute flares of gout3
Clinically relevant elevations in levels of
uricacid suppress production of IL1
receptor antagonist, independently of
monosodium urate crystals a unique
pathogenetic mechanism for uric acid in
inflammatorydiseases5
IL17 neutralization is effective in
psoriaticarthritis but deprives patients
ofneutrophil-mediated inflammation,
which is required for defence against
Candidaalbicans7,8
R H E U M AT O L O G Y
Charles A.Dinarello is at the Department of Medicine,
University of Colorado Denver, Aurora, Colorado
80045, USA; and at the Department of Medicine,
Radboud University Medical Centre, HB 6500
Nijmegen, Netherlands.
Leo A.B.Joosten is at the Department of Medicine,
Radboud University Medical Centre, HB 6500
Nijmegen, Netherlands.
3.
4.
Correspondence to C.A.D.
cdinare333@aol.com
doi:10.1038/nrrheum.2015.180
Published online 14 Jan 2016
1.
2.
5.
6.
7.
Acknowledgements
JANUARY 2016 | 75
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A Decade in Medicine
The past 10 years has seen great advances in the understanding and treatment of human disease. For expert
perspectives on the most important breakthroughs, dont miss the A Decade in Medicine eBook.
In this special collection of 47 articles commissioned to celebrate the 10th anniversary of the launch of the
clinical Nature Reviews journals leading experts highlight the most important advances in eight medical
specialties between 2004 and 2015, and comment on future developments in their fields.
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UROLOGY
S E X U A L DY S F U N C T I O N I N 2 0 1 5
U R O LO G Y
The results confirm the
importance of assessing
personal distress before
labelling a woman as sexually
dysfunctional
Research into the relationship between sex
hormones and sexual function and behaviour
in women currently receives much attention
potentially also driven by the discovery
and approval of flibanserin. The association
between sexual desire and androgens is bio
logically plausible, as levels of both decline
with age and testosterone treatment of post
menopausal women with sexual dysfunction
due to HSDD is effective and safe in the short
term. However, any attempt to directly link
low sexual desire with circulating low andro
gens (total or free testosterone) or androgen
precursors (androstenedione, dehydroepi
androsterone or its sulfate ester) has failed
to identify a minimum concentration that
could be used to diagnose women with sexual
dysfunction related to androgen deficiency.
In addition, the Endocrine Society Clinical
Practice Guideline confirmed the recommen
dations against making a clinical diagnosis of
androgen deficiency in women, unless using
accurate methods for testosterone quantifica
tion, such as mass spectrometry 7. Data corre
lating measurements of androgen levels and
specific signs and symptoms in women are
inconsistent, and monitoring plasma levels
during testosterone treatment with available
assays seems to beunreliable7.
By contrast, the situation in men is quite
different. A study in 2015 established a cut-off
level of <275ng/dl total testosterone measured
on two occasions as associated with decreased
sexual desire and activity 8. This study con
firms the significant positive correlation of
low endogenous total and free testosterone
Key advances
Flibanserin is the first medication approved to treat hypoactive sexual desire disorder (HSDD) in
premenopausal women, after three large phaseIII trials demonstrated significant improvements
in the number of satisfactory sexual events, level of sexual desire and distress versus placebo2
HSDD is a complex condition and prescribing flibanserin should be based on individual
assessment, particularly as psychological treatments might also be effective in alleviating low
desire; however, adequate trials are lacking3
Bremelanotide is another psychoactive agent with potential for benefit in women with HSDD that
indicated improved clinical outcomes in a phaseIIb trial and is set to be tested in a phaseIII trial6
In men aged 65years, cut-off points of testosterone levels were established correlating with
decreased sexual desire, activity and erectile function8, indicating a more direct relationship
between androgen levels and sexual dysfunction compared with women
Using novel methods, two studies in women found some correlation between androgen levels
and sexual desire and arousal, but also confirmed the importance of personal factors when
assessing sexual dysfunction in women9,10
77 | JANUARY 2016
FURTHER INFORMATION
FDA News Release Addyi approval: http://www.fda.gov/
NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
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U R O LO G Y
understood pathophysiology central and
peripheral disturbances in the processing of
pain and v iscerosensory signals are thought
to beinvolved.
The Multidisciplinary Approach to
the Study of Chronic Pelvic Pain (MAPP)
Research Network was created to study the
pathophysiology and treatment options
for patients with UCPPS (MAPP Research
Network). As part of the Trans-MAPP neuro
imaging study to characterize differences
inbrain activity and pathway connectivity in
patients with UCPPS structural and resting
functional MRI was used at five MAPP net
work sites across the USA. The most recent
report arising from this study is particu
larly interesting. Woodworth etal.4 focused
on microstructural changes in the brainof
patients with UCPPS. Control groups ofthis
study included healthy individuals, but also
patients with irritable bowel syndrome
(acommon gastrointestinal pain disorder)
to strengthen the studys comparisons and
results. The investigators used detrusor
tension imaging and track density imaging
analysis techniques, concluding that patients
with UCPPS have extensive microstructural
changes within white matter areas of the brain
that are responsible for the processing and
integration of sensory information from pel
vic areas. These alterations seemed specific to
patients with UCPPS and were not observed
in patients with irritable bowel syndrome. The
direct clinical implications of these findings
are not yet entirely clear; however, brain plas
ticity could be related to symptom severity
and pain duration, and might be a target for
specific intervention in the future.
Through the MAPP Research Network,
four landmark articles that use extensive
anatomical and functional neuroimaging
to establish a phenotype pattern of UCPPS
B L A D D E R DY S F U N C T I O N I N 2 0 1 5
Arseniy45/iStock/Thinkstock
JANUARY 2016 | 78
U R O LO G Y
have been published in the past year 47.
Comprehensive evaluation of these results
will enable clinicians to clearly recognize
the implications of these costly, complex and
technically challenging studies, and help to
develop a clear understanding of how to use
these data in patient phenotyping, diagnosis
and management.
Unfortunately, current treatments offer
limited effectiveness with considera ble
adverse effects, even when bladder dysfunc
tion is appropriately evaluated and charac
terized. Antimuscarinic agents are the most
commonly used oral therapeutics for bladder
dysfunction associated with urgency, fre
quency and urge urinary incontinence, but
these drugs have limited effectiveness and
poor patient compliance. Antimuscarinics
(a subcategory of anticholinergics) block the
effect of acetylcholine at muscarinic recep
tors. Drugs with anticholinergic effects are
found in a variety of medications, includ
ing antihistamines, tricyclic antidepressants
andantipsychotics.
Findings published in 2015 indicate that
cumulative exposure to anticholinergics
might lead to cognitive impairment. Gray
et al. 8 reported on the cumulative use of
anticholinergic medication and its association
with the risk of dementia using a population-
based prospective cohort of individuals
65 years of age. The investigators used
pharmacy dispensing data to define cumula
tive anticholinergic exposure as total stand
ardized daily doses (TSDD) prescribed over
10years. Data on 3,434 patients were ana
lysed and showed that 797 participants (23%)
developed dementia (specifically, 637 partici
pants developed Alzheimer disease) during
a mean followup period of 7.3years. The
adjusted hazard ratio for developing demen
tia was 0.92 for 190TSDD and increased
with increasing cumulative anticholinergic
use to a hazard ratio of 1.54 for >1,095TSDD.
The authors concluded that a sustained and
Key advances
Similarities in pressure-overload-induced remodelling of the heart and bladder include changes
inmicroRNA expression that influence tissue permeability, stiffness and smooth muscle
differentiation, indicating novel therapeutic targets1
Results from a MAPP network study show that patients with urological chronic pelvic pain
syndrome have extensive microstructural changes within brain white matter regions responsible
for sensory information from pelvic areas4
Findings that high cumulative use of anticholinergic drugs results in an increased risk of cognitive
deficits and dementia should raise concerns among urologists prescribing these medications
long-term for patients with overactive bladder8
A study of obstetric vesicovaginal fistula repair in Africa shows that 7day catheterization is not
inferior to 14day drainage, illustrating how evidence-based research might have a tremendous
effect on public health in areas of poorest resources9
79 | JANUARY 2016
FURTHER INFORMATION
MAPP Network: http://www.mappnetwork.org/
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
www.nature.com/reviews
2016 Macmillan Publishers Limited. All rights reserved
U R O LO G Y
of an 8mm asymptomatic lower-pole stone.
Patients preferred shockwave lithotripsy under
conscious sedation (45%) over ureteroscopy
(32%) or active surveillance (23%). This study
shows that patients place differing values on
procedural risk versus success. Accordingly, to
facilitate a shared medical decision, assessing
the degree to which risk or success is of higher
Sapan N. Ambani and Khurshid R. Ghani
priority for a patient is important.
In 2015, population-based studies in patients with urinary stones informed us
Although meta-analyses are a summary of
best available evidence, they are only as good
of the changing trends in contemporary stone management and identified
as the quality of the studies assessed. In 2015,
areas for improvement. Although meta-analyses aim to provide the highest
the findings of the UK National Health Service
level of evidence, a randomized controlled trial of medical expulsive therapy double-blind randomized SUSPEND trial
challenged current paradigms and was the defining publication of the year.
were published4, which challenge the find
ings of previous studies and meta-analyses on
theefficacy of medical expulsive therapy in the
Several key contributions to the scientific uro common procedure for the treatment of management of patients with ureteric colic. In
logical literature in 2015 will result in improve stone disease7. The increase in use of ureter the SUSPEND trial, 1,167 patients with ure
ments in the evaluation and management of oscopy was probably caused by the increasing teral stones were randomized to receive either
urinary tract calculi. Population-based studies availability of holmium lasers, in conjunc tamsulosin, nifedipine or placebo. No benefit
demonstrated a change of paradigms in surgi tion with advances in endoscopic equipment of medical expulsive therapy was demon
cal management1, which was also supported and ancillary instrumentation, which have strated, although there was a trend towards sig
by findings of a meta-analysis that assessed helped to improve the efficacy and cost- nificance versus placebo for stones >5mm and
the clinical effectiveness of surgical ther effectiveness of ureteroscopy in comparison stones in the lower ureter in patients receiving
apy for lower-pole stones2. However, more with s hockwavelithotripsy8.
tamsulosin. Per study protocol, stone passage
research is needed to be able to assess the
Although population-based studies enable did not need to be radiographically confirmed;
importance and effect of patient preferences us to appreciate changes in practice patterns, instead, the primary end point was the need
when determining treatment3. Importantly, definitive evidence is often sought to support for surgical intervention within 4weeks4.
one randomized controlled trial reported changing trends. Donaldson and colleagues2
The pragmatic nature of the endpoint in
potentially practice-changing results, making did just that by undertaking a meta-analysis the SUSPEND trial has been both applauded
the trial one of this years most debated studies to better understand the clinical effective and criticized. The absence of rigorous
in urology4. In addition, new guidelines from ness of different treatment modalities in the
the European Association of Urology were management of lower-pole stones. Limited
Key advances
published, which aim to reduce the complexity to seven randomized controlled trials total
of metabolic evaluation in patients with uri ling 691 patients, the authors were able to
Contemporary trends in the surgical
nary stones5. Indeed, medical management conclude what many in the field have long
management of upper tract calculi reflect
achange of paradigms with ureteroscopy
is one aspect of stone care sorely in need of surmised: for lower-pole stones >10mm, per
overtaking shockwave lithotripsy as the
qualityimprovement6.
cutaneous nephrolithotomy and ureteroscopy
main treatment approach1
Continuous technological innovations in have superior stone-free rates compared
Comparison
of clinical effectiveness of
the surgical management of urinary calculi with shockwave lithotripsy. Regarding stone
different
treatment
modalities demonstrates
make it particularly susceptible to changing clearance, percutaneous nephrolithotomy
that percutaneous nephrolithotomy and
practice patterns. Oberlin etal.1 reviewed outperformed both modalities, but ureter
ureteroscopy have superior stone-free rates
case logs submitted to the American Board oscopy was more effective than shockwave
compared with shockwave lithotripsy in
2
of Urology from 2003 to 2012 and found that lithotripsy for stones measuring 1020mm .
lower-pole stones >10mm2
ureteroscopy has now overtaken shockwave In their systematic review, the authors used
Patient appraisal of procedural risk and
lithotripsy as the main modality for managing Cochrane Collaboration methodology and
success differs and assessing the degree
upper urinary tract calculi in the USA. For quality-ofe vidence assessment according
towhich either is of higher priority for a
the young generation of practicing urologists to GRADE, and the study provides the first
patient is important to facilitate shared
whose training included a substantial amount level1a evidence for the surgical management
medical decision making3
of endoscopic surgery these findings might of lower-pole stones. Importantly, however,
The double-blind randomized SUSPEND
be intuitive, but the trend of increased ureter further study conclusions are limited, owing to
trial established that neither tamsulosin nor
oscopy use was also noted among senior urol heterogeneity among trials and other factors;
nifedipine are effective as medical expulsive
therapies in patients with ureteric colic4,
ogists applying for recertification. By contrast, for example, morbidity, retreatment, costs and
challenging current prescription patterns
the usage rates of percutaneous nephrolitho quality of life were not evaluated. Some of these
tomy have remained stable, accounting for outcomes certainly contribute to decision
Of >200,000 patients with 1 anomaly
atinitial urinary evaluation only 16%
45% of all surgeries during this time period1. making and patient preferences surrounding
underwent repeat testing within 6months;
These results support observations made in treatment options. In this regard, Omar etal.3
those seen by a urologist had 24% lower
a population-based study from the Canadian performed an interesting study in which they
odds of repeat testing than those seen in
state of Ontario published in 2014 in which surveyed 100 patients in a stone clinic and
primary care6
ureteroscopy was also noted to be the most enquired about the hypothetical management
S TO N E S I N 2 0 1 5
JANUARY 2016 | 80
U R O LO G Y
drest/iStock/Thinkstock
INFECTION IN 2015
81 | JANUARY 2016
U R O LO G Y
One innovative approach to decreasing
the spread of bacterial STIs is for clinicians to
give patients who are diagnosed with an STI
medication to treat sexual partners. One study
tested whether a public health intervention
that promotes partner services and patient-
delivered partner therapy (PDPT) could
decrease rates of chlamydia and gonorrhoea
infections in Washington, USA7. The primary
outcomes for this study were community-level
rates of chlamydia in a sentinel population of
women aged 1425years and gonorrhoea
infections in all women in Washington.
During the 22month duration of the study,
the use of PDPT increased while rates of
chlamydia and gonorrhoea both decreased
by around 10% when adjusted for temporal
trends; however, this decrease was not sta
tistically significant7. Currently, provision of
PDPT can be limited by legal and logistical
barriers, as PDPT is legally permissible in only
37 states in the USA, and its utility in popula
tions of individuals with multiple partners (for
example, some MSM and sex workers) is not
established. However, the promising results
from the PDPT study in Washington suggest
that PDPT should be legalized where it is cur
rently prohibited and that clinicians should be
encouraged to p
rovide PDPT.
Although PDPT represents a potential step
forward in the control of bacterial STIs, con
cerns about increasing antimicrobial resist
ance among bacterial isolates, particularly
gonorrhoea, suggest that substantial chal
lenges in managing these infections remain.
The prevalence of gonococcal isolates with
decreased susceptibility to multiple anti
microbial agents has been increasing, which
restricts the available treatment options
for gonorrhoea. One report documented a
novel strain of Neisseria gonorrhoeae that
has decreased susceptibility to ceftriaxone,
the first-line treatment for gonorrhoea8. This
Key advances
TonyBaggett/iStock/Thinkstock
HIV and bacterial sexually transmitted infection (STI) incidence is high among men who have sex
with men (MSM), and syphilis and other bacterial STIs increase the risk of HIV acquisition1
Oral HIV pre-exposure prophylaxis (PrEP), the use of antiretroviral drugs by individuals at risk
ofacquiring HIV, can decrease HIV transmission in MSM in clinical settings, even when rates of
bacterial STIs are high5
An innovative approach to decreasing rates of bacterial STIs is patient-delivered partner therapy,
the practice of treating partners of individuals with STIs without direct medical evaluation7
Increasing drug resistance has limited treatment options for Neisseria gonorrhoeae;
solithromycin, a macrolide antibiotic, shows promise as a novel oral treatment for gonorrhoea9
Advances in HIV prevention rely on training clinicians in providing PrEP to MSM and other
individuals at high risk of acquiring HIV, as well as intensive screening, treatment and counselling
regarding bacterial STIs
JANUARY 2016 | 82
U R O LO G Y
strain was isolated from a European woman
traveling in Australia, and it represents the
third strain of N.gonorrhoeae with signifi
cantly decreased susceptibility to ceftriaxone
globally. Other strains have previously been
isolated in Japan and Europe. These multi
resistant gonococcal isolates indicate a need
for additional treatment options for gonor
rhoea. To address this need, a phaseII trial
tested the efficacy and safety of solithromycin,
a novel macrolide antibiotic, for the treat
ment of uncomplicated gonorrhoea9. Single
dosesof solithromycin (either 1000mg or
1200mg) were administered to 46 patients
with cultures positive for gonorrhoea. All
patients were cured, including patients with
pharyngeal or rectal infections. The advan
tages of solithromycin include one-time oral
dosing, invitro activity against Chlamydia
trachomatis and Mycoplasma genitalium (both
of which are common coinfections of gonor
rhoea) and against gonococcal strains resist
ant to azithromycin. In addition, the structure
of solithromycin differs from lactams, so
that it can be used by patients who are aller
gic to cephalosporins. However, frequent
gastrointestinal intolerance was observed9.
A phase III trial comparing the efficacy
of solithromycin with standard firstline
treatment is currentlyunderway.
Finally, a notable publication from 2015
are the updated Sexually Transmitted Diseases
Treatment Guidelines from the Centers of
Disease Control and Prevention, which rep
resent a comprehensive and user-friendly
resource for all clinicians who diagnose or treat
STIs and are freely available10.
In conclusion, 2015 represents a year in
which studies have provided strong evidence
that provision of PrEP to MSM in clinical
settings is effective. Successful translation
of these findings will require clinicians to
become more comfortable and proficient in
discussing sex with their patients. However,
the provision of PrEP must be accompanied
by intensive screening, treatment and counsel
ling regarding bacterial STIs, so that advances
in HIV prevention are not overshadowed by
challenges in the control and management of
bacterial STIs.
Douglas S. Krakower is at the Division of Infectious
Diseases, Beth Israel Deaconess Medical Center,
110Francis Street, WLMOB, Suite GB, Boston,
Massachusetts 02215, USA.
Kenneth H. Mayer is at the FenwayInstitute,
1340Boylston Street, 8th Floor, Boston,
Massachusetts02215, USA.
Correspondence to K.H.M.
khmayer@gmail.com
doi:10.1038/nrurol.2015.282
Published online 1 Dec 2015
Acknowledgements
83 | JANUARY 2016
lkunl/iStock/Thinkstock
U R O LO G Y
U R O LO G Y
J. Alfred Witjes is at the Department of Urology,
Radboud University Nijmegen Medical Centre,
POBox9101, 6500 HB Nijmegen, Netherlands.
fred.witjes@radboudumc.nl
doi:10.1038/nrurol.2015.272
Published online 24 Nov 2015
1.
2.
van den Bosch,S. & Witjes,J.A. Long-term cancerspecific survival in patients with high-risk, nonmuscleinvasive bladder cancer and tumour progression:
asystematic review. Eur. Urol. 60, 493500 (2011).
Martin-Doyle,W., Leow,J.J., Orsola,A., Chang,S.L.
& Bellmunt,J. Improving selection criteria for early
cystectomy in high-grade T1 bladder cancer:
ametaanalysis of 15,215 patients. J.Clin. Oncol. 33,
643650 (2015).
85 | JANUARY 2016
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Conferences
You can meet the editors of Nature Reviews Urology at some of the meetings listed on our conferences page
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A Decade in Medicine
The past 10 years has seen great advances in the understanding and treatment of human disease. For expert
perspectives on the most important breakthroughs, dont miss the A Decade in Medicine eBook.
In this special collection of 47 articles commissioned to celebrate the 10th anniversary of the launch of the
clinical Nature Reviews journals leading experts highlight the most important advances in eight medical
specialties between 2004 and 2015, and comment on future developments in their fields.
Download the eBook free here: http://www.nature.com/reviews/collection/adecadeinmedicine/index.html
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