Professor
Brian Andrews NEJM Recommendations for Medical Students and Tutors
Week
of 25th August 2016 (#57)
University
of Notre Dame Australia (Fremantle Campus)
Occasional Editorial Comment
None
Must Read Articles
ORIGINAL ARTICLE
A
Randomized Trial of Focused Ultrasound Thalamotomy for Essential Tremor
In
this randomized, sham-controlled trial, MRI-guided focused ultrasound thalamotomy
reduced hand tremor in patients with essential tremor who had not had a
response to medication. Adverse effects of the procedure included sensory
deficits and gait disturbances.
EDITORIAL
Treatment
of Medically Refractory Essential Tremor
This is a significant study in patients with essential
tremor which employs ultrasound thalamotomy to induce a permanent lesion in the
contralateral ventro-intermediate nucleus of the thalamus. Patients had
moderately severe essential tremor, present for up to 30 years, which was resistant
to or non-responsive to propranolol or primidone. A major advantage of the technique is that no
surgery is required (burr holes with or without wire placement) in a patient
group that is surgery adverse. Reduction in severity of the tremor (Figure 1)
and improvement in social activities and ADLs (not speech) (Figure 2) are seen to
varying extents in the majority of patients. Major concerns with the study were
the short follow-up period after thalamotomy (up to 12 months) and the probable
lack of further improvement at 12 months (similar results with burr holes with induced
thalamotomy). Long term follow-up is undoubtedly underway. Further adverse
effects related to the procedure (Table 2) were paraesthesiae or numbness in
14% of patients, which were most common in the face or hand (9%). The question is
what improvement occurred in the tremor versus how severe the numbness and
paraesthesiae were; i.e. were the adverse effects worth the improvement in the
tremor?
Another procedure employed is burr hole placement with deep
brain stimulation with wires where no permanent major thalamic lesion is induced
and where the degree of stimulation can be adjusted.
Ideally the following studies should be done:
1. Continue
long-term follow-up of the current study.
2. Compare
the results of ultrasound thalamotomy with deep brain stimulation.
3. Re-introduce
medical therapy after ultrasound thalamotomy to determine if medical therapy is
now effective.
4. Repeat
the procedure on patients where minimal improvement was produced with the
initial thalamotomy and where no adverse effects occurred.
Recommended
learning:
1. Review
essential tremor, the neurobiology and pathways involved, and its management.
2. Review
the types of tremors observed in clinical practice, their mechanisms, and
management.
REVIEW ARTICLE
Treatment
of Patients with Cirrhosis
This
guide to the practical treatment of patients with cirrhosis summarizes recent
developments. It includes advice on medical management, invasive procedures,
nutrition, prevention, and strategies to protect the cirrhotic liver from harm.
This is a comprehensive review of cirrhosis which will
be the standard reference article for years to come. The article reviews
cirrhosis under the following areas: epidemiology and diagnosis, nutrition;
medications employed, invasive procedures; complications and how to avoid them,
and the clinical approach to the patient.
At a minimum, the three figures and
tables should be reviewed, even if the article is not read at this stage in its
entirety.
Recommended
learning: While I suggest you review what you have been taught
on cirrhosis in the curriculum, this review is by far the best resource, as it
also reviews such areas as hepatocellular cancer, degree of reversibility of
liver pathology following insult(s), and the public health aspects of cirrhosis
including its causes.
Articles Recommended for Medical Students
Perspective
Uncertainty
in the Era of Precision Medicine
Far
from ushering in an age of diagnostic and prognostic certainty,
precision-medicine tools will demand a greater tolerance of uncertainty and
greater facility for calculating and interpreting probabilities than we have
been used to as physicians and patients.
ORIGINAL ARTICLE
70-Gene
Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer
In
a study in women with early breast cancer, those with high-risk clinical
features and a low-risk gene-expression profile were assigned to chemotherapy
or no chemotherapy. At 5 years, omission of chemotherapy led to a
1.5-percentage-point lower rate of survival without distant metastasis.
EDITORIAL
Increasing
Precision in Adjuvant Therapy for Breast Cancer
The above three articles relate to both the concept and
the improvement of “precision medicine” which implies both precision based
diagnosis and precision in predicting the outcomes (both positive and negative)
of therapy. The Perspective provides an overview of “precision medicine” and if
only one article were to be read, this is the one I would choose. To date, the most widely studied patient group
in which genomic analysis has been applied is the group of patients with
malignant disease.
The study involves a cohort of 6693 patients with early
stage breast cancer and utilizes the 70-gene signature test (first described 14
years ago), the validity of which has been demonstrated in earlier studies in
defining patients with high and low risk genomic profile with a good and poor
prognosis respectively. Prognosis was based on the risk of distant recurrence
at 5 and 10 year follow-up. Experienced physicians have developed expertise in
the assessment of patients with breast cancer in determining clinical outcomes
(stage, grade, immunopathology, premorbid disease). Such techniques as genomic analysis in
improving clinical outcomes and assessing the effects of therapy will be
progressively added to the clinical outcomes in the future.
Patients in the study were divided into four groups
based on the presence of high or low genomic risk and high or low clinical risk
(Table 1). The hypothesis generated was: could patient groups be identified in
which adjuvant chemotherapy, with its attendant risks, be avoided but achieving
similar outcomes to those treated with chemotherapy? Based on available data,
patients with both low clinical and genetic risks did not receive adjuvant
chemotherapy and patients with both high clinical and genomic risks all
received adjuvant chemotherapy.
The study then focussed on those patients with high
clinical and low genomic risk (HCLG), although data was also generated for the
low clinical and high genomic (LCHG) risk group. The five year outcomes of this
study were:
1. Disease
free survival (Figure 2): chemotherapy improved the HCLG group (p=0.03) and
also the LCHG, although “not statistically significant” in the latter group.
2. Overall
survival (Figure 2): there was no difference with or without chemotherapy in
either group.
3. Survival
without distant metastases: there was no difference with or without
chemotherapy in either group.
4. The
overall survival without distant metastases did not differ significantly
between the HCLG and LCHG groups which were both significantly different from either
the HCHG and LCLG groups (Figure 3).
While this study provides significant new information,
more long term follow-up data and refinement of the genomic analyses will be
required before “precision medicine” correctly earns its title.
IMAGES IN CLINICAL MEDICINE
Giant
Thrombosed Intracranial Aneurysm
A
79-year-old woman presented with gradual neurologic decline involving
confusion, memory loss, imbalance, and incontinence. On examination, she was
oriented only to self and had mild nonfluent aphasia. CT revealed a large left
frontotemporal mass with areas of calcification.
This is a case of a 79 year-old woman who presented
with symptoms of low/normal pressure hydrocephalus (confusion, memory loss,
imbalance and urinary incontinence) and was found to have an old calcified,
giant thrombosed intracranial aneurysm involving the bifurcation of the left
middle cerebral artery. Surgery was not performed to remove the aneurysm
because of the surgical risk. However, with
less extensive surgery involving placement of a ventriculoperitoneal shunt and
an endoscopic transfrontal septostomy to relieve the hydrocephalus, there was
an overall improvement in the patient’s neurological status.
IMAGES IN CLINICAL MEDICINE
A
Sneeze
A human
sneeze can eject droplets of fluid and potentially infectious organisms. The
image sequence captures, in increments of 20 msec, the emission of a sneeze
cloud produced by a healthy person. Two videos show the same sneeze at normal
speed and at a much slower speed.
The video image of a normal sneeze demonstrates the
distance that droplets produced by the sneeze can travel and reminds us of the
importance of sneezing in spreading potentially infectious micro-organisms.
SPECIAL REPORT
Body
Fatness and Cancer — Viewpoint of the IARC Working Group
The
International Agency for Research on Cancer convened a workshop on the
relationship between body fatness and cancer, from which an IARC handbook on
the topic will appear. An executive summary of the evidence is presented.
This article summarises the current data generated by the
International Agency for Research on Cancer (IARC) regarding obesity and cancer
risk. The agency reviewed more than 1000 observational studies and compared the
cancer-preventive effect with the absence of body fat. Their results are
presented in Table 2. They compare the cancer site or type with the strength of
evidence in humans that the absence of excess body fatness lowers the risks of
most cancers. However the data indicate
that there is as yet no specific evidence that intentional weight loss lowers
the risks of developing specific cancers.
IARC have also identified an additional eight tumour
types where the absence of fat is associated with a lower risk of specific
cancers (gastric cardia, liver, gallbladder, pancreas, ovary, thyroid, multiple
myeloma and meningioma) (see Table 2 for full data).
Important Articles Related to Mechanisms of Disease and
Translational Research
None
Other Articles which should interest medical students
CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL
Case
26-2016 — A 28-Year-Old Woman with Back Pain and a Lesion in the Lumbar Spine
A
28-year-old woman presented with intractable back pain with radiation to the
leg. Examination of biopsy specimens revealed a giant-cell tumor of bone.
Management decisions were made.
The case is that of a 28 year old female presenting
with low back pain and found to have a giant-cell tumour of bone
(osteoclastoma) destroying L5 and extending into the spinal canal and into the surrounding
soft tissues. There is a detailed discussion of the management of this patient
and a differential diagnosis of the bony lesion.
Of interest is the use of denosumab, a humanized
monoclonal antibody directed against RANKL which is expressed on the surface of
osteoblasts as well as the surface of mononuclear stromal cells present within
the osteoclastoma. RANKL binds to RANK on the surface of osteoclasts and
osteoclast precursor cells leading to osteoclast activation and osteoclast
precursor differentiation.
It is believed that the neoplastic cell within the osteoclastoma
is the mesenchymal cell expressing RANKL which then leads secondarily to
osteoclast formation.
In osteoporosis, denosumab inhibits RANKL activation of
RANK on osteoclast precursors and thus inhibits osteoclastic bone remodelling.
Recommended
learning: Review the pathophysiological mechanisms involved in
osteoporosis and the mechanisms of actions of drugs used in the treatment.
New Pharmacological Therapies
The aim of this new section is to introduce new
therapies, particularly those that provide either a novel pharmacological group,
an established drug that is employed for a new indication or where a new
mechanism of action has been established for a drug.
ORIGINAL ARTICLE
Inotuzumab
Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia
Among
adults with relapsed acute lymphoblastic leukemia, treatment with the anti-CD22
drug conjugate inotuzumab ozogamicin produced a higher rate of complete
remission, as well as a higher rate of veno-occlusive disease, than did
standard chemotherapy.
Inotuzumab ozogamicin is an agent combining a humanized
anti-CD22 (a non-shed, cell surface glycoprotein expressed on the surface of
ALL B cells in 90% of patients) monoclonal antibody with a cytotoxic antibiotic
calicheamicin. The drug binds to the CD22 surface receptor and is then rapidly
internalized followed by release of the calicheamicin. Calicheamicin then binds
to the minor groove of DNA, inducing double-strand cleavage and subsequent
apoptosis. An uncommon side effect is hepatic veno-occlusive disease.
ORIGINAL ARTICLE
Daratumumab,
Bortezomib, and Dexamethasone for Multiple Myeloma
In
a study involving patients with refractory multiple myeloma, the anti-CD38
antibody daratumumab in combination with bortezomib and dexamethasone resulted
in longer progression-free survival and a higher rate of response than
bortezomib and dexamethasone alone.
Daratumumab is a human IgGκ monoclonal antibody that
targets CD38, which is highly expressed on the surface of myeloma cells and
other hematopoietic cell types. Daratumumab has direct and indirect
antitumor activity and diverse mechanisms of action, including:
1. Induction
of apoptosis;
2. Immune-mediated
actions, including complement-dependent cytotoxicity, antibody-dependent
cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis; and
3. Immunomodulatory
functions that target and deplete CD38-positive regulator immune suppressor
cells which lead to T-cell expansion and activation in patients who have a
response to this monoclonal antibody.
