correspondence
Cancer Stem Cells
To the Editor: With regard to the article by Jor-
dan et al. (Sept. 21 issue),1 if cancer stem cells are
characterized in experimental studies by their abil-
ity to regrow a tumor when injected into an im-
munodeficient animal, then what is evaluated is
the capability of a cancer cell to reinitiate a tu-
mor in a normal tissue.2 In such experiments,
therefore, cancer stem cells behave like tumori-
genic or metastatic cells. Hence, in a functional
sense, the concept of the cancer stem cell might
just be a restyling of the tumorigenicity concept.
Didier Wion, Ph.D.
Franois Berger, M.D., Ph.D.
INSERM Unit 318
38043 Grenoble, France
didier.wion@ujf-grenoble.fr
1. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl
J Med 2006;355:1253-61.
2. Singh SK, Hawkins C, Clarke ID, et al. Identification of hu-
man brain tumour initiating cells. Nature 2004;432:396-401.
The Authors Reply: As we noted in our review
article, not only do cancer stem cells regrow tu-
Cerebral Aneurysms
To the Editor: Hyponatremia, a common and
important complication of subarachnoid hemor-
rhage, is not mentioned in the review of cerebral
aneurysms by Brisman et al. (Aug. 31 issue).1 Hy-
ponatremia is associated with substantially in-
creased morbidity among neurosurgical patients.
A recent study2 indicated that hyponatremia de-
veloped in 66% of patients who underwent aneu-
rysmal clipping and 62% of patients who under-
went coiling after subarachnoid hemorrhage. The
pathophysiology of hyponatremia is often com-
plex and should influence the treatment approach.
Clinicians should be aware of the importance of
this problem so that appropriate measures can
be implemented to correct hyponatremia in a time-
ly fashion.
Francis M. Finucane, M.B.
Medical Research Council Epidemiology Unit
Cambridge CB1 9NL, United Kingdom
francis.finucane@mrc-epid.cam.ac.uk
n engl j med 355;25 www.nejm.org
mors, but they also undergo quantitative self-
renewal, recapitulate all cell types within a tumor,
and have extensive proliferative capacity. These
unique properties are not usually found in most
tumor cells and are not generally attributed to
the tumorigenicity concept. Thus, we suggest that
the explicit identification of a stem-cell compart-
ment in tumors whether its presence is due to
transformation of a stem cell itself or to reexpres-
sion of stemness properties as a result of the
transformation of a later cell represents a step
forward in attempts to understand the consid-
erable problem of cancer recurrence. Nonethe-
less, as we noted, it is important to acknowledge
that the concept is not new. Now, however, it is
possible to isolate and accurately define such
cells.
Craig T. Jordan, Ph.D.
Monica L. Guzman, Ph.D.
Mark Noble, Ph.D.
University of Rochester School of Medicine
Rochester, NY 14642
craig_jordan@urmc.rochester.edu
1. Brisman JL, Song JK, Newell DW. Cerebral aneurysms.
N Engl J Med 2006;355:928-39.
2. Sherlock M, OSullivan E, Agha A, et al. The incidence and
pathophysiology of hyponatraemia after subarachnoid haemor-
rhage. Clin Endocrinol (Oxf) 2006;64:250-4.
To the Editor: In their review article, Brisman
et al. state that 5 to 40% of patients with auto-
somal dominant polycystic kidney disease have
intracranial aneurysms and that screening with
intracranial magnetic resonance angiography is
indicated for all these patients. In studies of pa-
tients with autosomal dominant polycystic kid-
ney disease, prospective screening detected in-
tracranial aneurysms in 16% of 77 patients with
a family history of intracranial aneurysms and in
6% of 186 patients without such a family history.1
All these aneurysms were small (mean diameter,
3.5 mm; range, 1 to 7); most were in the anterior
circulation. According to the International Study
of Unruptured Intracranial Aneurysms, the ex-
december 21, 2006 2703
 The n e w e ng l a n d j o u r na l
pected rupture rate is very low.2 Among patients
with autosomal dominant polycystic kidney dis-
ease, no ruptures occurred during a decade of fol-
low-up in 27 patients with intracranial aneurysms
detected by screening that were smaller than 7 mm;
two aneurysms increased in size.3 Repeat imag-
ing after 9 years 10 months showed new aneu-
rysms in 1 of 76 patients with negative results on
initial screening.4
The claim for universal screening in autosomal
dominant polycystic kidney disease is based on
a 1996 decision-analysis study5 that used a 15.0%
prevalence for intracranial aneurysms and a 1.6%
annual rupture rate. Other analyses of at-risk popu-
lations have shown a marginal benefit or none.
In our practice, indications for screening pa-
tients with autosomal dominant polycystic kid-
ney disease who have a good life expectancy are
a family history of intracranial aneurysms, pre-
vious rupture of an aneurysm, major elective sur-
gery, a high-risk occupation, and anxiety on the
part of the patient despite adequate information.
Vicente E. Torres, M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
torres.vicente@mayo.edu
Yves Pirson, M.D.
Universit Catholique de Louvain
B-1200 Brussels, Belgium
David O. Wiebers, M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
1. Pirson Y, Chauveau D, Torres VE. Management of cerebral
aneurysms in autosomal dominant polycystic kidney disease.
J Am Soc Nephrol 2002;13:269-76.
2. Wiebers DO, Whisnant JP, Huston J III, et al. Unruptured
Table 1. Grading Scales for Subarachnoid Hemorrhage.
World Federation
Grade of Neurosurgical Societies Scale*
1 15
2 1314 with no focal deficit
3 1314 with focal deficit
4 712 with or without focal deficit
5 36 with or without focal deficit
* The numbers represent points on the Glasgow Coma Scale, on which scores can range from 3 to 15, with higher
scores indicating better function.
2704 n engl j med 355;25 www.nejm.org
of m e dic i n e
intracranial aneurysms: natural history, clinical outcome, and
risks of surgical and endovascular treatment. Lancet 2003;362:
103-10.
3. Gibbs GF, Huston J III, Qian Q, et al. Follow-up of intracra-
nial aneurysms in autosomal-dominant polycystic kidney dis-
ease. Kidney Int 2004;65:1621-7.
4. Schrier RW, Belz MM, Johnson AM, et al. Repeat imaging
for intracranial aneurysms in patients with autosomal domi-
nant polycystic kidney disease with initially negative studies:
a prospective ten-year follow-up. J Am Soc Nephrol 2004;15:
1023-8.
5. Butler WE, Barker FG II, Crowell RM. Patients with poly-
cystic kidney disease would benefit from routine magnetic
resonance angiographic screening for intracerebral aneurysms:
a decision analysis. Neurosurgery 1996;38:506-16.
To the Editor: Brisman et al. recommend the
use of the Hunt and Hess Scale in the assessment
of patients with recent subarachnoid hemorrhage.
However, this clinical scale has poor interobserv-
er reliability1 and does not predict the outcome
well. Furthermore, the Hunt and Hess Scale
measures both headache and neck stiffness,
neither of which has prognostic significance
and both of which can be difficult to assess re-
producibly.
The World Federation of Neurosurgical Soci-
eties has devised a preferable scale (Table 1). It
has reasonable interobserver reliability, is a potent
predictor of the outcome in both randomized,
controlled trials and observational cohorts,2 and
is based on the Glasgow Coma Scale, which is
familiar to most clinicians.
William Whiteley, M.A., M.R.C.P.
Rustam Al-Shahi Salman, Ph.D., M.R.C.P.
Western General Hospital
Edinburgh EH4 2XU, United Kingdom
wwhitele@staffmail.ed.ac.uk
Hunt and Hess Scale
Asymptomatic or mild headache and nuchal rigidity
Moderate-to-severe headache, nuchal rigidity, and cranial-
nerve palsy
Lethargy, confusion, or mild focal deficit
Stupor, moderate-to-severe hemiparesis, and early decere-
brate rigidity
Deep coma, decerebrate rigidity, and moribund appearance
december 21, 2006
 correspondence

1. Lindsay KW, Teasdale G, Knill-Jones RP, Murray L. Observer than 30 clinical grading scales for subarachnoid
variability in grading patients with subarachnoid hemorrhage.
J Neurosurg 1982;56:628-33.
hemorrhage have been described. The most com-
2. Al-Shahi R, White PM, Davenport RJ, Lindsay KW. Subarach- monly used scales are the World Federation of
noid haemorrhage. BMJ 2006;333:235-40. Neurosurgical Societies Scale and the Hunt and
Hess Scale. Both have reasonable interobserver
The Authors Reply: We agree with Finucane reliability and correlate well with the ultimate
that it is important to monitor and treat hypona- clinical outcome.3 Despite the recommendations
tremia after a ruptured cerebral aneurysm. He of the World Federation of Neurological Surgeons
cites a study that showed fewer instances of hy- to use their scale as a universal scale, most neu-
ponatremia among patients with spontaneous rosurgeons still prefer the Hunt and Hess Scale;
subarachnoid hemorrhage who were treated con- in a review of articles on subarachnoid hemor-
servatively than among those who were treated rhage that were published between 1985 and 1992,
with clipping or coiling.1 The group treated con- 71% of reported studies used the Hunt and Hess
servatively, however, consisted mostly of patients Scale, whereas only 19% used the World Federa-
with subarachnoid hemorrhage in which an an- tion of Neurosurgical Societies Scale.4
eurysm could not be detected. The natural his- Jonathan L. Brisman, M.D.
tory of nonaneurysmal subarachnoid hemorrhage JFK Medical Center
usually differs from that of aneurysmal subarach- Edison, NJ 08818
noid hemorrhage. Hyponatremia is infrequently jbrisman@solarishs.org
the cause of significant impairment or death in Joon K. Song, M.D.
patients with subarachnoid hemorrhage. For ex- Roosevelt Medical Center
ample, one recent multicenter review showed that New York, NY 10019
hyponatremia had no bearing on the outcome David W. Newell, M.D.
3 months after subarachnoid hemorrhage.2 Swedish Medical Center
Seattle, WA 98122
Torres et al. share their algorithm for screen-
ing patients with autosomal dominant polycystic 1. Sherlock M, OSullivan E, Agha A, et al. The incidence and
pathophysiology of hyponatraemia after subarachnoid haemor-
kidney disease. Although the incidence of cere- rhage. Clin Endocrinol (Oxf) 2006;64:250-4.
bral aneurysms in the population with this dis- 2. Qureshi AI, Suri MF, Sung GY, et al. Prognostic significance
ease is generally thought to be higher than that of hypernatremia and hyponatremia among patients with aneu-
rysmal subarachnoid hemorrhage. Neurosurgery 2002;50:749-
in the population without this disease, estimates 55.
of the prevalence have varied considerably. On 3. Oshiro EM, Walter KA, Piantadosi S, Witham TF, Tamargo
the basis of currently available data, the screening RJ. A new subarachnoid hemorrhage grading system based on
the Glasgow Coma Scale: a comparison with the Hunt and Hess
approach outlined by Torres and colleagues ap- and World Federation of Neurological Surgeons Scales in a clin-
pears to be reasonable. ical series. Neurosurgery 1997;41:140-7.
Whiteley and Al-Shahi point out the importance 4. van Gijn J, Bromberg JE, Lindsay KW, Hasan D, Vermeulen
M. Definition of initial grading, specific events, and overall out-
of the World Federation of Neurosurgical Socie- come in patients with aneurysmal subarachnoid hemorrhage:
ties Scale for subarachnoid hemorrhage. More a survey. Stroke 1994;25:1623-7.

Use of Statins and Outcome of BCG Treatment

for Bladder Cancer
To the Editor: The intravesical administration
of bacille CalmetteGurin (BCG) vaccine for high-
risk, nonmuscle-invasive bladder cancer and car-
cinoma in situ is one of the most successful im-
munotherapies to date.1 Studies in animals have
shown that the generation of effector cells, called
BCG-activated killer cells, depends on type 1 help-
er T (Th1)type cytokines.2 In humans, a high
Th1-biased urinary cytokine profile after several
weekly intravesical instillations of BCG correlates
with a better clinical response.3
Statins have cholesterol-lowering properties
and also immunomodulating actions. Several
reports have indicated that statins can induce

n engl j med 355;25 www.nejm.org december 21, 2006 2705

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