Hyperbaric oxygen treatment for haemorrhagic radiation
materais ana metnOas
severe haemorrhagic cystitis is difficult
January, 1986, until January, 1994, 40 patients with severe
haemorrhagic radiation-induced cystitis were treated with HBO.
Inclusion criteria were severe haemorrhagic cystitis due to
haematuria but do not affect the radiocystitis itself.
radiotherapy, not responding to other treatments. Exclusion
Hyperbaric oxygen treatment has been reported to do both.
criteria were tumour recurrence in the bladder at cystoscopy
We report the results of a prospective study of
before treatment, concomitant bleeding disorders, and severe
hyperbaric oxygen (20 sessions of 100% oxygen inhalation
pulmonary disease with pulmonary bullae. End points of the
at 3 bar for 90 min in a multiplace hyperbaric chamber) to
study were recurrence of severe haematuria, cystectomy, or
40 patients with biopsy-proven radiation cystitis and severe
death. 33 patients were referred to our centre from other
disappeared completely or
hospitals; 27 were male; mean age was 71-4 years (range 56-86).
improved in 37 patients after treatment. Mean follow-up
Patients had received radiotherapy for a pelvic cancer (table 1).
Mean interval between radiation-therapy and the development of
was 23·1 months (range 1-74); and the recurrence rate
haematuria was 53-1 months (range 4-253).
was 0·12/year. There were no adverse effects.
Patients had received one or more unsuccessful treatments for
Hyperbaric oxygen treatment should be considered for
haematuria: clot evacuation/electrocoagulation (40), tranexamic
patients with severe radiation-induced haematuria.
acid (12), alum (11), corticosteroids (3), neomycin (1),
Lancet 1995; 346: 803-05
etoglucide (1), propantheline (1), silver nitrate (1), unspecified
(17). Most patients required multiple blood transfusions (mean
[range 0-36]). A modified
Radiation therapy is used
classification was used to
as treatment for several pelvic
categorise the severity of haematuria,'4
according to transfusion needs during the 3 months preceding
cancers. Radiation-induced cystitis is a late adverse
during hyperbaric oxygen treatment: slight haematuria
can develop after a delay of up to 21 years.
required no transfusion, moderate haematuria required 1-6 units
Radiation causes a progressive obliterative endarteritis of
of blood; and severe haematuria required over 6 units (table 2).
the small blood vessels, resulting in cellular hypoxia.'
Severe haematuria was most often seen in patients who had had
Patients with severe haemorrhagic radiation-induced
radiotherapy for bladder carcinoma. Pretreatment investigations
cystitis may need regular blood transfusions. Different
were cystoscopy, intravenous urograms/or ultrasound of the
local treatments have been advocated, eg, aminocaproic
upper urinary tract, chest radiograph, blood examination,
acid; tranexamic acid;
exclusion of coagulation disorders, and urine culture.
antibiotics; prostaglandins; sodium pentosanpolysulphate;
HBO treatment was 20 sessions of 100% oxygen inhalation at
bladder distension; electrocoagulation; laser-coagulation;
3-bar pressure for 90 minutes in a multiplace hyperbaric
arterial ligation; embolisation; and intravesical instillation
chamber. Treatment was given in daily sessions 5 or 6 times aweek. In 4
with alum, silver nitrate, phenol
patients, 40 sessions were given because of persistence
or formalinY These
of haematuria. Most patients required bladder washouts during
treatments do not cure the radiation-induced cystitis
the early phase of treatment. Before patients entered the
itself, nor prevent recurrence of severe haematuria. The
chamber, eustachian-tube function was assessed, and a nasal
most successful (formalin and phenol) have serious side-
decongestive spray was given if necessary. When this was
effects and add to the bladder fibrosis brought on by
insufficient, tympanostomy tubes or a myringotomy were
considered. After HBO treatment, patients had a cystoscopy to
Hyperbaric oxygen (HBO) is a relatively new treatment
evaluate the effects. Further follow up was carried out at our
for radiation-induced haemorrhagic cystitis; 56 cases have
centre or by the referring urologist.
been reported,4 apart from our experience.'" It is the onlytreatment which is thought to reverse the vascular
Median follow up was 13 months. 11 patients died, after a
neovascularisation of the bladder wall and so increasing
mean of 23-8 months (range 1-61). Causes of death were:
tissue oxygen tension. HBO has potential side effects12
cancer metastasis (4), unrelated causes (3), unknown (4).
caused by barometric pressure changes or oxygen toxicity.
Four patients had a cystectomy for small bladder
However, serious complications such as central nervous
capacity (3) or recurrence of bladder cancer (1).
system toxicity and decompression sickness are rare in the
Recurrence of severe macroscopic haematuria occurred in
low-pressure, short-duration oxygen inhalation treatments
nine patients, leading to cystectomy in four. Figure 1
shows a Kaplan-Meier curve of cumulative freedom from
We report results of treatment in 40 patients with
recurrence of severe haematuria; cystectomy or death
radiation-induced severe haematuria.
were censored observations.
Overall recurrence of severe haematuria was 0'12/year.
Academic Medical Center (R F M Bevers MD, K H Kurth PhD),
Three groups of patients could be distinguished according
University of Amsterdam, Departments of Urology and Surgery
to their reaction to HBO: group 1 had no haematuria
J Bakker PhD), Amsterdam, The Netherlands
after treatment for at least 3 months; group 2 had
Correspondence to: Dr R F M Bevers, AMC University Hospital,
occasionally slight haematuria, and group 3 did not react
Meibergdreef 9, 1105 AZ, Amsterdam ZO, The Netherlands
*Good=no haematuria, moderate=occaslonal slight haematuna.
Table 4: Cancer type and results of HBO
Table 2: Cancer type, severity of haemorrhagic cystitis, andtransfusion requirements (blood units)
was seen only in patients with a very severe haemorrhagic
Group one (30 patients)
radiocystitis. However, the majority of patients with
Mean follow up was 29-3 months (range 3-74). In this
severe haematuria improved on HBO (table 3).
group, three patients had a recurrence of haematuriarequiring treatment after a mean period of 13-3 months;
haematuria was due to cancer recurrence in two. In three
These results confirm our initial findings" that HBO is
patients cystectomy was done because of small bladder
useful in patients with severe radiation-induced cystitis
capacity after a mean of 9-0 months. During follow up
(mean 27-6 months) 9 patients died without cystectomy.
Adverse effects of HBO
have been reported'2,13 but were
not observed in the present study. The effect of treatment
Group two (seven patients)
was not influenced by sex, age, or radiation dose.
Mean follow up was 5-1 months (range 1-13). Severe
Differences were seen according to the initial type of
recurrent haematuria was seen in 4 patients after a mean
cancer for which patients were treated (table 4). In group
of 2-3. In one patient, cystectomy was done for cancer
two (7 patients) occasional slight haematuria after
recurrence; one patient died from metastases. All patients
treatment was due to cancer recurrence. Cancer was only
in group two had recurrence of bladder (6) or prostate (1)
recognised after HBO when oedema disappeared and
cancer. In three patients, recurrence was seen 3 months
normal mucosa was restored in non-cancerous areas of
after HBO. In these patients judgment of bladder
the bladder-HBO may be even more effective if patients
pathology at pre-treatment cystoscopy was not possible
with cancer recurrence could be diagnosed with more
because of bleeding, oedema, and inflammation. Random
accuracy before starting treatment.
biopsy taken before treatment showed radiation-induced
HBO does not promote cancer growth. Feldmeier et al
cystitis but no cancer. After HBO had cured the radiation
conclude in a review article that most published reports
cystitis, the previously hidden cancer became apparent
show no evidence for tumour growth-enhancement by
HBO." Until now, HBO has been used only for patientswith severe end-stage haemorrhagic radiation cystitis. We
Group three (three patients)
treated patients who showed no reaction to conventional
These patients did not benefit from HBO. They had a
therapy. Because the only alternative treatment in such
mean transfusion need of 25-7 units blood. HBO was
patients is cystectomy, a prospective randomised trial is
stopped, and further treatment carried out in the referring
urologists' hospitals: 1 patient had a cystectomy and 2
In this study, bladder preservation (in regard to
died due to heart disease.
cystectomy for recurrent severe haematuria) was achieved
Comparison of the severity of initial haematuria and
in 36 patients. HBO deserves a position in the treatment
haematuria after HBO revealed that failure of treatment
of radiation-induced haemorrhagic cystitis and should notbe reserved only for severely affected and conventionaltherapy-resistant patients only.
Moss WT, Brand WN, Battifora H. Radiation Oncology: Rationale,Technique, Results. St. Louis: C V Mosby, 1979; 246-51.
2 Noordzij JW, Dabhoiwala NF. Hemorrhagic radiation cystitis.
Int Urogynecol J 1993; 4: 160-67.
3 Parsons CL. Successful management of radiation cystitis with sodium
pentosanpolysulfate. J Urol 1986; 136: 813-14.
4 Schoenrock GJ, Cianci P. Treatment of radiation cystitis with
hyperbaric oxygen. Urology 1986; 27: 271-72.
5 Nakada T, Yamaguchi T, Sasagawa I, Kubota Y, Suzuki H,
Izumiya K. Successful hyperbaric oxygenation for radiation cystitis dueto excessive irradiation to uterus cancer. Eur Urol 1992; 22: 294-97.
6 Norkool DM, Hampson NB, Gibbons RP, Weissman RM. Hyperbaric
10 Rijkmans BG, Bakker DJ, Dabhoiwala NF, Kurth KH. Successful
oxygen therapy for radiation-induced hemorrhagic cystitis. J Urol 1993;
treatment of radiation cystitis with hyperbaric oxygen. Eur Urol 1989;
7 Weiss JP, Mattei DM, Neville EC, Hanno PM. Primary treatment of
11 Kindwall EP. Hyperbaric oxygen treatment of radiation cystitis:
radiation-induced hemorrhagic cystitis with hyperbaric oxygen: 10 year
management of chronic radiation wounds. Clin Plast Surg 1993; 589-92.
experience. J Urol 1994; 151: 1514-17.
12 Gabb G, Robin ED. Hyperbaric oxygen: a therapy in search of
8 Lee HC, Liu CS, Chiao C, Lin SN. Hyperbaric oxygen therapy in
diseases. Chest 1987; 92: 1074-82.
haemorrhagic radiation cystitis: a report of 20 cases. Undersea Hyperb
13 Grim PS, Gottlieb LJ, Boddie A, Batson E. Hyperbaric oxygen therapy.
Med 1994; 21: 321-27.
JAMA 1990; 263: 2216-20.
9 Akiyama A, Ohkubo Y, Takashima R, Furugen N, Tochimoto M,
14 Feldmeier JJ, Heimbach RD, Davolt DA, Brakora MJ, Sheffield PJ,
Tsuchiya A. Hyperbaric oxygen therapy in the successful treatment of
Porter AT. Does hyperbaric oxygen have a cancer-causing or promoting
two cases of radiation-induced hemorrhagic cystitis (Japanese). Nippon
review of the pertinent literature. Undersea Hyperb Med 1994;
Hinyokika Gakkai Zasshi 1994; 85: 1269-72.
responses to available therapy, and 1-year survival remains
at 15% or less.5 CBL-1 is a murine IgM monoclonalantibody directed against a 15 kDa glycolipid antigen of
Response of steroid-resistant graft-versus-
unknown function on activated T
cells, natural killer cells,
host disease to lymphoblast antibody
and a subpopulation of monocytes.7 CBL-1 infusion canreverse rejection of human kidney allografts.8 Because of
the antibody's activity against a spectrum of cellsimplicated in established GVHD, we have assessed its
effect in patients with the severe, steroid-resistant form ofthe disease.
The study was approved by our institutional review board and
all patients gave informed consent. All ten patients (table)
Therapy of steroid-resistant graft-versus-host disease
received targeted-dose cyclosporin for GVHD prophylaxis. As
(GVHD) with antibodies to T cells or cytokines is of limited
additional prophylaxis, all marrow from HLA-mismatched familymembers
value because GVHD is mediated
or from matched unrelated donors was first
a pleomorphic group of
T cells.o Acute GVHD was graded' daily in these patients.
effective cells and cytokines. CBL-1, a murine monoclonal
Patients on study had grade II or greater GVHD that had
antibody, recognises an antigen on activated T cells, B
persisted or progressed despite 8-42 days' treatment with
cells, and natural killer cells. We administered CBL-1 to ten
steroids, including 5 mg/kg methylprednisolone for at least
patients with grade III or IV steroid-resistant GVHD.
5 days. CBL-1 was given as a test dose of 0-01 mL/kg
Complete remissions occurred in five cases and partial
(concentration varies with batch). 4 hours later, 0-1 mL/kg (up to
remissions in four. The
organ system(s) affected by GVHD
mL) was infused in 100 mL 5% dextrose and
saline intravenously over 1 hour. This dose was repeated for
was not a predictor of response. CBL-1 was well tolerated
3 days. CBL-1 was then given on alternate days in halving doses,
and did not exacerbate post-transplant immunodeficiency.
until 0-025 mUkg was reached. This lower dose was continued
Our findings support the use of CBL-1 in primary
weekly for up to 6 weeks if mild to moderate GVHD
prophylaxis for GVHD.
GVHD completely resolved in five patients and in four
Lancet 1995; 346 : 805-06
others the disease improved by at least two grades, whichgives an overall response rate of 90% (table). In allresponders, GVHD discernibly improved 2-14 days after
Graft-versus-host disease (GVHD) continues to be a
the antibody infusion was begun. Remissions were
major source of morbidity and mortality in patients
generally well maintained in complete responders, even
undergoing allogeneic bone-marrow transplantation.'
after the CBL-1 infusion had been discontinued. The
Whilst improved GVHD prophylaxis lowers the frequency
only recurrence of acute GVHD in a complete responder
and severity of this complication in recipients of MHC-
developed 4 weeks after cessation of therapy and, unlike
matched sibling allografts,' the increased use of MHC-
the primary condition, was steroid-responsive. One partial
mismatched or unrelated-donor grafts has allowed GVHD
responder (case 138) had a recurrence in the gut 2 weeks
to retain its status as the primary cause of death in
after CBL-1 was discontinued, which was eventually fatal.
allogeneic marrow-transplant recipients. Patients with
The child (case 167) who failed to respond to CBL-1
severe (grade III or IV) GVHD who fail to respond to
subsequently responded to anti-thymocyte globulin and is
steroid therapy have an especially poor prognosis.
alive with limited chronic skin GVHD at 1173+ days. Of
six evaluable patients, four went on to develop chronic
antagonists intended to inactivate cellular or cytokine
disease that was confined to the skin in three cases. The
components of the immune system'-5
are the most widely
median survival of patients who received CBL-1 was 194
used second-line therapies, but none are satisfactory.
days (range 37-1000+ days), and four patients are still
Most antibody therapies are directed at T lymphocytes.
Whereas these cells initiate GVHD, various additional
Whether or not a patient responded to CBL-1 did not
cellular and cytokine mechanisms contribute to its
appear to depend on the organ systems affected (table), so
persistence and progression. Although higher response
that even patients with severe involvement of skin, gut,
rates may be seen with agents that interrupt the action of:
and liver responded. CBL-1 administration was well
effector molecules, such as interleukin 1 or tumourv
tolerated. Two patients had fever, chills, muscle pain, and
necrosis factor, GVHD frequently recurs after the agents
mild hypotension 1-2 hours after their initial dose, but
have been stopped.4,1>
Overall, fewer than 30% of patients;
these side-effects were controlled with diphenhydramine
with steroid-resistant GVHD have complete or partialI
and hydrocortisone. No patient developed symptoms or
EMC-Gynécologie Obstétrique 2 (2005) 227–237 Petits maux de la grossesse Discomfort during pregnancy J.-M. Thoulon * Professeur honoraire de gynécologie obstétrique, Université Cl. Bernard Lyon I, 14, rue Duviard,69004 Lyon, France MOTS CLÉS Résumé Entre 45 et 89 % des femmes enceintes ont des nausées et des vomissements. Le
• Seiner Majestät Schiff „Novara" • Österreich auf Hoher See • Das Attentat auf den Thronfolger • Interview mit Gen.-Dir. Dietmar Spranz S.M.S. „Novara" Münzgeschichte und Münzgeschichten Österreich auf Hoher See Präsentation: 10-Euro-Münze „Schloss Hellbrunn" Das Attentat auf den Thronfolger MÜNZE ÖSTERREICH-SHOP Interview mit Gen.-Dir. Dietmar Spranz