Central nervous system event in patients with diffuse
large B-cell lymphoma in the rituximab era
Naoto Tomita,1,2,25Masahiro Yokoyama,1,3,4Wataru Yamamoto,5Reina Watanabe,2Yutaka Shimazu,6
Yasufumi Masaki,7Saburo Tsunoda,8Chizuko Hashimoto,5Kayoko Murayama,9Takahiro Yano,10Rumiko
Okamoto,11Ako Kikuchi,12Kazuo Tamura,13Kazuya Sato,14Kazutaka Sunami,15Hirohiko Shibayama,16
Rishu Takimoto,17Rika Ohshima,18Yoshihiro Hatta,19Yukiyoshi Moriuchi,20Tomohiro Kinoshita,21
Masahide Yamamoto,22Ayumi Numata,23Yoshiaki Ishigatsubo2and Kengo Takeuchi1,4,24
1Bay-area Lymphoma Information Network, Tokyo;2Department of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School
of Medicine, Yokohama;3Department of Hematology and Medical Oncology, Cancer Institute Hospital, Tokyo;4Ganken Ariake Lymphoma Study Group,
Tokyo;5Department of Medical Oncology, Kanagawa Cancer Center, Yokohama;6Department of Hematology and Oncology, Graduate School of Medicine,
Kyoto University, Kyoto;7Department of Hematology and Immunology, Kanazawa Medical University, Kanazawa;8Division of Hematology, Tochigi Cancer
Center, Utsunomiya;9Department of Hematology, Gunma Cancer Center, Ota;10Division of Hematology, Department of Internal Medicine, National Tokyo
Medical Center, National Hospital Organization, Tokyo;11Department of Chemotherapy, Tokyo Metropolitan Cancer and Infectious Disease Center
Komagome Hospital, Tokyo;12Department of Hematology ⁄Oncology, Tokai University School of Medicine, Isehara,13Department of Medicine, Division of
Medical Oncology, Hematology, and Infectious Diseases, School of Medicine, Fukuoka University, Fukuoka;14Division of Hematology, Department of
Medicine, Jichi Medical University, Shimotsuke;15Department of Hematology, National Hospital Organization, Okayama Medical Center, Okayama;
16Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Suita;17Fourth Department of Internal Medicine, Sapporo
Medical University School of Medicine, Sapporo;18Department of Hematology, Yokohama City University Medical Center, Yokohama;19Department of
Hematology and Rheumatology, Nihon University School of Medicine, Tokyo;20Department of Internal Medicine, Sasebo City General Hospital, Sasebo;
21Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya;22Department of Hematology, Tokyo Medical and
Dental University, Tokyo;23Department of Hematology ⁄Immunology, Fujisawa City Hospital, Fujisawa;24Pathology Project for Molecular Targets, Cancer
Institute Japanese Foundation for Cancer Research, Tokyo, Japan
(Received September 19, 2011 ⁄ Revised October 17, 2011 ⁄ Accepted October 24, 2011 ⁄ Accepted manuscript online November 2, 2011 ⁄ Article first published online November 29, 2011)
Central nervous system (CNS) events, including CNS relapse and
progression to CNS, are known to be serious complications in the
clinical course of patients with lymphoma. This study aimed to
evaluate the risk of CNS events in patients with diffuse large B-cell
lymphoma in the rituximab era. We performed a retrospective
survey of Japanese patients diagnosed with diffuse large B-cell
lymphoma who underwent primary therapy with R-CHOP chemo-
immunotherapy between September 2003 and December 2006.
Patients who had received any prophylactic CNS treatment were
excluded. Clinical data from 1221 patients were collected from 47
institutions. The median age of patients was 64 years (range,
15–91 years). We noted 82 CNS events (6.7%) and the cumulative
5-year probability of CNS events was 8.4%. Patients with a CNS
(P < 0.001). The 2-year overall survival rate after a CNS event was
27.1%. In a multivariate analysis, involvement of breast (relative
risk [RR] 10.5), adrenal gland (RR 4.6) and bone (RR 2.0) were iden-
tified as independent risk factors for CNS events. We conclude that
patients with these risk factors, in addition to patients with testic-
ular involvement in whom CNS prophylaxis has been already justi-
fied, are at high risk for CNS events in the rituximab era. The
efficacy and manner of CNS prophylaxis in patients for each
involvement site should be evaluated further. (Cancer Sci 2012;
py, such as rituximab (R) plus CHOP (cyclophosphamide
[CPA], doxorubicin [adriamycin, ADR], vincristine [VCR] and
prednisolone [PSL]), because standard doses of these drugs do
not adequately penetrate the CNS. Occurrence of a CNS event,
defined as CNS relapse during systemic complete remission or
CNS progression during concurrent systemic active lymphoma,
is associated with extremely poor prognosis, with median sur-
vival of <6 months.(1–6)Many studies concerning CNS prophy-
laxis have been conducted; however, the efficacy of such
prophylaxis in preventing CNS events is controversial.(5,7–12)
he central nervous system (CNS) is thought to be a sanctu-
ary for lymphoma cells from systemic chemoimmunothera-
The discrepancies between reports might be due to the differ-
ences in the various subtypes of lymphoma histology and the
variability of treatment of CNS prophylaxis.(13–16)In addition, R
has had a substantial impact on outcomes in patients with dif-
fuse large B-cell lymphoma (DLBCL).(17)It is thus necessary to
re-evaluate the risk of CNS events in the R era.
The present study comprises a multicenter retrospective analy-
sis of patients with uniform DLBCL histology who have
undergone uniform treatment with R-CHOP, widely accepted as
the standard therapy in the R era. Patients who received any
CNS prophylactic treatment, such as intrathecal chemotherapy,
intraveneous high-dose methotrexate or whole brain irradiation,
were excluded to evaluate the natural risk of CNS events
in R-CHOP therapy. This study also took particular note of the
evaluation of various extranodal involvement sites at presentation.
Materials and Methods
criteria. In October 2009, the Bay-area Lymphoma Information
Network (Bay-LINK) in Japan, a cooperative study group con-
sisting of the Cancer Institute of the Japanese Foundation for
Cancer Research and the Yokohama City University Hematol-
ogy Group, performed a mail and e-mail survey about CNS
involvement in patients with DLBCL. By June 2010, all clinical
data had been collected by Bay-LINK.
All patients had been diagnosed with de novo DLBCL and
had undergone primary therapy between September 2003 and
December 2006. R was approved for the treatment of CD20-
positive aggressive B-cell lymphoma in Japan in September
2003 by the Ministry of Health, Labour and Welfare. Patients
with distinct forms of DLBCL, such as intravascular lymphoma,
primary effusion lymphoma and primary mediastinal large B-
cell lymphoma, were excluded from the study. Primary CNS
lymphoma and intraocular lymphoma were also excluded in this
study. Pathological diagnosis was made by the pathologists in
25To whom correspondence should be addressed.
ª ª 2011 Japanese Cancer Association
| vol. 103| no. 2|
each institution, and no central pathological review was per-
formed. The primary therapy consisted of R-CHOP therapy in
all cases. The schedule of the drug dosing was as follows:
50 mg⁄m2ADR on day 1, 750 mg⁄m2CPA on day 1,
100 mg⁄body of PSL on days 1–5, and 375 mg⁄m2R per cycle.
All patients received at least one cycle of R-CHOP therapy with
curative intent. The chemoimmunotherapy was performed every
3 weeks. The number of patients who received the therapy at an
interval of more than 1 week postponement per cycle or who
received ADR or CPA with more than a 20% average dose
reduction was investigated. The number of patients who under-
went local irradiation as part of their primary therapy was also
investigated. Along with factors including age, gender, clinical
stage, serum lactate dehydrogenase (LDH) level, performance
status, bulky mass, B symptoms, revised International Prognos-
tic Index (R-IPI) and number of extranodal involvement sites,
the presence or absence of the following 26 extranodal involve-
ment sites was recorded: orbita, nasal sinus, paranasal sinus,
Waldeyer’s ring, salivary gland, thyroid gland, breast, thymus,
lung, pleura, stomach, small intestine, colon, peritoneum, liver,
uterus, bone, bone marrow, peripheral blood, skin and subcutis.
Patients were included if they were ‡15 years of age and
staged using, at minimum, physical examination, computed
tomography from neck to pelvis, and bone marrow examination.
Each factor of the R-IPI,(18)as well as the presence or absence
of bulky mass defined as having a diameter of at least 10 cm,
was assessed. The following exclusion criteria were applied: (i)
patients who received any CNS prophylaxis during the clinical
course; (ii) patients with initial CNS involvement at presenta-
tion; (iii) patients with active cancer; and (iv) patients with
human immunodeficiency virus infection. This study was
approved by the Yokohama City University Hospital Clinical
Research Ethics Board. The procedures of the present study
were in accordance with the Helsinki Declaration.
Central nervous system disease. Central nervous system dis-
ease was diagnosed when malignant cells were detected in cyto-
centrifuged preparations of cerebrospinal fluid (leptomeningeal
type) and⁄or when an intracranial or spinal mass was detected
by radiologic imaging, such as computed tomography or mag-
netic resonance imaging (parenchymal type). In the present
study, epidural spinal cord compression was not considered a
CNS disease. Patients with symptoms suggesting CNS disease
without cytological or radiological findings were not regarded as
having CNS disease. In the present study, CNS disease that
occurred during systemic complete remission and during sys-
temic active lymphoma was counted as a ‘‘CNS event.’’
Statistical analysis. Overall survival (OS) was calculated
from the date of initiation of the therapy or, where applicable,
from the date of the CNS event to the date of last follow up or
death from any cause. Time to CNS event (TTCNS) was calcu-
lated from the date of initiation of the therapy to the date of the
CNS event. Survival analysis and TTCNS were estimated using
the Kaplan–Meier method and compared using the log-rank test.
A P-value <0.05 indicated statistical significance. To evaluate
the risk factors for CNS events, a univariate analysis was carried
out using TTCNS as the end point. A Cox proportional hazards
model including all factors with P < 0.1 from the univariate
analysis was performed to determine the impact of those factors
on the risk of a CNS event. Data were analyzed using the Statis-
tical Package for the Social Sciences (IBM PASW Statistics
18.0, IBM Corporation, Armonk, NY, USA).
gland, testis, ovary⁄
Baseline characteristics. Clinical data from 1221 patients with
CD20-positive DLBCL were collected from 47 institutions in
Japan. The median age was 64 years, ranging from 15 to
91 years. Patient characteristics, including the five risk factors
of the International Prognostic Index (IPI), are listed in Table 1.
According to the R-IPI, 433 patients (35.2%) were included in
the ‘‘poor’’ risk group (‡3 risk factors).
Therapeutic factors are also summarized in Table 1. R-CHOP
therapy was performed in all 1221 patients as the primary treat-
ment. Of the 1221 patients, 910 (74.6%) were treated with 6–8
cycles of therapy. Dose reductions of ADR and CPA >20% were
noted in 24.5% and 22.7% of patients, respectively. Two hun-
dred and six patients (17.0%) were treated with an extended
interval per course of >1 week. Local irradiation was added in
297 patients (24.4%).
Table 1. Baseline characteristics and therapeutic factors
Characteristic or therapeutic factorsNumber of patients (%)
Number of R-CHOP courses
Dose reduction (‡20% of ADR)
Dose reduction (‡20% of CPA)
Extended interval per course over 1 week
ADR, doxorubicin; CPA, cyclophosphamide; HD, lactate
dehydrogenase; IPI, international prognostic index; N, upper limit of
normal range; PS, performance status.
ª ª 2011 Japanese Cancer Association
The OS for the entire cohort of 1221 patients is depicted in
Figure 1(A). The median observation period in living patients
was 47.9 months. The 5-year OS rate was 75.0%. The R-IPI was
predictive in identifying the three risk groups (Fig. 1B,
P < 0.001). The 5-year OS rate was 95.6% in the ‘‘very good’’
risk group (0 risk factors), 84.0% in the ‘‘good’’ risk group (one
or two risk factors) and 53.5% in the ‘‘poor’’ risk group.
Incidence of central nervous system events. In total, 82 CNS
events (6.7%) were recorded. More than half of the CNS events
were of the parenchymal type (53.7%), followed by the lepto-
meningeal type (31.7%) and both (14.6%). CNS events occurred
during the first complete remission (CR) in 38 patients (46.3%)
and in the second or later CR in eight patients (9.8%) as isolated
CNS recurrences (Table 2). The remaining 36 CNS events
occurred in patients with relapsed or primary refractory status. In
the 38 patients with CNS events during the first CR, median
TTCNS was 12 months and the types of CNS events were of the
parenchymal type in 24 patients (63.1%), the leptomeningeal
type in six patients (15.8%) and both in eight patients (21.1%). In
the 82 patients with CNS events, death from any cause was
recorded in 53 of these patients (64.6%) during the observation
period, with most deaths occurring due to lymphoma. Patients
with a CNS event showed significantly worse survival compared
to patients without a CNS event (Fig. 1C, P < 0.001). The
TTCNS curve of the entire cohort is depicted in Figure 2(A). The
5-year probability of a CNS event was 8.4%. The median time
interval between the date of initiation of therapy and the CNS
event was 9 months (range, 1–55 months). Of the 82 CNS events,
11 (13.4%) occurred after 36 months of observation and were
considered late CNS events, of which five were of the parenchy-
mal type, three of the leptomeningeal type and three were both.
The late CNS events occurred during the first CR in six cases, the
second later CR in four cases, and non-CR in one patient, who
had already relapsed systematically. Comparing the TTCNS
curves in patients with or without a dose reduction of more than
20% of ADR, the TTCNS observation was significantly inferior
in patients with a dose reduction (Fig. 2B, P = 0.012). The differ-
ence was marginally significant in patients with or without a dose
reduction of more than 20% of CPA (Fig. 2C, P = 0.057). Fur-
thermore, the extended interval per course over 1 week had no
influence on the TTCNS (data not shown).
Risk factors for central nervous system event. In the univari-
ate analysis, 36 risk factors were evaluated for increased risk of
a CNS event. Twenty-two risk factors with P-value <0.1 are
shown in Table 3. Among the general risk parameters, occur-
rence of a CNS event was associated with age over 60 years,
advanced stage, elevated LDH, more than twofold elevated
LDH, poor Eastern Cooperative Oncology Group performance
status, presence of B symptoms, poor risk group according to
R-IPI, and the presence of two or more extranodal involvement
sites with P-value <0.05. Among the local risk parameters,
involvement of the paranasal sinus, Waldeyer’s ring, salivary
gland, breast, pleura, peritoneum, spleen, kidney, adrenal gland,
bone, bone marrow and peripheral blood were also associated
with increased risk of a CNS event with P-value <0.05.
Multivariate Cox regression analysis including the 22 risk fac-
tors with P-value <0.1 by univariate analysis identified involve-
ment of breast (relative risk [RR] 10.5), adrenal gland (RR 4.6)
and bone (RR 2.0) as the risk factors for CNS events (Table 3).
Age over 60 years was also identified as a risk factor for CNS
events (RR 2.1). TTCNS curves significantly differed between
patients with and without any (one or more) of the three CNS
risk factors (Fig. 2D, P < 0.001). The 5-year probability of a
CNS event in patients with and without CNS risk factors was
22.2% and 6.9%, respectively.
Survival after central nervous system event. Figure 3(A)
shows the OS after a CNS event in 82 patients. The 2-year sur-
vival rate was 27.1%, and the 50% survival duration was
6.1 months. Among the three types of CNS events, no signifi-
cant differences were observed between any two types
(Fig. 3B). According to the systemic lymphoma status at the
time of the CNS event, patients who experienced CNS events in
the first CR did not show superior survival as compared with the
others (Fig. 3C, P = 0.16). Moreover, patients with CNS events
in any CR also did not show superior survival as compared with
the others (Fig. 3D, P = 0.12).
In the entire cohort of 1221 adult patients with DLBCL in the R
era, CNS events occurred in 6.7% of patients, and the 5-year
central nervous system (CNS) event. Patients with a CNS event showed significantly inferior survival compared with patients without a CNS
Overall survival curves. (A) Entire cohort (n = 1221). (B) According to the revised international prognostic index. (C) With or without
Table 2.Type of CNS event, systemic status, and outcome
Clinical factorN (%)
Type of CNS event
Second or more CR
Outcome at the latest contact
Death from lymphoma
Death from other causes
CNS, central nervous system; CR, complete response; N, number.
Tomita et al.Cancer Sci|
| vol. 103| no. 2|
ª ª 2011 Japanese Cancer Association
cumulative incidence of CNS events was 8.4%. Several reports
have focused on CNS events in patient cohorts of more than
1000;(19–21)however, these studies have included patients with
heterogeneous histological diagnoses. The present study is the
largest to investigate one uniform histological diagnosis and uni-
form treatment. The OS of the patients according to the R-IPI
was similar to that of the original report,(18)confirming that
DLBCL patients in this study had a regular disease risk. Previ-
ous reports have demonstrated a CNS event incidence of
approximately 5% in the pre-R era.(13)Although our results
from the R era cannot be directly compared with those findings,
we presume that the incidence of a CNS event has not decreased
in the R era. Intravenous R enters the CNS only at very low lev-
els and contributes only to the improved prognosis of systemic
lymphoma and not to the prevention of CNS events.(22)There-
fore, CNS events remain an important research issue in the R
era. In this study, we retrospectively collected data from multi-
ple centers in Japan for patients without CNS prophylaxis. The
role of CNS prophylaxis in patients with DLBCL is not clear,
except in patients with testicular involvement in whom the CNS
prophylactic strategy is already justified.(23,24)It was anticipated
that the subject and the method of CNS prophylaxis might vary
among institutions. Although the number of patients who
received CNS prophylaxis during the study period in the 47
institutions was unclear, we believe this is a reasonable method
for evaluating the risk of CNS events in R-CHOP therapy, even
if the possibility of excluding high-risk patients from the analy-
The 2-year OS after a CNS event in 82 patients was 27.1%.
Of the 54 deaths recorded during the observation period, most
(52⁄54 patients) occurred as a result of the progression of lym-
phoma. Although most reported cases of CNS events are of the
leptomeningeal type, the parenchymal type has been reported to
be predominant in patients with DLBCL.(25)Similarly, more
than half of the cases of CNS events in the present study (44⁄82
patients) were of the parenchymal type. Lymphoma cells might
penetrate the blood brain barrier into the CNS through the blood
stream. Among patients who experienced CNS events in the first
CR, approximately two-thirds of CNS events were of the paren-
chymal type (24⁄38). CNS prophylaxis, such as with high-dose
methotrexate, might be justified for preventing parenchymal
type CNS events in the first CR. However, no significant differ-
ences were observed between any pair of the three types of CNS
events in our study.
There are several reports concerning CNS prophylaxis in the
pre-R era.(5,7–12)The efficacy of CNS prophylaxis is controver-
sial, mainly because the incidence rate of CNS events is rather
low, at approximately 5%. Most reports have included varied
lymphoma histology, and their inclusion or exclusion of patients
who received CNS prophylaxis has varied. Five recent
reports(21,25–28)evaluate the effect of R on CNS events, includ-
ing two publications by our group.(26,28)Interestingly, R is found
to have no influence on the prevention of CNS events in two
studies involving patients without CNS prophylaxis,(25,28)but a
positive effect is noted in three studies involving patients who
received CNS prophylaxis.(21,26,27)
To resolve these discrepancies, we retrospectively analyzed a
large cohort of patients with DLBCL without CNS prophylaxis
in the R era. Each extranodal involvement site was also evalu-
ated. In the Cox proportional hazards model, three extranodal
involvement sites and age over 60 years were identified as risk
factors. It is unrealistic to propose that all patients aged over
treated with a reduction of more than 20% of adriamycin (ADR) showed a significantly inferior TTCNS curve compared with those without it
(P = 0.012); (C) Patients treated with a reduction of more than 20% of cyclophosphamide (CPA) showed a marginally inferior TTCNS curve
compared with those without it (P = 0.057). (D) With or without CNS risk factors consisting of breast, adrenal gland and bone involvement.
Cumulative risk of a central nervous system (CNS) event. (A) Time to CNS (TTCNS) curve in the entire cohort (n = 1221). (B) Patients
ª ª 2011 Japanese Cancer Association
Table 3. Factors associated with increase probability of CNS event
FactorCNS⁄all (n = 82⁄1221) Univariate P Multivariate PRR95% CI
<0.001 0.0691.6 1.0–2.7
<0.001 <0.00110.6 4.2–26.4
<0.0010.089 2.0 0.9–4.6
<0.0010.005 4.6 1.6–13.1
Tomita et al. Cancer Sci|
| vol. 103| no. 2|
ª ª 2011 Japanese Cancer Association
60 years receive CNS prophylactic treatment; therefore, the
realistic risk factors extracted from the current study are breast
involvement, adrenal gland involvement and bone involvement.
The testis is well known as a high-risk involvement site,23,24and
prophylactic irradiation to the contralateral testis after surgery to
remove the affected testis as well as CNS prophylactic intrathe-
cal chemotherapy are recommended in patients with testicular
lymphoma, according to National Comprehensive Cancer Net-
work guidelines.(29)Patients with testicular involvement were
likely to have undergone CNS prophylaxis, as described above,
and, therefore, were not included as subjects in the present
study. In contrast, the breast has only recently been reported as a
high-risk involvement site.(30)Therefore, most patients with
breast involvement from 2003–2006 were likely to have been
treated without CNS prophylaxis and were included as subjects
of the present study, resulting in a 35% incidence (6⁄17 patients)
of CNS events (RR 10.5).
In the present study, the frequency of CNS high-risk patients
with at least one of the three extranodal involvement sites was
10.9% (133⁄1221 patients). According to previous reports,
patients with testicular involvement account for 1–2% of all
non-Hodgkin lymphoma cases.(24)Consequently, we defined
CNS high-risk patients as those with the following four involve-
ment sites, who might account for approximately 12% of all
patients with DLBCL: testis, breast, adrenal gland and bone.
Notably, CNS events occurred in only approximately 22% of
CNS high-risk patients. In the four extranodal sites mentioned
above, the efficacy of CNS prophylaxis has been confirmed only
in patients with testicular involvement and has not yet been
established in the others. The best method of prophylaxis for
each involvement site remains to be elucidated. In addition, the
administration of an adequate dose of key drugs, such as ADR
and CPA, might be another important factor for preventing CNS
events, despite the use of R.
We identified CNS high-risk patients with DLBCL in the R
era. In the future, a randomized controlled study of CNS
high-risk patients to evaluate the role of prophylaxis is highly
anticipated. A new method for the early diagnosis of CNS
involvement at the time of presentation should also be
FactorCNS⁄all (n = 82⁄1221) Univariate P Multivariate P RR 95% CI
CI, confidence interval; CNS, central nervous system; EN, extranodal involvement sites; H; high risk; HI, high–intermediate risk; IPI, international
prognosis index; L, low risk; LDH, lactate dehydrogenase; LI, low–intermediate risk; N, upper limit of normal range; NS, not significant;
PS, performance status; RR, relative risk.
significant differences were observed between any pairs among the three types of CNS event. (C) According to the status of systemic disease
status (the first complete remission [CR] or the others) at the time of the CNS event. No significant difference was observed. (D) According to
the status of systemic disease status (CR or non-CR) at the time of the CNS event. No significant difference was observed.
Overall survival curves after a central nervous system (CNS) event. (A) Entire cohort (n = 82). (B) According to the type of CNS event. No
ª ª 2011 Japanese Cancer Association
Acknowledgments Download full-text
We are grateful to Yoshio Saburi (Oita Prefectural Hospital), Haruhisa
Nagoshi (St. Marianna University School of Medicine Yokohama City
Seibu Hospital), Jun Ishikawa (Osaka Medical Center for Cancer and
Cardiovascular Diseases), Takaaki Miyake (Shimane University Hospi-
tal), Masaaki Noda (Hiroshima City Hospital), Takashi Okamura (Kur-
ume University Hospital), Jun Takizawa (Niigata University Medical
and Dental Hospital), Shingo Yano (Jikei University Hospital), Morio
Matsumoto (Nishigunma National Hospital), Masanobu Nakata (Sapporo
Hokuyu Hospital), Norio Yokose (Nippon Medical School Chiba Hok-
usoh Hospital), Masayuki Hino (Osaka City University Hospital), Taka-
hiko Utsumi (Shiga Medical Center for Adults), Tomufumi Yano
(Okayama Rosai Hospital), Nobuhiko Uoshima (Matsushita Memorial
Hospital), Haruko Tashiro (Teikyo University Hospital), Yuji Kanisawa
(Oji General Hospital), Yoshinori Tanaka (Yamaguchi University Hospi-
tal), Yoshimasa Kura (Kasukabe Municipal Hospital), Michiaki Koike
(Juntendo University Shizuoka Hospita), Shiro Matsuura (Shizuoka Red
Cross Hospital), Gou Aoki (Keiju Medical Center), Juichi Tanabe (Fujie-
da Municipal General Hospital), Sadaya Matano (Tonami General Hos-
pital), Masanori Kume (Hiraka General Hospital), Tatsuyuki Hayashi
(Tokyo Metropolitan Police Hospital), Kunio Hayashi (Hirakata Kohsai
Hospital) and Takamasa Hayashi (Tenri Hospital). This work was sup-
ported in part by the Foundation for Promotion of Cancer Research in
The authors declare no competing financial interests.
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