Retrospective study on factors affecting the prognosis in oral cancer patients who underwent surgical treatment only

Abstract

This study was performed to evaluate their 5-year survival rates and identify the factors affecting the prognosis of oral cancer patients who had undergone surgical treatment only.
Among 130 patients who were diagnosed with malignant tumor of oral, maxillofacial, and surgical treated in the Department of Oral and Maxillofacial Surgery at Chonnam National University Hospital within a period from January 2000 to December 2010, for 11 years, 84 patients were investigated who were followed up for more than 5 years after radical surgery; oral cancer is primary and received only surgical treatment. The survival rate according to gender, age, type and site of cancer, TNM stage, cervical lymph node metastasis and its stage, recurrence or metastasis, time of recurrence and metastasis, and differentiation were investigated and analyzed.
Overall, 5-year survival rate in patients who received only surgical treatment was 81.2 %, and disease-specific 5-year survival rate was 83.1 %. The disease-specific 5-year survival rate based on TNM stage, metastasis of cervical lymph node, N stage, and presence of recurrence/metastasis was a significant difference (p < 0.05). The disease-specific 5-year survival rate based on sex, age, type of tumor, primary site, and differentiation was not a significant difference (p > 0.05).
These results suggest that good survival rate can be obtained with surgical treatment only, and stage of oral cancer, cervical lymph node metastasis and stage, recurrence or metastasis, time of recurrence, and metastasis have a significant effect on survival rate in oral cancer patients.

Full text

R E S E A R C H Open Access
Retrospective study on factors affecting the
prognosis in oral cancer patients who
underwent surgical treatment only
Byeong-Guk Kim, Jun-Hwa Kim, Myung-In Kim, Jeong Joon Han, Seunggon Jung, Min-Suk Kook, Hong-Ju Park,
Sun-Youl Ryu and Hee-Kyun Oh
*
Abstract
Background: This study was performed to evaluate their 5-year survival rates and identify the factors affecting the
prognosis of oral cancer patients who had undergone surgical treatment only.
Methods: Among 130 patients who were diagnosed with malignant tumor of oral, maxillofacial, and surgical
treated in the Department of Oral and Maxillofacial Surgery at Chonnam National University Hospital within a
period from January 2000 to December 2010, for 11 years, 84 patients were investigated who were followed up
for more than 5 years after radical surgery; oral cancer is primary and received only surgical treatment. The survival
rate according to gender, age, type and site of cancer, TNM stage, cervical lymph node metastasis and its stage,
recurrence or metastasis, time of recurrence and metastasis, and differentiation were investigated and analyzed.
Results: Overall, 5-year survival rate in patients who received only surgical treatment was 81.2 %, and disease-specific
5-year survival rate was 83.1 %. The disease-specific 5-year survival rate based on TNM stage, metastasis of cervical
lymph node, N stage, and presence of recurrence/metastasis was a significant difference (p< 0.05). The disease-specific
5-year survival rate based on sex, age, type of tumor, primary site, and differentiation was not a significant
difference (p> 0.05).
Conclusions: These results suggest that good survival rate can be obtained with surgical treatment only, and
stage of oral cancer, cervical lymph node metastasis and stage, recurrence or metastasis, time of recurrence,
and metastasis have a significant effect on survival rate in oral cancer patients.
Keywords: Neoplasm metastasis, Oral cancer, Recurrence, Survival rate, TNM classification
Background
For the treatment of oral cancer, it is still controversial,
but usually, surgical treatment is preferred in the initial
oral cancer and the cases of progressed oral cancer like
cervical lymph node metastasis or extracapsular spread
have been performed with surgical treatment along with
combination therapy and radiation therapy [1]. Recently,
it has emerged as an important factor of treatment
decisions, quality of life in addition to the possibility of
oral cancer recovery [2].
Radiation therapy and chemotherapy in patients with
oral cancer performed separately and also performed be-
fore surgery or after surgery. Radiation therapy may be
used for tongue cancer effectively but is performed limit-
edly because of the influence on the adjacent normal tis-
sues [3]. It induces side effects such as induction of
malignant neoplasm, osteoradionecrosis (ORN), pronun-
ciation disorders, dysphagia, dry mouth, and dental car-
ies [4]. In addition, it has limited radiation therapy to
perform radiation therapy again in the same site and it
makes more complicated that there is a salvage treat-
ment through surgery after radiotherapy [3]. Chemo-
therapy is applied to advanced stage, extracapsular
spread, recurrence or metastasis, and the case of pallia-
tive therapy.
* Correspondence: hkoh@jnu.ac.kr
Department of Oral and Maxillofacial Surgery, School of Dentistry, Dental
Science Research Institute, Chonnam National University, 77, Yongbongro,
Buk-Gu, Gwangju 500-757, South Korea
© 2016 Kim et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made.
Kim et al. Maxillofacial Plastic and Reconstructive Surgery (2016) 38:3
DOI 10.1186/s40902-015-0047-8

It is reported that the prognosis of oral cancer patients
undergoing radiation therapy or combination therapy
after surgical treatment is not significantly better than
those who received only surgical treatment [4]. Perform-
ing only surgical treatment is preferred since it prevents
the side effects of chemotherapy and radiation therapy
and obtains a good result. Wolfensberger et al. reported
thedisease-specific4-yearsurvivalrateof94%andrecur-
renceormetastasisrateof18%inthe93casesonly
through surgical procedures in oral cancer patients, and
Lim et al. reported the disease-specific 5-year survival rate
of 83 % and recurrence or metastasis rate of 21 % in the 76
cases [4, 5]. Liu et al. reported a 5-year survival rate of 72 %
and recurrence or metastasis rate of 25 % in 72 cases [6].
There are a few reports on the factors that affect the
prognosis of oral cancer patients. Massano et al. reported
that TNM stage, extracapsular spread, resection margins
of lesions, and the thickness of the tumor have high rele-
vance to the prognosis of oral squamous carcinoma pa-
tients; Rajapakshe et al. reported that factors which affect
the prognosis and survival of oral squamous carcinoma
patients are TNM staging, lymph node metastasis, and the
status of the resection margin of lesions [7–9].
This study was performed to evaluate their 5-year
survival rates and identify the factors affecting the
prognosis of oral cancer patients who had undergone
surgical treatment only.
Methods
1. Patients
a. Among oral cancer patients who have received the
surgical treatment in the Department of Oral and
Maxillofacial Surgery at Chonnam National
University Hospital within a period from January
2000 to December 2010, for 11 years, 84 patients
were investigated who were followed up for more
than 5 years, had primary oral cancer, and
received only surgical treatment.
2. Methods
(a)Examination of patients’medical records
The patient’s medical records were examined.
The clinical, pathological, and medical care
information were collected retrospectively.
Biopsy for diagnosis, computed tomography
(CT), whole body bone scan (WBBS), and positron
emission computed tomography-computed tomog-
raphy (PET-CT) findings of such were examined.
Overall survival rates, etc. were investigated
after categorization referring to the classification
table (AJCC cancer staging manual 7th edition)
recommended by AJCC for the distribution of
the survival status and location of the oral cavity
of the patient [10].
(b) Surgical treatment
Patients with tumor-free dissection boundaries
and who cannot get radiation treatment for can-
cer underwent surgical treatment. Radical resec-
tion was performed including a safety margin of
10 mm. Neck dissection was performed in 82 pa-
tients among 84 patients, bilateral supraomo-
hyoid neck dissection (SOHND) in 75 patients,
ipsilateral SOHND in 5 patients, ipsilateral
SOHND and opposite SND (Selective neck dis-
section: level I only) in a patient, and bilateral
modified radical neck dissection (MRND) in a
patient. Direct closure was performed in 46 cases
(55 %) of 84 cases and reconstruction in 38 cases
(45 %). Local flap (16 %) for reconstruction was
in 6 cases, and microvascular free flap was per-
formed in 32 cases (84 %).
(c) Prognosis assessment of patients
The 5-year survival rate and the disease-specific
5-year survival rate were calculated. Factors
affecting the prognosis of oral cancer patients,
including gender and age of patients, type, stage
and location of cancer, lymph node metastasis,
stage of lymph node, recurrence and metastasis,
time of recurrence and metastasis, and
differentiation, were investigated.
Standard of classification table (AJCC cancer
staging manual 7th edition) recommended by the
AJCC is applied to TNM classification for staging
of cancer [10].
(d) Statistical assessment
The survival rate was calculated using the
Kaplan Meier method, and the log rank test was
performed for significance test of the predicted
factors that affect the prognosis. Each analysis
was performed using the SPSS 20 (IBM, Chicago,
Illinois, USA).
Results
1. Prognosis according to gender and age
Oral cancer patients receiving surgery treatment
were 58 male and 26 female, and the rate was
higher 2.3 times in men, and overall, 5-year survival
rate was 81.2 %. The disease-specific 5-year survival
rate according to gender (women 84.6 %, men
82.5 %) showed no significant difference, and
results of log rank test showed that sex does not
affect prognosis (Table 1).
According to the age distribution of oral cancer
patients, affected age was 60 or more (55 patients,
65 %). Disease specific 5-year survival rate by age
decreased slightly with age, but there was not
statistically significant difference, and the result of
Kim et al. Maxillofacial Plastic and Reconstructive Surgery (2016) 38:3 Page 2 of 9

log rank test showed that age does not affect the
prognosis (Fig. 1).
2. Prognosis according to type, site, and stage of cancer
Squamous cell carcinoma among oral cancer was
the most common with 62 cases (71.2 %); the
disease-specific 5-year survival rate of these patients
was 82.0 %. The disease-specific 5-year survival rate
according to the type of oral cancer ranged from
100 to 0 %. Results of Kaplan Meier method and
log rank test showed that the type of oral cancer
does not affect prognosis (Table 2).
Areas most affected by oral cancer were anterior
two-thirds of the tongue followed by floor of the
mouth, inferior alveolar ridge. The disease-specific
5-year survival rate with the site of oral cancer
ranged from 100.0 to 69.2 %, and results of log
rank test showed that site of oral cancer does not
affect prognosis (Table 3).
In the stage of patients, 25 people belong to stage I,
23 people to stage II, 16 people to stage III, and
20 people to stage IV, as stage progresses, the
disease-specific 5-year survival rate decreases as
follows: 96.0 % of patients belong to stage I, 90.9 %
of patients to stage II, 86.7 % of patients to stage
III, 57.1 % of patients to stage IV, and the pvalue
is 0.003 by log rank test results, which showed
the stage was significant factor in the survival
rate (Fig 2).
3. Prognosis according to metastasis of cervical lymph
node and stage of cervical lymph node
Table 1 Vital status and disease specific 5-year survival rate
according to gender
Gender No.
of
cases
Alive Dead DSS
TFNR TFAR AWPRM DTF DWC DPO
Male 58 38 5 4 4 5 2 82.5
Female 26 17 2 2 2 2 1 84.6
Total 84 55 7 6 6 7 3 83.1
ATFNR alive; tumor-free; no recurrence, ATFAR alive; tumor-free; after recur-
rence, AWPRM alive; with persistent/recurrent/metastatic disease, DTF dead;
tumor-free, DWC dead; with cancer-primary/recurrent/metastatic, DPO dead;
postoperative, DSS disease specific 5-year survival rate
Fig. 1 Disease specific 5-year survival rate by age group (p= 0.093)
Table 2 Disease specific 5-year survival rate according to type
of neoplasm
Type No. of cases (%) Recur or meta DSS
SCC 62 (71.2) 15 82
ACC 7 (8.2) 1 100
MM 4 (4.7) 1 75
VC 4 (4.7) 0 100
Sar 3 (3.5) 1 66.6
MC 2 (2.3) 1 100
BCC 1 (1.8) 0 100
GCC 1 (1.8) 0 100
Total 84 (100.0) 18 83.1
SCC squamous cell carcinoma, ACC adenoid cystic carcinoma, MM malignant
melanoma, VC verrucous carcinoma, Sar sarcoma, MC mucoepidernoid
carcinoma, BCC basal cell carcinoma, GCC ghost cell carcinoma, Recur
recurrence, meta metastasis, DSS disease specific 5-year survival rate)
Kim et al. Maxillofacial Plastic and Reconstructive Surgery (2016) 38:3 Page 3 of 9

The disease-specific 5-year survival rate without
cervical lymph node metastasis was significantly
higher than that with cervical lymph node metastasis
(93.2 vs 58.3 % (Fig 3)). As N stage progressed, the
disease-specific 5-year survival rate significantly
decreased (p< 0.05) (Fig 4).
4. Prognosis according to recurrence/metastasis or
timing of recurrence/metastasis
The disease-specific 5-year survival rate according
to recurrence or metastasis recurrence or metastasis
was 89.1 % in the case without recurrence or
metastasis and 63.2 % with recurrence or metastasis,
and whether or not, recurrence and metastasis
were significant factors, since significant probabil-
ity was 0.011 by log rank test results, which
showed that recurrence and metastasis were
significant factors in the survival rate (Fig 5).
The survival rate varied according to the time of
recurrence or metastasis of 19 patients who
experienced postoperative recurrence or metastasis.
The disease-specific 5-year survival rate of patients
who experienced recurrence or metastasis within
1 year after surgery was 45.5 %, within 1–2 years
was 85.7 %, and within 2–3 years was 100 %, and
significant probability was 0.002 by log rank test
results, which showed that the time of recurrence
or metastasis after surgery was a significant factor in
the survival rate (Fig 6).
Recurrence or metastasis occurs to all 18 patients
(21.4 % of 84 patients), with local recurrence only
occurring to 7 patients, regional recurrence only to
8 patients, local recurrence and regional recurrence
to 1 patient, and with distant metastasis to 2
patients. One of 7 patients has local recurrence
only, 3 of 8 patients with regional recurrence only,
one patient with locoregional recurrence, and 1 of 2
patients with distant metastasis died (Table 4). It
was most common that recurrence or metastasis
occurred within 1 year to 10 (58 % of 18
patients) of 18 cases, within 1–2 years to
sevencases(37%ofthe18patients),within
2–3 years to one case (5 % of 18 patients),
Table 3 Disease specific 5-year survival rate according to
primary site of neoplasm
Primary site No. of cases (%) Recur or meta DSS
Tongue 18 (21.4) 4 88.9
FOM 14 (16.7) 4 76.9
LAR 13 (15.5) 3 69.2
HP 9 (10.7) 1 87.5
ML 9 (10.7) 1 100
RT 7 (8.3) 3 71.4
SP 6 (7.1) 0 83.3
BM 5 (6.0) 1 100
UAR 3 (3.6) 1 100
Total 84 (100.0) 18 83.1
Tongue anterior 2/3 of the tongue, FOM floor of mouth, LAR lower alveolar
ridge, HP hard palate, ML mucosal lip, RT retromolar trigone, SP soft palate,
BM buccal mucosa, UAR upper alveolar ridge
Fig. 2 Disease specific 5-year survival rate by TNM stage (p= 0.003)
Kim et al. Maxillofacial Plastic and Reconstructive Surgery (2016) 38:3 Page 4 of 9

and most recurrence or metastasis occurred
within 2 years (95 %) after surgery.
5. Prognosis according to differentiation
Depending on the histopathological differentiation,
the disease specific 5-year survival rate was 81.7 %
(58 out of 73 patients survival) for the well differ-
entiated type, 100.0 % (10 out of 10 patients sur-
vival) for the moderately differentiated type, and
100.0 % (1 out of 1 patients survival) for the poorly
differentiated type, and pvalue was 0.189 by log
rank test results, which showed that the histo-
pathological differentiation was not a significant
factor in the survival rate (Fig 7).
Out of the 7 patients with local recurrence, 5
patients were T1-2 stage and 2 patients were T3-4
stage. Categorizing according to differentiation,
Fig. 3 Disease specific 5-year survival rate by positive neck node (p= 0.000)
Fig. 4 Disease specific 5-year survival rate by N stage (p= 0.000)
Kim et al. Maxillofacial Plastic and Reconstructive Surgery (2016) 38:3 Page 5 of 9

well differentiated type was 5 % (4 of 73 patients)
and moderately differentiated type was 30 % (3 out
of 10 patients).
Discussion
Radiotherapy or chemotherapy after the surgical proced-
ure is largely determined by the histopathological find-
ings of the lesion in the treatment decision of oral
cancer [11, 12]. According to Brown et al., who reported
that the overall 5-year survival rate of surgical treatment
and surgical treatment accompanied by postoperative
radiotherapy was 71 and 54 %, respectively, for 193 pa-
tients with oral squamous cell carcinoma of TNM stage
I-II, good result can be obtained only through surgical
treatment in the clean resection boundaries and the le-
sion of low stage (Stage I-II) with low recurrence prob-
ability [13]. In this study, the effect that sex, age, type of
oral cancer, primary site, stage, cervical metastasis, stage
Fig. 5 Disease specific 5-year survival rate by recurrence / metastasis (p= 0.011)
Fig. 6 Disease specific 5-year survival rate by timing of recurrence/metastasis (p= 0.002)
Kim et al. Maxillofacial Plastic and Reconstructive Surgery (2016) 38:3 Page 6 of 9

of lymph node, metastasis depending on neck level, re-
currence or metastasis, time of recurrence or metastasis,
etc. has on survival rate was evaluated.
There are reports that showed excellent prognosis only
through surgical treatment in oral cancer patients. Lim
et al. reported a disease-specific 5-year survival rate of
83 % with only performing surgical procedure in 76 oral
cancer patients [4]. Magge et al. reported that the prog-
nosis of surgical treatment accompanied by postopera-
tive radiotherapy compared to only surgical treatment
did not improve [9]. In this study, disease-specific 5-year
survival rate was 83.1 % only through surgical treatment
for the oral cancer patients. This is similar when
compared to the results reported in the other literature
so far [14, 15].
In this study, with the gender distribution of oral
cancer patients about 2.3:1 ratio (58 male, 26 female),
the proportion of men was higher. The result was
similar to gender distribution of the literature researched
in Korea [4, 16]. There was no significant difference in
the disease-specific 5-year survival rate by gender (male
82.5 %, female 84.6 %) as other reports (Liu et al.,
Rogeretal.)[6,17].
The effect that the age of oral cancer patients with
surgical treatment has on prognosis has been controver-
sial. Rogers et al. reported that as the age of the patient
increase, disease-specific 5-year survival rate decreases,
but Liu et al. reported that there was no significant dif-
ferences statistically [6, 17]. In this study, year survival
rate was slightly lower in the elderly after 50, but there
was no significant difference.
With the result that squamous cell carcinoma patients
only got surgical treatment, Lim et al. reported that 5-
year survival rate was 83 % out of 76 patients, and Liu
et al. reported that 5-year survival rate was 77 % out of
72 patients [4, 6]. In this study, the disease-specific 5-
year survival rate was 82.0 % in the squamous cell
carcinoma, melanoma, and sarcoma compared to the
other tumor that showed a slightly lower survival rate,
so the result was similar to the other literature [18–20],
which was not statistically significant. The disease-
specific 5-year survival rate based on type of tumor was
not a significant difference.
Shah et al. reported that oral cancer showed another
biological aspect according to primary site [21]. On the
other hand, carcinomas on mucosal lip showed a good
prognosis; carcinomas on anterior 2/3 of the tongue,
floor of the mouth, and the lower alveolar ridge have
high risk of metastasis to adjacent lymph nodes and
showed a relatively poor prognosis. Rogers et al. re-
ported that the disease-specific 5-year survival rate de-
pending on primary site was 64–44 %, which was not
statistically significant in the 489 oral cancer patients
Table 4 The number of cases and death of the patients who
had recurrence or meta
Recur or meta No. of cases (%) No. of death
Local recur only 7 (38.9) 1
Regional recur only 8 (44.4) 3
Locoregional recur 1 (55.6) 1
Distant meta 2 (11.1) 1
Total 18 (100.0) 6
Recur recurrence, meta metastasis, DSS disease specific 5-year survival rate
Fig. 7 Disease specific 5-year survival rate by histopathological differentiation (p= 0.189)
Kim et al. Maxillofacial Plastic and Reconstructive Surgery (2016) 38:3 Page 7 of 9

[17]. In this study, the disease-specific 5-year survival
rate depending on primary site varied from 100.0 to
69.2 %, and there was no significant difference by the log
rank test results.
Rajapakshe et al. and Geum et al. reported that TNM
stage is the factor that has significant influence on the
prognosis of oral cancer patients [8, 22]. In this study, as
the stage increases, the disease-specific 5-year survival
rate decreases (p= 0.003).
With the result only treated surgically for the 489 oral
cancer patients, Rogers et al. reported that the disease
specific 5-year survival rate (87 %) of the case without
cervical lymph node metastasis was significantly higher
than that of the case (54 %) with cervical lymph node
metastasis [17]. In this study, the disease specific 5-year
survival rate of the case (93.2 %) without cervical lymph
node metastasis was significantly higher than that of the
case (58.3 %) with cervical lymph node metastasis, which
accorded with previous researches [4, 6, 17].
In study of Rogers et al., the disease-specific 5-year
survival rate of N0, N1, and N2-3 stage was 87, 68, and
40 %, respectively [17]. In this study, the disease-specific
5-year survival rate according to cervical lymph node
stage was 93.2 % for the N0 (60 patients), 66.7 % for the
N1 (13 patients), 0 % for the N2a (a patient), 50.0 % for
the N2b (8 patients), 100.0 % for the N2c (2 patients),
and by the log rank test results, cervical lymph node
stage had significant effects on oral cancer prognosis
(p= 0.000).
Geum et al. reported that the disease-specific 5-year
survival rate was 90.5 % for the patients without re-
currence or metastasis and 30.0 % for the patients
with recurrence or metastasis out of 37 oral cancer
patients [22]. In this study, the disease-specific 5-year
survival rate depending on recurrence or metastasis
was 89.1 % for the case without recurrence or metas-
tasis, was 63.2 % for the case with recurrence or me-
tastasis, and by the log rank test results, recurrence
or metastasis had an significant impact on oral cancer
prognosis (p= 0.011).
Liu et al. reported that 72.2 % experienced a recurrence
or metastasis after surgery within 2 years and 100 % did
within 3 years out of patients with recurrence or metasta-
sis [6]. In this study, 95 % experienced a recurrence or me-
tastasis after surgery within 2 years and 100 % did within
3 years out of 18 cases with recurrence and metastasis,
which was similar to report by Liu et al. [6].
Schwartz et al. reported that survival rate and progno-
sis of patients who experienced recurrence or metastasis
after 6 months of primary operation were satisfactory
than those of within 6 months in the study for 350 oral
squamous cell carcinoma patients [23]. The disease-
specific 5-year survival rate of those who experienced re-
currence or metastasis within 1 year after surgery was
45.5 %, within 1~2 years was 85.7 %, and within
2~3 years was 100 %. As the recurrence or metastasis
occurred early, prognosis was significantly poor, in re-
sults of the log rank test (p= 0.002).
Geum et al. reported that the disease-specific 5-year
survival rate was 94.7 % for the well-differentiated type,
57.1 % for the moderately differentiated type, and 25.0 %
for the poorly differentiated type related to survival rate
of oral squamous cell carcinoma according to histo-
pathological differentiation [22]. But Liu et al. reported
that overall 5-year survival rate was 77.3 % for the well-
differentiated type and 76.7 % for the moderately differ-
entiated type, which was not statistically significant [6].
In this study, histologic differentiation did not have a
significant impact on survival rate by the log rank test
results.
Conclusions
These results suggest that good survival rate can be ob-
tained with surgical treatment only, and stage of oral
cancer, cervical lymph node metastasis and stage, recur-
rence or metastasis, time of recurrence, and metastasis
have a significant effect on survival rate in oral cancer
patients.
Consent
Theauthorsdeclarethattheyhavenocompetinginterests.
Abbreviations
ACC: adenoid cystic carcinoma; ATFAR: alive; tumor-free; after recurrence;
ATFNR: alive; tumor-free; no recurrence; AWPRM: alive with persistent/
recurrent/metastaticdisease;BCC:basalcellcarcinoma;DPO:dead;
postoperative; DSS: disease specific 5-year survival rate; DTF: dead;
tumor-free; DWC: dead; with cancer (primary/recurrent/metastatic);
GCC: ghost cell carcinoma; MC: mucoepidernoid carcinoma;
Meta:metastasis;MM:malignantmelanoma;Recur:recurrence;
Sar: sarcoma; SCC: squamous cell carcinoma; VC: verrucous carcinoma.
Competing interests
The authors declare that they have no competing interests.
Authors’contributions
BGK obtained the measurements and data and wrote the manuscript. JHK
helped in obtaining the data. MIK helped in drafting the manuscript. JJH
made substantial contributions to the analysis and interpretation of the data.
SGJ made substantial contributions to the analysis and interpretation of the
data. HJP was involved in revising the manuscript. MSK participated in its
design and coordination. SYR gave final approval of the manuscript to be
published. HKO participated in its design and coordination and carefully
reviewed and revised the manuscript. All authors read and approved the
final manuscript.
Received: 3 November 2015 Accepted: 1 December 2015
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