Author's Accepted Manuscript Mortality After Radical Cystectomy: The Impact of Obesity Versus Adiposity After Adjusting for Skeletal Muscle Wasting Sarah P. Psutka , Stephen A. Boorjian , Michael R. Moynagh , Grant D. Schmit , Igor Frank , Alonso Carrasco , Suzanne B. Stewart , Robert Tarrell , Prabin Thapa , Matthew K. Tollefson PII: DOI: Reference:
S0022-5347(14)04940-4 10.1016/j.juro.2014.11.088 JURO 12025
To appear in: The Journal of Urology Accepted Date: 18 November 2014 Please cite this article as: Psutka SP, Boorjian SA, Moynagh MR, Schmit GD, Frank I, Carrasco A, Stewart SB, Tarrell R, Thapa P, Tollefson MK, Mortality After Radical Cystectomy: The Impact of Obesity Versus Adiposity After Adjusting for Skeletal Muscle Wasting, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.11.088. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
ACCEPTED MANUSCRIPT 1
1
MORTALITY AFTER RADICAL CYSTECTOMY: THE IMPACT OF OBESITY VERSUS
2
ADIPOSITY AFTER ADJUSTING FOR SKELETAL MUSCLE WASTING
3 Sarah P. Psutka MD1, Stephen A. Boorjian MD1, Michael R. Moynagh MD2, Grant D. Schmit
5
MD2, Igor Frank MD1, Alonso Carrasco MD1, Suzanne B. Stewart MD1, Robert Tarrell3, Prabin
6
Thapa3, Matthew K. Tollefson MD1
RI PT
4
7 1
Department of Urology, Mayo Clinic, Rochester, Minnesota, 55905
9
2
Department of Radiology, Mayo Clinic, Rochester, Minnesota, 55905
10
3
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, 55905
22 23
M AN U
Corresponding Author:
Matthew K. Tollefson, MD Department of Urology Mayo Clinic 200 First Street SW, Rochester, MN, 55905 Telephone: 507-266-4319 Fax: 507-284-4951 Email: [email protected]
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All authors have read and approved the manuscript.
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The manuscript is not under consideration elsewhere.
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Runninghead: Obesity and Mortality After Radical Cystectomy
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Manuscript Category: Original Article
28
Total number of Pages: 18
29
Total number of Tables: 4 + 2 Supplemental Tables
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Total number of Figures: 3
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Word count (abstract): 247/250 allowed
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Word count (manuscript): 2497/2500 allowed
33
References: 30/30 allowed
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1
ACCEPTED MANUSCRIPT 2
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Funding: This publication was supported by Grant Number UL1 TR000135 from the National
36
Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility
37
of the authors and do not necessarily represent the official views of the NIH.
38 Financial Disclosures: None
40
Keywords: Sarcopenia, Obesity, Mortality, Radical Cystectomy, Body Mass Index
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2
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ABSTRACT
43
Purpose: To assess the impact of obesity as measured conventionally by body mass index
44
(BMI) compared to excess adiposity as measured by fat-mass index (FMI) on mortality,
45
following radical cystectomy for bladder cancer, adjusting for the presence of skeletal muscle
46
wasting.
47
Materials and Methods: A retrospective cohort study of 262 patients treated with RC for
48
bladder cancer between 2000 and 2008 at the Mayo Clinic. Lumbar skeletal muscle and
49
adipose compartment areas were measured on preoperative imaging. Overall survival was
50
compared according to sex-specific consensus FMI and skeletal muscle index thresholds and
51
conventional BMI-based criteria. Predictors of all-cause mortality (ACM) were assessed by
52
multivariable modeling.
53
Results: Increasing BMI correlated with improved OS (p=0.03) while FMI-based obesity did not
54
(p=0.08). After stratification by sarcopenia, no obesity-related 5-years OS “benefit” was
55
observed (68% vs. 51.4%; p=0.2: obese vs. normal; and 40% vs. 37.4%; p=0.7: sarcopenia vs.
56
sarcopenic/obese). On multivariable analysis, class I obesity according to either BMI- (HR 0.79,
57
p=0.33) or FMI criteria (HR 0.85, p=0.45) was not independently associated with ACM after
58
adjusting for sarcopenia (HR 1.7, p=0.01) as well as age, performance status, pTN stage, and
59
smoking status. However, among patients with normal lean muscle mass, each 1 kg/m2
60
increase in weight or adipose mass was associated with a 7-14% decrease in ACM.
61
Conclusions: After adjusting for lean muscle wasting, neither measurements of obesity nor
62
adiposity were significantly associated with ACM among RC patients, although subanalyses
63
suggest a potential benefit among those with normal lean muscle mass.
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42
64
3
ACCEPTED MANUSCRIPT 4
65 66
INTRODUCTION Worldwide, approximately 1.1 billion adults are estimated to be overweight and an additional 475 million are obese. Despite the substantial adverse health outcomes associated
68
with obesity1, there is a growing body of literature suggesting that overweight and obese
69
surgical patients have decreased all-cause mortality (ACM) compared to leaner patients2. This
70
counterintuitive finding has been coined “the obesity paradox”3, 4 but has yet to be described
71
among radical cystectomy patients, in whom the impact of obesity remains unclear.5-8
SC
72
RI PT
67
In the United States, nearly 75,000 patients will be diagnosed with urothelial carcinoma of the bladder in 20149 of whom approximately 75% are overweight or obese6 for whom the
74
standard of care is neoadjuvant chemotherapy followed by radical cystectomy with bilateral
75
pelvic lymph node dissection and urinary diversion. Unfortunately, even in contemporary series,
76
the combined surgical and disease morbidity result in 5-year overall survival rates of only 42-
77
58% 10, 11.
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M AN U
73
In a recent study of a contemporary radical cystectomy cohort, we observed a significant
79
risk of increased mortality among patients with sarcopenia, or severe skeletal muscle wasting12.
80
Simultaneously, we observed an inverse trend, consistent with the “obesity paradox”, toward
81
decreased mortality with increasing BMI on unadjusted analysis. However, after adjusting for
82
tumor-specific factors, comorbidity, and skeletal muscle wasting, BMI was no longer
83
independently associated with all-cause mortality.
AC C
84
EP
78
We hypothesize that our previous findings were related to the nonspecificity of BMI as a
85
measure of body composition, such that patients with low BMI were likely those who also had
86
skeletal muscle wasting, which strongly predicts poor outcomes in cancer patients.12 Hence,
87
our objective was to explore the association between obesity as classified by BMI versus fat-
4
ACCEPTED MANUSCRIPT 5
88
mass index (FMI), a measure of adiposity, and overall survival following RC, adjusting for the
89
presence of lean muscle wasting.
AC C
EP
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M AN U
SC
RI PT
90
5
ACCEPTED MANUSCRIPT 6
91
METHODS
92
Patient Selection Following Institutional Review Board approval, we retrospectively identified 515
94
consecutive patients treated with RC and urinary diversion between 2000 and 2008. Patients
95
were excluded if preoperative digital imaging was not available within 30 days of surgery
96
(n=244) or if image analysis was precluded by poor image quality (n=9), leaving 262 patients
97
available for analysis13, 14.
98
Body Composition Analysis
SC M AN U
99
RI PT
93
A representative axial image at the level of L3 was identified by one of two radiologists (GDS, MRM). Then cross-sectional skeletal muscle and adipose areas were measured
101
according to attenuation-thresholds using Slice-O-Matic software (v.5.0, Tomovision, Quebec,
102
Canada) by one investigator (SPP) who was blinded to patient outcome. Skeletal muscle area
103
was identified using an attenuation threshold of -29 to +150 Hounsfield units (HU) 12, 15. Skeletal
104
muscle index (SMI) was calculated by normalizing the total skeletal muscle area by height
105
squared (cm2/m2)16. Patients were classified as sarcopenic according to sex-specific
106
international consensus reference values, which represent muscularity below the fifth percentile
107
for healthy young adults (male: SMI 9
6
ACCEPTED MANUSCRIPT 7 kg/m2, female: FMI>13 kg/m2)17. Table 1 compares the FMI- and BMI-based criteria for obesity.
115
Agreement of obesity classification was assessed using the kappa statistic for obesity as
116
categorized by BMI vs. FMI.
117
RI PT
114
Patients were then classified according to their combined SMI and FMI classifications: low SMI and high FMI (sarcopenic-obese), normal SMI and high FMI (obese), normal SMI and
119
FMI (normal), and low SMI and normal FMI (sarcopenic). For illustrative purposes, Figure 1
120
demonstrates representative axial CTs for patients from each group.
SC
118
122
123
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121
Statistical analysis
We compared clinicopathological variables across the four groups. Continuous features were summarized with means (standard deviation) or medians (interquartile ranges [IQRs]) as
125
appropriate and compared using the t-test or Wilcoxon Rank Sum test. Categorical features
126
were summarized with frequency counts (percentages) and compared using the Chi-Square
127
and Cochran-Armitage trend tests.
The primary outcome of interest was overall survival (OS), defined as the total length of
EP
128
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124
time between the dates of RC and patient death, for which time and cause were verified via
130
death certificate. OS was compared between BMI and FMI strata, as well as between the four
131
patient groups defined by FMI/SMI using the Log-Rank Test.
132
AC C
129
Associations with death from any cause were evaluated using univariable and
133
multivariable Cox proportional hazards regression models. Two multivariable models were
134
created, incorporating obesity as classified by BMI or FMI. A subanalysis was performed
135
assessing the impact of obesity among nonsarcopenic patients. C-statistics were calculated for
136
each model. 7
ACCEPTED MANUSCRIPT 8
137 138
Statistical analyses were performed using the SAS ® software package (SAS Institute, Cary, NC). All tests were two-sided and p-values 9
> 13
30.0 – 34.9
Obese class I
> 9 – 12
> 13 – 17
35 – 39.9
Obese class II
> 12 – 15
> 17 – 21
≥ 40.0
Obese class III
> 15
> 21
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EP
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Normal Overweight (pre-obese) Obese Obese class I (mild obesity) Obese class II (moderate obesity) Obese class III (morbid obesity)
< 18.5
Category
SC
Underweight
2
BMI (kg/m )
M AN U
Category
1
ACCEPTED MANUSCRIPT
Table 2. Comparison of clinicopathological features between patients who were sarcopenic alone, sarcopenic/overweight, overweight alone, and neither overweight nor sarcopenic Sarcopenic N = 103 (39.3%)
Obese N = 58 (22.1%)
Sarcopenic Obese N = 74 (28.2%)
61 (54, 76)
72 (66, 79)
68 (60, 74)
14 (51.9%) 13 (48.1%)
17 (16.5%) 86 (83.5%)
4 (6.9%) 54 (93.1%)
9 (8.1%) 94 (91.9%)
10 (16.7%) 48 (83.3%)
25 (24.3%) 27 (26.2%) 36 (35.0%) 15 (14.6%)
All patients N = 262
p-value
72 (67, 78)
71 (63, 78)
0.01
2 (2.7%) 72 (97.3%)
37 (14.1%) 225 (85.9%)
S0022-5347(14)04940-4 10.1016/j.juro.2014.11.088 JURO 12025
To appear in: The Journal of Urology Accepted Date: 18 November 2014 Please cite this article as: Psutka SP, Boorjian SA, Moynagh MR, Schmit GD, Frank I, Carrasco A, Stewart SB, Tarrell R, Thapa P, Tollefson MK, Mortality After Radical Cystectomy: The Impact of Obesity Versus Adiposity After Adjusting for Skeletal Muscle Wasting, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.11.088. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain.
Embargo Policy All article content is under embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date. Questions regarding embargo should be directed to [email protected].
ACCEPTED MANUSCRIPT 1
1
MORTALITY AFTER RADICAL CYSTECTOMY: THE IMPACT OF OBESITY VERSUS
2
ADIPOSITY AFTER ADJUSTING FOR SKELETAL MUSCLE WASTING
3 Sarah P. Psutka MD1, Stephen A. Boorjian MD1, Michael R. Moynagh MD2, Grant D. Schmit
5
MD2, Igor Frank MD1, Alonso Carrasco MD1, Suzanne B. Stewart MD1, Robert Tarrell3, Prabin
6
Thapa3, Matthew K. Tollefson MD1
RI PT
4
7 1
Department of Urology, Mayo Clinic, Rochester, Minnesota, 55905
9
2
Department of Radiology, Mayo Clinic, Rochester, Minnesota, 55905
10
3
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, 55905
22 23
M AN U
Corresponding Author:
Matthew K. Tollefson, MD Department of Urology Mayo Clinic 200 First Street SW, Rochester, MN, 55905 Telephone: 507-266-4319 Fax: 507-284-4951 Email: [email protected]
TE D
11 12 13 14 15 16 17 18 19 20 21
SC
8
All authors have read and approved the manuscript.
25
The manuscript is not under consideration elsewhere.
26
Runninghead: Obesity and Mortality After Radical Cystectomy
27
Manuscript Category: Original Article
28
Total number of Pages: 18
29
Total number of Tables: 4 + 2 Supplemental Tables
30
Total number of Figures: 3
31
Word count (abstract): 247/250 allowed
32
Word count (manuscript): 2497/2500 allowed
33
References: 30/30 allowed
AC C
EP
24
34
1
ACCEPTED MANUSCRIPT 2
35
Funding: This publication was supported by Grant Number UL1 TR000135 from the National
36
Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility
37
of the authors and do not necessarily represent the official views of the NIH.
38 Financial Disclosures: None
40
Keywords: Sarcopenia, Obesity, Mortality, Radical Cystectomy, Body Mass Index
RI PT
39
AC C
EP
TE D
M AN U
SC
41
2
ACCEPTED MANUSCRIPT 3
ABSTRACT
43
Purpose: To assess the impact of obesity as measured conventionally by body mass index
44
(BMI) compared to excess adiposity as measured by fat-mass index (FMI) on mortality,
45
following radical cystectomy for bladder cancer, adjusting for the presence of skeletal muscle
46
wasting.
47
Materials and Methods: A retrospective cohort study of 262 patients treated with RC for
48
bladder cancer between 2000 and 2008 at the Mayo Clinic. Lumbar skeletal muscle and
49
adipose compartment areas were measured on preoperative imaging. Overall survival was
50
compared according to sex-specific consensus FMI and skeletal muscle index thresholds and
51
conventional BMI-based criteria. Predictors of all-cause mortality (ACM) were assessed by
52
multivariable modeling.
53
Results: Increasing BMI correlated with improved OS (p=0.03) while FMI-based obesity did not
54
(p=0.08). After stratification by sarcopenia, no obesity-related 5-years OS “benefit” was
55
observed (68% vs. 51.4%; p=0.2: obese vs. normal; and 40% vs. 37.4%; p=0.7: sarcopenia vs.
56
sarcopenic/obese). On multivariable analysis, class I obesity according to either BMI- (HR 0.79,
57
p=0.33) or FMI criteria (HR 0.85, p=0.45) was not independently associated with ACM after
58
adjusting for sarcopenia (HR 1.7, p=0.01) as well as age, performance status, pTN stage, and
59
smoking status. However, among patients with normal lean muscle mass, each 1 kg/m2
60
increase in weight or adipose mass was associated with a 7-14% decrease in ACM.
61
Conclusions: After adjusting for lean muscle wasting, neither measurements of obesity nor
62
adiposity were significantly associated with ACM among RC patients, although subanalyses
63
suggest a potential benefit among those with normal lean muscle mass.
AC C
EP
TE D
M AN U
SC
RI PT
42
64
3
ACCEPTED MANUSCRIPT 4
65 66
INTRODUCTION Worldwide, approximately 1.1 billion adults are estimated to be overweight and an additional 475 million are obese. Despite the substantial adverse health outcomes associated
68
with obesity1, there is a growing body of literature suggesting that overweight and obese
69
surgical patients have decreased all-cause mortality (ACM) compared to leaner patients2. This
70
counterintuitive finding has been coined “the obesity paradox”3, 4 but has yet to be described
71
among radical cystectomy patients, in whom the impact of obesity remains unclear.5-8
SC
72
RI PT
67
In the United States, nearly 75,000 patients will be diagnosed with urothelial carcinoma of the bladder in 20149 of whom approximately 75% are overweight or obese6 for whom the
74
standard of care is neoadjuvant chemotherapy followed by radical cystectomy with bilateral
75
pelvic lymph node dissection and urinary diversion. Unfortunately, even in contemporary series,
76
the combined surgical and disease morbidity result in 5-year overall survival rates of only 42-
77
58% 10, 11.
TE D
M AN U
73
In a recent study of a contemporary radical cystectomy cohort, we observed a significant
79
risk of increased mortality among patients with sarcopenia, or severe skeletal muscle wasting12.
80
Simultaneously, we observed an inverse trend, consistent with the “obesity paradox”, toward
81
decreased mortality with increasing BMI on unadjusted analysis. However, after adjusting for
82
tumor-specific factors, comorbidity, and skeletal muscle wasting, BMI was no longer
83
independently associated with all-cause mortality.
AC C
84
EP
78
We hypothesize that our previous findings were related to the nonspecificity of BMI as a
85
measure of body composition, such that patients with low BMI were likely those who also had
86
skeletal muscle wasting, which strongly predicts poor outcomes in cancer patients.12 Hence,
87
our objective was to explore the association between obesity as classified by BMI versus fat-
4
ACCEPTED MANUSCRIPT 5
88
mass index (FMI), a measure of adiposity, and overall survival following RC, adjusting for the
89
presence of lean muscle wasting.
AC C
EP
TE D
M AN U
SC
RI PT
90
5
ACCEPTED MANUSCRIPT 6
91
METHODS
92
Patient Selection Following Institutional Review Board approval, we retrospectively identified 515
94
consecutive patients treated with RC and urinary diversion between 2000 and 2008. Patients
95
were excluded if preoperative digital imaging was not available within 30 days of surgery
96
(n=244) or if image analysis was precluded by poor image quality (n=9), leaving 262 patients
97
available for analysis13, 14.
98
Body Composition Analysis
SC M AN U
99
RI PT
93
A representative axial image at the level of L3 was identified by one of two radiologists (GDS, MRM). Then cross-sectional skeletal muscle and adipose areas were measured
101
according to attenuation-thresholds using Slice-O-Matic software (v.5.0, Tomovision, Quebec,
102
Canada) by one investigator (SPP) who was blinded to patient outcome. Skeletal muscle area
103
was identified using an attenuation threshold of -29 to +150 Hounsfield units (HU) 12, 15. Skeletal
104
muscle index (SMI) was calculated by normalizing the total skeletal muscle area by height
105
squared (cm2/m2)16. Patients were classified as sarcopenic according to sex-specific
106
international consensus reference values, which represent muscularity below the fifth percentile
107
for healthy young adults (male: SMI 9
6
ACCEPTED MANUSCRIPT 7 kg/m2, female: FMI>13 kg/m2)17. Table 1 compares the FMI- and BMI-based criteria for obesity.
115
Agreement of obesity classification was assessed using the kappa statistic for obesity as
116
categorized by BMI vs. FMI.
117
RI PT
114
Patients were then classified according to their combined SMI and FMI classifications: low SMI and high FMI (sarcopenic-obese), normal SMI and high FMI (obese), normal SMI and
119
FMI (normal), and low SMI and normal FMI (sarcopenic). For illustrative purposes, Figure 1
120
demonstrates representative axial CTs for patients from each group.
SC
118
122
123
M AN U
121
Statistical analysis
We compared clinicopathological variables across the four groups. Continuous features were summarized with means (standard deviation) or medians (interquartile ranges [IQRs]) as
125
appropriate and compared using the t-test or Wilcoxon Rank Sum test. Categorical features
126
were summarized with frequency counts (percentages) and compared using the Chi-Square
127
and Cochran-Armitage trend tests.
The primary outcome of interest was overall survival (OS), defined as the total length of
EP
128
TE D
124
time between the dates of RC and patient death, for which time and cause were verified via
130
death certificate. OS was compared between BMI and FMI strata, as well as between the four
131
patient groups defined by FMI/SMI using the Log-Rank Test.
132
AC C
129
Associations with death from any cause were evaluated using univariable and
133
multivariable Cox proportional hazards regression models. Two multivariable models were
134
created, incorporating obesity as classified by BMI or FMI. A subanalysis was performed
135
assessing the impact of obesity among nonsarcopenic patients. C-statistics were calculated for
136
each model. 7
ACCEPTED MANUSCRIPT 8
137 138
Statistical analyses were performed using the SAS ® software package (SAS Institute, Cary, NC). All tests were two-sided and p-values 9
> 13
30.0 – 34.9
Obese class I
> 9 – 12
> 13 – 17
35 – 39.9
Obese class II
> 12 – 15
> 17 – 21
≥ 40.0
Obese class III
> 15
> 21
AC C
EP
TE D
Normal Overweight (pre-obese) Obese Obese class I (mild obesity) Obese class II (moderate obesity) Obese class III (morbid obesity)
< 18.5
Category
SC
Underweight
2
BMI (kg/m )
M AN U
Category
1
ACCEPTED MANUSCRIPT
Table 2. Comparison of clinicopathological features between patients who were sarcopenic alone, sarcopenic/overweight, overweight alone, and neither overweight nor sarcopenic Sarcopenic N = 103 (39.3%)
Obese N = 58 (22.1%)
Sarcopenic Obese N = 74 (28.2%)
61 (54, 76)
72 (66, 79)
68 (60, 74)
14 (51.9%) 13 (48.1%)
17 (16.5%) 86 (83.5%)
4 (6.9%) 54 (93.1%)
9 (8.1%) 94 (91.9%)
10 (16.7%) 48 (83.3%)
25 (24.3%) 27 (26.2%) 36 (35.0%) 15 (14.6%)
All patients N = 262
p-value
72 (67, 78)
71 (63, 78)
0.01
2 (2.7%) 72 (97.3%)
37 (14.1%) 225 (85.9%)
