Accepted Manuscript “Editor Invited Expert Opinion” Evidence for thymectomy in myasthenia gravis: getting stronger? Marc de Perrot, MD, Karen McRae, MD PII:
S0022-5223(16)00015-5
DOI:
10.1016/j.jtcvs.2016.01.006
Reference:
YMTC 10260
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 3 January 2016 Accepted Date: 5 January 2016
Please cite this article as: de Perrot M, McRae K, “Editor Invited Expert Opinion” Evidence for thymectomy in myasthenia gravis: getting stronger?, The Journal of Thoracic and Cardiovascular Surgery (2016), doi: 10.1016/j.jtcvs.2016.01.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof 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.
ACCEPTED MANUSCRIPT
“Editor Invited Expert Opinion”
1 2
Evidence for thymectomy in myasthenia gravis: getting stronger?
4
Marc de Perrot¹, MD, Karen McRae², MD,
5
¹Division of Thoracic Surgery and ²Department of Anesthesia and Pain Management
6
Toronto General Hospital, University Health Network, University of Toronto, Canada
RI PT
3
No potential conflict of interest for Marc de Perrot and Karen McRae
9 10
Address for correspondence
12
Marc de Perrot, MD, MSc
13
Division of Thoracic Surgery
14
Toronto General Hospital, 9N-961
15
200 Elizabeth Street
16
Toronto, Ontario M5G 2C4
17
Tel: 416 340-5549
18
Fax: 416 340-3478
20
EP
AC C
19
TE D
11
M AN U
8
SC
7
1
ACCEPTED MANUSCRIPT
21
Central message
22
Patient subtypes and specific description of the operation performed could prove
23
important in future trials of thymectomy for myasthenia gravis
AC C
EP
TE D
M AN U
SC
RI PT
24
2
ACCEPTED MANUSCRIPT
25
Myasthenia gravis (MG) is characterized by autoantibodies against components of the neuromuscular junction. The clinical presentation and pathogenic mechanisms are
27
heterogenous with a first peak in incidence in the second and third decades of life
28
affecting mostly women and a second peak in the sixth and seventh decades affecting
29
both genders. Thymic hyperplasia is most frequently encountered in young patients and
30
thymoma in elderly patients.
RI PT
26
The first step in understanding the mechanisms of MG occurred in the early 1930s
32
when the similarity between curare poisoning and MG was recognized and cholinesterase
33
inhibitors were introduced as treatment. Only in 1973 was MG recognized as an auto-
34
immune disorder leading to the introduction of corticosteroids and other
35
immunosuppressive drugs. These developments have been associated with remarkable
36
progress demonstrated by a dramatic reduction in the mortality rate of MG patients and
37
improvement in their quality of life (1).
M AN U
TE D
38
SC
31
The mechanisms of MG have been refined in the past 15 years with the characterization of several new auto-immune antibodies affecting the neuromuscular
40
junction: muscle specific kinase (MuSK) antibodies, low-density lipoprotein receptor-
41
related protein 4 (LRP4) antibodies, Agrin antibodies, Titin and Ryanodine receptor
42
antibodies. These observations have led to the development of subgroup classification of
43
MG based on the types of auto-antibodies with implications for diagnosis, therapy and
44
prognosis (2). MG may be classified as: 1) the most prevalent MG subtype with
45
autoantibodies against the muscle-type acetylcholine receptor (“AChR MG”), 2) MG due
46
to antibodies against MuSK (“MuSK MG”), 3) MG due to antibodies against the agrin-
47
receptor LRP4 (“LRP4 MG”), and 4) MG without known target autoantigen (“triple sero-
AC C
EP
39
3
ACCEPTED MANUSCRIPT
negative MG”). The AChR MG group is further divided into 3 subgroups according to
49
the age of the patients at onset of symptoms and the presence of thymoma: a) Early onset
50
(patients less than 50 years old at presentation), b) late onset (patients older than 50 years
51
at presentation) and c) Thymoma (regardless of age).
RI PT
48
The concept of thymectomy for patients with MG was introduced by Alfred
53
Blalock in 1936 (3). Following his initial reports, thymectomy progressively gained
54
widespread acceptance in the treatment of MG in order to achieve more rapid
55
stabilization of the disease, reduction in the need of corticosteroids and in some patients
56
complete remission. The benefit from thymectomy, however, has so far not been
57
confirmed in a randomized trial. A multi-center, single-blind, randomized study
58
comparing thymectomy to no thymectomy in non-thymomatous MG patients with a pre-
59
defined prednisone protocol was recently completed and the results should be available in
60
the near future. This trial enrolled 200 patients and involved 70 centers in 22 countries
61
highlighting the notorious difficulty to randomize potential surgical candidates to a non-
62
surgical arm (4).
TE D
M AN U
SC
52
Currently, thymectomy is commonly considered for patients with early onset
64
AChR MG. Benefit in this group of patients was recently confirmed by a propensity
65
score analysis demonstrating that thymectomy was associated with a higher probability of
66
remission compared to patients who did not undergo surgery after controlling for age,
67
gender, time to diagnosis, severity of symptoms at diagnosis and the use of
68
immunosuppressive therapy (5). Besides the subgroup of patients with thymoma
69
requiring a thymectomy for oncological reasons, the role of thymectomy in other
70
subgroups of patients remains more controversial. Recent development in antibody
AC C
EP
63
4
ACCEPTED MANUSCRIPT
71
testing may help to refine the indications for surgery in some of these patients as
72
increasing evidence suggests that thymectomy is not beneficial in patients with MUSK
73
MG (2). The approach and extent of thymectomy remain a topic of intense discussion,
RI PT
74
particularly with the development of minimally invasive surgery. Although the presence
76
of extra-capsular thymic tissue is frequent and well described, the accessibility of these
77
ectopic thymic foci as well as their function and impact on outcome have been unclear,
78
leading to divergent views between proponents of a maximal cervico-mediastinal
79
thymectomy with en bloc resection of all fatty tissue between the thyroid grand and the
80
diaphragm and those of a minimally invasive approach.
M AN U
SC
75
A number of recent studies and observations do potentially mitigate the potential
82
benefit of a maximal approach: 1) Ectopic thymic foci are usually isolated to one or two
83
sites and are most frequently found in the anterior mediastinal fat. Other sites are often
84
found along the phrenic and recurrent nerves or in area not accessible to surgery (6,7), 2)
85
Maximal thymectomy with resection of all potential sites of ectopic thymic foci in the
86
neck and mediastinum is associated with a small but real risk of phrenic and recurrent
87
nerve injury (8), 3) The presence of ectopic thymic foci is potentially one of the
88
strongest predictor of poor outcome even after maximal thymectomy (9,10), and 4)
89
Ectopic thymic foci are found more frequently in patients with atrophic thymus than in
90
patients with hypertrophic thymus, thus possibly increasing the risk-benefit ratio of a
91
maximal approach in the latter group of patients (11).
92 93
AC C
EP
TE D
81
These findings suggest that resection of all active ectopic thymic tissue can be difficult and that the benefit may be limited. Considering that ectopic thymic foci are
5
ACCEPTED MANUSCRIPT
most frequently located in the anterior mediastinum and that this area is readily
95
accessible to surgery, an extended thymectomy involving the fat located between the
96
pericardium, both pleura and the diaphragm appears to be a very good option. Masaoka
97
and colleagues reported a complete remission rate of 46% at 5 years with this approach in
98
non-thymomatous MG patients (12). These results are better than in patients undergoing
99
a less extensive thymectomy and are very similar to the results achieved with a maximal
RI PT
94
thymectomy with resection of tissue in the pericardiophrenic angles, aorto-pulmonary
101
window, aorto-caval groove and along the thyroid gland (13-15). Hence, extending the
102
resection to areas other than the anterior mediastinal fat should continue to be
103
investigated as it may potentially provide benefit in some subgroups of patients, however
104
currently there is limited evidence to suggest that it should be done routinely.
M AN U
105
SC
100
An extended thymectomy involving the anterior mediastinal fat can be performed by an open approach through a sternotomy or by a minimally invasive approach through
107
a cervicotomy, transcervical-subxyphoid approach or unilateral or bilateral video-assisted
108
thoracoscopic surgery (VATS). More recently, robotic thymectomy has also been used
109
with success. The results from all minimally invasive approaches have been relatively
110
similar as long as an extended complete thymectomy with at least resection of the
111
anterior mediastinal fat was performed and it is ultimately the surgeon’s preference and
112
comfort that should dictate the type of approach.
EP
AC C
113
TE D
106
In the future, better definition of the type of thymectomy will be important,
114
particularly if prospective studies and randomized trials are performed to compare
115
different surgical approaches. One possibility would be to reserve the term “extended
116
thymectomy” to resection of the thymus with the anterior mediastinal fat between both
6
ACCEPTED MANUSCRIPT
pleura, the pericardium and diaphragm. More extensive surgery could be specified to
118
encompass sites such as the right and left pericardiophrenic angles, the aortopulmonary
119
window, the aorto-caval groove and retro-innominate space, and the peri-thyroid area
120
(Figure 1).
121
RI PT
117
In conclusion, the past 15 years have been associated with major changes in our
understanding of MG. These developments will undoubtedly lead towards better care for
123
these patients and help refine the indications for thymectomy targeting the most
124
appropriate group of patients. A randomized trial of patients requiring steroids therapy
125
for MG should soon provide additional information on the role of thymectomy in this
126
patient population and will hopefully lead to further surgical trials to determine the best
127
approach.
M AN U
SC
122
AC C
EP
TE D
128
7
ACCEPTED MANUSCRIPT
References
130
1. Sieb JP. Myasthenia gravis: an update for the clinician. Clin Exp Immunol
131
2013;175:408-18.
132
2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic
133
strategies. Lancet Neurol 2015;14:1023-36.
134
3. Blalock A. Thymectomy in the treatment of myasthenia gravis: report of 20 cases. J
135
Thorac Surg 1944;13:316-39.
136
4. Newsom-Davis J, Cutter G, Wolfe GI, Kaminski HJ, Jaretzki A, Minisman G, Aban I,
137
Conwit R. Status of the thymectomy trial for nonthymomatous myasthenia gravis patients
138
receiving prednisone. Ann NY Acad Sci 2008;1132:344-7.
139
5. Barnett C, Katzberg HD, Keshavjee S, BrilV. Thymectomy for non-thymomatous
140
myasthenia gravis: a propensity score matched study. Orphanet J Rare Dis 2014;9:214.
141
6. Klimek-Piotrowska W, Mizia E, Kuzdzal J, Lazar A, Lis M, Pankowski J. Ectopic
142
thymic tissue in the mediastinum: limitations for the operative treatment of myasthenia
143
gravis. Eur J Cardiothorac Surg 2012;42:61-5.
144
7. Fukai I, Funato Y, Mizuno T, Hashimoto T, Masaoka A. Distribution of thymic tissue
145
in the mediastinal adipose tissue. J Thorac Cardiovasc Surg 1991;101:1099-102.
146
8. Bulkley GB, Bass KN, Stepheson GR, Diener-West M, George S, Reilly PA, Baker
147
RR, Drachman DB. Extended cervicomediastinal thymectomy in the integrated
148
management of myasthenia gravis. Ann Surg 1997;226:324-35.
149
9. Ambrogi V,Mineo TC. Active ectopic thymus predicts poor outcome after thymectomy
150
in class III myasthenia gravis. J Thorac Cardiovasc Surg 2012;143:601-6.
AC C
EP
TE D
M AN U
SC
RI PT
129
8
ACCEPTED MANUSCRIPT
10.Ozdemir N, Kara M, Dikmen E, Nadir A, Akal M, Yucemen N, Yavuzer S. Predictors
152
of clinical outcome following extended thymectomy in myasthenia gravis. Eur J
153
Cardiothorac Surg 2003;23:233-7.
154
11. Chen Z, Luo H, Peng Y, Cai L, Zhang J, Su C, Zou J. Comparative clinical features
155
and immune responses after extended thymectomy for myasthenia gravis in patients with
156
atrophic versus hyperplastic thymus. Ann Thorac Surg 2011;91:212-8.
157
12. Masaoka A,Yamakawa Y, Niwa H,Fukai I, Kondo S, Kobayashi M, Fujii Y, Monden
158
Y. Extended thymectomy for myasthenia gravis patients: a 20-year review. Ann Thorac
159
Surg 1996;62:853-9.
160
13. Masaoka A, Monden Y. Comparison of the results of transsternal simple,transcervical
161
simple, and extended thymectomy. Ann NY Acad Sci 1981;377:755-65.
162
14. Jaretzki A, Penn AS, Younger DS, Wolff M, Olarte MR, Lovelace RE, Rowland LP.
163
"Maximal" thymectomy for myasthenia gravis. J Thorac Cardiovasc Surg 1988;95:747-
164
57.
165
15. Zielinski M, Hauer L, Hauer J, Pankowski J, Nabialek T, Szlubowski A. Comparison
166
of complete remission rates after 5 year follow-up of three different techniques of
167
thymectomy for myasthenia gravis. Eur J Cardiothorac Surg 2010;37:1137-43.
169 170
SC
M AN U
TE D
EP
AC C
168
RI PT
151
9
ACCEPTED MANUSCRIPT
Figure 1.
172
Extended thymectomy should encompass resection of the thymus with the anterior
173
mediastinal fat between both pleura, the pericardium and diaphragm. More extensive
174
surgery could include sites such as the right and left pericardiophrenic angles (A, B), the
175
aortopulmonary window (C), the aorto-caval groove and retro-innominate space (D), and
176
the peri-thyroid area (E).
RI PT
171
SC
177 178
AC C
EP
TE D
M AN U
179
10
ACCEPTED MANUSCRIPT
180
Central figure
181
Thymectomy for myasthenia gravis can include specific additional sites in the
182
mediastinum
AC C
EP
TE D
M AN U
SC
RI PT
183
11
ACCEPTED MANUSCRIPT
D
AC C
B
EP
TE D
M AN U
C
SC
RI PT
E
A
S0022-5223(16)00015-5
DOI:
10.1016/j.jtcvs.2016.01.006
Reference:
YMTC 10260
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 3 January 2016 Accepted Date: 5 January 2016
Please cite this article as: de Perrot M, McRae K, “Editor Invited Expert Opinion” Evidence for thymectomy in myasthenia gravis: getting stronger?, The Journal of Thoracic and Cardiovascular Surgery (2016), doi: 10.1016/j.jtcvs.2016.01.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof 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.
ACCEPTED MANUSCRIPT
“Editor Invited Expert Opinion”
1 2
Evidence for thymectomy in myasthenia gravis: getting stronger?
4
Marc de Perrot¹, MD, Karen McRae², MD,
5
¹Division of Thoracic Surgery and ²Department of Anesthesia and Pain Management
6
Toronto General Hospital, University Health Network, University of Toronto, Canada
RI PT
3
No potential conflict of interest for Marc de Perrot and Karen McRae
9 10
Address for correspondence
12
Marc de Perrot, MD, MSc
13
Division of Thoracic Surgery
14
Toronto General Hospital, 9N-961
15
200 Elizabeth Street
16
Toronto, Ontario M5G 2C4
17
Tel: 416 340-5549
18
Fax: 416 340-3478
20
EP
AC C
19
TE D
11
M AN U
8
SC
7
1
ACCEPTED MANUSCRIPT
21
Central message
22
Patient subtypes and specific description of the operation performed could prove
23
important in future trials of thymectomy for myasthenia gravis
AC C
EP
TE D
M AN U
SC
RI PT
24
2
ACCEPTED MANUSCRIPT
25
Myasthenia gravis (MG) is characterized by autoantibodies against components of the neuromuscular junction. The clinical presentation and pathogenic mechanisms are
27
heterogenous with a first peak in incidence in the second and third decades of life
28
affecting mostly women and a second peak in the sixth and seventh decades affecting
29
both genders. Thymic hyperplasia is most frequently encountered in young patients and
30
thymoma in elderly patients.
RI PT
26
The first step in understanding the mechanisms of MG occurred in the early 1930s
32
when the similarity between curare poisoning and MG was recognized and cholinesterase
33
inhibitors were introduced as treatment. Only in 1973 was MG recognized as an auto-
34
immune disorder leading to the introduction of corticosteroids and other
35
immunosuppressive drugs. These developments have been associated with remarkable
36
progress demonstrated by a dramatic reduction in the mortality rate of MG patients and
37
improvement in their quality of life (1).
M AN U
TE D
38
SC
31
The mechanisms of MG have been refined in the past 15 years with the characterization of several new auto-immune antibodies affecting the neuromuscular
40
junction: muscle specific kinase (MuSK) antibodies, low-density lipoprotein receptor-
41
related protein 4 (LRP4) antibodies, Agrin antibodies, Titin and Ryanodine receptor
42
antibodies. These observations have led to the development of subgroup classification of
43
MG based on the types of auto-antibodies with implications for diagnosis, therapy and
44
prognosis (2). MG may be classified as: 1) the most prevalent MG subtype with
45
autoantibodies against the muscle-type acetylcholine receptor (“AChR MG”), 2) MG due
46
to antibodies against MuSK (“MuSK MG”), 3) MG due to antibodies against the agrin-
47
receptor LRP4 (“LRP4 MG”), and 4) MG without known target autoantigen (“triple sero-
AC C
EP
39
3
ACCEPTED MANUSCRIPT
negative MG”). The AChR MG group is further divided into 3 subgroups according to
49
the age of the patients at onset of symptoms and the presence of thymoma: a) Early onset
50
(patients less than 50 years old at presentation), b) late onset (patients older than 50 years
51
at presentation) and c) Thymoma (regardless of age).
RI PT
48
The concept of thymectomy for patients with MG was introduced by Alfred
53
Blalock in 1936 (3). Following his initial reports, thymectomy progressively gained
54
widespread acceptance in the treatment of MG in order to achieve more rapid
55
stabilization of the disease, reduction in the need of corticosteroids and in some patients
56
complete remission. The benefit from thymectomy, however, has so far not been
57
confirmed in a randomized trial. A multi-center, single-blind, randomized study
58
comparing thymectomy to no thymectomy in non-thymomatous MG patients with a pre-
59
defined prednisone protocol was recently completed and the results should be available in
60
the near future. This trial enrolled 200 patients and involved 70 centers in 22 countries
61
highlighting the notorious difficulty to randomize potential surgical candidates to a non-
62
surgical arm (4).
TE D
M AN U
SC
52
Currently, thymectomy is commonly considered for patients with early onset
64
AChR MG. Benefit in this group of patients was recently confirmed by a propensity
65
score analysis demonstrating that thymectomy was associated with a higher probability of
66
remission compared to patients who did not undergo surgery after controlling for age,
67
gender, time to diagnosis, severity of symptoms at diagnosis and the use of
68
immunosuppressive therapy (5). Besides the subgroup of patients with thymoma
69
requiring a thymectomy for oncological reasons, the role of thymectomy in other
70
subgroups of patients remains more controversial. Recent development in antibody
AC C
EP
63
4
ACCEPTED MANUSCRIPT
71
testing may help to refine the indications for surgery in some of these patients as
72
increasing evidence suggests that thymectomy is not beneficial in patients with MUSK
73
MG (2). The approach and extent of thymectomy remain a topic of intense discussion,
RI PT
74
particularly with the development of minimally invasive surgery. Although the presence
76
of extra-capsular thymic tissue is frequent and well described, the accessibility of these
77
ectopic thymic foci as well as their function and impact on outcome have been unclear,
78
leading to divergent views between proponents of a maximal cervico-mediastinal
79
thymectomy with en bloc resection of all fatty tissue between the thyroid grand and the
80
diaphragm and those of a minimally invasive approach.
M AN U
SC
75
A number of recent studies and observations do potentially mitigate the potential
82
benefit of a maximal approach: 1) Ectopic thymic foci are usually isolated to one or two
83
sites and are most frequently found in the anterior mediastinal fat. Other sites are often
84
found along the phrenic and recurrent nerves or in area not accessible to surgery (6,7), 2)
85
Maximal thymectomy with resection of all potential sites of ectopic thymic foci in the
86
neck and mediastinum is associated with a small but real risk of phrenic and recurrent
87
nerve injury (8), 3) The presence of ectopic thymic foci is potentially one of the
88
strongest predictor of poor outcome even after maximal thymectomy (9,10), and 4)
89
Ectopic thymic foci are found more frequently in patients with atrophic thymus than in
90
patients with hypertrophic thymus, thus possibly increasing the risk-benefit ratio of a
91
maximal approach in the latter group of patients (11).
92 93
AC C
EP
TE D
81
These findings suggest that resection of all active ectopic thymic tissue can be difficult and that the benefit may be limited. Considering that ectopic thymic foci are
5
ACCEPTED MANUSCRIPT
most frequently located in the anterior mediastinum and that this area is readily
95
accessible to surgery, an extended thymectomy involving the fat located between the
96
pericardium, both pleura and the diaphragm appears to be a very good option. Masaoka
97
and colleagues reported a complete remission rate of 46% at 5 years with this approach in
98
non-thymomatous MG patients (12). These results are better than in patients undergoing
99
a less extensive thymectomy and are very similar to the results achieved with a maximal
RI PT
94
thymectomy with resection of tissue in the pericardiophrenic angles, aorto-pulmonary
101
window, aorto-caval groove and along the thyroid gland (13-15). Hence, extending the
102
resection to areas other than the anterior mediastinal fat should continue to be
103
investigated as it may potentially provide benefit in some subgroups of patients, however
104
currently there is limited evidence to suggest that it should be done routinely.
M AN U
105
SC
100
An extended thymectomy involving the anterior mediastinal fat can be performed by an open approach through a sternotomy or by a minimally invasive approach through
107
a cervicotomy, transcervical-subxyphoid approach or unilateral or bilateral video-assisted
108
thoracoscopic surgery (VATS). More recently, robotic thymectomy has also been used
109
with success. The results from all minimally invasive approaches have been relatively
110
similar as long as an extended complete thymectomy with at least resection of the
111
anterior mediastinal fat was performed and it is ultimately the surgeon’s preference and
112
comfort that should dictate the type of approach.
EP
AC C
113
TE D
106
In the future, better definition of the type of thymectomy will be important,
114
particularly if prospective studies and randomized trials are performed to compare
115
different surgical approaches. One possibility would be to reserve the term “extended
116
thymectomy” to resection of the thymus with the anterior mediastinal fat between both
6
ACCEPTED MANUSCRIPT
pleura, the pericardium and diaphragm. More extensive surgery could be specified to
118
encompass sites such as the right and left pericardiophrenic angles, the aortopulmonary
119
window, the aorto-caval groove and retro-innominate space, and the peri-thyroid area
120
(Figure 1).
121
RI PT
117
In conclusion, the past 15 years have been associated with major changes in our
understanding of MG. These developments will undoubtedly lead towards better care for
123
these patients and help refine the indications for thymectomy targeting the most
124
appropriate group of patients. A randomized trial of patients requiring steroids therapy
125
for MG should soon provide additional information on the role of thymectomy in this
126
patient population and will hopefully lead to further surgical trials to determine the best
127
approach.
M AN U
SC
122
AC C
EP
TE D
128
7
ACCEPTED MANUSCRIPT
References
130
1. Sieb JP. Myasthenia gravis: an update for the clinician. Clin Exp Immunol
131
2013;175:408-18.
132
2. Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic
133
strategies. Lancet Neurol 2015;14:1023-36.
134
3. Blalock A. Thymectomy in the treatment of myasthenia gravis: report of 20 cases. J
135
Thorac Surg 1944;13:316-39.
136
4. Newsom-Davis J, Cutter G, Wolfe GI, Kaminski HJ, Jaretzki A, Minisman G, Aban I,
137
Conwit R. Status of the thymectomy trial for nonthymomatous myasthenia gravis patients
138
receiving prednisone. Ann NY Acad Sci 2008;1132:344-7.
139
5. Barnett C, Katzberg HD, Keshavjee S, BrilV. Thymectomy for non-thymomatous
140
myasthenia gravis: a propensity score matched study. Orphanet J Rare Dis 2014;9:214.
141
6. Klimek-Piotrowska W, Mizia E, Kuzdzal J, Lazar A, Lis M, Pankowski J. Ectopic
142
thymic tissue in the mediastinum: limitations for the operative treatment of myasthenia
143
gravis. Eur J Cardiothorac Surg 2012;42:61-5.
144
7. Fukai I, Funato Y, Mizuno T, Hashimoto T, Masaoka A. Distribution of thymic tissue
145
in the mediastinal adipose tissue. J Thorac Cardiovasc Surg 1991;101:1099-102.
146
8. Bulkley GB, Bass KN, Stepheson GR, Diener-West M, George S, Reilly PA, Baker
147
RR, Drachman DB. Extended cervicomediastinal thymectomy in the integrated
148
management of myasthenia gravis. Ann Surg 1997;226:324-35.
149
9. Ambrogi V,Mineo TC. Active ectopic thymus predicts poor outcome after thymectomy
150
in class III myasthenia gravis. J Thorac Cardiovasc Surg 2012;143:601-6.
AC C
EP
TE D
M AN U
SC
RI PT
129
8
ACCEPTED MANUSCRIPT
10.Ozdemir N, Kara M, Dikmen E, Nadir A, Akal M, Yucemen N, Yavuzer S. Predictors
152
of clinical outcome following extended thymectomy in myasthenia gravis. Eur J
153
Cardiothorac Surg 2003;23:233-7.
154
11. Chen Z, Luo H, Peng Y, Cai L, Zhang J, Su C, Zou J. Comparative clinical features
155
and immune responses after extended thymectomy for myasthenia gravis in patients with
156
atrophic versus hyperplastic thymus. Ann Thorac Surg 2011;91:212-8.
157
12. Masaoka A,Yamakawa Y, Niwa H,Fukai I, Kondo S, Kobayashi M, Fujii Y, Monden
158
Y. Extended thymectomy for myasthenia gravis patients: a 20-year review. Ann Thorac
159
Surg 1996;62:853-9.
160
13. Masaoka A, Monden Y. Comparison of the results of transsternal simple,transcervical
161
simple, and extended thymectomy. Ann NY Acad Sci 1981;377:755-65.
162
14. Jaretzki A, Penn AS, Younger DS, Wolff M, Olarte MR, Lovelace RE, Rowland LP.
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"Maximal" thymectomy for myasthenia gravis. J Thorac Cardiovasc Surg 1988;95:747-
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57.
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15. Zielinski M, Hauer L, Hauer J, Pankowski J, Nabialek T, Szlubowski A. Comparison
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of complete remission rates after 5 year follow-up of three different techniques of
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thymectomy for myasthenia gravis. Eur J Cardiothorac Surg 2010;37:1137-43.
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Figure 1.
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Extended thymectomy should encompass resection of the thymus with the anterior
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mediastinal fat between both pleura, the pericardium and diaphragm. More extensive
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surgery could include sites such as the right and left pericardiophrenic angles (A, B), the
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aortopulmonary window (C), the aorto-caval groove and retro-innominate space (D), and
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the peri-thyroid area (E).
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Central figure
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Thymectomy for myasthenia gravis can include specific additional sites in the
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mediastinum
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D
AC C
B
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C
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E
A
