Surg Endosc DOI 10.1007/s00464-014-3890-2
and Other Interventional Techniques
Laparoscopic distal pancreatectomy: analysis of trends in surgical techniques, patient selection, and outcomes Giuseppe Malleo • Isacco Damoli • Giovanni Marchegiani Alessandro Esposito • Tiziana Marchese • Roberto Salvia • Claudio Bassi • Giovanni Butturini
•
Received: 10 April 2014 / Accepted: 10 September 2014 Ó Springer Science+Business Media New York 2014
Abstract Background This study analyzed the time trends of demographic, operative, and pathologic variables in a consecutive series of patients undergoing laparoscopic distal pancreatectomy (LDP). In addition, we assessed the parameters potentially related to the learning curve, and evaluated the long-term outcomes. Methods LDP performed between 1999 and 2012 (minimum follow-up of 1 year) were included in the study. The time trends were studied categorizing the operative sequence in three equal groups, and the parameters related to the learning curve were assessed using local regression techniques. All the analyses were stratified by operation type (associated splenectomy vs. spleen-preserving procedures). Results The study population consisted of 100 patients. There were 57 LDP with associated splenectomy and 41 spleen-preserving LDP; conversion was necessary in 2 cases. The time trend analysis showed that there was not a tendency toward broadening the indications or selecting more difficult cases. Similarly, the study of learning curve components did not show any significant variation over time. Only 45 splenectomized patients received prophylactic vaccinations, and one unvaccinated patient developed an overwhelming post-splenectomy infection. At a
G. Malleo (&) I. Damoli G. Marchegiani A. Esposito T. Marchese R. Salvia C. Bassi G. Butturini Unit of Surgery B, The Pancreas Institute, Department of Surgery and Oncology, G.B. Rossi Hospital, University of Verona Hospital Trust, P.Le L.A. Scuro 10, 37134 Verona, Italy e-mail: [email protected] G. Butturini e-mail: [email protected]
median follow-up of 72.5 months, 12 patients developed diabetes mellitus, while 8 patients undergoing spleen-preserving LDP developed gastric and perigastric varices. Conclusion This analysis did not identify parameters related to the patient selection process and the learning curve in LDP. The incidence of new-onset diabetes was lower than reported in other series. The possibility of serious infections following splenectomy has to be taken into account, such that a strict adherence to vaccine protocols is strongly recommended. Keywords
Pancreatic Pancreato bilio Cancer
The laparoscopic approach for distal pancreatectomy (LDP) has been shown to improve different outcome metrics when compared with open surgery, including lower intraoperative blood loss, less postoperative pain, less surgical complications, and a quicker time to recovery from the operation [1]. The better complication profile of LDP and the growing surgical experience has led to an increase in the number of centers employing these techniques for patients with comorbidities, large lesions, and for selected cancer patients [2]. Different case series and multi-institutional studies assessing the safety and efficacy of LDP have been published, but only few reports analyzed the progress in this area and evaluated time trends in patient selection, surgical techniques, and postoperative morbidity [3]. Furthermore, the long-term, clinically significant complications associated with splenectomy or with spleen-preserving procedures have been seldom assessed. The uptake of minimally invasive techniques has in fact given more opportunity to preserve the spleen, thanks to a better anatomical vision; the issue of preserving the spleen has long been a matter of controversy among surgeons.
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The objective of this study was to describe the results of one hundred consecutive laparoscopic distal pancreatectomies performed at a single center, with a focus on differences in operative outcomes between LDP with or without associated splenectomy. Furthermore, the operative sequence was categorized in three equal groups to assess the time trend of demographic, operative, and pathologic variables. Outcome measures that indirectly act as a proxy in the measurement of the learning curve were also assessed. Finally, we evaluated long-term outcomes, including complications related to splenectomy or to spleen preservation.
Materials and methods Study design and preoperative details After institutional review board approval, the electronic surgical database of the Pancreas Institute, University of Verona Hospital Trust, was queried to identify the first one hundred consecutive patients who underwent LDP, with or without splenectomy. Limiting the analysis to the first one hundred cases allowed a minimum follow-up of one year. Data were analyzed retrospectively. The decision of whether to perform a laparoscopic resection was made by senior surgeons, mainly in case of benign or low-grade neoplasms. Demographic details and presenting symptoms were recorded. Tumor location in the pancreatic body or tail was determined based on preoperative cross-sectional imaging. Surgical technique and operative details Laparoscopic distal pancreatectomy was carried out as already described by this group [4]. In benign neoplasms, spleen preservation was always attempted, unless the neoplasm was located close to the splenic hilum. The preferred technique for splenic salvage was that described by Kimura (conservation of splenic artery and vein) [5]. However, when it was not possible to dissect the pancreas off the splenic vessels or in case of an uncontrolled bleeding, splenic preservation was achieved using the Warshaw technique (ligation of splenic vessels and preservation of short gastric vessels) [6]. A formal distal pancreatectomy with splenectomy and regional lymphadenectomy was performed for tumors with malignant appearance on preoperative cross-sectional imaging. The pancreatic body was transected using a linear endostapler (35–48 mm, according to the pancreatic thickness) or ultrasonic devices, according to the surgeon’s preference. Laparoscopic cases that were converted to open procedures were included in the analysis as intent to treat.
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Operative variables were captured. EBL was calculated from the suction canister content, minus irrigations. Postoperative complications were graded according to the system proposed by Dindo et al. [7], grade III, IV, and V complications were considered major. Pancreatic fistula (PF) and post-pancreatectomy hemorrhage (PPH) were defined according to the ISGPF and ISGPS criteria [8, 9]. Grade B and C fistulae were considered clinically significant. A routine transabdominal postoperative ultrasonography was carried out to rule out fluid collections in the resection bed, contrast-enhanced computed tomography was performed in case of deviation from the normal clinical course. Reoperations within the index admission, discharge with abdominal drains, and hospital readmission were tracked and included in the analysis. Pathology reports were reviewed; the pathologic diagnoses were grouped into cystic neoplasms, neuroendocrine neoplasms, ductal adenocarcinoma, and other. Time trends and learning curve Operative experience was represented as case sequence number. The operative sequence was categorized into three levels of increasing operative experience. During the first period, an external tutor with a broad experience in laparoscopic surgery performed or supervised the procedures, while the second and third period constitute the early and late experience after completion of the learning phase. A set of selected variables was compared across these three time periods. Operative time, tumor size, specimen length, and number of lymph nodes harvested were considered surrogates of the learning curve and of patient selection process, and a model to fit their time trend was investigated. Follow-up information Follow-up was performed on a 6-month basis for the first 1–2 years, and yearly thereafter. It included a detailed clinical examination, blood tests, and cross-sectional imaging or transabdominal ultrasound as appropriate. Fasting blood glucose values were used for the diagnosis of new-onset diabetes, and an oral glucose tolerance test was performed in doubtful cases. Exocrine pancreatic insufficiency was defined as the presence of steatorrhea and weight loss requiring pancreatic enzymes supplementation in the absence of clinical and radiological evidence of tumor recurrence. The occurrence of port-site hernias was recorded. In patients who underwent splenectomy, compliance to post-splenectomy vaccine schedule, secondary thrombocytosis (defined as platelet count greater than 400.000/lL), and administration of ASA were tracked. In patients who underwent a spleen-preserving procedure, the
Surg Endosc
occurrence of splenic infarction and the development of gastric/perigastric varices were recorded. Gastric and perigastric varices were defined as tortuous venous structures larger than 5 mm on cross-sectional imaging. For the purposes of this study, last follow-up visit was carried out on September 2013. Statistical analysis Continuous variables were expressed as means with standard deviation; Student’s t test was used to compare means between two groups, one-way ANOVA with Levene’s test for homogeneity of variance and Tukey post hoc correction was used to compare means between three groups. Nonparametric tests were used when appropriate. v2 test (with Yates continuity correction in a 2 9 2 contingency table) was used for nominal data; Fisher’s exact test was used when appropriate. All tests were 2-tailed. For continuous variables potentially related to the laparoscopic learning curve and patient selection process, time trend components were investigated applying curvefit functions and nonparametric alternatives, such as local regression techniques. The time trend was plotted applying the LOESS (locally weighed scatterplot smoothing) method; the Epanechnikov kernel function was used to create the LOESS fit line [10]. Time to resolution of post-splenectomy thrombocytosis was evaluated using the method of Kaplan and Meier. Resolution of thrombocytosis was defined as the time from splenectomy to normalization of platelet count, and was censored at the last follow-up if no events had occurred. A p value \0.05 was considered significant; the statistical analysis was performed using SPSS release 20 (SPSS Inc., an IBM company, Chicago, IL).
Results Demographic, operative, and pathologic details One hundred consecutive LDP were performed at our Unit between May 1999 and July 2012. Figure 1 displays the yearly surgical volume, divided by operation type. The demographic and operative details of the study population, as well as the comparison between DP-S and SPDP, are displayed in Table 1. In the SPDP group, 32 patients were managed by splenic vessels conservation, and 9 patients by splenic vessels resection. The tumor diameter was greater in patients undergoing DP-S (39.5 vs. 27.5 mm, p = 0.0001); and the operative time was longer than the spleen-preserving procedures (227.1 vs. 178.0 min, p = 0.0001). Conversion to an open procedure was necessary in two cases because of an uncontrolled bleeding. The remaining 98 procedures were completed laparoscopically. The
Fig. 1 Yearly operative caseload, stratified by operation type. DP-S indicates distal pancreatectomy with splenectomy; SPDP indicates spleen-preserving distal pancreatectomy
complication profile was similar in the two operation types. Reoperation within the index admission was necessary in 10 patients, six undergoing a DP-S and four a SPDP. Among the six DP-S patients, three underwent laparoscopic drainage of infected collections, and three re-exploration and hemostasis due to PPH (one procedure was performed laparoscopically). Two patients who underwent a spleenpreserving procedure with splenic vessels resection (Warshaw’s operation) developed a splenic infarction and needed splenectomy, both on postoperative day 10. The remaining two patients, who had been managed with SPDP and splenic vessels conservation, underwent drainage of infected collections. In one patient, concomitant splenectomy was necessary because the abscess involved the splenic hilum. Postoperative mortality was nil. There was no difference in the frequency of neoplasm types between the two groups, cystic neoplasms being the most commonly resected lesions. Lymph node yielding (mean = 11 lymph nodes) was greater in DP-S patients (12.9 vs. 5.4 lymph nodes, p = 0.0001). Time trends and learning curve Table 2 outlines the mean values of continuous variables across the three time periods. Significant differences were identified in operative times. In the entire study population (ANOVA p value = 0.001), the mean operative time was longer in period 2 and 3 as compared with period 1 (Tukey post hoc correction, period 1 vs. 2 p = 0.0001, period 1 vs. 3 p = 0.001). In DP-S patients (ANOVA p value = 0.002), there was a significant difference between period 1 and 2 (Tukey post hoc correction, p = 0.001). Similarly, operative
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Surg Endosc Table 1 Clinical, surgical, and pathologic characteristics of the study population; comparison between laparoscopic distal pancreatectomy with splenectomy (DP-S) and laparoscopic spleen-preserving distal pancreatectomy (SPDP) Study population
Overall (n = 100)
DP-S (n = 59)
SPDP (n = 41)
p value (DP-S vs. SPDP)
Female Mean age (SD) Mean BMI (SD)
Study population
Overall (n = 100)
DP-S (n = 59)
SPDP (n = 41)
p value (DP-S vs. SPDP)
Yes
13
9
4
0.802
No
14
8
6
Yes
14
7
7
No
86
52
34
Intra-abdominal collection
Sex Male
Table 1 continued
21
15
6
79
44
35
47.0 (15.40)
48.8 (14.38)
44.4 (16.59)
23.6 (3.80)
0.292 0.161
23.7 (3.28)
23.4 (4.47)
0.652
0.631
Post-pancreatectomy hemorrhage Yes
8
5
3
No
92
54
38
Yes
22
14
8
No
78
45
33
Incidental
52
29
23
Symptoms
48
30
18
26.3 (90.88)
27.9 (103.7)
21.9 (43.75)
0.807
Body
45
28
17
0.698
Tail
55
31
24
Mean tumor size, mm (SD)
34.6 (16.13)
39.5 (17.02)
27.5 (11.74)
0.0001
Mean length of hospital stay, days (SD)
Mean operative time (min) (SD)
207.0 (65.63)
227.14 (64.19)
178.0 (56.82)
0.0001
Discharge with abdominal drain
Yes
2
2
0
No
98
57
41
7
3
4
No
93
56
37
Yes
10
6
4
No
90
53
37
8.7 (6.18)
9.2
8.0 (4.20)
0.367
0.509
Yes
20
10
10
No
80
49
31
Yes
3
1
2
No
97
58
39
SCN
22
5
17
MCN
32
23
9
I-MCN
4
3
1
SPN
10
5
5
NF-NEN
18
14
4
F-NEN
6
1
5
IPMN
3
3
0
PDAC
4
4
0
Pseudocyst
1
1
0
Cystic neoplasms
71
39
32
Neuroendocrine neoplasms
24
15
9
0.588
Ductal adenocarcinoma
4
4
0
0.518
Mean specimen length (mm)
0.511
Pancreas transection Stapler
88
52
36
Ultrasonic devices
10
5
5
Sutures
2
2
0
35–38 mm
46
29
17
48 mm
42
23
19
0.422
Stapler thickness (n = 88) 0.567
Use of staple line reinforcement (n = 88) Yes
6
2
4
No
82
50
32
0.221
Intraoperative transfusion Yes
4
3
1
No
96
56
40
0.642
Estimated blood loss \150 mL
59
33
26
C150 mL
41
26
15
0.440
Yes
49
31
18
No
51
28
23
1.000
Readmission 0.566
Pathologic diagnosis
Other
Any postoperative complication
0.253
1
1
0
72.7 (26.27)
74.7 (26.79)
69.8 (25.54)
0.363
R0
98
57
41
0.511
R1
2
2
0
R2
0
0
0
11.0 (8.05)
12.9 (8.22)
5.4
R-Status
Major complication 12 88
7 52
5
1.000
36
Any pancreatic fistula Yes
27
17
10
No
73
42
31
A
14
8
6
B
10
7
3
C
3
2
1
0.794
Mean number of lymph nodes harvested
0.0001
Bold values are statistically significant
ISGPF grade (n = 27)
Clinically relevant pancreatic fistula
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Yes Reoperation
Conversion to open procedures
No
0.799
Percutaneous drain placement
Tumor location
Yes
1.000
Pulmonary complications
Diagnosis
Mean serum Ca 19.9 (SD)
0.656
0.805
SD standard deviation, SCN serous cystic neoplasm, MCN mucinous cystic neoplasm, I-MCN invasive mucinous cystic neoplasm, SPN solid pseudopapillary neoplasm, NF-NEN non-functional neuroendocrine neoplasm, F-NEN functional neuroendocrine neoplasm, IPMN intraductal papillary mucinous neoplasm, PDAC pancreatic ductal adenocarcinoma
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time in period 2 was significantly longer than period 1 in SPDP patients (Tukey post hoc correction, p = 0.046, ANOVA p value = 0.024). Figure 2A shows that the frequency of spleen-preserving procedures was significantly greater in the earliest experience (p = 0.005), while resections of solid neoplasms (as compared with cystic) increased over time, although the difference was not significant (p = 0.06; Fig. 2B). Table 3 summarizes the longitudinal comparison of categorical operative and pathologic variables. There was an increase in the use of smaller stapler cartridges (even when stratifying by operation type), and a reduction of pulmonary complications in patients undergoing DP-S (p = 0.015). The frequency of all the other variables was comparable. We tried to study the learning process and the patient selection process constructing a curve set that has the best fit to the observed data points of operative time, length of hospital stay, tumor size, and specimen length. The curvefit function showed a cubic trend for operative time in the overall population (p = 0.002, r2 = 0.380) and in DP-S patients (p = 0.01, r2 = 0.418). Despite significant coefficients, r2 values and the analysis of residual plot indicated that the model did not explain well the variability of the response data, presumably because of outliers. In the
absence of a suitable parametric form of the regression surface, smoothing functions based on local regression methods (LOESS) were employed, and the resulting curves are plotted in Fig. 3. Follow-up Eight patients were lost to follow-up and are not included in the long-term outcome analysis. The median follow-up in the overall population (n = 92) was 72.5 months (14–169). Patients who initially underwent a spleen-preserving procedure and were splenectomized during the index admission because of splenic infarction of splenic abscess were included in the splenectomy group. The median follow-up was significantly longer in patients who underwent a spleen-preserving procedure [95 months (14–169) vs. 58 months (15–161), p = 0.024]. One patient undergone DP-S for a ductal adenocarcinoma died of disease 48 months after the operation; the other one—who underwent SPDP for a serous cystic neoplasm—died of other causes 31 months after the operation. Of the 57 DP-S patients, 45 (78.9 %) received prophylactic vaccinations after the operation. The majority of patients (30 individuals) were administered Pneumococcal vaccine (23-valent
Table 2 Trend of continuous surgical and pathologic variables across three time periods, stratified by operation type Variable
Mean age, years (95 % CI)
Mean BMI, Kg/m2 (95 % CI)
Type of operation
Length of stay, days (95 % CI)
Lymph nodes harvested (95 % CI)
67–100
52.39 (42.39–62.39)
46.31 (40.28–52.35)
49.33 (43.41–55.24)
0.481
42.99 (35.14-50.83)
46.22 (35.24–57.19)
46.20 (33.81–58.58)
0.833
Overall
46.48 (40.42–52.54)
46.29 (41.31–51.26)
48.41 (43.22–53.59)
0.826
DP-S
24.93 (22.95–26.90)
23.27 (21.86–24.67)
23.55 (22.12–24.98)
0.333
SPDP
22.55 (20.73–24.38)
22.77 (18.75–26.78)
25.74 (22.79–28.68)
0.158
23.43 (22.08–24.79)
23.12 (21.73–24.51)
24.19 (22.91–25.48)
0.504
DP-S
177.38 (144.80–209.97)
253.18 (233.95–272.42)
230.21 (200.06–260.36)
0.002
SPDP
156.14 (133.64–178.63)
207.78 (180.46–235.10)
199.50 (150.71–248.29)
0.024
Overall DP-S
166.03 (146.10–181.96) 10.23 (7.19–13.26)
233.00 (223.22–256.78) 9.18 (4.93–13.43)
221.18 (196.44–245.91) 8.75 (6.26–11.23)
0.001 0.842
7.50 (4.22–10.77)
0.132
Overall
Specimen length, mm (95 % CI)
34–66
DP-S
SPDP Tumor size, mm (95 % CI)
1–33
p value
SPDP
Overall Operative time, min (95 % CI)
Operative experience (case number)
9.22 (7.20–11.25)
6.00 (5.23–6.76)
9.60 (7.98–11.21)
8.25 (5.26–11.25)
8.38 (6.46–10.29)
0.618
DP-S
43.92 (32.83–55.01)
38.00 (30.30–45.69)
38.54 (31.66–45.42)
0.578
SPDP
28.31 (22.94–33.68)
24.22 (14.39–34.04)
28.90 (21.36–36.43)
0.634
Overall
34.14 (28.49–39.73)
34.00 (27.70–40.30)
35.70 (30.35–41.05)
0.892
DP-S
72.69 (57.06–88.33)
77.50 (66.71–88.29)
73.21 (60.48–85.93)
0.829
SPDP
74.77 (63.65–85.89)
66.11 (43.07–89.15)
62.20 (46.27–78.13)
0.396
Overall
74.00 (65.41–82.59)
74.19 (64.62–83.77)
69.97 (60.14–79.80)
0.762
DP-S
12.22 (7.41–17.03)
10.77 (8.13–13.41)
15.20 (10.92–19.49)
0.183
SPDP
3.80 (2.26–5.33)
7.20 (4.69–19.09)
6.20 (4.66–7.73)
0.327
Overall
7.78 (4.80–10.77)
10.11 (7.46–12.75)
12.55 (9.23–15.87)
0.109
Bold values are statistically significant
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Fig. 2 A Frequency of spleen preservation over the three time periods. * indicates statistical significance. B Frequency of laparoscopic distal pancreatectomy for solid and cystic neoplasms. DP-S
indicates distal pancreatectomy with splenectomy; SPDP indicates spleen-preserving distal pancreatectomy
formulation) plus meningococcal conjugated vaccine (MCV4) plus haemophilus influenzae type-B vaccine (HibPRP). One unvaccinated patient developed an overwhelming post-splenectomy infection 11 years after the index operation (DP-S), but eventually survived. 23 patients (39.7 %) developed thrombocytosis after splenectomy, of these 19 were given acetylsalicylic acid for thrombosis prevention. The thrombocytosis resolved in 21/23 patients, with a median time to resolution of 28 months (95 % CI 8.25–47.74), as shown in Fig. 4. No thrombotic events or hemorrhages occurred. Of the 35 SPDP patients, 8 developed left-sided venous hypertension with evident gastric and perigastric varices. The incidence of varices was greater in patients who underwent splenic vessels resection (p = 0.033). The incidence of diabetes, exocrine insufficiency, and port-site hernias did not differ between DP-S and SPDP patients. The occurrence of diabetes was not correlated with the specimen length (p = 0.175). Results of long-term followup are outlined in Table 4.
neoplasms, although in recent years there has been an increase in the number of surgical centers employing minimally invasive techniques for the resection of pancreatic ductal adenocarcinoma [2, 11]. The postoperative course was complicated in more than 49 % of patients, with a rate of any pancreatic fistula of 27 %, and a reoperation rate of 10 %. The principal factors leading to reoperation were grade C pancreatic fistula, or PPH. Noticeably, 2/9 patients who underwent a SPDP according to the Warshaw’s technique needed splenectomy because of a splenic infarction on postoperative day 10, resulting in a failure rate of 22.2 %. These findings emphasize the concept that minimally invasive distal pancreatectomy is a major procedure, and that fistula formation remains a relevant and unsolved issue. Nevertheless, nearly half of pancreatic fistulae were grade A (thus clinically irrelevant), and major complications, defined according to the Clavien and Dindo classification, accounted for only 12 % of cases. For the time trend study, the case sequence was categorized into three levels of increasing operative experience, and the analysis was stratified by operation type. During the first 30 cases, an external trainer with experience in complex minimally invasive procedures performed or supervised the operations. Gradually our case volume increased, but in the latest years the caseload remained constant because a robotic surgical system became available, and a number of cases suitable for laparoscopy started being carried out robotically. The frequency of SPDP significantly decreased over time, whereas there was a trend
Discussion The present analysis of one hundred consecutive LDP focused on postoperative and long-term results, and investigated the time trend of outcome metrics that could provide insight into the patient selection process and the learning curve. At the authors’ institution, the laparoscopic approach has been deployed for benign or low-grade
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Surg Endosc Table 3 Trend of categorical surgical and pathologic variables across three time periods, stratified by operation type Parameter
Type of operation
Operative experience (case number) 1–33
Diagnosis
Tumor location
4
10
15
8
13
9
SPDP
14
5
4
7
5
6
Overall
18
15
19
15
18
15
8
9
11
4
14
13
10
4
3
DP-S
Body Tail
SPDP Overall
Stapler thickness (n = 88) 35–38 mm
9 10
11 1
3 6
0.037
8
8
3
13
12
21
17
19
6
4
12
10
8
11
14
9
4
2
12
6
8
13
16
12
20
17
22
DP-S
5
13
13
7
10
11
SPDP
12
2
4
9
8
6
17 16
15 18
17 17
0.877 0.748
SPDP
No Overall Any pancreatic fistula Yes
DP-S SPDP
No Overall
2
3
2
10
20
22
4
0
1
17
10
9
6
3
3
27
30
31
2
6
9
10
17
15
6
2
2
15
8
8
8
8
11
25
25
23
DP-S SPDP
No Overall
SPDP
DP-S
Pulmonary complications
0.400 0.005
SPDP
SPDP
No
Yes 0.645
15
Overall
Yes
0.295
20
DP-S
DP-S
Overall
11
Yes
Severe complications
14
Type of operation
0.651
20
Overall
No
7
13
Clinically relevant pancreatic fistula Yes
0.340
3
Yes
Any complication
6
18
0.201
15
Overall
No
11
Parameter
p value
DP-S
48 mm
EBL C 150 mL
67–100
DP-S
Incidental Symptoms
34–66
Table 3 continued
Reoperation
DP-S
Yes 0.451 0.553 0.691 0.144
0.308 0.410 0.401 0.815 0.688
11
19
20
1
4
4
20
9
9
1
1
1
31
28
29
2
5
5
2
10
2
10
13
22
0.439 0.015
0
1
0.062
10 10
9 3
0.071
24
23
31 2
3
0
1
18
10
9
5
2
3
28
31
31
10
19
20
2
4
4
SPDP
16
8
7
5
2
3
Overall
26
27
27
7
6
7
No
0.813
7
22
DP-S
0.755
14 9
2
0.006 Discharge with abdominal drain
67–100
21
Overall
0.541
34–66
2
SPDP
p value
1–33
10
Yes No
Operative experience (case number)
0.705 0.456 0.451 0.997 0.870 0.948
Bold values are statistically significant
toward performing DP-S for solid lesions, especially neuroendocrine neoplasms. There was no difference in mean age, BMI, tumor size, tumor location, and specimen length, indicating that we did not attempt more technically challenging cases in the later periods (e.g., larger and more proximally located tumors). There was instead an increase in the use of smaller stapler cartridges in the third period. Perioperative outcomes did not differ between the analyzed time periods, excepting for a reduction of pulmonary complication in DP-S patients. Noticeably, the mean operative time increased significantly after the first period (both for DP-S and SPDP). These results are opposed to the findings of Kneuertz et al. who reported a linear decrease in the operative times and a progressive increase in the operative complexity [3]. Then, we selected continuous variables that indirectly act as a proxy in the measurement of the learning process and patient selection practice, and
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Fig. 3 Trend of operative time, tumor size, specimen length, and number of lymph nodes harvested plotted applying the locally weighed scatter plot smoothing (LOESS) method
we tried to construct a model to fit the trend curve. The curvefit function showed a cubic relationship between operative experience and operative time, especially in DPS patients. However, the regression model did not explain well the variation in the data points. Therefore, we analyzed the same variables using local regression methods based on the LOESS procedure, stratified by operation type. These methods work by fitting simple models to localized subsets of the data to build up a function that describes the deterministic part of the variation in the data, point by point [10]. The LOESS curves depicted a
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fluctuation in operative time, which initially increased, then decreased, and—in DP-S patients—again increased. The interpretation of this trend is somewhat difficult. One would expect a progressive reduction of operative times with increasing experience, but this may not be the case of academic institutions where surgeons in training are involved in the operation. Tumor size and specimen length had minimal fluctuations over time, with a trend toward resecting more distal lesions in the latest 25 cases. The number of lymph nodes harvested increased slightly in SPDP, whereas in DP-S it showed a fluctuation within the
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Fig. 4 Kaplan–Meier curve displaying time to normalization of platelet count in patients with thrombocytosis secondary to distal pancreatectomy with splenectomy (n = 23)
last time period, probably depending on the underlying disease. The last objective of our analysis was to evaluate the long-term results, with particular emphasis on complications associated with splenectomy or spleen preservation. Immunization against pneumococcus, Haemophilus influenzae type B, and meningococcus can prevent infectious risk in patients undergoing splenectomy [12]. However, multiple reviews have documented that vaccination after splenectomy is far from systematic [13], and this concept is consistent to our findings, being the adherence to the vaccine protocol of 78.9 %. The most relevant risk in splenectomized patients is overwhelming sepsis due to encapsulated bacteria, a very uncommon event (0.42–2.3 cases/100 person year) [14] that occurred 11 years after DP-S in an unvaccinated patient, who eventually survived. Splenectomy has been also associated with secondary thrombocytosis [15]. The rate of thrombocytosis after splenectomy was 30.7 %, this complication resolved in almost all the patients, and none experienced thrombotic or hemorrhagic complications. This may be related to the adherence to the anti-aggregation therapy that, in the lack of specific guidelines, we recommended to all patients who developed thrombocytosis. Another long-term endpoint was the development of gastric and perigastric varices in patients who underwent SPDP, which yet has been the focus of a previous publication from this group [16]. The pathophysiology of varices differs based on the technique employed to preserve the spleen. In the Warshaw’s operation, the increased flow in the short gastric vessels and left gastroepiploic vein results in vascular dilation [6], whereas
in SPDP with splenic vessels conservation, the dilation of collateral vasculature may result from total or partial splenic vein thrombosis, as a consequence of operative manipulation or infected collections in the resection bed [17]. At a median follow-up of 95 months (SPDP patients), the incidence of gastric and perigastric varices was 22.9 %, and resulted to be significantly greater after Warshaw’s operation. This can be interpreted as a paraphysiologic phenomenon, and there were no consequences of varices in any patient during follow-up. Our results are similar to those reported by the Dr. Warshaw’s group in a large series of procedures (25 % of perigastric varices and no bleeding during a follow-up period up to 21 years) [6]. Post-pancreatectomy diabetes is of growing importance due to the long life expectancy of patients with benign or low-grade tumors. A recent study analyzed the functional consequences of distal pancreatectomy in 61 non-diabetic patients, showing that 22 patients developed new-onset diabetes within a median onset time of 8 months postoperatively. Interestingly, the remaining 39 patients showed impaired glucose metabolism. The percent-resected volume, determined via computed tomography volumetry, resulted to be a risk factor for new-onset diabetes [18]. In our study (median follow-up of the overall population of 72.5 months), the incidence of postoperative diabetes was 13.3 %, an impaired glucose tolerance was seen in 14.5 % of patients, and 72.2 % of patients were found with a normal glucose metabolism. Although a volumetric assessment of the pancreatic parenchyma was not performed, the occurrence of diabetes was not correlated with the specimen length (p = 0.175). In summary, our study did not show substantial differences in postoperative outcomes between DP-S and SPDP, although this concept has to be interpreted with caution, because of the retrospective nature of the analysis and the lack of standardization in patient selection and in the choice of surgical techniques. With growing surgical experience, there was not a trend toward broadening the indications or selecting more difficult cases. The learning curve of LDP is a multidimensional phenomenon that can be hardly inferred by single metrics, especially at academic institutions where surgeons in training participate to the operation or perform part of the procedure. In the longterm, the results of LDP are satisfactory, with a lower incidence of new-onset DM than reported in other series. Because of the possibility of serious infections (e.g., overwhelming sepsis), the spleen should be preserved whenever possible. When concomitant splenectomy is performed, strict adherence to vaccine protocols against encapsulated bacteria is strongly recommended.
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Surg Endosc Table 4 Follow-up details of patients undergoing laparoscopic distal pancreatectomy (n = 92)
Distal pancreatectomy with splenectomy (n = 57a) Follow-up parameters
n
Post-splenectomy vaccine Yes No
45 12
Reactive thrombocytosis Yes
23
No
35
ASA for thrombocytosis (n = 22) Yes
19
No
3
Severe infections during follow-up Yes
1
No
58
Spleen-preserving distal pancreatectomy (n = 35a) Follow-up parameters
N
p value (Kimura vs. Warshaw technique)
Yes
8
0.033
No
27
Gastric/perigastric varices
Kimura technique (n = 28) Bold value is statistically significant ASA acetylsalicylic acid, DM diabetes mellitus a
3 patients who initially underwent a spleen-preserving distal pancreatectomy received emergency splenectomy during the index admission because of splenic infarction or splenic abscess, and—for follow-up details—were included in the distal pancreatectomy with splenectomy group
b
2 patients who were diabetics preoperatively were excluded from this calculation
c
8 patients were excluded from this calculation due to conversion to open surgery (n = 2) or reoperation with open technique during the index admission (n = 6)
Yes No Warshaw technique (n = 7)
4 24
Yes
4
No
3
Other follow-up parameters
Overall (n = 92)
SPDP (n = 35)
p value (DP-S vs. SPDP)
0.782
Endocrine insufficiency (n = 90)b Newly diagnosed DM
12
8
4
Impaired glucose tolerance
13
7
6
No
65
40
25
Yes
4
3
1
No
88
54
34
Yes
3
1
2
No
81
49
32
Exocrine insufficiency 0.982
Port-site hernia (n = 84)c
Acknowledgments This paper is dedicated to Professor Gianluigi Melotti MD, who pioneered minimally invasive surgery in Italy and minimally invasive surgery of the pancreas in Verona. Giuseppe Malleo was supported by the Fondazione Italiana per la Ricerca sulle Malattie del Pancreas (FIMP). Disclosures Doctors Giuseppe Malleo, Isacco Damoli, Giovanni Marchegiani, Alessandro Esposito, Tiziana Marchese, Roberto Salvia, Claudio Bassi, and Giovanni Butturini have no conflicts of interest to disclose.
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DP-S (n = 57)
0.563
References 1. Venkat R, Edil BH, Schulick RD, Lidor AO, Makary MA, Wolfgang CL (2012) Laparoscopic distal pancreatectomy is associated with significantly less overall morbidity compared to the open technique: a systematic review and meta-analysis. Ann Surg 255:1048–1059 2. Abu Hilal M, Takhar AS (2013) Laparoscopic left pancreatectomy: current concepts. Pancreatology 13:443–448
Surg Endosc 3. Kneuertz PJ, Patel SH, Chu CK, Fisher SB, Maithel SK, Sarmiento JM, Weber SM, Staley CA, Kooby DA (2012) Laparoscopic distal pancreatectomy: trends and lessons learned through an 11-year experience. J Am Coll Surg 215:167–176 4. Melotti G, Butturini G, Piccoli M, Casetti L, Bassi C, Mullineris B, Lazzaretti MG, Pederzoli P (2007) Laparoscopic distal pancreatectomy: results on a consecutive series of 58 patients. Ann Surg 246:77–82 5. Kimura W, Inoue T, Futakawa N, Shinkai H, Han I, Muto T (1996) Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein. Surgery 120:885–890 6. Ferrone CR, Konstantinidis IT, Sahani DV, Wargo JA, Fernandez-del Castillo C, Warshaw AL (2011) Twenty-three years of the Warshaw operation for distal pancreatectomy with preservation of the spleen. Ann Surg 253:1136–1139 7. Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213 8. Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, Neoptolemos J, Sarr M, Traverso W, Buchler M (2005) Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 138:8–13 9. Wente MN, Veit JA, Bassi C, Dervenis C, Fingerhut A, Gouma DJ, Izbicki JR, Padbury RT, Sarr MG, Yeo CJ, Buchler MW (2007) Postpancreatectomy hemorrhage (PPH): an international study group of pancreatic surgery (ISGPS) definition. Surgery 142:20–25 10. Mu¨ller HG (1987) Weighted local regression and kernel methods for nonparametric curve fitting. J Am Stat Assoc 82:231–238
11. Rehman S, John SK, Lochan R, Jaques BC, Manas DM, Charnley RM, French JJ, White SA (2014) Oncological feasibility of laparoscopic distal pancreatectomy for adenocarcinoma: a singleinstitution comparative study. World J Surg 38:476–483 12. Di Sabatino A, Carsetti R, Corazza GR (2011) Post-splenectomy and hyposplenic states. Lancet 378:86–97 13. Coignard-Biehler H, Lanternier F, Hot A, Salmon D, Berger A, de Montalembert M, Suarez F, Launay O, Lecuit M, Lortholary O (2011) Adherence to preventive measures after splenectomy in the hospital setting and in the community. J Infect Public Health 4:187–194 14. Mourtzoukou EG, Pappas G, Peppas G, Falagas ME (2008) Vaccination of asplenic or hyposplenic adults. Br J Surg 95:273–280 15. Tezuka K, Kimura W, Hirai I, Moriya T, Watanabe T, Yano M (2012) Postoperative hematological changes after spleen-preserving distal pancreatectomy with preservation of the splenic artery and vein. Dig Surg 29:157–164 16. Butturini G, Inama M, Malleo G, Manfredi R, Melotti GL, Piccoli M, Perandini S, Pederzoli P, Bassi C (2012) Perioperative and long-term results of laparoscopic spleen-preserving distal pancreatectomy with or without splenic vessels conservation: a retrospective analysis. J Surg Oncol 105:387–392 17. Yoon Y-S, Lee KH, Han H-S, Cho JY, Ahn KS (2009) Patency of splenic vessels after laparoscopic spleen and splenic vessel-preserving distal pancreatectomy. Br J Surg 96:633–640 18. Shirakawa S, Matsumoto I, Toyama H, Shinzeki M, Ajiki T, Fukumoto T, Ku Y (2012) Pancreatic volumetric assessment as a predictor of new-onset diabetes following distal pancreatectomy. J Gastrointest Surg 16:2212–2219
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and Other Interventional Techniques
Laparoscopic distal pancreatectomy: analysis of trends in surgical techniques, patient selection, and outcomes Giuseppe Malleo • Isacco Damoli • Giovanni Marchegiani Alessandro Esposito • Tiziana Marchese • Roberto Salvia • Claudio Bassi • Giovanni Butturini
•
Received: 10 April 2014 / Accepted: 10 September 2014 Ó Springer Science+Business Media New York 2014
Abstract Background This study analyzed the time trends of demographic, operative, and pathologic variables in a consecutive series of patients undergoing laparoscopic distal pancreatectomy (LDP). In addition, we assessed the parameters potentially related to the learning curve, and evaluated the long-term outcomes. Methods LDP performed between 1999 and 2012 (minimum follow-up of 1 year) were included in the study. The time trends were studied categorizing the operative sequence in three equal groups, and the parameters related to the learning curve were assessed using local regression techniques. All the analyses were stratified by operation type (associated splenectomy vs. spleen-preserving procedures). Results The study population consisted of 100 patients. There were 57 LDP with associated splenectomy and 41 spleen-preserving LDP; conversion was necessary in 2 cases. The time trend analysis showed that there was not a tendency toward broadening the indications or selecting more difficult cases. Similarly, the study of learning curve components did not show any significant variation over time. Only 45 splenectomized patients received prophylactic vaccinations, and one unvaccinated patient developed an overwhelming post-splenectomy infection. At a
G. Malleo (&) I. Damoli G. Marchegiani A. Esposito T. Marchese R. Salvia C. Bassi G. Butturini Unit of Surgery B, The Pancreas Institute, Department of Surgery and Oncology, G.B. Rossi Hospital, University of Verona Hospital Trust, P.Le L.A. Scuro 10, 37134 Verona, Italy e-mail: [email protected] G. Butturini e-mail: [email protected]
median follow-up of 72.5 months, 12 patients developed diabetes mellitus, while 8 patients undergoing spleen-preserving LDP developed gastric and perigastric varices. Conclusion This analysis did not identify parameters related to the patient selection process and the learning curve in LDP. The incidence of new-onset diabetes was lower than reported in other series. The possibility of serious infections following splenectomy has to be taken into account, such that a strict adherence to vaccine protocols is strongly recommended. Keywords
Pancreatic Pancreato bilio Cancer
The laparoscopic approach for distal pancreatectomy (LDP) has been shown to improve different outcome metrics when compared with open surgery, including lower intraoperative blood loss, less postoperative pain, less surgical complications, and a quicker time to recovery from the operation [1]. The better complication profile of LDP and the growing surgical experience has led to an increase in the number of centers employing these techniques for patients with comorbidities, large lesions, and for selected cancer patients [2]. Different case series and multi-institutional studies assessing the safety and efficacy of LDP have been published, but only few reports analyzed the progress in this area and evaluated time trends in patient selection, surgical techniques, and postoperative morbidity [3]. Furthermore, the long-term, clinically significant complications associated with splenectomy or with spleen-preserving procedures have been seldom assessed. The uptake of minimally invasive techniques has in fact given more opportunity to preserve the spleen, thanks to a better anatomical vision; the issue of preserving the spleen has long been a matter of controversy among surgeons.
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The objective of this study was to describe the results of one hundred consecutive laparoscopic distal pancreatectomies performed at a single center, with a focus on differences in operative outcomes between LDP with or without associated splenectomy. Furthermore, the operative sequence was categorized in three equal groups to assess the time trend of demographic, operative, and pathologic variables. Outcome measures that indirectly act as a proxy in the measurement of the learning curve were also assessed. Finally, we evaluated long-term outcomes, including complications related to splenectomy or to spleen preservation.
Materials and methods Study design and preoperative details After institutional review board approval, the electronic surgical database of the Pancreas Institute, University of Verona Hospital Trust, was queried to identify the first one hundred consecutive patients who underwent LDP, with or without splenectomy. Limiting the analysis to the first one hundred cases allowed a minimum follow-up of one year. Data were analyzed retrospectively. The decision of whether to perform a laparoscopic resection was made by senior surgeons, mainly in case of benign or low-grade neoplasms. Demographic details and presenting symptoms were recorded. Tumor location in the pancreatic body or tail was determined based on preoperative cross-sectional imaging. Surgical technique and operative details Laparoscopic distal pancreatectomy was carried out as already described by this group [4]. In benign neoplasms, spleen preservation was always attempted, unless the neoplasm was located close to the splenic hilum. The preferred technique for splenic salvage was that described by Kimura (conservation of splenic artery and vein) [5]. However, when it was not possible to dissect the pancreas off the splenic vessels or in case of an uncontrolled bleeding, splenic preservation was achieved using the Warshaw technique (ligation of splenic vessels and preservation of short gastric vessels) [6]. A formal distal pancreatectomy with splenectomy and regional lymphadenectomy was performed for tumors with malignant appearance on preoperative cross-sectional imaging. The pancreatic body was transected using a linear endostapler (35–48 mm, according to the pancreatic thickness) or ultrasonic devices, according to the surgeon’s preference. Laparoscopic cases that were converted to open procedures were included in the analysis as intent to treat.
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Operative variables were captured. EBL was calculated from the suction canister content, minus irrigations. Postoperative complications were graded according to the system proposed by Dindo et al. [7], grade III, IV, and V complications were considered major. Pancreatic fistula (PF) and post-pancreatectomy hemorrhage (PPH) were defined according to the ISGPF and ISGPS criteria [8, 9]. Grade B and C fistulae were considered clinically significant. A routine transabdominal postoperative ultrasonography was carried out to rule out fluid collections in the resection bed, contrast-enhanced computed tomography was performed in case of deviation from the normal clinical course. Reoperations within the index admission, discharge with abdominal drains, and hospital readmission were tracked and included in the analysis. Pathology reports were reviewed; the pathologic diagnoses were grouped into cystic neoplasms, neuroendocrine neoplasms, ductal adenocarcinoma, and other. Time trends and learning curve Operative experience was represented as case sequence number. The operative sequence was categorized into three levels of increasing operative experience. During the first period, an external tutor with a broad experience in laparoscopic surgery performed or supervised the procedures, while the second and third period constitute the early and late experience after completion of the learning phase. A set of selected variables was compared across these three time periods. Operative time, tumor size, specimen length, and number of lymph nodes harvested were considered surrogates of the learning curve and of patient selection process, and a model to fit their time trend was investigated. Follow-up information Follow-up was performed on a 6-month basis for the first 1–2 years, and yearly thereafter. It included a detailed clinical examination, blood tests, and cross-sectional imaging or transabdominal ultrasound as appropriate. Fasting blood glucose values were used for the diagnosis of new-onset diabetes, and an oral glucose tolerance test was performed in doubtful cases. Exocrine pancreatic insufficiency was defined as the presence of steatorrhea and weight loss requiring pancreatic enzymes supplementation in the absence of clinical and radiological evidence of tumor recurrence. The occurrence of port-site hernias was recorded. In patients who underwent splenectomy, compliance to post-splenectomy vaccine schedule, secondary thrombocytosis (defined as platelet count greater than 400.000/lL), and administration of ASA were tracked. In patients who underwent a spleen-preserving procedure, the
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occurrence of splenic infarction and the development of gastric/perigastric varices were recorded. Gastric and perigastric varices were defined as tortuous venous structures larger than 5 mm on cross-sectional imaging. For the purposes of this study, last follow-up visit was carried out on September 2013. Statistical analysis Continuous variables were expressed as means with standard deviation; Student’s t test was used to compare means between two groups, one-way ANOVA with Levene’s test for homogeneity of variance and Tukey post hoc correction was used to compare means between three groups. Nonparametric tests were used when appropriate. v2 test (with Yates continuity correction in a 2 9 2 contingency table) was used for nominal data; Fisher’s exact test was used when appropriate. All tests were 2-tailed. For continuous variables potentially related to the laparoscopic learning curve and patient selection process, time trend components were investigated applying curvefit functions and nonparametric alternatives, such as local regression techniques. The time trend was plotted applying the LOESS (locally weighed scatterplot smoothing) method; the Epanechnikov kernel function was used to create the LOESS fit line [10]. Time to resolution of post-splenectomy thrombocytosis was evaluated using the method of Kaplan and Meier. Resolution of thrombocytosis was defined as the time from splenectomy to normalization of platelet count, and was censored at the last follow-up if no events had occurred. A p value \0.05 was considered significant; the statistical analysis was performed using SPSS release 20 (SPSS Inc., an IBM company, Chicago, IL).
Results Demographic, operative, and pathologic details One hundred consecutive LDP were performed at our Unit between May 1999 and July 2012. Figure 1 displays the yearly surgical volume, divided by operation type. The demographic and operative details of the study population, as well as the comparison between DP-S and SPDP, are displayed in Table 1. In the SPDP group, 32 patients were managed by splenic vessels conservation, and 9 patients by splenic vessels resection. The tumor diameter was greater in patients undergoing DP-S (39.5 vs. 27.5 mm, p = 0.0001); and the operative time was longer than the spleen-preserving procedures (227.1 vs. 178.0 min, p = 0.0001). Conversion to an open procedure was necessary in two cases because of an uncontrolled bleeding. The remaining 98 procedures were completed laparoscopically. The
Fig. 1 Yearly operative caseload, stratified by operation type. DP-S indicates distal pancreatectomy with splenectomy; SPDP indicates spleen-preserving distal pancreatectomy
complication profile was similar in the two operation types. Reoperation within the index admission was necessary in 10 patients, six undergoing a DP-S and four a SPDP. Among the six DP-S patients, three underwent laparoscopic drainage of infected collections, and three re-exploration and hemostasis due to PPH (one procedure was performed laparoscopically). Two patients who underwent a spleenpreserving procedure with splenic vessels resection (Warshaw’s operation) developed a splenic infarction and needed splenectomy, both on postoperative day 10. The remaining two patients, who had been managed with SPDP and splenic vessels conservation, underwent drainage of infected collections. In one patient, concomitant splenectomy was necessary because the abscess involved the splenic hilum. Postoperative mortality was nil. There was no difference in the frequency of neoplasm types between the two groups, cystic neoplasms being the most commonly resected lesions. Lymph node yielding (mean = 11 lymph nodes) was greater in DP-S patients (12.9 vs. 5.4 lymph nodes, p = 0.0001). Time trends and learning curve Table 2 outlines the mean values of continuous variables across the three time periods. Significant differences were identified in operative times. In the entire study population (ANOVA p value = 0.001), the mean operative time was longer in period 2 and 3 as compared with period 1 (Tukey post hoc correction, period 1 vs. 2 p = 0.0001, period 1 vs. 3 p = 0.001). In DP-S patients (ANOVA p value = 0.002), there was a significant difference between period 1 and 2 (Tukey post hoc correction, p = 0.001). Similarly, operative
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Surg Endosc Table 1 Clinical, surgical, and pathologic characteristics of the study population; comparison between laparoscopic distal pancreatectomy with splenectomy (DP-S) and laparoscopic spleen-preserving distal pancreatectomy (SPDP) Study population
Overall (n = 100)
DP-S (n = 59)
SPDP (n = 41)
p value (DP-S vs. SPDP)
Female Mean age (SD) Mean BMI (SD)
Study population
Overall (n = 100)
DP-S (n = 59)
SPDP (n = 41)
p value (DP-S vs. SPDP)
Yes
13
9
4
0.802
No
14
8
6
Yes
14
7
7
No
86
52
34
Intra-abdominal collection
Sex Male
Table 1 continued
21
15
6
79
44
35
47.0 (15.40)
48.8 (14.38)
44.4 (16.59)
23.6 (3.80)
0.292 0.161
23.7 (3.28)
23.4 (4.47)
0.652
0.631
Post-pancreatectomy hemorrhage Yes
8
5
3
No
92
54
38
Yes
22
14
8
No
78
45
33
Incidental
52
29
23
Symptoms
48
30
18
26.3 (90.88)
27.9 (103.7)
21.9 (43.75)
0.807
Body
45
28
17
0.698
Tail
55
31
24
Mean tumor size, mm (SD)
34.6 (16.13)
39.5 (17.02)
27.5 (11.74)
0.0001
Mean length of hospital stay, days (SD)
Mean operative time (min) (SD)
207.0 (65.63)
227.14 (64.19)
178.0 (56.82)
0.0001
Discharge with abdominal drain
Yes
2
2
0
No
98
57
41
7
3
4
No
93
56
37
Yes
10
6
4
No
90
53
37
8.7 (6.18)
9.2
8.0 (4.20)
0.367
0.509
Yes
20
10
10
No
80
49
31
Yes
3
1
2
No
97
58
39
SCN
22
5
17
MCN
32
23
9
I-MCN
4
3
1
SPN
10
5
5
NF-NEN
18
14
4
F-NEN
6
1
5
IPMN
3
3
0
PDAC
4
4
0
Pseudocyst
1
1
0
Cystic neoplasms
71
39
32
Neuroendocrine neoplasms
24
15
9
0.588
Ductal adenocarcinoma
4
4
0
0.518
Mean specimen length (mm)
0.511
Pancreas transection Stapler
88
52
36
Ultrasonic devices
10
5
5
Sutures
2
2
0
35–38 mm
46
29
17
48 mm
42
23
19
0.422
Stapler thickness (n = 88) 0.567
Use of staple line reinforcement (n = 88) Yes
6
2
4
No
82
50
32
0.221
Intraoperative transfusion Yes
4
3
1
No
96
56
40
0.642
Estimated blood loss \150 mL
59
33
26
C150 mL
41
26
15
0.440
Yes
49
31
18
No
51
28
23
1.000
Readmission 0.566
Pathologic diagnosis
Other
Any postoperative complication
0.253
1
1
0
72.7 (26.27)
74.7 (26.79)
69.8 (25.54)
0.363
R0
98
57
41
0.511
R1
2
2
0
R2
0
0
0
11.0 (8.05)
12.9 (8.22)
5.4
R-Status
Major complication 12 88
7 52
5
1.000
36
Any pancreatic fistula Yes
27
17
10
No
73
42
31
A
14
8
6
B
10
7
3
C
3
2
1
0.794
Mean number of lymph nodes harvested
0.0001
Bold values are statistically significant
ISGPF grade (n = 27)
Clinically relevant pancreatic fistula
123
Yes Reoperation
Conversion to open procedures
No
0.799
Percutaneous drain placement
Tumor location
Yes
1.000
Pulmonary complications
Diagnosis
Mean serum Ca 19.9 (SD)
0.656
0.805
SD standard deviation, SCN serous cystic neoplasm, MCN mucinous cystic neoplasm, I-MCN invasive mucinous cystic neoplasm, SPN solid pseudopapillary neoplasm, NF-NEN non-functional neuroendocrine neoplasm, F-NEN functional neuroendocrine neoplasm, IPMN intraductal papillary mucinous neoplasm, PDAC pancreatic ductal adenocarcinoma
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time in period 2 was significantly longer than period 1 in SPDP patients (Tukey post hoc correction, p = 0.046, ANOVA p value = 0.024). Figure 2A shows that the frequency of spleen-preserving procedures was significantly greater in the earliest experience (p = 0.005), while resections of solid neoplasms (as compared with cystic) increased over time, although the difference was not significant (p = 0.06; Fig. 2B). Table 3 summarizes the longitudinal comparison of categorical operative and pathologic variables. There was an increase in the use of smaller stapler cartridges (even when stratifying by operation type), and a reduction of pulmonary complications in patients undergoing DP-S (p = 0.015). The frequency of all the other variables was comparable. We tried to study the learning process and the patient selection process constructing a curve set that has the best fit to the observed data points of operative time, length of hospital stay, tumor size, and specimen length. The curvefit function showed a cubic trend for operative time in the overall population (p = 0.002, r2 = 0.380) and in DP-S patients (p = 0.01, r2 = 0.418). Despite significant coefficients, r2 values and the analysis of residual plot indicated that the model did not explain well the variability of the response data, presumably because of outliers. In the
absence of a suitable parametric form of the regression surface, smoothing functions based on local regression methods (LOESS) were employed, and the resulting curves are plotted in Fig. 3. Follow-up Eight patients were lost to follow-up and are not included in the long-term outcome analysis. The median follow-up in the overall population (n = 92) was 72.5 months (14–169). Patients who initially underwent a spleen-preserving procedure and were splenectomized during the index admission because of splenic infarction of splenic abscess were included in the splenectomy group. The median follow-up was significantly longer in patients who underwent a spleen-preserving procedure [95 months (14–169) vs. 58 months (15–161), p = 0.024]. One patient undergone DP-S for a ductal adenocarcinoma died of disease 48 months after the operation; the other one—who underwent SPDP for a serous cystic neoplasm—died of other causes 31 months after the operation. Of the 57 DP-S patients, 45 (78.9 %) received prophylactic vaccinations after the operation. The majority of patients (30 individuals) were administered Pneumococcal vaccine (23-valent
Table 2 Trend of continuous surgical and pathologic variables across three time periods, stratified by operation type Variable
Mean age, years (95 % CI)
Mean BMI, Kg/m2 (95 % CI)
Type of operation
Length of stay, days (95 % CI)
Lymph nodes harvested (95 % CI)
67–100
52.39 (42.39–62.39)
46.31 (40.28–52.35)
49.33 (43.41–55.24)
0.481
42.99 (35.14-50.83)
46.22 (35.24–57.19)
46.20 (33.81–58.58)
0.833
Overall
46.48 (40.42–52.54)
46.29 (41.31–51.26)
48.41 (43.22–53.59)
0.826
DP-S
24.93 (22.95–26.90)
23.27 (21.86–24.67)
23.55 (22.12–24.98)
0.333
SPDP
22.55 (20.73–24.38)
22.77 (18.75–26.78)
25.74 (22.79–28.68)
0.158
23.43 (22.08–24.79)
23.12 (21.73–24.51)
24.19 (22.91–25.48)
0.504
DP-S
177.38 (144.80–209.97)
253.18 (233.95–272.42)
230.21 (200.06–260.36)
0.002
SPDP
156.14 (133.64–178.63)
207.78 (180.46–235.10)
199.50 (150.71–248.29)
0.024
Overall DP-S
166.03 (146.10–181.96) 10.23 (7.19–13.26)
233.00 (223.22–256.78) 9.18 (4.93–13.43)
221.18 (196.44–245.91) 8.75 (6.26–11.23)
0.001 0.842
7.50 (4.22–10.77)
0.132
Overall
Specimen length, mm (95 % CI)
34–66
DP-S
SPDP Tumor size, mm (95 % CI)
1–33
p value
SPDP
Overall Operative time, min (95 % CI)
Operative experience (case number)
9.22 (7.20–11.25)
6.00 (5.23–6.76)
9.60 (7.98–11.21)
8.25 (5.26–11.25)
8.38 (6.46–10.29)
0.618
DP-S
43.92 (32.83–55.01)
38.00 (30.30–45.69)
38.54 (31.66–45.42)
0.578
SPDP
28.31 (22.94–33.68)
24.22 (14.39–34.04)
28.90 (21.36–36.43)
0.634
Overall
34.14 (28.49–39.73)
34.00 (27.70–40.30)
35.70 (30.35–41.05)
0.892
DP-S
72.69 (57.06–88.33)
77.50 (66.71–88.29)
73.21 (60.48–85.93)
0.829
SPDP
74.77 (63.65–85.89)
66.11 (43.07–89.15)
62.20 (46.27–78.13)
0.396
Overall
74.00 (65.41–82.59)
74.19 (64.62–83.77)
69.97 (60.14–79.80)
0.762
DP-S
12.22 (7.41–17.03)
10.77 (8.13–13.41)
15.20 (10.92–19.49)
0.183
SPDP
3.80 (2.26–5.33)
7.20 (4.69–19.09)
6.20 (4.66–7.73)
0.327
Overall
7.78 (4.80–10.77)
10.11 (7.46–12.75)
12.55 (9.23–15.87)
0.109
Bold values are statistically significant
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Surg Endosc
Fig. 2 A Frequency of spleen preservation over the three time periods. * indicates statistical significance. B Frequency of laparoscopic distal pancreatectomy for solid and cystic neoplasms. DP-S
indicates distal pancreatectomy with splenectomy; SPDP indicates spleen-preserving distal pancreatectomy
formulation) plus meningococcal conjugated vaccine (MCV4) plus haemophilus influenzae type-B vaccine (HibPRP). One unvaccinated patient developed an overwhelming post-splenectomy infection 11 years after the index operation (DP-S), but eventually survived. 23 patients (39.7 %) developed thrombocytosis after splenectomy, of these 19 were given acetylsalicylic acid for thrombosis prevention. The thrombocytosis resolved in 21/23 patients, with a median time to resolution of 28 months (95 % CI 8.25–47.74), as shown in Fig. 4. No thrombotic events or hemorrhages occurred. Of the 35 SPDP patients, 8 developed left-sided venous hypertension with evident gastric and perigastric varices. The incidence of varices was greater in patients who underwent splenic vessels resection (p = 0.033). The incidence of diabetes, exocrine insufficiency, and port-site hernias did not differ between DP-S and SPDP patients. The occurrence of diabetes was not correlated with the specimen length (p = 0.175). Results of long-term followup are outlined in Table 4.
neoplasms, although in recent years there has been an increase in the number of surgical centers employing minimally invasive techniques for the resection of pancreatic ductal adenocarcinoma [2, 11]. The postoperative course was complicated in more than 49 % of patients, with a rate of any pancreatic fistula of 27 %, and a reoperation rate of 10 %. The principal factors leading to reoperation were grade C pancreatic fistula, or PPH. Noticeably, 2/9 patients who underwent a SPDP according to the Warshaw’s technique needed splenectomy because of a splenic infarction on postoperative day 10, resulting in a failure rate of 22.2 %. These findings emphasize the concept that minimally invasive distal pancreatectomy is a major procedure, and that fistula formation remains a relevant and unsolved issue. Nevertheless, nearly half of pancreatic fistulae were grade A (thus clinically irrelevant), and major complications, defined according to the Clavien and Dindo classification, accounted for only 12 % of cases. For the time trend study, the case sequence was categorized into three levels of increasing operative experience, and the analysis was stratified by operation type. During the first 30 cases, an external trainer with experience in complex minimally invasive procedures performed or supervised the operations. Gradually our case volume increased, but in the latest years the caseload remained constant because a robotic surgical system became available, and a number of cases suitable for laparoscopy started being carried out robotically. The frequency of SPDP significantly decreased over time, whereas there was a trend
Discussion The present analysis of one hundred consecutive LDP focused on postoperative and long-term results, and investigated the time trend of outcome metrics that could provide insight into the patient selection process and the learning curve. At the authors’ institution, the laparoscopic approach has been deployed for benign or low-grade
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Surg Endosc Table 3 Trend of categorical surgical and pathologic variables across three time periods, stratified by operation type Parameter
Type of operation
Operative experience (case number) 1–33
Diagnosis
Tumor location
4
10
15
8
13
9
SPDP
14
5
4
7
5
6
Overall
18
15
19
15
18
15
8
9
11
4
14
13
10
4
3
DP-S
Body Tail
SPDP Overall
Stapler thickness (n = 88) 35–38 mm
9 10
11 1
3 6
0.037
8
8
3
13
12
21
17
19
6
4
12
10
8
11
14
9
4
2
12
6
8
13
16
12
20
17
22
DP-S
5
13
13
7
10
11
SPDP
12
2
4
9
8
6
17 16
15 18
17 17
0.877 0.748
SPDP
No Overall Any pancreatic fistula Yes
DP-S SPDP
No Overall
2
3
2
10
20
22
4
0
1
17
10
9
6
3
3
27
30
31
2
6
9
10
17
15
6
2
2
15
8
8
8
8
11
25
25
23
DP-S SPDP
No Overall
SPDP
DP-S
Pulmonary complications
0.400 0.005
SPDP
SPDP
No
Yes 0.645
15
Overall
Yes
0.295
20
DP-S
DP-S
Overall
11
Yes
Severe complications
14
Type of operation
0.651
20
Overall
No
7
13
Clinically relevant pancreatic fistula Yes
0.340
3
Yes
Any complication
6
18
0.201
15
Overall
No
11
Parameter
p value
DP-S
48 mm
EBL C 150 mL
67–100
DP-S
Incidental Symptoms
34–66
Table 3 continued
Reoperation
DP-S
Yes 0.451 0.553 0.691 0.144
0.308 0.410 0.401 0.815 0.688
11
19
20
1
4
4
20
9
9
1
1
1
31
28
29
2
5
5
2
10
2
10
13
22
0.439 0.015
0
1
0.062
10 10
9 3
0.071
24
23
31 2
3
0
1
18
10
9
5
2
3
28
31
31
10
19
20
2
4
4
SPDP
16
8
7
5
2
3
Overall
26
27
27
7
6
7
No
0.813
7
22
DP-S
0.755
14 9
2
0.006 Discharge with abdominal drain
67–100
21
Overall
0.541
34–66
2
SPDP
p value
1–33
10
Yes No
Operative experience (case number)
0.705 0.456 0.451 0.997 0.870 0.948
Bold values are statistically significant
toward performing DP-S for solid lesions, especially neuroendocrine neoplasms. There was no difference in mean age, BMI, tumor size, tumor location, and specimen length, indicating that we did not attempt more technically challenging cases in the later periods (e.g., larger and more proximally located tumors). There was instead an increase in the use of smaller stapler cartridges in the third period. Perioperative outcomes did not differ between the analyzed time periods, excepting for a reduction of pulmonary complication in DP-S patients. Noticeably, the mean operative time increased significantly after the first period (both for DP-S and SPDP). These results are opposed to the findings of Kneuertz et al. who reported a linear decrease in the operative times and a progressive increase in the operative complexity [3]. Then, we selected continuous variables that indirectly act as a proxy in the measurement of the learning process and patient selection practice, and
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Surg Endosc
Fig. 3 Trend of operative time, tumor size, specimen length, and number of lymph nodes harvested plotted applying the locally weighed scatter plot smoothing (LOESS) method
we tried to construct a model to fit the trend curve. The curvefit function showed a cubic relationship between operative experience and operative time, especially in DPS patients. However, the regression model did not explain well the variation in the data points. Therefore, we analyzed the same variables using local regression methods based on the LOESS procedure, stratified by operation type. These methods work by fitting simple models to localized subsets of the data to build up a function that describes the deterministic part of the variation in the data, point by point [10]. The LOESS curves depicted a
123
fluctuation in operative time, which initially increased, then decreased, and—in DP-S patients—again increased. The interpretation of this trend is somewhat difficult. One would expect a progressive reduction of operative times with increasing experience, but this may not be the case of academic institutions where surgeons in training are involved in the operation. Tumor size and specimen length had minimal fluctuations over time, with a trend toward resecting more distal lesions in the latest 25 cases. The number of lymph nodes harvested increased slightly in SPDP, whereas in DP-S it showed a fluctuation within the
Surg Endosc
Fig. 4 Kaplan–Meier curve displaying time to normalization of platelet count in patients with thrombocytosis secondary to distal pancreatectomy with splenectomy (n = 23)
last time period, probably depending on the underlying disease. The last objective of our analysis was to evaluate the long-term results, with particular emphasis on complications associated with splenectomy or spleen preservation. Immunization against pneumococcus, Haemophilus influenzae type B, and meningococcus can prevent infectious risk in patients undergoing splenectomy [12]. However, multiple reviews have documented that vaccination after splenectomy is far from systematic [13], and this concept is consistent to our findings, being the adherence to the vaccine protocol of 78.9 %. The most relevant risk in splenectomized patients is overwhelming sepsis due to encapsulated bacteria, a very uncommon event (0.42–2.3 cases/100 person year) [14] that occurred 11 years after DP-S in an unvaccinated patient, who eventually survived. Splenectomy has been also associated with secondary thrombocytosis [15]. The rate of thrombocytosis after splenectomy was 30.7 %, this complication resolved in almost all the patients, and none experienced thrombotic or hemorrhagic complications. This may be related to the adherence to the anti-aggregation therapy that, in the lack of specific guidelines, we recommended to all patients who developed thrombocytosis. Another long-term endpoint was the development of gastric and perigastric varices in patients who underwent SPDP, which yet has been the focus of a previous publication from this group [16]. The pathophysiology of varices differs based on the technique employed to preserve the spleen. In the Warshaw’s operation, the increased flow in the short gastric vessels and left gastroepiploic vein results in vascular dilation [6], whereas
in SPDP with splenic vessels conservation, the dilation of collateral vasculature may result from total or partial splenic vein thrombosis, as a consequence of operative manipulation or infected collections in the resection bed [17]. At a median follow-up of 95 months (SPDP patients), the incidence of gastric and perigastric varices was 22.9 %, and resulted to be significantly greater after Warshaw’s operation. This can be interpreted as a paraphysiologic phenomenon, and there were no consequences of varices in any patient during follow-up. Our results are similar to those reported by the Dr. Warshaw’s group in a large series of procedures (25 % of perigastric varices and no bleeding during a follow-up period up to 21 years) [6]. Post-pancreatectomy diabetes is of growing importance due to the long life expectancy of patients with benign or low-grade tumors. A recent study analyzed the functional consequences of distal pancreatectomy in 61 non-diabetic patients, showing that 22 patients developed new-onset diabetes within a median onset time of 8 months postoperatively. Interestingly, the remaining 39 patients showed impaired glucose metabolism. The percent-resected volume, determined via computed tomography volumetry, resulted to be a risk factor for new-onset diabetes [18]. In our study (median follow-up of the overall population of 72.5 months), the incidence of postoperative diabetes was 13.3 %, an impaired glucose tolerance was seen in 14.5 % of patients, and 72.2 % of patients were found with a normal glucose metabolism. Although a volumetric assessment of the pancreatic parenchyma was not performed, the occurrence of diabetes was not correlated with the specimen length (p = 0.175). In summary, our study did not show substantial differences in postoperative outcomes between DP-S and SPDP, although this concept has to be interpreted with caution, because of the retrospective nature of the analysis and the lack of standardization in patient selection and in the choice of surgical techniques. With growing surgical experience, there was not a trend toward broadening the indications or selecting more difficult cases. The learning curve of LDP is a multidimensional phenomenon that can be hardly inferred by single metrics, especially at academic institutions where surgeons in training participate to the operation or perform part of the procedure. In the longterm, the results of LDP are satisfactory, with a lower incidence of new-onset DM than reported in other series. Because of the possibility of serious infections (e.g., overwhelming sepsis), the spleen should be preserved whenever possible. When concomitant splenectomy is performed, strict adherence to vaccine protocols against encapsulated bacteria is strongly recommended.
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Surg Endosc Table 4 Follow-up details of patients undergoing laparoscopic distal pancreatectomy (n = 92)
Distal pancreatectomy with splenectomy (n = 57a) Follow-up parameters
n
Post-splenectomy vaccine Yes No
45 12
Reactive thrombocytosis Yes
23
No
35
ASA for thrombocytosis (n = 22) Yes
19
No
3
Severe infections during follow-up Yes
1
No
58
Spleen-preserving distal pancreatectomy (n = 35a) Follow-up parameters
N
p value (Kimura vs. Warshaw technique)
Yes
8
0.033
No
27
Gastric/perigastric varices
Kimura technique (n = 28) Bold value is statistically significant ASA acetylsalicylic acid, DM diabetes mellitus a
3 patients who initially underwent a spleen-preserving distal pancreatectomy received emergency splenectomy during the index admission because of splenic infarction or splenic abscess, and—for follow-up details—were included in the distal pancreatectomy with splenectomy group
b
2 patients who were diabetics preoperatively were excluded from this calculation
c
8 patients were excluded from this calculation due to conversion to open surgery (n = 2) or reoperation with open technique during the index admission (n = 6)
Yes No Warshaw technique (n = 7)
4 24
Yes
4
No
3
Other follow-up parameters
Overall (n = 92)
SPDP (n = 35)
p value (DP-S vs. SPDP)
0.782
Endocrine insufficiency (n = 90)b Newly diagnosed DM
12
8
4
Impaired glucose tolerance
13
7
6
No
65
40
25
Yes
4
3
1
No
88
54
34
Yes
3
1
2
No
81
49
32
Exocrine insufficiency 0.982
Port-site hernia (n = 84)c
Acknowledgments This paper is dedicated to Professor Gianluigi Melotti MD, who pioneered minimally invasive surgery in Italy and minimally invasive surgery of the pancreas in Verona. Giuseppe Malleo was supported by the Fondazione Italiana per la Ricerca sulle Malattie del Pancreas (FIMP). Disclosures Doctors Giuseppe Malleo, Isacco Damoli, Giovanni Marchegiani, Alessandro Esposito, Tiziana Marchese, Roberto Salvia, Claudio Bassi, and Giovanni Butturini have no conflicts of interest to disclose.
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DP-S (n = 57)
0.563
References 1. Venkat R, Edil BH, Schulick RD, Lidor AO, Makary MA, Wolfgang CL (2012) Laparoscopic distal pancreatectomy is associated with significantly less overall morbidity compared to the open technique: a systematic review and meta-analysis. Ann Surg 255:1048–1059 2. Abu Hilal M, Takhar AS (2013) Laparoscopic left pancreatectomy: current concepts. Pancreatology 13:443–448
Surg Endosc 3. Kneuertz PJ, Patel SH, Chu CK, Fisher SB, Maithel SK, Sarmiento JM, Weber SM, Staley CA, Kooby DA (2012) Laparoscopic distal pancreatectomy: trends and lessons learned through an 11-year experience. J Am Coll Surg 215:167–176 4. Melotti G, Butturini G, Piccoli M, Casetti L, Bassi C, Mullineris B, Lazzaretti MG, Pederzoli P (2007) Laparoscopic distal pancreatectomy: results on a consecutive series of 58 patients. Ann Surg 246:77–82 5. Kimura W, Inoue T, Futakawa N, Shinkai H, Han I, Muto T (1996) Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein. Surgery 120:885–890 6. Ferrone CR, Konstantinidis IT, Sahani DV, Wargo JA, Fernandez-del Castillo C, Warshaw AL (2011) Twenty-three years of the Warshaw operation for distal pancreatectomy with preservation of the spleen. Ann Surg 253:1136–1139 7. Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240:205–213 8. Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, Neoptolemos J, Sarr M, Traverso W, Buchler M (2005) Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 138:8–13 9. Wente MN, Veit JA, Bassi C, Dervenis C, Fingerhut A, Gouma DJ, Izbicki JR, Padbury RT, Sarr MG, Yeo CJ, Buchler MW (2007) Postpancreatectomy hemorrhage (PPH): an international study group of pancreatic surgery (ISGPS) definition. Surgery 142:20–25 10. Mu¨ller HG (1987) Weighted local regression and kernel methods for nonparametric curve fitting. J Am Stat Assoc 82:231–238
11. Rehman S, John SK, Lochan R, Jaques BC, Manas DM, Charnley RM, French JJ, White SA (2014) Oncological feasibility of laparoscopic distal pancreatectomy for adenocarcinoma: a singleinstitution comparative study. World J Surg 38:476–483 12. Di Sabatino A, Carsetti R, Corazza GR (2011) Post-splenectomy and hyposplenic states. Lancet 378:86–97 13. Coignard-Biehler H, Lanternier F, Hot A, Salmon D, Berger A, de Montalembert M, Suarez F, Launay O, Lecuit M, Lortholary O (2011) Adherence to preventive measures after splenectomy in the hospital setting and in the community. J Infect Public Health 4:187–194 14. Mourtzoukou EG, Pappas G, Peppas G, Falagas ME (2008) Vaccination of asplenic or hyposplenic adults. Br J Surg 95:273–280 15. Tezuka K, Kimura W, Hirai I, Moriya T, Watanabe T, Yano M (2012) Postoperative hematological changes after spleen-preserving distal pancreatectomy with preservation of the splenic artery and vein. Dig Surg 29:157–164 16. Butturini G, Inama M, Malleo G, Manfredi R, Melotti GL, Piccoli M, Perandini S, Pederzoli P, Bassi C (2012) Perioperative and long-term results of laparoscopic spleen-preserving distal pancreatectomy with or without splenic vessels conservation: a retrospective analysis. J Surg Oncol 105:387–392 17. Yoon Y-S, Lee KH, Han H-S, Cho JY, Ahn KS (2009) Patency of splenic vessels after laparoscopic spleen and splenic vessel-preserving distal pancreatectomy. Br J Surg 96:633–640 18. Shirakawa S, Matsumoto I, Toyama H, Shinzeki M, Ajiki T, Fukumoto T, Ku Y (2012) Pancreatic volumetric assessment as a predictor of new-onset diabetes following distal pancreatectomy. J Gastrointest Surg 16:2212–2219
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