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Laparoscopic ultrasonography‑guided cryoablation of locally advanced pancreatic cancer: a preliminary report

27 Mar.,2025

Patients and methods From April 2018 to December 2018, ten patients (five women, five men; mean age 58.2 ± 9.4 years) with LAPC underwent the operation. LUS was used to guide the cryoablation. Computed tomography (CT) imaging, bio- chemical analysis and pain score analysis by numeric rating scale (NRS) were used to assess treatment outcomes at 1 week and 3 months after the operation.

Yingchun Wu1 · Yuqing Gu2 · Bin Zhang2 · Xin Zhou2 · Yanan Li2 · Zhuyin Qian2

Received: 4 March 2021 / Accepted: 13 July 2021

Abstract

Objective To evaluate safety and feasibility of laparoscopic ultrasonography (LUS)-guided cryoablation of locally advanced pancreatic cancer (LAPC).

Results Cryoablation was performed by the operation in all cases. Seven patients received complete ablation and the success

rate of operation was 70%. Two cryoablation cycles and an average of 1.4 ± 0.5 cryoprobes were used. The average freezing time and operation time were 23.8 ± 1.0 and 110.5 ± 24.7 min, respectively. The mean blood loss was 52.0 ± 16.6 ml. No major complications were observed after the operation. The mean maximum tumor diameter determined by CT decreased from 4.9 ± 0.7 cm before the operation to 4.7 ± 1.0 cm at 1 week and 4.6 ± 1.3 cm at 3 months, with P values of 0.53 and 0.51 (relative to the preoperative values), respectively. Postoperative CT imaging results suggested tumor necrosis in cryoablation- treated areas. The mean CA19-9 levels decreased from 347.5 ± 345.7 U/mL before operation to 190.4 ± 153.8 U/mL at 1 week and 182.7 ± 165.6 U/mL at 3 months, with P values of 0.15 and 0.14 (relative to the preoperative values), respectively. The average pain scores declined from 6.9 ± 1.1 before operation to 1.3 ± 1.2 at 1 week and 2.0 ± 0.8 at 3 months, with both P values of < 0.01 (relative to the preoperative values).

Conclusion This preliminary study suggested that LUS-assisted cryoablation was a safe and feasible treatment for LAPC.

Keywords Locally advanced pancreatic cancer · Laparoscopic ultrasonography · Laparoscopy · Cryoablation

Introduction

Locally advanced pancreatic cancer (LAPC), defined as irresectable pancreatic tumors without distant metastases, constitutes up to 30% of the pancreatic cancer cases [1, 2]. While chemotherapy and chemoradiotherapy currently serve

as the mainstays for LAPC treatment, the 5-year overall sur- vival rate for patients is still less than 5% [3–5]. Therefore, LAPC is generally treated as advanced-stage disease without effective treatment options [6].

Owing to the controllability and minimal invasiveness, locally ablative therapies via heating or freezing tumor tissues to promote tumor cell death have displayed great promise in focal treatment of various malignancies, includ-

Yingchun Wu and Yuqing Gu have contributed equally.

* Zhuyin Qian qianzhusilver@163.com

1 Ultrasonic Department, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, People’s Republic of China

2 Pancreas Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210003, People’s Republic of China ing LAPC [7–10]. For example, radiofrequency ablation (RFA) generates high-frequency alternating current to produce heat in tumor, which makes the protein denatured and coagulated to destroy tumor cells; microwave ablation (MWA) relies on the heat generated by high-speed oscil- lation of molecules under the action of microwave, which makes tumor cells coagulate and necrotic [11, 12]. Never- theless, due to the high risk in damaging the surrounding tissues, RFA and MWA have not been widely used in the treatment of pancreatic cancer. Additionally, irreversible electroporation (IRE) is also a local ablative approach that can cause irreversible electroporation of cell membrane through instantaneous high voltage direct current, which finally induces tumor cell apoptosis [11]. Although up to 16% of complete tumor remission rate and up to 38.2% of partial tumor response rate are demonstrated using surgical and percutaneous IRE to treat LAPC [13], its safety and efficacy still need further clinical validation.

Compared to the ablative approaches described above, cryoablation is superior in terms of safety, due to its less damages toward vascular integrity [8]. Notably, this feature of cryoablation is especially important for LAPC treatment because pancreas tissue is adjacent to many important blood vessels [14]. Cryoablation of LAPC is thus actively pursued in recent years with a main focus on imaging-guided per- cutaneous approach [15]. For example, Arcidiacono et al. reports that percutaneous cryoablation for LAPC is suc- cessfully applied in 72.8% patients, and the rates of partial response and stable disease are 18.7 and 81.3%, respectively [16]. Notably, the median post-ablation survival time was 6 months. However, considering the complicated microen- vironment of pancreas that is deeply seated in the back of abdominal organs such as stomach and colon, success of percutaneous cryoablation heavily relies on doctors’ experi- ences on the number, depth and angle of the needles required for cryoablation [17]. Therefore, to improve the accuracy, safety and efficacy for LAPC therapy, cryoablation to treat tumors under laparoscopic imaging [18] is more appealing, which however has yet to be explored.

Compared with laparoscopy that only provides two-dimensional laparoscopic images of tissues, laparoscopic ultrasonography (LUS) allows to visualize tissues in a three-dimensional manner, thereby enriching the informa- tion with high quantity and quality for doctors [19]. In this study, taking the advantage of LUS in precisely monitoring the location and size of tumors as well as their connection with nearby vessels or organs, we explored the use of LUS to assist laparoscopic cryoablation of LAPC. The feasibil- ity and safety of LUS-guided cryoablation of LAPC were evaluated and reported.

Patients and methods

This retrospective study was approved by the Ethics Com- mittee of our hospital according to the Declaration of Helsinki.

Patient selection

LAPC was diagnosed by CT imaging. For patients with lim- ited responses to systemic chemotherapy and chemoradiation therapy, they volunteered to receive the LUS-guided cryoa- blation. Written informed consent was obtained from each patient before enrollment. Between April 2018 and Decem- ber 2018, 15 patients with LAPC who met the inclusion criteria were enrolled. Inclusion criteria were as following:

(1) the eighth edition of American Joint Committee on Cancer staging criteria and National Comprehensive Can- cer Network guideline for pancreatic cancer, LAPC tumor contact of > 180° with the superior mesenteric artery (SMA) or celiac artery (CA), tumor contact with the CA and aor- tic involvement, or unreconstructible superior mesenteric vein or portal vein due to tumor involvement or occlusion;

(2) no biliary or gastrointestinal obstruction; (3) an Eastern Cooperative Oncology Group performance status score of 0, 1 or 2. Then, five patients were excluded according to the exclusion criteria. The exclusion criteria were as following:

(1) inapplicability due to previous operative history (one patient); (2) intolerance of general anesthesia (one patient);

(3) distant metastasis revealed by laparoscopic exploration (three patients). Finally, ten patients underwent the operation were included in this study.

Instruments

An argon-helium gas-based freeze–thaw cryoablation sys- tem (CRYOCARE, Health Tronics, USA) was used. The number of cryoprobes used to ensure that the ice ball com- pletely covered the tumor tissue was based on the tumor size monitored by LUS. Tumor specimens were obtained with a biopsy needle (Tru-cut, Bard, USA) before cryoablation. LUS monitoring was performed during pathological biopsy, cryoprobe puncture and the whole process of ice ball forma- tion using an endoscopic ultrasound (S8 Exp, SonoScape, China).

Cryoablation procedure

The patient was placed in the supine position and given gen- eral anesthesia. A 10 mm umbilical incision was taken and a CO2 pneumoperitoneum was established. The abdominal pressure was maintained at 12 mm Hg. Laparoscopy was inserted, and under direct vision, 5, 12 and 5 mm Trocar was placed into the right upper, right lower and left upper abdomen in the midclavicular line, respectively. The dis- tant metastasis of abdominal cavity was explored routinely. Gastrocolic ligament was incised to expose the pancreas and tumor. The location, texture, size of the tumor and relation- ship with vessels and surrounding organs were explored by LUS. Intraoperative LUS was performed by an ultrasound physician with more than 10 years’ experience. Puncture needle was inserted under the guidance by LUS and laparos- copy. Tumor biopsy was performed at 2–3 sites in different directions at the same puncture point guided by LUS. The puncture point was compressed with hemostatic cotton, and sutured with 4–0 Prolene suture if the bleeding could not stop.

Guided by LUS, the operation scheme, number of cryo- probe, position and direction of probe insertion, freezing power and time were carefully designed. The surrounding organs (stomach, duodenum, jejunum, colon and omentum majus) closed to pancreatic tumor was isolated and protected carefully using gauze. We used the cryoprobe with a diam- eter of 1.7 mm to puncture into the tumor according to the design plan until reaching the bottom of the tumor. The cryo- probe was pre-frozen and kept at – 10 °C. The ice ball size was positively correlated with the diameter of cryoprobe, freezing power and time. The freezing power we used was 60–100%. Under low power, the ice ball was in the shape of long droplets, and the higher the power was, the fuller the ice ball was. The freezing time was in the range of 8–15 min. It is difficult to distinguish the lower edge of ice ball, so it is required to observe the shape of ice ball from multi- ple angles. To achieve complete ablation (A0), the ice ball was formed 0.5 cm larger than the tumor size. If the tumor had invaded and could not be separated from critical struc- tures, the ice ball only covered the tumor without extending beyond the border. After freezing tumor tissues to − 150 to– 160 °C, rewarming to 30 °C was performed. The process

of freezing and rewarming was regarded as a cycle. Gener- ally, two freeze cycles were used. At the end of cryoablation, the probe was gently rotated and pulled out after being loos- ened. After cryoablation, the puncture point was compressed with hemostatic cotton and sutured with 4–0 Prolene suture. A drainage tube was routinely placed beside the pancreas, and if there was no evidence of pancreatic fistula or hemor- rhage, the drainage tube was removed on the third day after the operation.

Evaluation of therapeutic outcomes

The primary endpoint was to assess the feasibility and safety of LUS-guided cryoablation for treatment of LAPC. The operation was defined as feasible if the pancreatic tumor received complete ablation, and success rate of operation was the ratio of patients received complete abla- tion. Postoperative complications were evaluated accord- ing to the Clavien-Dindo classification [20] and included acute pancreatitis, pseudocysts, pancreatic fistula, hemor- rhage, delayed gastric emptying, infections or abscesses. We used laboratory and radiologic follow-up to detect the potential possible complications. Blood tests (white blood cell count (WBC), hemoglobin (Hb), serum amyl- ase, C reactive protein (CRP) and serum tumor marker CA19-9 were scheduled within 3 days before, at 1 week and 3 months after the operation. Abdominal enhanced CT scan was performed within 3 days before, 1 week and 3 months after the operation to detect the potential com- plications and estimate the size and density of the tumor. Any complications arising from the primary tumor within 3 months were considered as postoperative complication related to the procedure. We used the criteria of Response Evaluation Criteria in Solid Tumors (RECIST) for the imaging response. Also, preoperative and postoperative pain scores were assessed by numeric rating scale (NRS). Pain scale can be divided into 0–10: 0, no pain at all; 10, most intense pain imaginable.

Statistical analysis

The results were shown as mean ± standard deviation (SD). The differences between pre-operative and post-operative values of WBC, Hb, CRP, serum amylase values, pain score, CA19-9 and tumor size were compared using the paired t tests. P < 0.05 was considered statistically significant.

Results

Patients

Baseline patient demographics are given in Table 1. Patients were comprised of five men and five women with a mean age of 58.2 ± 9.4 years. The lesions were located in the body tail (n = 7) and the neck (n = 3). Six patients had CA invasion, and four patients had both CA and common hepatic artery invasion. Moreover, six patients had comorbidities such as hysterectomy, hypertension and diabetes.

Feasibility

All processes were successfully performed according to the plan (Fig. 1) without using laparotomy. Operative data moni- tored during the operation are shown in Table 2. The mean number of ports introduced by Trocar was 4.3 ± 0.5. Tumors of all the ten patients were pancreatic ductal adenocarcino- mas according to hematoxylin and eosin staining results. The average tumor size determined by LUS was (4.9 ± 0. 7 cm) × (3.4 ± 0.8 cm). According to the shape and size of the tumor, six patients were treated by one cryoprobe and four patients were treated by two cryoprobes. Guided by LUS, seven patients successfully received complete ablation (A0). The success rate of operation was 70%. Two cycles of cryoablation were used for all ten patients and the average freezing time was 23.8 ± 1.0 min. The average operative time was 110.5 ± 24.7 min, and the average bleeding volume dur- ing the operation was 52.0 ± 16.6 ml.

Table 1 Baseline patient demographics

No	Age (years)	Sex (F/M)	Tumor location	Vascular invasion	Comorbidities
1	69	F	Body, tail	CA	Hysterectomy
2	59	M	Body, tail	CA	Hypertension
3	60	F	Body, tail	CA	None
4	47	F	Neck	CA	None
5	61	M	Body, tail	CA and CHA	None
6	61	M	Neck	CA and CHA	duodenal ulcer
7	76	F	Neck	CA and CHA	Hypertension
8	51	M	Body, tail	CA	Hypertension
9	48	M	Body, tail	CA	None
10	50	F	Body, tail	CA and CHA	Diabetes
Total	58.2 ± 9.4 (mean ± SD)	M = 5 F = 5	Body, tail = 7 Neck = 3	CA = 6 CA and CHA = 4	–

F female; M male; CA celiac artery; CHA common hepatic artery

Laparoscopic ultrasonographyâ€‘guided cryoablation of locally advanced pancreatic cancer: a preliminary report

Fig. 1 A Intraoperative ultrasound image of the frozen tumor. B Optical image of frozen pancreatic tumor tissues under laparoscopy. C Optical image of the pancreatic tumor after cryoablation

Table 2 Intraoperative data

No	No. of ports	Biopsy result	Tumor size determined by LUS (cm)	No. of cryo- probes	Cryo cycles	freezing time (min)	A0 ablation	Blood loss (ml)	Operative time (min)
1	4	AD	4.2 × 3.2	1	2	23	Yes	40	90
2	4	AD	4.5 × 4.0	1	2	23	Yes	50	80
3	4	AD	5.5 × 5.2	2	2	23	No	100	100
4	5	AD	4.0 × 3.5	1	2	23	Yes	50	90
5	4	AD	6.0 × 2.5	2	2	25	No	40	150
6	5	AD	6.2 × 4.0	2	2	25	No	50	125
7	5	AD	5.0 × 3.0	2	2	23	Yes	50	150
8	4	AD	4.2 × 2.0	1	2	23	Yes	50	130
9	4	AD	4.5 × 3.0	1	2	25	Yes	40	100
10	4	AD	4.5 × 3.5	1	2	25	Yes	50	90
Total	–	AD = 10	–	–	–	–	Yes = 7 No = 3	–	–
Mean ± SD	4.3 ± 0.5	-	(4.9 ± 0.7)× (3.4 ± 0.8)	1.4 ± 0.5	–	23.8 ± 1.0	–	52.0 ± 16.6	110.5 ± 24.7

AD: Adenocarcinoma; A0 ablation: ice ball was formed 0.5 cm larger than the tumor

Safety

Patient characteristics were acquired at 1 week and 3 months post the operation and are shown in Table 3. Adjuvant therapy was used after the operation in seven patients. For all ten patients, the average extubation time was 2.4 ± 0.7 days, and the mean duration of hospitali- zation was 7.4 ± 1.3 days. The body temperatures of all

patients were below 37.3 °C during the perioperative period. Complications such as acute pancreatitis, pseudo- cysts, pancreatic fistula, hemorrhage, delayed gastric emp- tying, infections or abscesses were not observed after the operation. Blood test data including WBC, Hb, CRP and serum amylase are shown in Table 3. Briefly, no signifi- cant changes in biochemical analysis data were observed. Notably, in case 5 and 7, even though CRP values reached

Table 3 Patient characteristics after the operation

No	Complication	Recovery time (day)	Extubation time (day)	CA19-9 (U/mL) (Preop-eration 1 week 3 months)	NRS (Preop-eration 1 week 3 months)	Maximum tumor diameter by CT (cm) (Preop-eration 1 week 3 months)	Postoperative adjuvant therapy
1	None	6	2	350.7 210.3 137.6	8 0 2	4.7 4.1 4.0	Chemotherapy(G + S)
2	None	8	2	958.4 261.3 236.0	6 0 1	4.7 5.3 4.8	Chemotherapy(G + S)
3	None	7	2	21.6 12.2 11.5	7 0 1	5.7 5.7 5.4	None
4	None	7	3	4.4 3.1 1.8	8 2 2	4.2 3.8 3.2	Chemotherapy(G + S) +Radiotherapy
5	None	5	2	> 1000 > 1000 > 1000	5 2 3	5.8 5.6 6.5	None
6	None	8	2	638.5 441.9 475.1	6 1 3	6.3 6.3 6.8	Chemotherapy(S)
7	None	8	2	290.4 257.3 282.1	7 3 2	4.5 4.7 4.5	Chemotherapy(S)
8	None	8	3	> 1000 > 1000 > 1000	8 3 2	4.0 4.0 4.2	Chemotherapy(G + S)
9	None	10	2	> 1000 > 1000 > 1000	8 2 3	4.1 2.8 2.5	Chemotherapy(S)
10	None	7	4	168.4 164.9 134.7	6 0 1	4.7 4.7 4.5	None
Mean ± SD (P)	–	7.4 ± 1.3	2.4 ± 0.7	347.5 ± 345.7 190.4 ± 153.8 (P = 0.15) 182.7 ± 165.6 (P = 0.14)	6.9 ± 1.1 1.3 ± 1.2 (P < 0.01) 2.0 ± 0.8 (P < 0.01)	4.9 ± 0.7 4.7 ± 1.0 (P = 0.53) 4.6 ± 1.3 (P = 0.51)	–

Table 3 (continued)

No	WBC (× 10^9/L) (Preopera-	Hb(g/L) (Preoperation 1 week 3 months)	CRP(μg/L) (Preoperation 1 week 3 months)	Serum amylase (U/L) (Preoperation 1 week 3 months)
1	4.8	105	0.5	83
	4.1	106	1.5	58
	4.3	109	1.9	60
2	4.8	126	1.7	85
	5.1	122	2.0	115
	4.1	128	0.5	59
3	4.8	116	0.5	68
	5.7	107	5.4	93
	6.3	120	2.3	87
4	5.1	85	2.4	84
	4.7	90	1.2	76
	3.5	91	1.4	86
5	4.7	137	10.4	53
	5.8	140	21.1	104
	4.4	136	10.7	68
6	5.4	130	1.8	73
	4.8	126	3.3	121
	5.7	125	8.8	82
7	7.1	116	15.8	58
	6.7	111	18.3	64
	7.3	113	13.0	74
8	9.0	139	0.5	87
	9.3	136	0.6	62
	7.8	129	0.5	57
9	4.1	109	0.5	71
	4.0	116	0.9	63
	5.1	101	0.5	85
10	5.7	113	0.5	94
	6.0	118	0.5	68
	7.4	119	1.8	73
Mean ±	5.6 ± 1.4 5.6 ± 1.5 (P = 0.73) 5.6 ± 1.5 (P = 0.91)	117.6 ± 15.4 117.2 ± 14.1 (P = 0.82) 117.1 ± 13.1 (P = 0.79)	3.5 ± 5.0 5.5 ± 7.3 (P = 0.10) 4.1 ± 4.5 (P = 0.43)	75.6 ± 12.6 82.4 ± 22.6 (P = 0.49) 73.1 ± 11.1 (P = 0.70)

G: Gemcitabine; S: S-1; For CA19-9 analysis, cases 5, 8 and 9 were not considered

WBC White blood cell count; Hb hemoglobin; CRP C-reactive protein more than 10 μg/L, these patients did not have any abnor- mal clinical symptoms or signs.

Oncological outcomes

The average scores of lumbar and back pain determined by NRS for all ten patients before the operation was 6.9 ± 1.1 (Table 3). In comparison, the mean pain scores at 1 week and 3 months after the operation remarkably decreased to 1.3 ± 1.2 and 2.0 ± 0.8 with P values of < 0.01, respectively. As shown in Table 3, serum CA19-9 levels in cases 5, 8 and 9 were not considered since they were beyond the detection range (> 1000 U/mL). For the other seven patients, aver- age pre-operative CA19-9 levels were 347.5 ± 345.7 U/ mL. CA19-9 levels decreased to 190.4 ± 153.8 U/mL and 182.7 ± 165.6 U/mL at 1 week and 3 months post the opera- tion, with P values of 0.15 and 0.14 (relative to the preopera- tive values), respectively.

Imaging response

Abdominal enhanced CT was used to evaluate the tumor size before, at 1 week and 3 months after the operation (Fig. 2). The mean maximum tumor diameter decreased from 4.9 ± 0.7 cm before the operation to 4.7 ± 1.0 cm at 1 week and 4.6 ± 1.3 cm at 3 months, with P values of 0.53 and 0.51 (relative to the preoperative values), respec- tively (Table 3). Despite only a minor tumor shrinkage was observed after the operation, the low-density areas in the tumor center were detected in CT images, indicating tumor necrosis in cryoablation-treated areas. Moreover, the CT imaging results indicated that the ten patients at 3 months after the operation all had stable disease.

Laparoscopic ultrasonographyâ€‘guided cryoablation of locally advanced pancreatic cancer: a preliminary report

Fig. 2 CT images of pancreatic tumor (case 2) indicated by

red circle in plane of superior mesenteric artery. A Before the operation, at B 1 week and C

3 months after the operation. White arrows indicate low- density necrosis areas

Discussion

The life quality and prognosis of LAPC patients are poor [21], urging the development of safe and effective thera- peutic approaches. Although cryoablation is a new option, LAPC is relatively intractable to cryoablation, due to the deep position of pancreas and close proximity of abdominal organs. As such, strategies to improve the accuracy, safety and efficacy of cryoablation of LAPC are highly desirable.

While intraoperative cryoablation during open operation is a potential method to address aforementioned challenges, its shortcomings are also obvious, which cause large opera- tive trauma [22]. In comparison, laparoscopic cryoablation is superior in LAPC treatment, as it can be accomplished with minimal invasiveness. This advantage thus makes lapa- roscopic cryoablation attractive in LAPC treatment, which however has not been investigated before. In this study, for the first time, we explored the potential of laparoscopic cry- oablation in treatment of LAPC. To ensure the tumor loca- tion, size as well as the surrounding tissue connections, we used LUS that could provide three-dimensional information. In our work, staging laparoscopy was combined with LUS to locate tumor tissues and determine the blood vessel invasion of CA and SMA, providing a proper staging of pancreatic cancer. Guided by LUS, pancreatic tumor was fully exposed and measured to introduce puncture needles with suitable direction and angle. Furthermore, accidental damage of major blood vessels and pancreatic duct was avoided, and the formation of ice ball was monitored in real time. There were seven patients received complete ablation. The reason for the other three patients received incomplete ablation was that the tumor had invaded and could not be separated from stomach or jejunum. In addition, while LUS is suitable for evaluating multi-organ infiltration and encasement of portal vein and arteries, its use for boundary evaluation with the stomach or intestine is not ideal, which may also account for the incomplete ablation. There were no trauma and seri- ous complications. In two patients, although CRP levels increased to over 10 μg/L, they did not have any infectious symptoms or signs. We speculated that this was related to tumor cell necrosis and operative stress response. Lumbar and back pain is often found in pancreatic cancer patients for the peripheral nerves invasion [23, 24]. Due to tumor cell damage and subsequent inhibition of neural invasion, backache of patients enrolled in this study were relieved significantly. Serum CA19-9 is a good indicator to predict the therapeutic effect of pancreatic cancer patients [25]. In this study, CA19-9 levels markedly decreased, suggesting the reduction of tumor burden. Postoperative follow-up indi- cated that cryoablation of LAPC could safely induce tumor necrosis, thus providing a basis for further development of cryoablation for LAPC.

There are also some limitations in this preliminary study. For example, the small population, short-term evaluation and retrospective design need to be improved in future study. Moreover, although the LUS detector is flexible in many directions and can directly contact with pancreatic tissue to provide high-resolution images, we also realize that LUS is a highly technical, which needs experienced ultrasound doctors to operate. Another limitation of cryoablation for PC may be the difficulty in accurate evaluation of necrosis even on dynamic CT images, because PC is not hypervascular originally. While positron emission tomography may be a good method for necrosis assessment [26], it was not used in this study due to its high cost. Additionally, postoperative adjuvant therapy might also contribute to the observed thera- peutic outcomes, which may confound the evaluation in this study. However, this preliminary study still indicates that LUS-guided cryoablation procedure is a potential approach to treat LAPC, which deserves further assessment in the future.

In summary, our initial results revealed that cryoabla-tion of pancreatic cancer can be performed safely under the guidance by LUS.

Funding No funding for the present study.

Declarations

Conflict of interest The authors declare that they have no conflict of interest.

Ethical approval This retrospective study was approved by our insti- tutional review board.

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