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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 7  |  Page : 1945-1951

Pancreatic intra-arterial infusion chemotherapy for the treatment of patients with advanced pancreatic carcinoma: A pilot study


1 Department of Oncology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, Shandong, China
2 Department of Cardiology, The First Affiliated Hospital of Shandong First Medical University and Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Cardiac Electrophysiology and Arrhythmia, Jinan, Shandong, China

Date of Submission15-Apr-2022
Date of Decision26-Jun-2022
Date of Acceptance13-Jul-2022
Date of Web Publication11-Jan-2023

Correspondence Address:
Xin Ye
Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute. Jinan - 250014, Shandong
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_819_22

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 > Abstract 


Objective: To preliminarily evaluate the efficacy and safety of pancreatic intra-arterial infusion chemotherapy (PAIC) with nab-paclitaxel in patients with advanced pancreatic carcinoma.
Methods: Fifteen patients with advanced pancreatic carcinoma received monthly, inpatient, 3-h, continuous PAIC of nab-paclitaxel at 180 mg/m2, combined with 60 mg oral tegafur gimeracil oteracil potassium capsule for 2 weeks. The therapeutic courses were repeated every 4 weeks. All patients had a preliminary diagnosis based on clinical symptoms, imaging data (computed tomography or magnetic resonance imaging or positron emission tomography/computed tomography), and tumor markers. The adverse effects, clinical benefit response (CBR), objective response rate (ORR), median progression free survival (mPFS), and median overall survival (mOS) were monitored.
Results: Fifteen patients with advanced pancreatic carcinoma were enrolled in this study, including 10 male and 5 female patients. The mean age at the time of treatment was 66.3 years (53–84 years). A total of 49 cycles of PAIC (mean = 3.27 cycles/patient) were performed. The most common treatment-related toxicities were alopecia, diarrhea, and nausea/vomiting. No procedure-related complications were observed. The longest overall survival observed was 22 months and the maximum number of treatments for the same patient was six cycles. PAIC contributed a high rate (13/15 [86.67%]) and fast (10/15 [66.67%]) easement of pain, with apparent symptom relief within 24 h, especially local pain symptom. The pain anesis rate was 13 (86.67%). CBR was achieved in 13 (86.67%) patients (95%CI [59.54,98.34]). ORR was achieved in four (26.67%) patients (95%CI [7.79,55.10]). Disease Control Rate was achieved in 14 (93.33%) patients. The mPFS was 5.22 months (interquartile range [IQR], 4.27–7.85 months). The mOS was 8.97 months (IQR, 5.65–13.70 months).
Conclusions: In this study, the dose of the chemotherapeutics and the schedule of the transcatheter pancreatic arterial chemotherapy perfusion were shown to be safe, well-tolerated, and effective for the relief of clinical symptoms and CBR. These advantages can quickly establish the treatment belief and improve patient quality of life. This regimen requires further investigation in patients with advanced pancreatic carcinoma.

Keywords: Chemotherapy, infusion, life quality, pancreatic carcinoma, superselective arterial intubation


How to cite this article:
Wang N, Xu J, Wang G, Cao P, Ye X. Pancreatic intra-arterial infusion chemotherapy for the treatment of patients with advanced pancreatic carcinoma: A pilot study. J Can Res Ther 2022;18:1945-51

How to cite this URL:
Wang N, Xu J, Wang G, Cao P, Ye X. Pancreatic intra-arterial infusion chemotherapy for the treatment of patients with advanced pancreatic carcinoma: A pilot study. J Can Res Ther [serial online] 2022 [cited 2023 Jan 27];18:1945-51. Available from: https://www.cancerjournal.net/text.asp?2022/18/7/1945/367479




 > Introduction Top


Pancreatic carcinoma is a life-threatening malignancy. Compared with most other cancers, such as breast and colorectal cancer, the 5-year survival rate of pancreatic carcinoma has not improved in nearly three decades. It has been reported to have a 5-year survival rate of 2.5% in 1970–1977 and 8% in 2007–2013.[1],[2] The bottleneck in improving the survival rate of pancreatic carcinoma is the difficulty of early screening and the lack of effective treatment.[3] More than 80% of patients present with advanced stage carcinoma when the disease is first diagnosed. For most of these patients, radiotherapy techniques and cytotoxic chemotherapy remain the mainstay treatment, which have made relevant but only modest incremental progress in recent decades.[4] At present, the use of some local treatments, such as brachytherapy with iodine-125 (125I) particles, physical ablation techniques, irreversible electroporation, and transarterial chemoembolization, have achieved positive results.[5] The efficacy and safety of nab-paclitaxel and gemcitabine have been proven in advanced pancreatic cancer.[6] However, there are two main reasons that limit the use of nab-paclitaxel in these patients. First, large doses of intravenous drugs increase systemic toxicity and second, the amount drug delivered to the tumor area can be insufficient. These are also the main factors for poor prognosis of intravenous chemotherapy in advanced pancreatic carcinoma.[7],[8] Arterial perfusion chemotherapy, which can provide high concentrations of the drug at the tumor site while reducing high-dose drug exposure of normal tissues, is theoretically an alternative method to solve these problems.[9] Arterial perfusion chemotherapy has also shown better tumor response, fewer complications, longer median overall survival (OS), and higher 1-year survival rate.[10] Multiple preliminary studies have demonstrated the superiority of intra-arterial chemotherapy. However, only a few studies have evaluated the efficacy and safety of pancreatic intra-arterial infusion chemotherapy (PAIC). We conducted a pilot study of PAIC to determine the clinical response, toxic effects, and antitumor activity of monthly 4-h PAIC of albumin-bound paclitaxel in patients with advanced pancreatic carcinoma.


 > Materials and Methods Top


Patients

Between September 2020 and November 2021, 15 patients with locally advanced pancreatic cancer (LAPC) and predominant liver involvement were enrolled in a pilot clinical trial to evaluate the safety and antitumor activity of PAIC with nab-paclitaxel. The clinical protocol involved in this study was reviewed and was approved by the Ethics Committee of the First Affiliated Hospital of Shandong First Medical University. All the participants provided written informed consent before therapy. Study eligibility of the participants had the following criteria: Eastern Cooperative Oncology Group performance status of 0–2,[11] normal functions of the liver and kidney, hematopoiesis, including a total bilirubin concentration of 1.0 mg/dL and a serum creatinine concentration of 1.5 mg/dL, prothrombin time <13 s, activated partial thromboplastin time <30 s, and a normal complete blood count (CBC). Patients with deep vein thrombosis, secondary ascites, obstructive jaundice, and complete intestinal obstruction were excluded from the study.

Treatment

All procedures were performed under local anesthesia administered via the cutaneous femoral artery. Patients underwent angiography placement with a PAIC catheter guided by Digital Subtraction Angiography (DSA). The catheter tip was placed at the proximal end of the supplying artery of the pancreatic tumor. A 5-French catheter was inserted into the right common femoral artery, then a 2.8-French microcatheter (WMST125-27HFA ASAHI 150 cm) was placed at the opening of the supplying artery to the tumor, the gastroduodenal artery (10/15, 66.67%), the proper hepatic artery (2/15, 13.33%), the splenic artery branches of the pancreas (2/15, 13.33%), and the superior mesenteric artery (1/15, 6.67%). The chemotherapeutic, Abraxane, was delivered via the microcatheter to the tumor-supplying artery for 3 h in the inpatient unit. The regimen was repeated every 4 weeks until mortality, tumor progression, or occurrence of life-threatening toxic effects, such as severe neurotoxicity, bone marrow suppression, or other toxicities greater than grade 3.

Therapy evaluation

The baseline evaluation included basic patient information, medical history, disease-related complications, toxicity assessment, and abdominal computed tomography (CT) or magnetic resonance imaging (MRI) scans. Laboratory analysis included a CBC, coagulation profile, total bilirubin, serum albumin, blood urea nitrogen, serum creatinine, and associated tumor markers, including CA19-9 and CEA. At the beginning and end of each course of treatment, the CBCs, liver and renal functions, and tumor marker measurements of the patients were evaluated. Abdominal CT or MRI were performed every two courses of the therapy until there was definite radiographic progress, as determined by the principal investigator.

Response criteria

Assessment of the clinical responses was according to the response evaluation criteria in solid tumors.[11] Complete response (CR) was defined as the disappearance of all lesions. Partial response (PR) was defined as at least a 30% reduction in the tumor load, estimated as the sum of the longest diameters of all measurable lesions, taking as a reference the baseline sum of the longest diameters. Progressive disease (PD) was defined as at least a 20% increase in the tumor load, taking as a reference the smallest sum of the longest diameters recorded since the treatment started or development of new lesions in a previously uninvolved site. Stable disease (SD) was defined as diseases that showed neither sufficient shrinkage nor increase to qualify as either PR or PD. Toxicities were evaluated and graded each cycle of intra-arterial infusion. Treatment would be terminated if the following conditions occurred: (i) progression of disease, (ii) unacceptable toxic effects, (iii) patients declined further treatment. Clinical benefits response (CBR) included one “positive” of three primary measures: Pain intensity, analgesic consumption, and Karnofsky performance status, and one “positive” secondary parameter: Weight gain.[12]

Toxicity assessment

Assessment criteria

The National Cancer Institute Common Toxicity Criteria guidelines, version 2.0.

Assessment content

CBCs, liver function studies, and serum electrolyte measurements were obtained once between monthly treatments.

Statistical analysis

Statistical analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC, USA). Continuous data were expressed as mean ± standard deviation (SD), categorical data were expressed as proportion (%). The two-sided 95% confidence intervals (CIs) for CBR, ORR, and disease control rate were calculated by the Clopper–Pearson method. For time-to-event endpoints, the median was estimated using the Kaplan–Meier method and the corresponding two-sided 95% CIs were calculated using the log-log transformation method.


 > Results Top


Patients and procedure details

The 15 patients, with 10 men and five women, had an age range of 53–84 years (mean age, 66.3 years; median age, 68 years). The demographics and clinical characteristics of the patients are presented in [Table 1]. Eastern Oncology Collaborative Group (ECOG) score was between 1 and 2. In approximately 40% of the patients, the tumor was locally advanced and there was no chance for local excision. Nine patients or 60% had distant metastasis, whereas 10 patients developed complications before treatment, including four patients with diabetes (26.67%), three patients with jaundice (20%), one patient with biliary tract infection (6.67%), one patient with nerve damage (6.67%), and one patient with chronic gastritis (6.67%). Technical success was achieved in all (100%) patients. The chemotherapeutic, nab-paclitaxel, was administered through a 2.8-French microcatheter placed at the opening of the supplying artery to the tumor, including the gastroduodenal artery (10/15, 66.67%), the proper hepatic artery (2/15, 13.33%), the splenic artery branches of the pancreas (2/15, 13.33%), and the superior mesenteric artery (1/15, 6.67%). The longest OS observed was 22 months and the maximum number of treatments was 6 cycles. We observed that PAIC had a rapid relief rate for local pain symptoms in 13/15 (86.67%) of patients. Among them, 10/15 (66.67%) patients had apparent symptom relief within 24 h. CBR was achieved in 13 (86.67%) patients (95%CI (59.54,98.34)).
Table 1: Baseline characteristics of treated patients

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One patient showed PR after four cycles of PAIC. The disease progressed after PAIC was halted in favor of intravenous chemotherapy in cycle 5. The patient was subsequently treated with two cycles of PAIC, which continued to show therapeutic efficacy. A month later, the patient opted to be treated with High intensity focused ultrasound (HIFU) at another hospital. Because of poor perioperative management, the patient's condition deteriorated rapidly and eventually died of biliary tract and intestinal obstruction. The OS of this patient was 11 months.

The disease of another patient continued to progress after surgical resection, radiotherapy, and chemotherapy. The patient presented with abdominal and lumbar back pain with progressive aggravation and refused to continue intravenous chemotherapy because of serious neurotoxic side effects. After two cycles of PAIC, the patient's pain symptoms were significantly relieved without aggravated neurotoxic side effects.

PAIC treatment and toxic effects

A total of 49 cycles of PAIC were conducted during the study period, among which, 10 patients (66.67%) received more than two cycles. The common side effects observed during the study are presented in [Table 2]. As the number of treatment cycles (at least four cycles) increased, the most severe adverse effects (grade 3), diarrhea and rash, were observed more. Alopecia was the most commonly observed side effect, occurring in eight (16.33%) of the 49 treatment courses administered. The next most common treatment-related toxicity was nausea and vomiting (grades 1 and 2, respectively), mainly caused by oral chemotherapy drugs, which was reported in five (10.20%) of the 49 courses administered. Neurotoxicity was observed in five patients but one of them had systemic chemotherapy-induced neurotoxicity before enrollment, without significant exacerbation during the study. A few complications (grades 1 and 2) were observed in patients who underwent more treatment cycles, mainly diarrhea (5/49,10.20%), rash (3/49,6.12%), myelosuppression (2/49,4.08%), mucositis (2/49, 4.08%), and urinary tract infection (1/49,2.04%). There were no catheter-related complications or hypersensitivity reactions to the drugs.
Table 2: Drug-related toxicity profile

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Tumor response and survival

Tumor response was noted in the patients as follows: CR in 0 (0%) patients, PR in four (26.67%) patients, and SD in 10 (66.67%) patients. Objective remission rate (ORR) was achieved in four (26.67%) patients (95%CI (7.79,55.10)). Disease control was achieved in 14 (93.33%) patients [Table 3]. As of November 30, 2021, six (40%) patients were alive and two (13.33%) of them had no disease progression, which was supplemented as deleted data up to the observation date. The median progression free survival (PFS) was 5.22 months (interquartile range [IQR], 4.27–7.85 months) [Table 4]. The median OS was 8.97 months (IQR, 5.65–13.70 months) [Table 5]. [Figure 1] showed the overall survival curve of these patients.
Table 3: Efficacy evaluation

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Table 4: Progression-free survival analysis

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Table 5: Overall survival analysis

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Figure 1: Overall Survival curves

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 > Discussion Top


Pancreatic carcinoma is one of the most common malignant tumors with major treatment challenges.[13] The treatment difficulty is mainly reflected in the improvement in survival with reported 5-year survival rates of 2.5% in 1970–1977 and 8% percent in 2007–2013.[1] Reasons for the poor survival rates are as follows: First, there is no appropriate screening method for the whole population and screening of high-risk groups is difficult. As a result, approximately 80–85% of patients are diagnosed at the advanced stage.[4] Second, surgical resection is the only way to cure the disease, but most patients, following surgical resection, relapse and metastasize in a short term. The 5-year survival rate is about 10–25%.[14] Third, for advanced pancreatic carcinoma patients, cytotoxic chemotherapy, including nab-paclitaxel plus gemcitabine and FOLFIRINOX, remains the mainstay treatment, which provide only modest improvements in OS and last for only a few weeks to months.[15]

Gemcitabine, a nucleoside analog, has been used for the chemotherapy treatment of advanced pancreatic carcinoma with FDA approval since 1996.[16] It has shown a significant advantage for the treatment of advanced pancreatic carcinoma compared to 5-fluorouracil in clinical trials. Until paclitaxel (PTX), gemcitabine has been considered to have a better clinical response and lead to a longer OS time of advanced pancreatic carcinoma patients.[17] However, gemcitabine and PTX have not achieved ideal efficacy because of chemoresistance, the main reason for the poor effects of chemotherapy on pancreatic carcinoma. Various factors such as cell plasticity, tumor heterogeneity, tumor stroma composition, epithelial-to-mesenchymal transition, altered metabolism, and cancer cell-derived vesicles can highly affect treatment outcomes.[18],[19]

In the process of exploring and overcoming chemoresistance, new drugs have been discovered, such as Abraxane, which showed favorable pharmacokinetic properties and reasonable adverse effects. In September 2013, nab-paclitaxel, in combination with gemcitabine, was approved by the FDA as first-line treatment for patients with metastatic adenocarcinoma of the pancreas.[15] Nab-paclitaxel, an anti-tubule agent that inhibits microtubule dynamics, prevents microscopic rearrangement by binding α-tubulins to the polymer, resulting in cell arrest (G2/M phase) and, ultimately, cell death. Nab-paclitaxel, a new member of the taxane family, overcame the shortcomings of traditional taxane drugs with significantly improved efficacy on advanced pancreatic carcinoma.[20]

With the elucidation of the chemoresistance mechanism and the development of new drugs, many trials attempted to solve the problems of combination chemotherapy. De Luca et al.[21] conducted a retrospective analysis of 80 patients between June 2015 and June 2017, which showed that the combination of nab-paclitaxel plus gemcitabine was effective, well-tolerated, and safe for patients with metastatic pancreatic adenocarcinoma and that the toxicity associated with the treatment is acceptable. The advantages of combination therapy were reflected on the pain response rates and improved quality of life (QOL).[22] Fernando Rivera et al.[23] conducted a phase 2 trial of gemcitabine plus nab-paclitaxel for the treatment of pancreatic carcinoma. According to their statistical analysis, the median OS and 1-year survival rate of the combined treatment group were better than those treated with gemcitabine alone, but the combination of nab-paclitaxel and gemcitabine reported a higher number of hematologic toxicities and peripheral neuropathy. Corrie et al.[24] reported that in 146 patients, nab-paclitaxel plus gemcitabine improved PFS and ORR of metastatic pancreatic adenocarcinoma with manageable toxicity, but did not significantly improve OS. It is worth mentioning that the neutropenia incidence of the combined treatment group is twice that of the single drug group, but neutropenia is not detrimental to QOL. Combination treatment was also reported useful in pancreatic carcinoma with severe complications. A retrospective analysis of treatment in patients with cholestatic hyperbilirubinemia indicates that nab-paclitaxel plus gemcitabine could be a feasible and safe treatment option for these patients with severe complications.[25]

Although the treatment of nab-paclitaxel plus gemcitabine showed a longer PFS in patients with advanced pancreatic carcinoma, its adverse effects still affect the overall outcomes. As mentioned above, the main side effects are neutropenia and neurotoxicity. Severe levels (grade ≥3) of neutropenia and neurotoxicity prevent further use in patients, although some studies have reported an association between neutropenia and longer survival.[26] Thus, the search for more effective, less toxic, and easier to use combination therapies is imperative. A study that enrolled a total of 110 patients equally randomized to receive nab-paclitaxel plus S-1 or Nab-paclitaxel plus gemcitabine concluded no difference in PFS or OS between the two groups and an improved safety profile of the former. This trial indicated that the first-line nab-paclitaxel plus tegafur gimeracil oteracil potassium capsule (S-1) maybe a promising and convenient alternative with a more favorable safety profile in advanced pancreatic carcinoma.[27] In this study, we used the combination of nab-paclitaxel plus S-1. Nab-paclitaxel was continuously administered for 3 h after arterial intubation and S-1 was given for 14 days. Results proved the effectiveness of this method and its minimized systemic side effects and enhanced security.

Because of the lack of breakthroughs for the treatment of pancreatic carcinoma, scholars have made great efforts not only in selecting drug but also in selecting the drug-delivery route. A regional chemotherapy technique called total abdominal perfusion (TAP), which could provide higher locoregional drug exposure with lower systemic toxicity, was reported in 1994. TAP enabled an almost complete and safe isolation and perfusion of the abdominal vascular segment.[28] Some reports recorded that irreversible electroporation in combination with radiotherapy prolonged survival and improved survival for patients with LAPC.[29] Similarly, transarterial chemoembolization (TACE) had been mentioned in some other studies.[30] Another report focused on the clinical effectiveness of combined interventional therapy in pancreatic carcinoma, concluding that combined TACE and 125I and/or radiofrequency ablation treatment may prolong the survival time compared with TACE alone and that the complications and the adverse effects from the combination of these treatments could be resolved following active management.[31]

Previous studies have focused on the use of chemotherapy drugs in the artery, mainly including drug-loaded microspheres and arterial intubation mass injection. This study presents a new drug-delivery method that selects tumor-supplying arteries for continuous arterial perfusion. The theoretical basis of this method is as follows: First, mass injection is the main method of intra-arterial chemotherapy, which is suitable for tumors with rich blood supply. However, in mass injection, only a small amount of the drug enters the tumor and because the pancreatic tumor is mostly hypovascular, its supplying arteries are narrow.[8] Second, chemotherapeutic drugs tend to cause transient spasms on local small blood vessels, significantly reducing the first pass effect and further reducing the total amount of drugs delivered to the tumor.[32] Third, nab-paclitaxel is a resistance-dependent and toxic drug. Arterial perfusion can improve drug concentrations at the tumor site and decrease the systemic side effects of chemotherapy. Prolonging the infusion time will allow the drugs to enter the tumor effectively. Compared with the mass infusion method, continuous pumping drug concentration could further improve the concentration and exposure time, amplifying the tumor-killing effect.[33] It has been reported that high doses and/or prolonged exposure of the tumor to paclitaxel may overcome drug resistance.[33]

The results of this study suggest that PAIC is tolerated well and effective for the treatment of LAPC. The most serious treatment-related toxicities were alopecia, diarrhea, and rash (grade 3), which appeared a few days after more than four cycles of PAIC. These toxicities did not affect continued treatment and tumor control rate in the patients. We observed that PAIC was effective in patients who had previously been resistant to intravenous chemotherapy and had experienced neurotoxicity. Camacho et al.[34] conducted a study with three patients with breast carcinoma metastatic to the liver who previously received treatment with taxanes and were treated with hepatic intra-arterial paclitaxel. All three patients attained a partial response.[34] This result was consistent with our study and we compared the toxicity of arterial and intravenous chemotherapy.[35]

Possible analgesic mechanisms

Studies have found that the mechanisms of pain caused by pancreatic carcinoma in patients are as follows: First, neuropathic pain is the dominant mechanism. The main pathophysiological mechanism is the invasion of the nerve plexus caused by local tumor progression and distant metastasis.[36] Another part is the nerve damage and dysfunction caused by pancreatic tumor cells invading nerves and producing a series of abnormal growth factors.[37],[38] A link between pancreatic carcinoma and depression has also been reported.[39] Second, compression and obstruction caused by local tumor progression also cause pain from pancreatic carcinoma. The pancreas is located in the retroperitoneal position of the upper abdomen. Growth of the local tumor can easily lead to the compression of the retroperitoneal plexus and adjacent organs. The peritoneum, omentum, and liver are some of the most common areas of pain because pancreatic tumors often metastasize to these areas.[40] In addition, biliary and intestinal obstruction caused by the pancreatic tumor are also sources of pain.[41]

Based on the above theoretical basis, PAIC can provide high concentration and sustained nab-paclitaxel in the tumor tissue for a short period of time[33] that can directly kill and reverse the drug resistance of tumor cells, further promoting drug-delivery deep into the tumor tissue and changing tumor structure and texture.[33] These changes directly lead to the reduction of local tumor compression and nerve damage and to the inhibition of the release of pain-related factors, achieving fast and effective analgesic effect. Nerve damage, one of the side effects of nab-paclitaxel, may cause direct damage to the retroperitoneal plexus, causing pain relief. All these, of course, require further verification.

The limitations of this study were the small number of cases and the short follow-up period. Although this study had encouraging results, further studies are needed to prove the safety and efficacy of PAIC for patients with advanced pancreatic carcinoma.

Nan Wang was responsible for performing the experiments and drafted the manuscript. Nan Wang and Jingwen Xu were responsible for acquisition and analysis of data. Gang Wang and Pikun Cao provided and collected the clinical data. Xin Ye was responsible for designing the experiments and supervising the study. All authors read and approved the final manuscript.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Financial support and sponsorship

This article is supported by Traditional Chinese Medicine Science and Technology Project of Shandong Province (no. 2020Q036) and National Natural Science Foundation of Qianfoshan Hospital, Shandong Province (no. QYPY2021NSFC0608). This article is supported by Academic promotion programme of Shandong First Medical University (2019LJ005).

Conflicts of interest

There are no conflicts of interest.



 
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