Home Life Sciences Endostar plus pembrolizumab combined with a platinum-based dual chemotherapy regime for advanced pulmonary large-cell neuroendocrine carcinoma as a first-line treatment: A case report
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Endostar plus pembrolizumab combined with a platinum-based dual chemotherapy regime for advanced pulmonary large-cell neuroendocrine carcinoma as a first-line treatment: A case report

  • Sijia Zhang , Yu Xiao , Leichong Chen , Zhenyu Li , Yan Zong , Kuikui Zhu and Rui Meng EMAIL logo
Published/Copyright: June 15, 2022
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Open Life Sciences
From the journal Open Life Sciences Volume 17 Issue 1

Abstract

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare and highly aggressive cancer with a very poor prognosis. The proper treatment decision and possible prognosis outcome for advanced LCNEC is always an enormous challenge due to its scarcity. Here, we presented a 59-year-old male patient with advanced LCNEC with a non-neuroendocrine immunophenotype who received endostar plus pembrolizumab combined with a platinum-based dual chemotherapy regime as a first-line treatment. At present, the patient’s condition is well controlled by medication only and has a progression-free survival of more than 2 years. Adverse effects recorded for this patient during treatment courses include nausea, vomiting, II–III quality bone marrow toxicity, and PD-1 blockage-related hypothyroidism. This case report discussed the feasibility of immunotherapy, anti-angiogenesis agents, and chemotherapy as a first-line therapy in advanced LCNEC.

Keywords: pulmonary large-cell neuroendocrine carcinoma; immunotherapy; anti-angiogenesis; chemotherapy; combination therapy

1 Introduction

Pulmonary large-cell neuroendocrine carcinoma (LCENC) is a high-grade neuroendocrine (NE) carcinoma, accounting for 1.7–3.0% of all diagnosed lung cancer [1]. Liver (47%), bone (32%), and brain (23%) metastases were found at initial diagnosis in more than half of LCNEC patients, with a median overall survival (mOS) of 4.0 months [95% confidence interval (CI) 3.5–4.6] [1]. Up to date, the optimal treatment strategy for LCNEC is rarely known. Due to the similarity to small-cell lung carcinoma (SCLC) in clinical characteristics, common LCENC is treated with SCLC-like platinum-based doublet chemotherapeutic regimens, such as cisplatin–etoposide or cisplatin–irinotecan [2]. However, poor control rates and low progression-free survival (PFS)/overall survival (OS) are still important limitations.

Immunotherapy, PD-1/PD-L1 blockade, and anti-angiogenesis agents have antitumor activity. Synergic therapy of the above drugs with cytotoxic agents has been confirmed to prolong the survival time of patients with NSCLC and/or SCLC as first-line therapy. Currently, the efficiency of synergic therapy is still unclear in metastasis LCNEC. Here, we reported a case of advanced LCNEC that responded well to irinotecan–nedaplatin chemotherapy combined with immunotherapy and antiangiogenic as the first-line therapy.

2 Case presentation

In May 2018, a 59-year-old male patient was diagnosed at a local hospital with left lung space and left pleural effusion due to sudden left chest pain. He was admitted to our hospital (Union Hospital of Tongji Medical College, Wuhan, China) the next month. The patient complained of hypertension and long history of smoking with a smoking index of over 400. Admission physical examination revealed no positive signs and the Eastern Cooperative Oncology Group (ECOG) performance status of the patient was 1. A positron emission tomography–computed tomography (CT) scan showed multiple nodules in the lingual segment of the left upper lobe, with a maximum of 2.1 cm × 2.2 cm, which was closely related to the pleura. Part of them had abnormally increased metabolism. Bilateral pleural and interlobular fissures were unevenly thickened, and multiple nodules were concentrated on the left side with increased metabolic dispersion. Multiple lymph nodes enlargement occurred in the mediastinum (areas 3R, 4R/L, 5, 7) and hilar of both lungs with abnormal metabolism (Figure 1). Malignant tumor lesions are mostly considered according to those mentioned above. The primary left lung with bilateral pleura, interlobular fissure, mediastinum, and bilateral hilar lymph node metastasis was likely to be left pleural effusion; there were no signs of tumor metastasis in the rest of the exploration site. On June 13, 2018, a CT-guided biopsy of the left lung was performed. Histopathology showed a non-small-cell carcinoma with NE morphology (shown in Figure 2a), which was suspected to be LCENC, but the NE marker was negative. Immunohistochemical (IHC) results are summarized in Table 1, and all the positive staining is presented in Figure 2b–f. PD-L1 expression status was not tested due to the deficiency of the puncture biopsy. Brain magnetic resonance imaging (MRI) excluded brain metastases. Next-generation sequencing (NGS) analysis using 556 cancer-related gene panels revealed a total of 6 non-synonymous somatic mutations (4 missenses, 2 introns). Based on the above results, this patient was diagnosed with c-stage IVA, cT2N3M1b (pleura) (AJCC8th TNM classification).

Figure 1 Chest CT scan revealed multiple solid small nodules were scattered in both lungs, multiple nodules in bilateral pleura, multiple enlarged lymph nodes in mediastinum and bilateral hilum. A patchy soft tissue density shadow with a cross-sectional area of about 1.6 cm × 0.9 cm was seen near the heart margin of the lingual segment of the left lung, which was significantly enhanced by enhanced scan.
Figure 1

Chest CT scan revealed multiple solid small nodules were scattered in both lungs, multiple nodules in bilateral pleura, multiple enlarged lymph nodes in mediastinum and bilateral hilum. A patchy soft tissue density shadow with a cross-sectional area of about 1.6 cm × 0.9 cm was seen near the heart margin of the lingual segment of the left lung, which was significantly enhanced by enhanced scan.

Figure 2 Morphologic and IHC features. (a) Pathological examination of puncture biopsy of the left lung by hematoxylin and eosin (H&E) (100× magnification), scale bar 250 μm, (b–f) IHC positive staining for KI67 (∼90% of the cells stained), PCK (punctate beside the nucleus), CK8-18, TIF-1 and PGP 9.5, (100× magnification), scale bar 250 μm.
Figure 2

Morphologic and IHC features. (a) Pathological examination of puncture biopsy of the left lung by hematoxylin and eosin (H&E) (100× magnification), scale bar 250 μm, (b–f) IHC positive staining for KI67 (∼90% of the cells stained), PCK (punctate beside the nucleus), CK8-18, TIF-1 and PGP 9.5, (100× magnification), scale bar 250 μm.

Table 1

Results of IHC staining

Immunohistochemistry Status
Puncture biopsy of the left lung (tumor cells)
PCK (paranuclear punctate+), CK8/18, TTF-1, PGP9.5, Ki67 (Li90%) Positive
CD117, SOX10, Syn, CgA, CD56, CK7, NapsinA, P40 Negative
Pericardial effusion sediment (dyskaryotic cells)
Claudin-4, PCK Positive
CK8/18, Calretinin, CK5/6, CD68, TTF-1, PGP9.5 Negative

A standard platinum-based doublet chemotherapy regime (nedaplatin 60 mg and irinotecan 100 mg) was utilized for two treatment cycles. Post-treatment CT showed stable disease (SD). To make the persistent control of the patient’s condition, standard chemotherapy was used in combination with both 100 mg pembrolizumab once per cycle and continual 48KU/micropump endostar 1 week per cycle. The platinum-based regime was abandoned after four cycles. One hundred milligrams of pembrolizumab once per cycle and continual 48KU/micropump endostar 1 week per cycle continued nine cycles. During the whole treatment, CT still showed SD, which is shown in Figure 3a and b. Occasionally nausea and discomfort that occurred in a patient during the chemotherapy could be relieved by himself. Hypothyroidism associated with PD-1 blockade was diagnosed in a patient after 11 cycles of using pembrolizumab and was rapidly relieved by oral administration of thyroxine tablets. Serum levels of FT3, FT4, and TSH during this period are shown in Figure 4 and Table A1.

Figure 3 Treatment process and therapeutic effect. (a) Schematic diagram of the patient’s clinical treatment process. (b) Chest CT (computed tomography) scanning. PD, progressive disease.
Figure 3

Treatment process and therapeutic effect. (a) Schematic diagram of the patient’s clinical treatment process. (b) Chest CT (computed tomography) scanning. PD, progressive disease.

Figure 4 Time course of thyroid function of the patient during treatment with pembrolizumab.
Figure 4

Time course of thyroid function of the patient during treatment with pembrolizumab.

The maintenance of the treatment plan was discontinued from January 2020 to May 2020 due to the unexpected COVID-19. On May 27, 2020, the patient returned to our hospital and was found with a large amount of pericardial effusion. Fortunately, pericardial puncture and drainage and pericardial perfusion therapy maintained good control of effusion. Subsequent pathological examination of pericardial drainage fluid sediment showed a very few dyskaryotic cells. Immunohistochemistry was then performed and the results were as follows: paranuclear punctate (PCK) (+), CK8/18 (+), TTF-1 (+), PGP9.5 (+), Ki67 (+), CD117 (−), SOX10 (−), Syn (−), CgA (−), CD56 (−), CK7 (−), NapsinA (−), and P40 (−) in the tumor cells and Claudin-4 (+), PCK (+), CK8/18 (−), Calretinin (−), CK5/6 (−), CD68 (−), TTF-1 (−), and PGP9.5 (−) (shown in Table 1). In addition, no new lesions were found in neck, chest, and abdomen enhanced CT, brain enhanced MRI, and systemic bone emission computed tomography ECT as shown in Figure 3b. However, the serum CA125 level was elevated to 46.4 ng/mL. Therefore, experts of in-hospital MDT (multi-disciplinary team) were required to reevaluate his situation, but there was no adequate evidence to support disease progression. These experts advised that the patient should continuously receive 100 mg pembrolizumab once per cycle. Thereafter, the disease remained stable under observation for approximately 6 months, during which the CA125 level slowly increased from 46.4 to 79.9 ng/mL. Up to December 2020, CA125 rapidly increased to 287.8 ng/mL as shown in Figure 5. The patient’s disease progressed after 30 months of antitumor treatment.

Figure 5 The patient’s CA125 dropped to normal after treatment. Then slowly elevated from 46.4 to 79.9 ng/mL in the SD period. Up to Dec 2020, CA125 rapidly jumped to 287.8 ng/mL.
Figure 5

The patient’s CA125 dropped to normal after treatment. Then slowly elevated from 46.4 to 79.9 ng/mL in the SD period. Up to Dec 2020, CA125 rapidly jumped to 287.8 ng/mL.

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The research related to human use has been complied with all the relevant national regulations and institutional policies and in accordance with the tenets of the Declaration of Helsinki and has been approved by the authors’ institutional review board or equivalent committee.

3 Discussion

Pulmonary LCENC is a high-grade non-small-cell NE carcinoma classified as a variant of large-cell carcinoma in the updated WHO classification of lung tumors [3]. There are four major types of NE phenotypes in large-cell carcinoma. One of them is large-cell carcinoma with NE morphology but non-NE immunophenotype [4], which is generally similar to LCENC [5,6]. The optimal chemotherapy regimen of stage IV pLCNEC as a first-line treatment remains controversial. Because LCNEC and SCLC have similar neuroendocrine morphology and biomarker expression, it is difficult to distinguish the difference between them. Generally speaking, there is no clear standard treatment for LCNEC in clinics and some scholars recommend EP as the first choice for treatment. Our case report showed an experience of treatment of advanced pLCENC without NE phenotype as the first-line therapy.

In the first-line treatment, two prospective single-arm phase II studies for advanced LCNEC that performed a platin-based doublet regimen of SCLC like had a positive effect during the short term. One study enrolled a total of 44 patients with the treatment of cisplatin–irinotecan, and the response rate was 54.5%, with the median PFS (mPFS) and mOS of 5.9 and 15.1 months, respectively [7]. Another trial showed an objective response rate of 38% and a disease control rate of 64% among 42 patients with cisplatin and etoposide treatment. The mPFS and mOS were 5.3 and 7.7 months, respectively [8].

With the development of NGS technology, studies of the genetic environment in LCNEC have explained a series of variants that differed from normal tissue and brought great benefits in identifying therapeutic drugs. George et al. provided a very comprehensive multi-omics analysis of LCNEC and revealed TP53 (92%), RB1 (42%), LKB1(STK11) (30%), as well as KEAP1 (22%) mutations [9]. Furthermore, they found that loss of heterozygosity, biallelic alterations, and larger genomic rearrangements were the main reasons for somatic alterations of RB1 and STK11/KEAP1, and these were mutually exclusive. Thus, two separate subtypes can be divided molecularly based on mutation evidence. Type I is defined by STK11/KEAP1 alterations and has an NE phenotype with the high expression of ASCL1 and DLL3 but the downregulation of the NOTCH pathway. In contrast, type II is characterized by RB1 alterations but predominantly non-NE phenotype, high expression of REST and NOTCH, and activation of immune cell response. Lantuejoul et al. indicated that type I can benefit from a treatment of NSCLC chemotherapy ± IC inhibitors and type II from SCLC treatment [10]. RB1 expression by IHC staining is another significant evaluation indicator. Derks et al. showed that pLCNEC patients with RB1 wild-type and/or expressing RB1 have superior overall survival when treated with NSCLC-like chemotherapy compared to SCLC-like (9.6 vs 5.6 months), but with no difference in the outcome for patients with inactivated RB1 [11]. Our patient accepted NGS analysis and revealed a total of six non-synonymous somatic mutations (four missenses, two introns). Unfortunately, none of the related gene mutations reported above were found. According to these results, we preliminarily speculated that the better response of immunotherapy might be related to the type of the detected mutations because some patients with LCNEC are not effective against immune checkpoint inhibitor drugs. Like literature reported by Han et al., this patient (staged at IIIA with pLCNEC) was treated with thoracoscopic radical surgery for upper left lung cancer and postoperative chemotherapy with a double-drug regimen holding platinum. Then, bevacizumab, paclitaxel, and the PDL1 checkpoint inhibitor nivolumab were applied, but the patient’s disease progressed rapidly. Even with positive PD-L1 expression, immunotherapy is an ineffective treatment for these patients. Researchers thought that a possible contributing factor is the timing of immunotherapy too late [12]. In addition, the tumor was effectively controlled when the patient in our study achieved nedaplatin-irinotecan agents. We speculated that the molecular phenotype of the patient might be SCLC like because of non-NE markers and high Ki-67 index (90%), but the platinum-based dual regimen did not make his tumor essentially regress. The risk of recurrence in the short term because of potential SCLC-like characteristics. Among other variant targets, KRAS mutations in LCENC are the most common (approximately 22–24%) and can be associated with adverse responses to chemotherapy [13,14]. Nonetheless, EGFR and BRAF mutations in LCNEC are very low, nearly 2 and 1%, respectively, which is different from NSCLC [14]. Therefore, EGFR-TKIs may not be satisfactory for the efficacy of LCNEC.

In immunotherapy, PD-1/PD-L1 inhibitors, which activate natural antitumor immune responses by disrupting the linkage of PD-1 to PD-1 ligand, have been observed to be effective in treating NSCLC, SCLC, and/or LCNEC. Studies by Sherman et al. [15] and Levra et al. [16] showed that single-agent immune checkpoint inhibitors (ICI) as a second line or multiple line for the treatment of patients with advanced LCNEC were associated with 33 and 60% of total ORR, respectively. Eleven percentage (2/21) of patients had a complete response (CR) in Sherman’s study. mPFS was 4.2 months and 57 weeks. In addition, synergistic regimens of ICI plus chemotherapy have not only been testified to shrink tumor diameter and achieve a major pathological response (MPR) in the period of neoadjuvant therapy [17] but also have been found to control disease progression[18] in advanced LCNEC. To date, information on the use of PD-1/PD-L1 inhibitors in first-line advanced LCNEC is very sparse. Recently, PD-L1 blockades, atezolizumab, and durvalumab in combination with platinum-based chemotherapy have sequentially been approved for the first-line treatment of extensive-stage SCLC (ES-SCLC) patients deriving from Impower130 trail and CASPIN trail, respectively. It implied that metastatic LCNEC, like ES-SCLC, could be used in synergic therapy with immunochemotherapy as the first-line therapy. Both PD-L1 expression and tumor mutation burden (TMB) are important biomarkers for response to immunotherapy in NSCLC or SCLC. In advanced LCNEC, several prior studies reported that PD-L1 expression rates were 10–20% [19,20]. The median TMB has been represented to be 9.9 muts/Mb in pLCNEC [21], compared to NSCLC (median 5.7 muts/Mb) [19], which indicated that LCNEC patients have a potential advantage in making a PD-1/PD-L1 inhibitor efficient. Zhang et al. described an LCENC patient with high TMB (25.8 muts/Mb) but negative PD-L1 who achieved a CR after nivolumab treatment when the tumor rapidly progressed after surgery and adjuvant therapy [22]. Xu et al. reported a case of a patient who was staged at cT1bN3M0 IIIB with locally advanced pulmonary LCNEC. After surgical resection and chemoradiotherapy, the patient achieved complete remission. PD-L1 (+) results were >50% in this case, so PD-L1 inhibitor durvalumab was then started to consolidate the treatment. After six courses of immune maintenance therapy, the patient developed grade 2 immune-related pneumonitis and took prednisone orally until the symptoms resolved, and then reached complete remission again [12,23]. In our case, TMB is 2.77 muts/Mb, and PD-L1 expression is undetected due to the inadequacy of biopsy. To strive for more than survival time, pembrolizumab was synergized with nedaplatin-irinotecan treatment for our patient. However, low TMB for our patient prompted the integration of other treatment manners.

Angiogenesis inhibitors directly fight against vascular endothelial growth factor (VEGF), which influences tumor growth inhibition. In the GOIRC-AIFA trial, bevacizumab was added to the first-line dual chemotherapy for ED-SCLC treatment, which showed a small, statistically significant improvement in PFS (5.7 vs 6.7 months; hazard ratio, 0.72; 95% CI, 0.54–0.97), but with no difference in OS [24]. In pLCENC, angiogenesis inhibitors are rarely experienced. A few studies reported overexpression of VEGF in pLCENC. Iyoda et al. explored potential molecular targets in pLCNEC, and they found that 13/13 (100%) tumors exhibited high VEGF expression as compared to 13/14 (92.9%) tumors of lung adenocarcinomas (ACs), suggesting a possible role for anti-VEGF therapy in the treatment of pLCNEC [25]. Recently, Muto et al. [26] reported a salvage therapy case with combined LCNEC with adenocarcinoma harboring an EGFR mutation (exon19, E746–A750 deletion) achieved afatinib, erlotinib, and bevacizumab treatment, and the disease remained stable for 10 months [25]. Meanwhile, Wu et al. confirmed anti-angiogenesis agent, endostar, collaborated with PD-1 blockade and had a dramatically synergic effect to suppress tumor growth in the LCC mice model through up-regulating PI3K/AKT/mTOR-mediated autophagy and angiogenesis [27]. In the first-line treatment, our patient took a synergistic method, with endostar and immunochemotherapy and reached a persistent SD over 30 months.

In conclusion, our case provides a potentially effective and safe treatment option in advanced and/or metastasis pulmonary LCNEC as the first-line therapy. The limitation of our study is that we reported only one case, which was insufficient to further explore the OS, PFS, and other indices for this malignant disease. Perhaps, the model can be appropriate in a herd of patients with IV stage pLCENC with negative NE markers, high mitotic rates, no RB1 and/or TP53 mutations, high TMB, or positive PD-L1 expression. However, it is difficult to draw definitive conclusions based on such limited experience. Our case report may provide a reference for treatment among our peers. At present, immunotherapy has made a breakthrough for NSCLC patients, and it is expected that more clinical studies will be conducted to explore its effectiveness in the treatment of LCNEC.

# Authors equally contributed to this manuscript.

Acknowledgments

The authors thank Shanghai Tongshu Biotechnology Co., Ltd. for technical support.

  1. Funding information: Authors state no funding is involved.

  2. Author contributions: Rui Meng conceived the study. Yu Xiao and Sijia Zhang collected the materials for this case. Zhenyu Li and Yan Zong drafted and revised the manuscript. Leichong Chen and Kuikui Zhu prepared the figures and participated in writing. Both authors approved the final manuscript.

  3. Conflict of interest: Authors state no conflict of interest.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Appendix

Table A1

The serum CA125, FT3, FT4, and TSH levels during the patient’s diagnosis and treatment

Number Date CA125 Number Date TSH FT3 FT4
1 2018.6.4 170.7 1 2018.7.31 1.2882 2 10.2
2 2018.7.5 157.8 2 2018.8.26 2.2358 2.5 10.6
3 2018.7.27 21.9 3 2018.10.15 2.4252 2.7 11.2
4 2018.8.21 15.6 4 2018.11.22 5.2652 3.6 12.1
5 2018.9.18 19.8 5 2018.12.25 3.3175 3.8 10.4
6 2018.10.15 21.9 6 2019.1.29 5.7141 4 9.9
7 2018.11.22 14.6 7 2019.4.9 16.6002 4.2 10
8 2018.12.25 15.3 8 2019.8.6 128.048 2 5.3
9 2019.1.29 14.2 9 2019.9.5 75.041 1.8 6.7
10 2019.3.5 14.4 10 2019.10.12 46.2223 3.5 10.2
11 2019.4.9 14 11 2020.5.28 104.7989 3.8 7.6
12 2019.5.17 16 12 2020.7.22 101.9509 3.2 6
13 2019.6.27 17.3 13 2020.12.2 131.5156 2.3 5.9
14 2019.8.6 19.8 14 2020.12.30 147.5986 2.3 6.4
15 2019.9.5 25
16 2019.10.12 37.5
17 2019.11.19 31.3
18 2019.12.24 21.2
19 2020.5.28 46.4
20 2020.7.22 53.4
21 2020.12.2 79.9
22 2020.12.30 287.8
23 2021.1.23 92.6

References

[1] Derks JL, Hendriks LE, Buikhuisen WA, Groen HJM, Thunnissen E, van Suylen R-J, et al. Clinical features of large cell neuroendocrine carcinoma: a population-based overview. Eur Respir J. 2016;47(2):615–24.10.1183/13993003.00618-2015Search in Google Scholar

[2] Atieh T, Huang CH. Treatment of advanced-stage large cell neuroendocrine cancer (LCNEC) of the lung: a tale of two diseases. Front Oncol. 2021;11:667468.10.3389/fonc.2021.667468Search in Google Scholar

[3] Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243–60.10.1097/JTO.0000000000000630Search in Google Scholar

[4] Travis WD. Advances in neuroendocrine lung tumors. Ann Oncol. 2010;21(Suppl 7):vii65–71.10.1093/annonc/mdq380Search in Google Scholar

[5] Zacharias J, Nicholson AG, Ladas GP, Goldstraw P. Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection. Ann Thorac Surg. 2003;75(2):348–52.10.1016/S0003-4975(02)04118-8Search in Google Scholar

[6] Derks JL, Rijnsburger N, Hermans BCM, Moonen L, Hillen LM, von der Thüsen JH, et al. Clinical-pathologic challenges in the classification of pulmonary neuroendocrine neoplasms and targets on the horizon for future clinical practice. J Thorac Oncol. 2021;16(10):1632–46.10.1016/j.jtho.2021.05.020Search in Google Scholar PubMed

[7] Niho S, Kenmotsu H, Sekine I, Ishii G, Ishikawa Y, Noguchi M, et al. Combination chemotherapy with irinotecan and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicenter phase II study. J Thorac Oncol. 2013;8(7):980–4.10.1097/JTO.0b013e31828f6989Search in Google Scholar PubMed

[8] Le Treut J, Sault MC, Lena H, Souquet PJ, Vergnenegre A, Le Caer H, et al. Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study. Ann Oncol. 2013;24(6):1548–52.10.1093/annonc/mdt009Search in Google Scholar PubMed

[9] George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, et al. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 2018;9(1):1048.10.1038/s41467-018-03099-xSearch in Google Scholar PubMed PubMed Central

[10] Lantuejoul S, Fernandez-Cuesta L, Damiola F, Girard N, McLeer A. New molecular classification of large cell neuroendocrine carcinoma and small cell lung carcinoma with potential therapeutic impacts. Transl Lung Cancer Res. 2020;9(5):2233–44.10.21037/tlcr-20-269Search in Google Scholar PubMed PubMed Central

[11] Derks JL, Leblay N, Thunnissen E, van Suylen RJ, den Bakker M, Groen HJM, et al. Molecular subtypes of pulmonary large-cell neuroendocrine carcinoma predict chemotherapy treatment outcome. Clin Cancer Res. 2018;24(1):33–42.10.1158/1078-0432.CCR-17-1921Search in Google Scholar PubMed

[12] Han Y, Pang L, Huang J, Chen J. Large cell neuroendocrine carcinoma of the lungs: case report and literature review. Ann Palliat Med. 2020;9(5):3705–9.10.21037/apm-20-1667Search in Google Scholar PubMed

[13] Naidoo J, Santos-Zabala ML, Iyriboz T, Woo KM, Sima CS, Fiore JJ, et al. Large cell neuroendocrine carcinoma of the lung: clinico-pathologic features, treatment, and outcomes. Clin Lung Cancer. 2016;17(5):e121–9.10.1016/j.cllc.2016.01.003Search in Google Scholar PubMed PubMed Central

[14] Rekhtman N, Pietanza MC, Hellmann MD, Naidoo J, Arora A, Won H, et al. Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin Cancer Res. 2016;22(14):3618–29.10.1158/1078-0432.CCR-15-2946Search in Google Scholar PubMed PubMed Central

[15] Sherman S, Rotem O, Shochat T, Zer A, Moore A, Dudnik E. Efficacy of immune check-point inhibitors (ICPi) in large cell neuroendocrine tumors of lung (LCNEC). Lung Cancer (Amsterdam). 2020;143:40–6.10.1016/j.lungcan.2020.03.008Search in Google Scholar PubMed

[16] Levra MG, Mazieres J, Valette CA, Molinier O, Planchard D, Frappat V, et al. P1.07-012 Efficacy of immune checkpoint inhibitors in large cell neuroendocrine lung cancer: results from a french retrospective cohort: topic: drug treatment alone and in combination with radiotherapy. J Thorac Oncol. 2017;12(1):S702–3.10.1016/j.jtho.2016.11.923Search in Google Scholar

[17] Chen F, Hua H, Huang H. Neoadjuvant chemotherapy combined with immunotherapy for pulmonary large-cell neuroendocrine carcinoma: a case report. Ann Palliat Med. 2021;10(7):8479–83.10.21037/apm-20-2536Search in Google Scholar PubMed

[18] Komiya T, Ravindra N, Powell E. Role of immunotherapy in stage IV large cell neuroendocrine carcinoma of the lung. Asian Pac J Cancer Prev. 2021;22(2):365–70.10.31557/APJCP.2021.22.2.365Search in Google Scholar PubMed PubMed Central

[19] Sabari JK, Julian RA, Ni A, Halpenny D, Hellmann MD, Drilon AE, et al. Outcomes of advanced pulmonary large cell neuroendocrine carcinoma stratified by RB1 loss, SLFN11 expression, and tumor mutational burden. J Clin Oncol. 2018;36(15_suppl):e20568.10.1200/JCO.2018.36.15_suppl.e20568Search in Google Scholar

[20] Tsuruoka K, Horinouchi H, Goto Y, Kanda S, Fujiwara Y, Nokihara H, et al. PD-L1 expression in neuroendocrine tumors of the lung. Lung Cancer (Amsterdam). 2017;108:115–20.10.1016/j.lungcan.2017.03.006Search in Google Scholar PubMed

[21] Chae YK, Tamragouri K, Chung J, Schrock AB, Kolla B, Ganesan S, et al. Genomic alterations (GA) and tumor mutational burden (TMB) in large cell neuroendocrine carcinoma of lung (L-LCNEC) as compared to small cell lung carcinoma (SCLC) as assessed via comprehensive genomic profiling (CGP). J Clin Oncol. 2017;35(15_suppl):8517.10.1200/JCO.2017.35.15_suppl.8517Search in Google Scholar

[22] Zhang X, Sun Y, Miao Y, Xu S. Immune checkpoint inhibitor therapy achieved complete response for drug-sensitive egfr/alk mutation-negative metastatic pulmonary large-cell neuroendocrine carcinoma with high tumor mutation burden: a case report. OncoTargets Ther. 2020;13:8245.10.2147/OTT.S259893Search in Google Scholar PubMed PubMed Central

[23] Xu J, Feng Q, Chen Y, Liu XL, Jiang O. Complete remission of combined pulmonary large cell neuroendocrine carcinoma: a case report. J Int Med Res. 2021;49(11):3000605211055387.10.1177/03000605211055387Search in Google Scholar PubMed PubMed Central

[24] Tiseo M, Boni L, Ambrosio F, Camerini A, Baldini E, Cinieri S, et al. Italian, multicenter, phase III, randomized study of cisplatin plus etoposide with or without bevacizumab as first-line treatment in extensive-disease small-cell lung cancer: The GOIRC-AIFA FARM6PMFJM trial. J Clin Oncol. 2017;35(12):1281–7.10.1200/JCO.2016.69.4844Search in Google Scholar PubMed

[25] Iyoda A, Travis WD, Sarkaria IS, Jiang S-X, Amano H, Sato Y, et al. Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma. Exp Ther Med. 2011;2(6):1041–5.10.3892/etm.2011.343Search in Google Scholar PubMed PubMed Central

[26] Muto S, Ozaki Y, Okabe N, Matsumura Y, Hasegawa T, Shio Y, et al. Successful treatment of combined large cell neuroendocrine carcinoma harboring an egfr mutation with EGFR-TKIs plus bevacizumab: a case report. Case Rep Oncol. 2020;13(3):1387–92.10.1159/000511112Search in Google Scholar PubMed PubMed Central

[27] Wu J, Zhao X, Sun Q, Jiang Y, Zhang W, Luo J, et al. Synergic effect of PD-1 blockade and endostar on the PI3K/AKT/mTOR-mediated autophagy and angiogenesis in Lewis lung carcinoma mouse model. Biomed Pharmacother. 2020;125:109746.10.1016/j.biopha.2019.109746Search in Google Scholar PubMed

Received: 2021-10-17
Revised: 2022-02-18
Accepted: 2022-02-26
Published Online: 2022-06-15

© 2022 Sijia Zhang et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  3. The mother of all battles: Viruses vs humans. Can humans avoid extinction in 50–100 years?
  4. Knockdown of G1P3 inhibits cell proliferation and enhances the cytotoxicity of dexamethasone in acute lymphoblastic leukemia
  5. LINC00665 regulates hepatocellular carcinoma by modulating mRNA via the m6A enzyme
  6. Association study of CLDN14 variations in patients with kidney stones
  7. Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook
  8. Regulation of miR-30b in cancer development, apoptosis, and drug resistance
  9. Informatic analysis of the pulmonary microecology in non-cystic fibrosis bronchiectasis at three different stages
  10. Swimming attenuates tumor growth in CT-26 tumor-bearing mice and suppresses angiogenesis by mediating the HIF-1α/VEGFA pathway
  11. Characterization of intestinal microbiota and serum metabolites in patients with mild hepatic encephalopathy
  12. Functional conservation and divergence in plant-specific GRF gene family revealed by sequences and expression analysis
  13. Application of the FLP/LoxP-FRT recombination system to switch the eGFP expression in a model prokaryote
  14. Biomedical evaluation of antioxidant properties of lamb meat enriched with iodine and selenium
  15. Intravenous infusion of the exosomes derived from human umbilical cord mesenchymal stem cells enhance neurological recovery after traumatic brain injury via suppressing the NF-κB pathway
  16. Effect of dietary pattern on pregnant women with gestational diabetes mellitus and its clinical significance
  17. Potential regulatory mechanism of TNF-α/TNFR1/ANXA1 in glioma cells and its role in glioma cell proliferation
  18. Effect of the genetic mutant G71R in uridine diphosphate-glucuronosyltransferase 1A1 on the conjugation of bilirubin
  19. Quercetin inhibits cytotoxicity of PC12 cells induced by amyloid-beta 25–35 via stimulating estrogen receptor α, activating ERK1/2, and inhibiting apoptosis
  20. Nutrition intervention in the management of novel coronavirus pneumonia patients
  21. circ-CFH promotes the development of HCC by regulating cell proliferation, apoptosis, migration, invasion, and glycolysis through the miR-377-3p/RNF38 axis
  22. Bmi-1 directly upregulates glucose transporter 1 in human gastric adenocarcinoma
  23. Lacunar infarction aggravates the cognitive deficit in the elderly with white matter lesion
  24. Hydroxysafflor yellow A improved retinopathy via Nrf2/HO-1 pathway in rats
  25. Comparison of axon extension: PTFE versus PLA formed by a 3D printer
  26. Elevated IL-35 level and iTr35 subset increase the bacterial burden and lung lesions in Mycobacterium tuberculosis-infected mice
  27. A case report of CAT gene and HNF1β gene variations in a patient with early-onset diabetes
  28. Study on the mechanism of inhibiting patulin production by fengycin
  29. SOX4 promotes high-glucose-induced inflammation and angiogenesis of retinal endothelial cells by activating NF-κB signaling pathway
  30. Relationship between blood clots and COVID-19 vaccines: A literature review
  31. Analysis of genetic characteristics of 436 children with dysplasia and detailed analysis of rare karyotype
  32. Bioinformatics network analyses of growth differentiation factor 11
  33. NR4A1 inhibits the epithelial–mesenchymal transition of hepatic stellate cells: Involvement of TGF-β–Smad2/3/4–ZEB signaling
  34. Expression of Zeb1 in the differentiation of mouse embryonic stem cell
  35. Study on the genetic damage caused by cadmium sulfide quantum dots in human lymphocytes
  36. Association between single-nucleotide polymorphisms of NKX2.5 and congenital heart disease in Chinese population: A meta-analysis
  37. Assessment of the anesthetic effect of modified pentothal sodium solution on Sprague-Dawley rats
  38. Genetic susceptibility to high myopia in Han Chinese population
  39. Potential biomarkers and molecular mechanisms in preeclampsia progression
  40. Silencing circular RNA-friend leukemia virus integration 1 restrained malignancy of CC cells and oxaliplatin resistance by disturbing dyskeratosis congenita 1
  41. Endostar plus pembrolizumab combined with a platinum-based dual chemotherapy regime for advanced pulmonary large-cell neuroendocrine carcinoma as a first-line treatment: A case report
  42. The significance of PAK4 in signaling and clinicopathology: A review
  43. Sorafenib inhibits ovarian cancer cell proliferation and mobility and induces radiosensitivity by targeting the tumor cell epithelial–mesenchymal transition
  44. Characterization of rabbit polyclonal antibody against camel recombinant nanobodies
  45. Active legumain promotes invasion and migration of neuroblastoma by regulating epithelial-mesenchymal transition
  46. Effect of cell receptors in the pathogenesis of osteoarthritis: Current insights
  47. MT-12 inhibits the proliferation of bladder cells in vitro and in vivo by enhancing autophagy through mitochondrial dysfunction
  48. Study of hsa_circRNA_000121 and hsa_circRNA_004183 in papillary thyroid microcarcinoma
  49. BuyangHuanwu Decoction attenuates cerebral vasospasm caused by subarachnoid hemorrhage in rats via PI3K/AKT/eNOS axis
  50. Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart
  51. Monosodium iodoacetate-induced subchondral bone microstructure and inflammatory changes in an animal model of osteoarthritis
  52. A rare presentation of type II Abernethy malformation and nephrotic syndrome: Case report and review
  53. Rapid death due to pulmonary epithelioid haemangioendothelioma in several weeks: A case report
  54. Hepatoprotective role of peroxisome proliferator-activated receptor-α in non-cancerous hepatic tissues following transcatheter arterial embolization
  55. Correlation between peripheral blood lymphocyte subpopulations and primary systemic lupus erythematosus
  56. A novel SLC8A1-ALK fusion in lung adenocarcinoma confers sensitivity to alectinib: A case report
  57. β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes
  58. Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer
  59. BTBD10 inhibits glioma tumorigenesis by downregulating cyclin D1 and p-Akt
  60. Mucormycosis co-infection in COVID-19 patients: An update
  61. Metagenomic next-generation sequencing in diagnosing Pneumocystis jirovecii pneumonia: A case report
  62. Long non-coding RNA HOXB-AS1 is a prognostic marker and promotes hepatocellular carcinoma cells’ proliferation and invasion
  63. Preparation and evaluation of LA-PEG-SPION, a targeted MRI contrast agent for liver cancer
  64. Proteomic analysis of the liver regulating lipid metabolism in Chaohu ducks using two-dimensional electrophoresis
  65. Nasopharyngeal tuberculosis: A case report
  66. Characterization and evaluation of anti-Salmonella enteritidis activity of indigenous probiotic lactobacilli in mice
  67. Aberrant pulmonary immune response of obese mice to periodontal infection
  68. Bacteriospermia – A formidable player in male subfertility
  69. In silico and in vivo analysis of TIPE1 expression in diffuse large B cell lymphoma
  70. Effects of KCa channels on biological behavior of trophoblasts
  71. Interleukin-17A influences the vulnerability rather than the size of established atherosclerotic plaques in apolipoprotein E-deficient mice
  72. Multiple organ failure and death caused by Staphylococcus aureus hip infection: A case report
  73. Prognostic signature related to the immune environment of oral squamous cell carcinoma
  74. Primary and metastatic squamous cell carcinoma of the thyroid gland: Two case reports
  75. Neuroprotective effects of crocin and crocin-loaded niosomes against the paraquat-induced oxidative brain damage in rats
  76. Role of MMP-2 and CD147 in kidney fibrosis
  77. Geometric basis of action potential of skeletal muscle cells and neurons
  78. Babesia microti-induced fulminant sepsis in an immunocompromised host: A case report and the case-specific literature review
  79. Role of cerebellar cortex in associative learning and memory in guinea pigs
  80. Application of metagenomic next-generation sequencing technique for diagnosing a specific case of necrotizing meningoencephalitis caused by human herpesvirus 2
  81. Case report: Quadruple primary malignant neoplasms including esophageal, ureteral, and lung in an elderly male
  82. Long non-coding RNA NEAT1 promotes angiogenesis in hepatoma carcinoma via the miR-125a-5p/VEGF pathway
  83. Osteogenic differentiation of periodontal membrane stem cells in inflammatory environments
  84. Knockdown of SHMT2 enhances the sensitivity of gastric cancer cells to radiotherapy through the Wnt/β-catenin pathway
  85. Continuous renal replacement therapy combined with double filtration plasmapheresis in the treatment of severe lupus complicated by serious bacterial infections in children: A case report
  86. Simultaneous triple primary malignancies, including bladder cancer, lymphoma, and lung cancer, in an elderly male: A case report
  87. Preclinical immunogenicity assessment of a cell-based inactivated whole-virion H5N1 influenza vaccine
  88. One case of iodine-125 therapy – A new minimally invasive treatment of intrahepatic cholangiocarcinoma
  89. S1P promotes corneal trigeminal neuron differentiation and corneal nerve repair via upregulating nerve growth factor expression in a mouse model
  90. Early cancer detection by a targeted methylation assay of circulating tumor DNA in plasma
  91. Calcifying nanoparticles initiate the calcification process of mesenchymal stem cells in vitro through the activation of the TGF-β1/Smad signaling pathway and promote the decay of echinococcosis
  92. Evaluation of prognostic markers in patients infected with SARS-CoV-2
  93. N6-Methyladenosine-related alternative splicing events play a role in bladder cancer
  94. Characterization of the structural, oxidative, and immunological features of testis tissue from Zucker diabetic fatty rats
  95. Effects of glucose and osmotic pressure on the proliferation and cell cycle of human chorionic trophoblast cells
  96. Investigation of genotype diversity of 7,804 norovirus sequences in humans and animals of China
  97. Characteristics and karyotype analysis of a patient with turner syndrome complicated with multiple-site tumors: A case report
  98. Aggravated renal fibrosis is positively associated with the activation of HMGB1-TLR2/4 signaling in STZ-induced diabetic mice
  99. Distribution characteristics of SARS-CoV-2 IgM/IgG in false-positive results detected by chemiluminescent immunoassay
  100. SRPX2 attenuated oxygen–glucose deprivation and reperfusion-induced injury in cardiomyocytes via alleviating endoplasmic reticulum stress-induced apoptosis through targeting PI3K/Akt/mTOR axis
  101. Aquaporin-8 overexpression is involved in vascular structure and function changes in placentas of gestational diabetes mellitus patients
  102. Relationship between CRP gene polymorphisms and ischemic stroke risk: A systematic review and meta-analysis
  103. Effects of growth hormone on lipid metabolism and sexual development in pubertal obese male rats
  104. Cloning and identification of the CTLA-4IgV gene and functional application of vaccine in Xinjiang sheep
  105. Antitumor activity of RUNX3: Upregulation of E-cadherin and downregulation of the epithelial–mesenchymal transition in clear-cell renal cell carcinoma
  106. PHF8 promotes osteogenic differentiation of BMSCs in old rat with osteoporosis by regulating Wnt/β-catenin pathway
  107. A review of the current state of the computer-aided diagnosis (CAD) systems for breast cancer diagnosis
  108. Bilateral dacryoadenitis in adult-onset Still’s disease: A case report
  109. A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma
  110. The role of erythrocytes and erythroid progenitor cells in tumors
  111. Relationship between platelet activation markers and spontaneous abortion: A meta-analysis
  112. Abnormal methylation caused by folic acid deficiency in neural tube defects
  113. Silencing TLR4 using an ultrasound-targeted microbubble destruction-based shRNA system reduces ischemia-induced seizures in hyperglycemic rats
  114. Plant Sciences
  115. Seasonal succession of bacterial communities in cultured Caulerpa lentillifera detected by high-throughput sequencing
  116. Cloning and prokaryotic expression of WRKY48 from Caragana intermedia
  117. Novel Brassica hybrids with different resistance to Leptosphaeria maculans reveal unbalanced rDNA signal patterns
  118. Application of exogenous auxin and gibberellin regulates the bolting of lettuce (Lactuca sativa L.)
  119. Phytoremediation of pollutants from wastewater: A concise review
  120. Genome-wide identification and characterization of NBS-encoding genes in the sweet potato wild ancestor Ipomoea trifida (H.B.K.)
  121. Alleviative effects of magnetic Fe3O4 nanoparticles on the physiological toxicity of 3-nitrophenol to rice (Oryza sativa L.) seedlings
  122. Selection and functional identification of Dof genes expressed in response to nitrogen in Populus simonii × Populus nigra
  123. Study on pecan seed germination influenced by seed endocarp
  124. Identification of active compounds in Ophiopogonis Radix from different geographical origins by UPLC-Q/TOF-MS combined with GC-MS approaches
  125. The entire chloroplast genome sequence of Asparagus cochinchinensis and genetic comparison to Asparagus species
  126. Genome-wide identification of MAPK family genes and their response to abiotic stresses in tea plant (Camellia sinensis)
  127. Selection and validation of reference genes for RT-qPCR analysis of different organs at various development stages in Caragana intermedia
  128. Cloning and expression analysis of SERK1 gene in Diospyros lotus
  129. Integrated metabolomic and transcriptomic profiling revealed coping mechanisms of the edible and medicinal homologous plant Plantago asiatica L. cadmium resistance
  130. A missense variant in NCF1 is associated with susceptibility to unexplained recurrent spontaneous abortion
  131. Assessment of drought tolerance indices in faba bean genotypes under different irrigation regimes
  132. The entire chloroplast genome sequence of Asparagus setaceus (Kunth) Jessop: Genome structure, gene composition, and phylogenetic analysis in Asparagaceae
  133. Food Science
  134. Dietary food additive monosodium glutamate with or without high-lipid diet induces spleen anomaly: A mechanistic approach on rat model
  135. Binge eating disorder during COVID-19
  136. Potential of honey against the onset of autoimmune diabetes and its associated nephropathy, pancreatitis, and retinopathy in type 1 diabetic animal model
  137. FTO gene expression in diet-induced obesity is downregulated by Solanum fruit supplementation
  138. Physical activity enhances fecal lactobacilli in rats chronically drinking sweetened cola beverage
  139. Supercritical CO2 extraction, chemical composition, and antioxidant effects of Coreopsis tinctoria Nutt. oleoresin
  140. Functional constituents of plant-based foods boost immunity against acute and chronic disorders
  141. Effect of selenium and methods of protein extraction on the proteomic profile of Saccharomyces yeast
  142. Microbial diversity of milk ghee in southern Gansu and its effect on the formation of ghee flavor compounds
  143. Ecology and Environmental Sciences
  144. Effects of heavy metals on bacterial community surrounding Bijiashan mining area located in northwest China
  145. Microorganism community composition analysis coupling with 15N tracer experiments reveals the nitrification rate and N2O emissions in low pH soils in Southern China
  146. Genetic diversity and population structure of Cinnamomum balansae Lecomte inferred by microsatellites
  147. Preliminary screening of microplastic contamination in different marine fish species of Taif market, Saudi Arabia
  148. Plant volatile organic compounds attractive to Lygus pratensis
  149. Effects of organic materials on soil bacterial community structure in long-term continuous cropping of tomato in greenhouse
  150. Effects of soil treated fungicide fluopimomide on tomato (Solanum lycopersicum L.) disease control and plant growth
  151. Prevalence of Yersinia pestis among rodents captured in a semi-arid tropical ecosystem of south-western Zimbabwe
  152. Effects of irrigation and nitrogen fertilization on mitigating salt-induced Na+ toxicity and sustaining sea rice growth
  153. Bioengineering and Biotechnology
  154. Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes
  155. Development of alkaline phosphatase-scFv and its use for one-step enzyme-linked immunosorbent assay for His-tagged protein detection
  156. Development and validation of a predictive model for immune-related genes in patients with tongue squamous cell carcinoma
  157. Agriculture
  158. Effects of chemical-based fertilizer replacement with biochar-based fertilizer on albic soil nutrient content and maize yield
  159. Genome-wide identification and expression analysis of CPP-like gene family in Triticum aestivum L. under different hormone and stress conditions
  160. Agronomic and economic performance of mung bean (Vigna radiata L.) varieties in response to rates of blended NPS fertilizer in Kindo Koysha district, Southern Ethiopia
  161. Influence of furrow irrigation regime on the yield and water consumption indicators of winter wheat based on a multi-level fuzzy comprehensive evaluation
  162. Discovery of exercise-related genes and pathway analysis based on comparative genomes of Mongolian originated Abaga and Wushen horse
  163. Lessons from integrated seasonal forecast-crop modelling in Africa: A systematic review
  164. Evolution trend of soil fertility in tobacco-planting area of Chenzhou, Hunan Province, China
  165. Animal Sciences
  166. Morphological and molecular characterization of Tatera indica Hardwicke 1807 (Rodentia: Muridae) from Pothwar, Pakistan
  167. Research on meat quality of Qianhua Mutton Merino sheep and Small-tail Han sheep
  168. SI: A Scientific Memoir
  169. Suggestions on leading an academic research laboratory group
  170. My scientific genealogy and the Toronto ACDC Laboratory, 1988–2022
  171. Erratum
  172. Erratum to “Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study”
  173. Erratum to “A two-microRNA signature predicts the progression of male thyroid cancer”
  174. Retraction
  175. Retraction of “Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis”
https://doi.org/10.1515/biol-2022-0062
Keywords for this article
pulmonary large-cell neuroendocrine carcinoma; immunotherapy; anti-angiogenesis; chemotherapy; combination therapy
Creative Commons
BY 4.0

Articles in the same Issue

  1. Biomedical Sciences
  2. Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits
  3. The mother of all battles: Viruses vs humans. Can humans avoid extinction in 50–100 years?
  4. Knockdown of G1P3 inhibits cell proliferation and enhances the cytotoxicity of dexamethasone in acute lymphoblastic leukemia
  5. LINC00665 regulates hepatocellular carcinoma by modulating mRNA via the m6A enzyme
  6. Association study of CLDN14 variations in patients with kidney stones
  7. Concanavalin A-induced autoimmune hepatitis model in mice: Mechanisms and future outlook
  8. Regulation of miR-30b in cancer development, apoptosis, and drug resistance
  9. Informatic analysis of the pulmonary microecology in non-cystic fibrosis bronchiectasis at three different stages
  10. Swimming attenuates tumor growth in CT-26 tumor-bearing mice and suppresses angiogenesis by mediating the HIF-1α/VEGFA pathway
  11. Characterization of intestinal microbiota and serum metabolites in patients with mild hepatic encephalopathy
  12. Functional conservation and divergence in plant-specific GRF gene family revealed by sequences and expression analysis
  13. Application of the FLP/LoxP-FRT recombination system to switch the eGFP expression in a model prokaryote
  14. Biomedical evaluation of antioxidant properties of lamb meat enriched with iodine and selenium
  15. Intravenous infusion of the exosomes derived from human umbilical cord mesenchymal stem cells enhance neurological recovery after traumatic brain injury via suppressing the NF-κB pathway
  16. Effect of dietary pattern on pregnant women with gestational diabetes mellitus and its clinical significance
  17. Potential regulatory mechanism of TNF-α/TNFR1/ANXA1 in glioma cells and its role in glioma cell proliferation
  18. Effect of the genetic mutant G71R in uridine diphosphate-glucuronosyltransferase 1A1 on the conjugation of bilirubin
  19. Quercetin inhibits cytotoxicity of PC12 cells induced by amyloid-beta 25–35 via stimulating estrogen receptor α, activating ERK1/2, and inhibiting apoptosis
  20. Nutrition intervention in the management of novel coronavirus pneumonia patients
  21. circ-CFH promotes the development of HCC by regulating cell proliferation, apoptosis, migration, invasion, and glycolysis through the miR-377-3p/RNF38 axis
  22. Bmi-1 directly upregulates glucose transporter 1 in human gastric adenocarcinoma
  23. Lacunar infarction aggravates the cognitive deficit in the elderly with white matter lesion
  24. Hydroxysafflor yellow A improved retinopathy via Nrf2/HO-1 pathway in rats
  25. Comparison of axon extension: PTFE versus PLA formed by a 3D printer
  26. Elevated IL-35 level and iTr35 subset increase the bacterial burden and lung lesions in Mycobacterium tuberculosis-infected mice
  27. A case report of CAT gene and HNF1β gene variations in a patient with early-onset diabetes
  28. Study on the mechanism of inhibiting patulin production by fengycin
  29. SOX4 promotes high-glucose-induced inflammation and angiogenesis of retinal endothelial cells by activating NF-κB signaling pathway
  30. Relationship between blood clots and COVID-19 vaccines: A literature review
  31. Analysis of genetic characteristics of 436 children with dysplasia and detailed analysis of rare karyotype
  32. Bioinformatics network analyses of growth differentiation factor 11
  33. NR4A1 inhibits the epithelial–mesenchymal transition of hepatic stellate cells: Involvement of TGF-β–Smad2/3/4–ZEB signaling
  34. Expression of Zeb1 in the differentiation of mouse embryonic stem cell
  35. Study on the genetic damage caused by cadmium sulfide quantum dots in human lymphocytes
  36. Association between single-nucleotide polymorphisms of NKX2.5 and congenital heart disease in Chinese population: A meta-analysis
  37. Assessment of the anesthetic effect of modified pentothal sodium solution on Sprague-Dawley rats
  38. Genetic susceptibility to high myopia in Han Chinese population
  39. Potential biomarkers and molecular mechanisms in preeclampsia progression
  40. Silencing circular RNA-friend leukemia virus integration 1 restrained malignancy of CC cells and oxaliplatin resistance by disturbing dyskeratosis congenita 1
  41. Endostar plus pembrolizumab combined with a platinum-based dual chemotherapy regime for advanced pulmonary large-cell neuroendocrine carcinoma as a first-line treatment: A case report
  42. The significance of PAK4 in signaling and clinicopathology: A review
  43. Sorafenib inhibits ovarian cancer cell proliferation and mobility and induces radiosensitivity by targeting the tumor cell epithelial–mesenchymal transition
  44. Characterization of rabbit polyclonal antibody against camel recombinant nanobodies
  45. Active legumain promotes invasion and migration of neuroblastoma by regulating epithelial-mesenchymal transition
  46. Effect of cell receptors in the pathogenesis of osteoarthritis: Current insights
  47. MT-12 inhibits the proliferation of bladder cells in vitro and in vivo by enhancing autophagy through mitochondrial dysfunction
  48. Study of hsa_circRNA_000121 and hsa_circRNA_004183 in papillary thyroid microcarcinoma
  49. BuyangHuanwu Decoction attenuates cerebral vasospasm caused by subarachnoid hemorrhage in rats via PI3K/AKT/eNOS axis
  50. Effects of the interaction of Notch and TLR4 pathways on inflammation and heart function in septic heart
  51. Monosodium iodoacetate-induced subchondral bone microstructure and inflammatory changes in an animal model of osteoarthritis
  52. A rare presentation of type II Abernethy malformation and nephrotic syndrome: Case report and review
  53. Rapid death due to pulmonary epithelioid haemangioendothelioma in several weeks: A case report
  54. Hepatoprotective role of peroxisome proliferator-activated receptor-α in non-cancerous hepatic tissues following transcatheter arterial embolization
  55. Correlation between peripheral blood lymphocyte subpopulations and primary systemic lupus erythematosus
  56. A novel SLC8A1-ALK fusion in lung adenocarcinoma confers sensitivity to alectinib: A case report
  57. β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes
  58. Identification of metabolic genes for the prediction of prognosis and tumor microenvironment infiltration in early-stage non-small cell lung cancer
  59. BTBD10 inhibits glioma tumorigenesis by downregulating cyclin D1 and p-Akt
  60. Mucormycosis co-infection in COVID-19 patients: An update
  61. Metagenomic next-generation sequencing in diagnosing Pneumocystis jirovecii pneumonia: A case report
  62. Long non-coding RNA HOXB-AS1 is a prognostic marker and promotes hepatocellular carcinoma cells’ proliferation and invasion
  63. Preparation and evaluation of LA-PEG-SPION, a targeted MRI contrast agent for liver cancer
  64. Proteomic analysis of the liver regulating lipid metabolism in Chaohu ducks using two-dimensional electrophoresis
  65. Nasopharyngeal tuberculosis: A case report
  66. Characterization and evaluation of anti-Salmonella enteritidis activity of indigenous probiotic lactobacilli in mice
  67. Aberrant pulmonary immune response of obese mice to periodontal infection
  68. Bacteriospermia – A formidable player in male subfertility
  69. In silico and in vivo analysis of TIPE1 expression in diffuse large B cell lymphoma
  70. Effects of KCa channels on biological behavior of trophoblasts
  71. Interleukin-17A influences the vulnerability rather than the size of established atherosclerotic plaques in apolipoprotein E-deficient mice
  72. Multiple organ failure and death caused by Staphylococcus aureus hip infection: A case report
  73. Prognostic signature related to the immune environment of oral squamous cell carcinoma
  74. Primary and metastatic squamous cell carcinoma of the thyroid gland: Two case reports
  75. Neuroprotective effects of crocin and crocin-loaded niosomes against the paraquat-induced oxidative brain damage in rats
  76. Role of MMP-2 and CD147 in kidney fibrosis
  77. Geometric basis of action potential of skeletal muscle cells and neurons
  78. Babesia microti-induced fulminant sepsis in an immunocompromised host: A case report and the case-specific literature review
  79. Role of cerebellar cortex in associative learning and memory in guinea pigs
  80. Application of metagenomic next-generation sequencing technique for diagnosing a specific case of necrotizing meningoencephalitis caused by human herpesvirus 2
  81. Case report: Quadruple primary malignant neoplasms including esophageal, ureteral, and lung in an elderly male
  82. Long non-coding RNA NEAT1 promotes angiogenesis in hepatoma carcinoma via the miR-125a-5p/VEGF pathway
  83. Osteogenic differentiation of periodontal membrane stem cells in inflammatory environments
  84. Knockdown of SHMT2 enhances the sensitivity of gastric cancer cells to radiotherapy through the Wnt/β-catenin pathway
  85. Continuous renal replacement therapy combined with double filtration plasmapheresis in the treatment of severe lupus complicated by serious bacterial infections in children: A case report
  86. Simultaneous triple primary malignancies, including bladder cancer, lymphoma, and lung cancer, in an elderly male: A case report
  87. Preclinical immunogenicity assessment of a cell-based inactivated whole-virion H5N1 influenza vaccine
  88. One case of iodine-125 therapy – A new minimally invasive treatment of intrahepatic cholangiocarcinoma
  89. S1P promotes corneal trigeminal neuron differentiation and corneal nerve repair via upregulating nerve growth factor expression in a mouse model
  90. Early cancer detection by a targeted methylation assay of circulating tumor DNA in plasma
  91. Calcifying nanoparticles initiate the calcification process of mesenchymal stem cells in vitro through the activation of the TGF-β1/Smad signaling pathway and promote the decay of echinococcosis
  92. Evaluation of prognostic markers in patients infected with SARS-CoV-2
  93. N6-Methyladenosine-related alternative splicing events play a role in bladder cancer
  94. Characterization of the structural, oxidative, and immunological features of testis tissue from Zucker diabetic fatty rats
  95. Effects of glucose and osmotic pressure on the proliferation and cell cycle of human chorionic trophoblast cells
  96. Investigation of genotype diversity of 7,804 norovirus sequences in humans and animals of China
  97. Characteristics and karyotype analysis of a patient with turner syndrome complicated with multiple-site tumors: A case report
  98. Aggravated renal fibrosis is positively associated with the activation of HMGB1-TLR2/4 signaling in STZ-induced diabetic mice
  99. Distribution characteristics of SARS-CoV-2 IgM/IgG in false-positive results detected by chemiluminescent immunoassay
  100. SRPX2 attenuated oxygen–glucose deprivation and reperfusion-induced injury in cardiomyocytes via alleviating endoplasmic reticulum stress-induced apoptosis through targeting PI3K/Akt/mTOR axis
  101. Aquaporin-8 overexpression is involved in vascular structure and function changes in placentas of gestational diabetes mellitus patients
  102. Relationship between CRP gene polymorphisms and ischemic stroke risk: A systematic review and meta-analysis
  103. Effects of growth hormone on lipid metabolism and sexual development in pubertal obese male rats
  104. Cloning and identification of the CTLA-4IgV gene and functional application of vaccine in Xinjiang sheep
  105. Antitumor activity of RUNX3: Upregulation of E-cadherin and downregulation of the epithelial–mesenchymal transition in clear-cell renal cell carcinoma
  106. PHF8 promotes osteogenic differentiation of BMSCs in old rat with osteoporosis by regulating Wnt/β-catenin pathway
  107. A review of the current state of the computer-aided diagnosis (CAD) systems for breast cancer diagnosis
  108. Bilateral dacryoadenitis in adult-onset Still’s disease: A case report
  109. A novel association between Bmi-1 protein expression and the SUVmax obtained by 18F-FDG PET/CT in patients with gastric adenocarcinoma
  110. The role of erythrocytes and erythroid progenitor cells in tumors
  111. Relationship between platelet activation markers and spontaneous abortion: A meta-analysis
  112. Abnormal methylation caused by folic acid deficiency in neural tube defects
  113. Silencing TLR4 using an ultrasound-targeted microbubble destruction-based shRNA system reduces ischemia-induced seizures in hyperglycemic rats
  114. Plant Sciences
  115. Seasonal succession of bacterial communities in cultured Caulerpa lentillifera detected by high-throughput sequencing
  116. Cloning and prokaryotic expression of WRKY48 from Caragana intermedia
  117. Novel Brassica hybrids with different resistance to Leptosphaeria maculans reveal unbalanced rDNA signal patterns
  118. Application of exogenous auxin and gibberellin regulates the bolting of lettuce (Lactuca sativa L.)
  119. Phytoremediation of pollutants from wastewater: A concise review
  120. Genome-wide identification and characterization of NBS-encoding genes in the sweet potato wild ancestor Ipomoea trifida (H.B.K.)
  121. Alleviative effects of magnetic Fe3O4 nanoparticles on the physiological toxicity of 3-nitrophenol to rice (Oryza sativa L.) seedlings
  122. Selection and functional identification of Dof genes expressed in response to nitrogen in Populus simonii × Populus nigra
  123. Study on pecan seed germination influenced by seed endocarp
  124. Identification of active compounds in Ophiopogonis Radix from different geographical origins by UPLC-Q/TOF-MS combined with GC-MS approaches
  125. The entire chloroplast genome sequence of Asparagus cochinchinensis and genetic comparison to Asparagus species
  126. Genome-wide identification of MAPK family genes and their response to abiotic stresses in tea plant (Camellia sinensis)
  127. Selection and validation of reference genes for RT-qPCR analysis of different organs at various development stages in Caragana intermedia
  128. Cloning and expression analysis of SERK1 gene in Diospyros lotus
  129. Integrated metabolomic and transcriptomic profiling revealed coping mechanisms of the edible and medicinal homologous plant Plantago asiatica L. cadmium resistance
  130. A missense variant in NCF1 is associated with susceptibility to unexplained recurrent spontaneous abortion
  131. Assessment of drought tolerance indices in faba bean genotypes under different irrigation regimes
  132. The entire chloroplast genome sequence of Asparagus setaceus (Kunth) Jessop: Genome structure, gene composition, and phylogenetic analysis in Asparagaceae
  133. Food Science
  134. Dietary food additive monosodium glutamate with or without high-lipid diet induces spleen anomaly: A mechanistic approach on rat model
  135. Binge eating disorder during COVID-19
  136. Potential of honey against the onset of autoimmune diabetes and its associated nephropathy, pancreatitis, and retinopathy in type 1 diabetic animal model
  137. FTO gene expression in diet-induced obesity is downregulated by Solanum fruit supplementation
  138. Physical activity enhances fecal lactobacilli in rats chronically drinking sweetened cola beverage
  139. Supercritical CO2 extraction, chemical composition, and antioxidant effects of Coreopsis tinctoria Nutt. oleoresin
  140. Functional constituents of plant-based foods boost immunity against acute and chronic disorders
  141. Effect of selenium and methods of protein extraction on the proteomic profile of Saccharomyces yeast
  142. Microbial diversity of milk ghee in southern Gansu and its effect on the formation of ghee flavor compounds
  143. Ecology and Environmental Sciences
  144. Effects of heavy metals on bacterial community surrounding Bijiashan mining area located in northwest China
  145. Microorganism community composition analysis coupling with 15N tracer experiments reveals the nitrification rate and N2O emissions in low pH soils in Southern China
  146. Genetic diversity and population structure of Cinnamomum balansae Lecomte inferred by microsatellites
  147. Preliminary screening of microplastic contamination in different marine fish species of Taif market, Saudi Arabia
  148. Plant volatile organic compounds attractive to Lygus pratensis
  149. Effects of organic materials on soil bacterial community structure in long-term continuous cropping of tomato in greenhouse
  150. Effects of soil treated fungicide fluopimomide on tomato (Solanum lycopersicum L.) disease control and plant growth
  151. Prevalence of Yersinia pestis among rodents captured in a semi-arid tropical ecosystem of south-western Zimbabwe
  152. Effects of irrigation and nitrogen fertilization on mitigating salt-induced Na+ toxicity and sustaining sea rice growth
  153. Bioengineering and Biotechnology
  154. Poly-l-lysine-caused cell adhesion induces pyroptosis in THP-1 monocytes
  155. Development of alkaline phosphatase-scFv and its use for one-step enzyme-linked immunosorbent assay for His-tagged protein detection
  156. Development and validation of a predictive model for immune-related genes in patients with tongue squamous cell carcinoma
  157. Agriculture
  158. Effects of chemical-based fertilizer replacement with biochar-based fertilizer on albic soil nutrient content and maize yield
  159. Genome-wide identification and expression analysis of CPP-like gene family in Triticum aestivum L. under different hormone and stress conditions
  160. Agronomic and economic performance of mung bean (Vigna radiata L.) varieties in response to rates of blended NPS fertilizer in Kindo Koysha district, Southern Ethiopia
  161. Influence of furrow irrigation regime on the yield and water consumption indicators of winter wheat based on a multi-level fuzzy comprehensive evaluation
  162. Discovery of exercise-related genes and pathway analysis based on comparative genomes of Mongolian originated Abaga and Wushen horse
  163. Lessons from integrated seasonal forecast-crop modelling in Africa: A systematic review
  164. Evolution trend of soil fertility in tobacco-planting area of Chenzhou, Hunan Province, China
  165. Animal Sciences
  166. Morphological and molecular characterization of Tatera indica Hardwicke 1807 (Rodentia: Muridae) from Pothwar, Pakistan
  167. Research on meat quality of Qianhua Mutton Merino sheep and Small-tail Han sheep
  168. SI: A Scientific Memoir
  169. Suggestions on leading an academic research laboratory group
  170. My scientific genealogy and the Toronto ACDC Laboratory, 1988–2022
  171. Erratum
  172. Erratum to “Changes of immune cells in patients with hepatocellular carcinoma treated by radiofrequency ablation and hepatectomy, a pilot study”
  173. Erratum to “A two-microRNA signature predicts the progression of male thyroid cancer”
  174. Retraction
  175. Retraction of “Lidocaine has antitumor effect on hepatocellular carcinoma via the circ_DYNC1H1/miR-520a-3p/USP14 axis”
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