The effect of <i>Pseudomonas aeruginosa</i> injection on the prognosis of medullary thyroid carcinoma patients with abnormal serum calcitonin after surgery_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YI Cheng , LIU Jiaye ,  LI Zhihui

Division of Thyroid Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, P. R. China;

Corresponding author：

LI Zhihui, Email: rockoliver@vip.sina.com

Keywords：

medullary thyroid carcinoma; Pseudomonas aeruginosa injection; prognosis; propensity score matching; retrospective cohort study

DOI：

10.7507/1007-9424.202411050

Video：

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Objective To investigate the impact of postoperative application of Pseudomonas aeruginosa injection on recurrence free survival (RFS) and overall survival (OS) in patients with abnormal serum calcitonin levels following surgery for medullary thyroid carcinoma (MTC). Methods A retrospective collection of data was conducted for 214 patients with abnormal serum calcitonin levels following MTC surgery at West China Hospital of Sichuan University from January 2015 to April 2024. Propensity score matching (1∶2) was utilized to match patients’ data to reduce confounding bias, comparing RFS and OS between patients who used (Pseudomonas group) and did not use (control group) Pseudomonas aeruginosa injection. Results After propensity score matching, 72 patients with abnormal postoperative calcitonin levels were included, with 24 in the Pseudomonas group and 48 in the control group. The median follow-up time for the 72 patients was 66 months (11–168 months). The 1-year RFS rates for the Pseudomonas group and the control group were 100% and 75.0%, respectively, and the 2-year RFS rates were 87.5% and 56.3%, respectively. The RFS in the Pseudomonas group was superior to that in the control group (χ²=4.791, P=0.029). The 5-year OS rates for the Pseudomonas group and the control group were 90.9% and 93.5%, respectively, with no significant difference between the two groups (χ²=0.469, P=0.491). The Cox proportional hazards regression model indicated that the median RFS was extended in the Pseudomonas group [25 months vs. 21 months, RR=0.350, 95%CI (0.135, 0.900), P=0.029], but there was no significant impact on OS [66 months vs. 69 months, RR=2.22, 95%CI (0.229, 21.444), P=0.503]. Conclusion Postoperative use of Pseudomonas aeruginosa injection in MTC patients with abnormal serum calcitonin level shows significant improvement in RFS, but no significant change in OS.

1.	Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 2015, 25(6): 567-610.
2.	Chen DW, Lang BHH, McLeod DSA, et al. Thyroid cancer. Lancet, 2023, 401(10387): 1531-1544.
3.	Zheng X, Rui S, Wang XF, et al. circPVT1 regulates medullary thyroid cancer growth and metastasis by targeting miR-455-5p to activate CXCL12/CXCR4 signaling. J Exp Clin Cancer Res, 2021, 40(1): 157. doi: 10.1186/s13046-021-01964-0. doi: 10.1186/s13046-021-01964-0.
4.	National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma (Version 3.2024) 2024. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf.
5.	Li T, Dong ZR, Guo ZY, et al. Mannose-mediated inhibitory effects of PA-MSHA on invasion and metastasis of hepatocellular carcinoma via EGFR/Akt/IκBβ/NF-κB pathway. Liver Int, 2015, 35(4): 1416-1429.
6.	Zhang C, Zhang Z, Wang L, et al. Pseudomonas aeruginosa-mannose sensitive hemagglutinin injection treated cytokine-induced killer cells combined with chemotherapy in the treatment of malignancies. Int Immunopharmacol, 2017, 51: 57-65.
7.	Zheng X, Fang Y, Zou X, et al. Therapeutic potential of Pseudomonas aeruginosa-mannose sensitive hemagglutinin (PA-MSHA) in cancer treatment. Microb Pathog, 2023, 185: 106422. doi: doi: 10.1016/j.micpath.2023.106422.
8.	Bozic D, Živanović J, Živančević K, et al. Trends in anti-tumor effects of Pseudomonas aeruginosa mannose-sensitive-hemagglutinin (PA-MSHA): an overview of positive and negative effects. Cancers (Basel), 2024, 16(3): 524. doi: 10.3390/cancers16030524.
9.	Wang Z, Tang C, Wang Y, et al. Inclusion of the number of metastatic lymph nodes in the staging system for medullary thyroid cancer: validating a modified American joint committee on cancer tumor-node-metastasis staging system. Thyroid, 2022, 32(5): 536-543.
10.	Amin MB, Edge SB, Greene FL. AJCC cancer staging manual (8th ed). Switzerland: Springer International Publishing, 2018.
11.	Baek S, Park SH, Won E, et al. Propensity score matching: a conceptual review for radiology researchers. Korean J Radiol, 2015, 16(2): 286-296.
12.	Wang H, Zu Q, Lu M, et al. Application of medical knowledge graphs in cardiology and cardiovascular medicine: a brief literature review. Adv Ther, 2022, 39(9): 4052-4060.
13.	Koperek O, Bergner O, Pichlhöfer B, et al. Expression of hypoxia-associated proteins in sporadic medullary thyroid cancer is associated with desmoplastic stroma reaction and lymph node metastasis and may indicate somatic mutations in the VHL gene. J Pathol, 2011, 225(1): 63-72.
14.	Walgama E, Busaidy N, Zafereo M. Novel therapeutics and treatment strategies for medullary thyroid cancer. Endocrinol Metab Clin North Am, 2022, 51(2): 379-389.
15.	Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer, 2021, 21(6): 345-359.
16.	Savage SR, Yi X, Lei JT, et al. Pan-cancer proteogenomics expands the landscape of therapeutic targets. Cell, 2024, 187(16): 4389-4407. e15.
17.	Liu J, Duan X. PA-MSHA induces apoptosis and suppresses metastasis by tumor associated macrophages in bladder cancer cells. Cancer Cell Int, 2017, 17: 76. doi: 10.1186/s12935-017-0445-3.
18.	檀碧波, 狄岩, 李勇, 等. 铜绿假单胞菌注射液联合洛铂腹腔注射治疗胃癌恶性腹腔积液的效果. 河北医药, 2021, 43(3): 434-436, 442.
19.	李伟, 刘昊. 铜绿假单胞菌注射液膀胱灌注预防非肌层浸润性膀胱癌术后复发的有效性及对患者生活质量和血清VEGF的影响. 临床泌尿外科杂志, 2020, 35(2): 133-136.
20.	林涛, 宋纯, 王辉. 晚期结直肠癌术中使用铜绿假单胞菌注射液的长期疗效探讨. 中国肿瘤临床, 2014, 41(8): 526-529.
21.	王涛, 田坤, 刘雅婷, 等. 铜绿假单胞菌注射液联合深部热疗治疗恶性胸腹腔积液的回顾性研究. 生物医学转化, 2022, 3(1): 70-74.
22.	邱烽, 吴建军, 胡进勇, 等. 肝癌术后铜绿假单胞菌注射液治疗的临床研究. 中华临床医师杂志(电子版), 2014, 8(16): 2957-2959.
23.	Wang C, Hu Z, Zhu Z, et al. The MSHA strain of Pseudomonas aeruginosa (PA-MSHA) inhibits gastric carcinoma progression by inducing M1 macrophage polarization. Tumour Biol, 2016, 37(5): 6913-6921.
24.	Huang M, He F, Li D, et al. PA-MSHA induces inflamed tumor microenvironment and sensitizes tumor to anti-PD-1 therapy. Cell Death Dis, 2022, 13(11): 931. doi: 10.1038/s41419-022-05368-6.
25.	Lv F, Cao J, Liu Z, et al. Phase Ⅱ study of Pseudomonas aeruginosa-mannose-sensitive hemagglutinin in combination with capecitabine for Her-2-negative metastatic breast cancer pretreated with anthracycline and taxane. PLoS One, 2015, 10(3): e0118607. doi: 10.1371/journal.pone.0118607.
26.	Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase Ⅲ trial. J Clin Oncol, 2012, 30(2): 134-141.
27.	Clark JR, Fridman TR, Odell MJ, et al. Prognostic variables and calcitonin in medullary thyroid cancer. Laryngoscope, 2005, 115(8): 1445-1450.
28.	Fialkowski E, DeBenedetti M, Moley J. Long-term outcome of reoperations for medullary thyroid carcinoma. World J Surg, 2008, 32(5): 754-765.
29.	van Heerden JA, Grant CS, Gharib H, et al. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg, 1990, 212(4): 395-400.

1. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 2015, 25(6): 567-610.
2. Chen DW, Lang BHH, McLeod DSA, et al. Thyroid cancer. Lancet, 2023, 401(10387): 1531-1544.
3. Zheng X, Rui S, Wang XF, et al. circPVT1 regulates medullary thyroid cancer growth and metastasis by targeting miR-455-5p to activate CXCL12/CXCR4 signaling. J Exp Clin Cancer Res, 2021, 40(1): 157. doi: 10.1186/s13046-021-01964-0. doi: 10.1186/s13046-021-01964-0.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma (Version 3.2024) 2024. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf.
5. Li T, Dong ZR, Guo ZY, et al. Mannose-mediated inhibitory effects of PA-MSHA on invasion and metastasis of hepatocellular carcinoma via EGFR/Akt/IκBβ/NF-κB pathway. Liver Int, 2015, 35(4): 1416-1429.
6. Zhang C, Zhang Z, Wang L, et al. Pseudomonas aeruginosa-mannose sensitive hemagglutinin injection treated cytokine-induced killer cells combined with chemotherapy in the treatment of malignancies. Int Immunopharmacol, 2017, 51: 57-65.
7. Zheng X, Fang Y, Zou X, et al. Therapeutic potential of Pseudomonas aeruginosa-mannose sensitive hemagglutinin (PA-MSHA) in cancer treatment. Microb Pathog, 2023, 185: 106422. doi: doi: 10.1016/j.micpath.2023.106422.
8. Bozic D, Živanović J, Živančević K, et al. Trends in anti-tumor effects of Pseudomonas aeruginosa mannose-sensitive-hemagglutinin (PA-MSHA): an overview of positive and negative effects. Cancers (Basel), 2024, 16(3): 524. doi: 10.3390/cancers16030524.
9. Wang Z, Tang C, Wang Y, et al. Inclusion of the number of metastatic lymph nodes in the staging system for medullary thyroid cancer: validating a modified American joint committee on cancer tumor-node-metastasis staging system. Thyroid, 2022, 32(5): 536-543.
10. Amin MB, Edge SB, Greene FL. AJCC cancer staging manual (8th ed). Switzerland: Springer International Publishing, 2018.
11. Baek S, Park SH, Won E, et al. Propensity score matching: a conceptual review for radiology researchers. Korean J Radiol, 2015, 16(2): 286-296.
12. Wang H, Zu Q, Lu M, et al. Application of medical knowledge graphs in cardiology and cardiovascular medicine: a brief literature review. Adv Ther, 2022, 39(9): 4052-4060.
13. Koperek O, Bergner O, Pichlhöfer B, et al. Expression of hypoxia-associated proteins in sporadic medullary thyroid cancer is associated with desmoplastic stroma reaction and lymph node metastasis and may indicate somatic mutations in the VHL gene. J Pathol, 2011, 225(1): 63-72.
14. Walgama E, Busaidy N, Zafereo M. Novel therapeutics and treatment strategies for medullary thyroid cancer. Endocrinol Metab Clin North Am, 2022, 51(2): 379-389.
15. Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer, 2021, 21(6): 345-359.
16. Savage SR, Yi X, Lei JT, et al. Pan-cancer proteogenomics expands the landscape of therapeutic targets. Cell, 2024, 187(16): 4389-4407. e15.
17. Liu J, Duan X. PA-MSHA induces apoptosis and suppresses metastasis by tumor associated macrophages in bladder cancer cells. Cancer Cell Int, 2017, 17: 76. doi: 10.1186/s12935-017-0445-3.
18. 檀碧波, 狄岩, 李勇, 等. 铜绿假单胞菌注射液联合洛铂腹腔注射治疗胃癌恶性腹腔积液的效果. 河北医药, 2021, 43(3): 434-436, 442.
19. 李伟, 刘昊. 铜绿假单胞菌注射液膀胱灌注预防非肌层浸润性膀胱癌术后复发的有效性及对患者生活质量和血清VEGF的影响. 临床泌尿外科杂志, 2020, 35(2): 133-136.
20. 林涛, 宋纯, 王辉. 晚期结直肠癌术中使用铜绿假单胞菌注射液的长期疗效探讨. 中国肿瘤临床, 2014, 41(8): 526-529.
21. 王涛, 田坤, 刘雅婷, 等. 铜绿假单胞菌注射液联合深部热疗治疗恶性胸腹腔积液的回顾性研究. 生物医学转化, 2022, 3(1): 70-74.
22. 邱烽, 吴建军, 胡进勇, 等. 肝癌术后铜绿假单胞菌注射液治疗的临床研究. 中华临床医师杂志(电子版), 2014, 8(16): 2957-2959.
23. Wang C, Hu Z, Zhu Z, et al. The MSHA strain of Pseudomonas aeruginosa (PA-MSHA) inhibits gastric carcinoma progression by inducing M1 macrophage polarization. Tumour Biol, 2016, 37(5): 6913-6921.
24. Huang M, He F, Li D, et al. PA-MSHA induces inflamed tumor microenvironment and sensitizes tumor to anti-PD-1 therapy. Cell Death Dis, 2022, 13(11): 931. doi: 10.1038/s41419-022-05368-6.
25. Lv F, Cao J, Liu Z, et al. Phase Ⅱ study of Pseudomonas aeruginosa-mannose-sensitive hemagglutinin in combination with capecitabine for Her-2-negative metastatic breast cancer pretreated with anthracycline and taxane. PLoS One, 2015, 10(3): e0118607. doi: 10.1371/journal.pone.0118607.
26. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase Ⅲ trial. J Clin Oncol, 2012, 30(2): 134-141.
27. Clark JR, Fridman TR, Odell MJ, et al. Prognostic variables and calcitonin in medullary thyroid cancer. Laryngoscope, 2005, 115(8): 1445-1450.
28. Fialkowski E, DeBenedetti M, Moley J. Long-term outcome of reoperations for medullary thyroid carcinoma. World J Surg, 2008, 32(5): 754-765.
29. van Heerden JA, Grant CS, Gharib H, et al. Long-term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg, 1990, 212(4): 395-400.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

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