Purpose:Â To investigate the endoscopic injection of recombinant human adenovirus type 5 (H101) in the treatment of gastric cancer. Method:Â The diagnosis and treatment data of one patient with advanced gastric cancer were collected and discussed.Â Result: The patient ,a 51-year-old middle-aged male,Â was diagnosed with gastric malignant tumor (adenocarcinoma stage IV) with liver metastasis and lymph node metastasis combined with the results of gastroscopy, imaging and pathological examination. The patient underwent endoscopic injection of recombinant human adenovirus type 5 (H101) and chemotherapy.After 4 times of endoscopic treatment, the patient had no serious adverse reactions,pyloric obstruction was relieved,Â carcinoembryonic antigen was significantly reduced, intragastric ulcerated-like tumor was healed,the range of liver metastases was reduced.In outpatient follow-up, no tumor recurrence or metastasis was found, and the general condition was good.Â Conclusion: Endoscopic injection of recombinant human adenovirus type 5 showed good efficacy and safety and tolerability in patients with advanced gastric cancer.It is worthy of further promotion in clinical practice

Hu, Doudou

Jiang, Guidong

Jiang, Xiangjun

English

Advanced Emergency Medicine (E-Journal)

Volume 11 | Issue 3 - 195 -Endoscopic Injection of Recombinant Human Adenovirus Type 5Combined with Chemotherapy in the Treatment of GastricCancer: A Case ReportGuidong Jiang1, Doudou Hu2, Xiangjun Jiang2*1. Dalian Medical University, Dalian 116000, China.2. Qingdao Municipal Hospital, Qingdao 266071, China.Abstracts: Purpose: To investigate the endoscopic injection of recombinant human adenovirus type 5 (H101) in thetreatment of gastric cancer. Method: The diagnosis and treatment data of one patient with advanced gastric cancer werecollected and discussed. Result: The patient ,a 51-year-old middle-aged male, was diagnosed with gastric malignant tumor(adenocarcinoma stage IV) with liver metastasis and lymph node metastasis combined with the results of gastroscopy,imaging and pathological examination. The patient underwent endoscopic injection of recombinant human adenovirus type 5(H101) and chemotherapy.After 4 times of endoscopic treatment, the patient had no serious adverse reactions,pyloricobstruction was relieved, carcinoembryonic antigen was significantly reduced,intragastric ulcerated-like tumor washealed,the range of liver metastases was reduced.In outpatient follow-up, no tumor recurrence or metastasis was found, andthe general condition was good. Conclusion: Endoscopic injection of recombinant human adenovirus type 5 showed goodefficacy and safety and tolerability in patients with advanced gastric cancer.It is worthy of further promotion in clinicalpractice.Keywords: Gastric Cancer; Adenovirus; Chemotherapy; Case-Reporting1. IntroductionGastric cancer is one of the most common digestive malignancies worldwide.There were 1.08 million new casesglobally in 2020.It is the fifth most common cancer and the fourth leading cause of death worldwide.[1]At present,chemoradiotherapy is the main therapeutic measure to delay the progression of middle and advanced gastric cancer.However,the overall treatment effect was suboptimal.Oncolytic virus treatment is a new therapy of tumor biology andimmunotherapy.It uses the virus's ability to replicate to selectively infect and destroy tumor cells while preserving normalcells and tissues.[2]Recombinant human Adenovirus type 5 injection (H101)is the application of genetic engineeringtechnology to reconstruct human adenovirus type 5.It has achieved some curative effect in the treatment of some middle andadvanced malignancies.A case of advanced gastric cancer treated with endoscopic recombinant human adenovirus type 5(H101) injection combined with SOX regimen in our hospital is reported as follows.2. Case dataThe patient, a 51 years old male, was admitted to our hospital due to abdominal pain for half a month on May 26,2017.More than 10 days before admission,Previous gastroscopy in another hospital suggested that he had gastric mucosallesions and pyloric obstruction.Pathological examination was performed that he had adenocarcinoma of gastricantrum.Abdominal CT showed that he had gastric cancer in the antrum and gastric horn and multiple liver metastases withintraperitoneal lymph node metastases.He was diagnosed with gastric malignancy (adenocarcinoma stage IV) with livermetastasis and lymph node metastasis.The patient was healthy and had no history of hepatitis or tumor,and no history of drugallergy.The patient vomited at admission and lost 8kg of weight with 1 point according to the Stomach Outlet ObstructionScore System (GOOSS) and 5 points for nutritional risk screening score (NRS-2002).Physical examination on admissionAdvanced Emergency Medicine- 196 -showed clear consciousness and general spirit, no obvious abnormality was found in cardiopulmonary percussion andpalpation, the abdomen was flat and soft, stomach type was visible, no mural varicose veins were observed, mild tendernessin the upper abdomen, no rebound pain, no tenderness or rebound pain in the rest of the abdomen, Murphy negative, andnegative mobility dullness. The patient underwent a SOX regimen (oxaliplatin 200mg d1 + tiggio 50mg bid) combined withfour endoscopic recombinant human type 5 adenovirus (H101)1.5ml multipoint injection). During the treatment, the patientonly occasionally had mild abdominal pain and abdominal distension, without nausea, vomiting, fever, anemia and otherserious adverse reactions.His GOOSS score was 4, and the NRS-2002 was 1. Abdominal CT showed that the range ofmultiple liver metastases was reduced and the carcinoembryonic antigen was significantly reduced.The patient was in goodmental state, had a fair diet, felt better quality of life, and gained 5kg in weight.Patients were followed up after discharge andregularly reviewed at local hospitals. Due to personal economic reasons, the patients could not continue to receive endoscopicadenovirus injection combined with chemotherapy in our hospital. Specific examination and laboratory tests duringhospitalization in our hospital are shown in Table 1. The image data are shown in Figure 1.3. ConclusionThe incidence and case fatality rate of gastric cancer both ranked the third place among malignant tumors inChina.According to global cancer statistics, there were 478,508 new cases of gastric cancer and 373,798 deaths in China in2020, accounting for 44% and 49% of the world, respectively.[3]The treatment of gastric cancer includes surgery,chemoradiotherapy, targeted and immunotherapy.At present, it is believed that although the radical resection of early gastriccancer can completely remove the lesion, 30% of the patients will still have local or distal recurrence after surgery.[4,5]Patientswith advanced palliative chemotherapy have many adverse effects, with a 5-year survival rate of 25 – 30%.[6]Targeted drugshave limited efficacy due to the complex tumor microenvironment, genetic instability, and heterogeneity of HER2 expressionin both primary and metastatic sites.[7]Immunotherapy requires the selection of appropriate patients based on specificmolecular markers, and some elderly cancer patients may be affected by immune system dysfunction.[8]So new treatments forgastric cancer are urgently needed. Oncolytic virus is a new type of tumor immunotherapy, which can change "cold" tumorinto "hot" tumor by inducing chemokines and cytokines, promote anti-tumor immune response, and further enhance theefficacy of immunotherapy, with good safety and no serious adverse reactions.Common complications of advanced gastric cancer include pyloric obstruction, gastrointestinal bleeding, perforation,etc.Pyloric obstruction is more common, which not only seriously affects the quality of life of patients, but also may promotethe spread and metastasis of gastric cancer.Current common treatments are surgical procedures and self-expanded metalstenting (SEMS).Although both methods can relieved clinical symptoms, they did not inhibit tumorprogression. Complications such as stent migration, tumor stent growth and anastomotic tumor recurrence will occur.[9]Thepatient's first gastroscopy revealed a large ulcer-like tumor in the gastric horn with pyloric obstruction, with a GOOSS scoreof 1. After 4 injections of recombinant human adenovirus type 5 (H101), the gastric horn ulcer-like tumor was healed andpyloric obstruction was relieved by gastroscopy. GOOSS score was 4.The patient was in good mental state and could eatnormally without symptoms such as vomiting and food. The weight gain was about 5kg, and the NRS-2002 score was1.Haemoglobin and albumin levels were also identified as indicators of dietary improvement.[10]After treatment, hemoglobin,total protein and albumin increased by 12g/L, 6.87g/L and 3.68g/L respectively.It can be concluded that endoscopicadenovirus injection can not only dynamically observe the pathological conditions of gastric lesions, but also directly injectadenovirus into the tumor to inhibit the tumor progression, thereby alleviating pyloric obstruction and improving the qualityof life of patients. When necessary, endoscopic hemostasis and pathological biopsy can also be performed.Patients withadvanced gastric cancer have a poor prognosis, usually palliative chemotherapy, and the SOX regimen is commonly used inChina.However, more adverse reactions appeared, such as anemia, leukopenia, thrombocytopenia, fever, nausea andvomiting.Peripheral sensory neuropathy and oral mucositis also appeared in some studies.[11,12]In this case, the patient had noabove adverse effects during the chemotherapy treatment of H101 injection combined with SOX regimen, with only mildabdominal pain and abdominal distension, and the pain score (NRS) was 1.A study by ZHANG et al found that adverseeffects such as nausea, vomiting, constipation, granulocopenia, anemia, and alopecia were less common in single H101Volume 11 | Issue 3 - 197 -treatment compared with monotherapy, chemotherapy plus H101.[13]Therefore, H101 injection is currently considered to havea good safety and tolerability.Adenovirus (Ads) is a non-enveloped virus with a double stranded DNA genome of about 36KB, which is one of themost studied oncolytic viruses.[14]Ads monotherapy or combination chemotherapy has been widely used in the treatment ofsolid tumors such as head and neck tumors, oesophageal cancer, gastric cancer, lung cancer, and liver cancer.A study byCHEN et al showed that rAd-p53 inhibited the growth of gastric cancer cells and that cells with more differentiation weremore sensitive to the treatment of rAd-p53.[15]Rad-p53 is a weakened adenovirus carrying the wild-type p53 gene. Previousstudies have shown that rad-p53 inhibits tumor growth, promotes apoptosis and enhances the sensitivity of tumor cells tochemoradiotherapy by inducing the expression of Puma, Bax, Bak and Fas.[16]Recombinant human adenovirus type 5 (H101)is also a kind of oncolytic adenovirus, but it is relatively poorly studied in gastric cancer.H101 was obtained by geneticengineering techniques for the deletion of some human type 5 adenovirus E1B-55kD protein and the E3 region.[17]Thedeletion of E3 fragments can transmit tumor antigen information to the human immune system, activate T lymphocytes, andinduce the body to produce an immune response against adenovirus, thus killing tumor cells infected with adenovirus andestablishing lasting antitumor immunity.H101 can not replicate in the p53 normal cells, and p53 expression in gastric cancer,so the virus can replicate in the body and infect tumor cells, inhibit the production of vascular endothelial growth factor andthe formation of tumor neovascularization, eventually lysis kill tumor cells, release the offspring virus to infection thesurrounding tumor cells, thus play the anti-tumor role of targeted killing.H101 can also improve the efficacy ofchemoradiotherapy.Therefore, consider that H101 may inhibit tumor progression and prolong the survival cycle of tumorpatients through the above mechanisms.In conclusion, endoscopic adenovirus injection can flexibly observe gastric lesions,directly act on the tumor, relieve pyloric obstruction, improve patient quality of life, with no obvious adverse reactions, andgood tolerance and safety.However, this paper only discusses a single case and is not extensive.Therefore, H101 needs to befurther explored clinically in the treatment of gastric cancer.Table 1result2017.06.02(First injection ofadenovirus)2017.06.28（Second injection ofadenovirus）2017.08.16（Third injection ofadenovirus）2017.11.15（Fourth injectionof adenovirus）W.B.C. （10^9/L） 7.56 4.40 4.31 3.63neutrophile granulocyte（10^9/L）5.24 2.58 2.30 1.96oxyphorase （g/L） 138 136 140 150blood cells（10^9/L） 122 98 106 123AFP (ng/ml) 1.68 2.59 3.11 2.55carcinoembryonicantigen (ng/ml)94.17 254.30 22.29 8.10CA199(ng/ml) <0.600 <0.600 <0.600 <0.600CA125(ng/ml) 18.61 15.69 6.38 5.16CA724(ng/ml) NA 2.22 3.25 3.01ALT(U/L) 38.16 39.10 55.43 19.41AST(U/L) 58.10 43.65 38.39 22.71total protein （g/L） 58.69 58.88 66.20 65.56albumin（g/L） 41.69 40.09 46.77 45.37total bilirubin（umol/L）15.60 12.50 15.80 12.60BRD（umol/L） 4.10 3.40 3.40 2.50Indirect bilirubin 11.50 9.10 12.40 10.10Advanced Emergency Medicine- 198 -（umol/L）creatinine （umol/L） 95.70 75.90 79.34 63.63usea nitrogen（mmol/L）7.28 4.62 4.56 7.17Figure 1GastroscopeFirst injection of adenovirus Second injection of adenovirus Third injection of adenovirusCTFirst injection of adenovirus Second injection of adenovirusThird injection of adenovirus Fourth injection of adenovirusReferences[1] Hyuna Sung, PhD, Jacques Ferlay, MSc, ME, Rebecca L. Siegel, MPH, et al. Global Cancer Statistics 2020:GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA CANCER J CLIN 2021;71: 209–249.[2] Rogulski KR, Freytag SO, Zhang K, et al. In vivo antitumor activity of ONYX-015 is influenced by p53 status and isaugmented by radiotherapy[J]. Cancer Res, 2000, 60(5):1193-1196[3] WHO. Globocan 2020 Stomach. In: WHO, Globocan 2020 China. China:International Agency for Research on Cancer.March 2021. Available at:https://gco.iarc.fr/today/data/factsheets/ cancers/7-Stomach-fact-sheet.pdf2.[4] Nakagawa N, Kanda M, Ito S, et al. Pathological tumor infiltrative pattern and sites of initial recurrence in stage II/IIIgastric cancer: propensity score matching analysis of a multi-institutional dataset. Cancer Med. 2018;7(12):6020–9.[5] Kim JH, Lee HH, Seo HS, et al. Borrmann type 1 Cancer is associated with a high recurrence rate in locally advancedgastric Cancer. 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Endoscopic Injection of Recombinant Human Adenovirus Type 5 Combined with Chemotherapy in the Treatment of Gastric Cancer: A Case Report

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Endoscopic Injection of Recombinant Human Adenovirus Type 5 Combined with Chemotherapy in the Treatment of Gastric Cancer: A Case Report

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Advanced Emergency Medicine (E-Journal)