Toripalimab combined with targeted therapy and chemotherapy achieves pathologic complete response in gastric carcinoma: A case report

lNTRODUCTlON

Gastric carcinoma has a high incidence in China. Surgery might be a radical cure for gastric carcinoma;however, it is limited to only early-stage gastric carcinoma (stage I). The 5-year survival rate of patients with locally advanced gastric carcinoma (late stage) is 30%-50%[1], even with an extended area of resection and lymph node dissection. Many studies have confirmed that the combination of adjuvant/neoadjuvant chemotherapy/chemoradiotherapy can improve patients’ prognosis, enhance R0 resection rates, reduce distant metastases and recurrence rates, and improve survival rates through tumor downstaging[2-4]. In the European randomized controlled phase III AIO-fluorouracil (FLOT)-4 trial, resectable gastric carcinoma patients received either the FLOT (docetaxel, oxaliplatin, calcium folinate, and fluorouracil) or epirubicin, cisplatin, and fluorouracil (ECF) regimen before and after surgery. The results showed that the FLOT regimen had better efficacy, higher R0 resection rate, better disease-free survival (DFS), and better overall survival (OS) than the ECF regimen, which laid the foundation for the FLOT regimen to become a new standard perioperative therapy for advanced gastric carcinoma. Therefore, a regimen that combines surgery with neoadjuvant or perioperative chemotherapy has been recommended by the guidelines of the Chinese Society of Clinical Oncology, the European Society for Medical Oncology, and the National Comprehensive Cancer Network (NCCN).

The KEYNOTE-059[5] and ATTRACTION-02[6] trials have suggested that programmed death-1 (PD-1) inhibitors are effective for advanced gastric carcinoma/adenocarcinoma of the gastroesophageal junction. The United States Food and Drug Administration (FDA) and the National Medical Products Administration have approved the indications for pembrolizumab in patients with a programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 and nivolumab in the third-line and posteriorline treatment of advanced gastric carcinoma. The CheckMate-649[7] and ATTRACTION-04[8] trials have revealed that nivolumab plus chemotherapy has significantly better efficacy than chemotherapy alone in the first-line treatment of advanced gastric carcinoma/adenocarcinoma. In China, as the first approved immunotherapy targeting PD-1, toripalimab (JS001) induces the endocytosis of PD-1, reduces the expression of PD-1 on the membrane surface, and relieves the immunosuppression of T cells,thereby achieving strong antitumor effects. In 2020, the American Society of Clinical Oncology reported the clinical response and biomarker analysis of first-line toripalimab combined with standard chemotherapy for solid tumors in a phase II cohort study[9]. The study found that the objective response rate (ORR) was 54.5%, the disease control rate was 84.8%, and the duration of response was 8.3 mo. Moreover, in the randomized controlled phase III KEYNOTE-585[10] trial, which is currently enrolling patients, therapy-naive patients with locally advanced gastric carcinoma/adenocarcinoma of the gastroesophageal junction in the experimental group will receive pembrolizumab combined with neoadjuvant chemotherapy before surgery and pembrolizumab combined with adjuvant chemotherapy after surgery, whereas those in the control group will receive placebo combined with chemotherapy.

The patient has been suffering from hepatitis B virus (HBV) infection for more than 30 years, without history of hypertension, coronary heart disease, diabetes, or tuberculosis.

Human epidermal growth factor receptor 2 (HER2), also known as erythroblastic oncogene B2(ERBB2), is a proto-oncogenic protein encoded by thegene on human chromosome 17. Tyrosine kinase receptor that binds to the membrane is a protein product of this gene. This receptor can promote cell proliferation and inhibit apoptosis, leading to neoplasm formation[11].overexpression or amplification is found in 13%-22% of patients with gastric carcinoma or adenocarcinoma of the esophagogastric junction[12]. Immunohistochemistry (IHC) staining and fluorescenthybridization (FISH) are recommended by the guidelines for the detection ofoverexpression in patients with advanced gastric adenocarcinoma. In 2010, trastuzumab was approved by the FDA as a first-line drug in combination chemotherapy for HER2-positive gastric carcinoma. In another study[13],preliminary results were obtained for combined immunotherapy, trastuzumab, and chemotherapy for gastric carcinoma/esophageal cancer/adenocarcinoma of the esophagogastric junction. The study found that the 6-mo progression-free survival (PFS) rate was 75%, the ORR was 91%, the median PFS was 13 mo, and the median OS was 27.3 mo. The above data were better than the previous data for HER2-positive advanced gastric carcinoma.

由于N組信號的內積值得到積累，尤其對于弱信號而言，內積值得到提高，因此信噪比下仍然可以較好的實現重構，降低重構誤差.

In this study, we report a case in which pathologic complete response (pCR) was achieved by neoadjuvant toripalimab, Herceptin, and FLOT chemotherapy followed by surgery for HER2- and PDL1-positive locally advanced gastric carcinoma. We hope to provide more evidence for neoadjuvant therapies in gastric carcinoma patients by reporting this case.

CASE PRESENTATlON

Chief complaints

A 63-year-old male patient experienced dysphagia, poor appetite, night sweats, and fatigue on July 2,2020, and sought medical attention at the Hulunbuir People’s Hospital in Inner Mongolia, China.

History of present illness

Apart from the above aspects,is a crucial tumor suppressor gene, andmutation occurs at an incidence of approximately 45% in gastric carcinoma[21]. The efficacy of immunotherapy varies with themutation. According to the retrospective meta-analysis mentioned above,mutation was negatively correlated with the patients’ OS with either colon cancer or gastric carcinoma who received immunotherapy but was positively correlated with the efficacy of immunotherapy for lung cancer[21].In this study,c.329G＞C p.Arg110Pro mutation was detected using NGS in the baseline tissues of the patient. Therefore, additional prospective cohort studies are required to conclude and explore the correlation betweenmutation and the efficacy of immunotherapy for gastric carcinoma.

History of past illness

3）規范化原則：系統設計中的所有參數與技術指標均應參照現行的國家標準、行業標準和技術規范，并從系統實際需求出發，制定出科學合理的數據標準與規范，推動信息系統進一步規范化與標準化的實現。

我國理財市場發展處于初級階段，銀監會對銀行、信托公司等進行監管，正確、基金、期貨等公司由證監會監管，保險公司則由保監會監管，銀行理財產品涉及以上監管多項內容，對產品的審批、份額管理以及保底承諾管控深度不同，對資金托管、風險控制以及信息披露等問題管控程度有限，造成監管機構監管執行力度不足，監管效率不高，為行業發展帶來影響。

直到這時，周教授方才明白一切都是那個當導演的朋友搞的惡作劇。周教授心情一下頗不舒暢起來，氣極敗壞地走到院外撥通了那個導演朋友的電話，大聲說，你怎么能這樣么，玩笑開得太大了么。說完，像懷了深仇大恨似的，猛地摁了關機鍵。

Personal and family history

The patient’s family history is not applicable.

Physical examination

The tissues obtained from the bite biopsy were tested for PD-1, revealing CPS positivity (CPS = 1)(Figure 1C) and TPS negativity.

Laboratory examinations

On July 22, 2020, gastroscopy revealed protuberant lesions in the cardia and fundus; bite biopsy revealed adenocarcinoma of the cardia; IHC revealed HER-2 positivity (2+, FISH was recommended);hybridization revealed(-); and FISH revealedpositivity. Next-generation sequencing(NGS) revealed tumor protein p53 () c.329G＞C p.Arg110Pro (abundance 33.82%), andcopy number amplification (= 4.5).

Imaging examinations

On July 30, 2020, a computed tomography (CT) scan was performed (Figure 2A).

FlNAL DlAGNOSlS

(1) Thickened wall of the cardia and adjacent lesser curvature of the stomach, suggestive of carcinoma of the cardia, and invaded fundus and multiple lymph nodes in the hepatogastric ligament region, for which clinical and endoscopic examination needed to be performed; (2) Multiple cysts in the liver; (3)Cyst of the right kidney; (4) Slightly thickened left adrenal gland, with follow-up visits recommended;(5) Prostatic calcification; (6) Subpleural ground-glass opacity in the right lung and scattered nodules and granules on the pleura of both lungs and under the interlobar pleura, with follow-up visits recommended; and (7) A dot-like compact shadow on the 5right rib, for which follow-up visits were recommended.

TREATMENT

From July 30, 2020 to September 2020, four-cycle targeted therapy, chemotherapy, and immunotherapy were administered. The specific regimen was as follows: Trastuzumab: 420 mg in the first cycle and 280 mg in the second cycle; docetaxel: 90 mg, ivd, d1; oxaliplatin: 150 mg, ivd, d1; calcium folinate: 700 mg,ivd, d1; fluorouracil: 4800, civ, 46 h; and toripalimab: 240 mg, ivd, d2; Q2W. Grade I gastrointestinal reaction occurred and improved after symptomatic treatment.

The imaging findings (CT on October 15, 2020, compared with that on July 30, 2020) after the four cycles of therapy were as follows (Figure 2B): The wall thickness of the cardia and adjacent lesser curvature was less than that before therapy; lymph nodes in the hepatogastric ligament region were reduced in size; and subpleural infiltration in the right lower lobe was more absorbed. No other significant changes were noted. Upper gastrointestinal tract radiography revealed carcinoma of the cardia.

Here, we demonstrated that in a patient with HER2-positive locally advanced gastric carcinoma, there was scope for resection; therefore, a regimen composed of Herceptin, chemotherapy, and immunotherapy was carefully selected to achieve higher efficacy and better surgical resection. The patient was administered with the perioperative regimen comprising Herceptin, FLOT, and toripalimab. The postoperative pathological findings revealed that this regimen led to complete tumor response and the levels of tumor biomarkers returned to normal. Furthermore, no circulating tumor cell was detected and no significant immune-related adverse effects were noted, demonstrating that this regimen had sufficient efficacy and safety. The four-cycle chemotherapy was continued postoperatively and completed in the patient, in line with the principle of “effective treatment should be continued if the symptoms are relieved”. This patient is currently in the quarterly follow-up period. A previous study suggested that the ability to achieve postoperative pCR in patients with neoadjuvant therapy is positively correlated with longer durations of survival[22]. Thus far, all tumors have been removed from this patient using this regimen, and we hope that this regimen will lead to long-time survival benefits.

Under general anesthesia, the patient underwent laparoscopic radical D2 gastrectomy for gastric carcinoma on October 23, 2020. Surgical findings revealed a neoplasm at the fundus of the stomach from the cardia, which presented as a 4 cm × 2 cm ulcer with local serosal invasion. No significantly enlarged lymph nodes were found around the stomach. The lesions presented post-chemotherapy scar-like changes. Multiple small lymph nodes were noted around the stomach, most of which were postchemotherapy changes. The postoperative pathological findings revealed focal (proximal stomach) mild atypical glandular hyperplasia with chronic mucosal inflammation, no clear residual tumor (tumor regression grade 0), no regional lymph node metastasis, and negative upper and lower cut ends. The grading was as follows: Station 10/9, Station 20/6, Station 3A 0/12, Station 3B 0/2, Station 4SA soft tissue (-), Station 4SB 0/1 and soft tissue (-), Station 4D 0/2, Station 5 soft tissue (-), Station 60/1,Station 7 soft tissue (-), Station 8 soft tissue (-), Station 90/4, Station 12A soft tissue (-), Station 190/1,and Station 200/2. No circulating tumor microemboli or circulating tumor cells were detected. A retest of tumor markers showed a return to normal levels.

OUTCOME AND FOLLOW-UP

Informed written consent was obtained from the patient for the publication of this

DlSCUSSlON

report and any accompanying images.

It is believed that the basis for immunotherapy to benefit HER2-positive patients is that trastuzumab induces antibody-dependent cell-mediated cytotoxicity, improves the presentation of tumor antigens,and paves the way for immune reaction of tumors[14]. Clinical data also show that HER2-positive breast cancer has more types of tumor-infiltrating lymphocytes than average, which demonstrates the importance of trastuzumab in immunity induction[15]. In addition, studies have confirmed that trastuzumab can increase the expression level of PD-L1 in immune cells of patients with breast cancer[16]. Combined with the encouraging clinical outcome of this patient, it is promising to investigate the systemic immune responses in depth, for instance, the lymphocyte infiltration, immune marker dynamics, and functional cytokine secretion. Moreover, this patient has been infected with HBV for many years, which may have an impact on his immune system. Large cohorts are necessary to draw conclusions regarding this aspect if feasible.

There are many ongoing studies of neoadjuvant immunotherapy combined with chemotherapy or radiotherapy; however, most of these studies are phase II studies with small cohorts. According to some of the results reported thus far, these combined regimens have shown promising efficacy and safety[17-19] (Table 1). Many studies have shown that chemotherapy can: (1) Boost the release of damageassociated molecular patterns from tumor cells and improve tumor cell immunogenicity; and (2) Elevate the levels of major histocompatibility complex molecules and enhance tumor antigen presentation[20].Additionally, chemotherapy promotes the expression of PD-1/PD-L1 through a variety of signaling pathways. Therefore, in this case, chemotherapy and immunotherapy were applied for the patient before the surgical removal. For gastric carcinoma, first-line immunotherapy combined with chemotherapy is recommended by NCCN guidelines for patients with a PD-L1 CPS ≥ 5. However, the CheckMate 649 study[7] suggested that nivolumab combined with chemotherapy improves the OS and DFS of all patients, including those with a CPS ≥ 5 and CPS ≥ 1. In line with this, our patient’s IHC results revealed PD-L1 with a CPS of 1. More prospective cohort studies are needed to determine the selection of biomarkers in neoadjuvant therapies involving immunotherapy and chemotherapy.

On July 22, 2020, gastroscopy revealed protuberant lesions in the cardia and fundus; bite biopsy revealed adenocarcinoma of the cardia (Figure 1A); IHC revealed HER2 positivity (2+, FISH was recommended);hybridization revealed(-); and FISH revealedpositivity (Figure 1B).

區塊鏈：描繪物聯網安全新愿景………………………………………………………… 徐恪，吳波，沈蒙 24-6-52

CONCLUSlON

在實驗三中做了下列手術，這個手術的設計相當于將實驗二中具有“庫身份”的A段連接在實驗二被實驗證明必死的B段上方。

FOOTNOTES

Liu R designed the experiments, processed the data, applied for fund support, and wrote the first draft; Wang X performed the data collection; Ji Z, Deng T, Li HL, Zhang YH, Yang YC, Ge SH, Zhang L, Bai M and Ning T performed the data analysis; Ba Y modified the article.

本研究從全金安區四個級別隨機抽取159個定級單元作為檢驗樣點，通過采用統計分析軟件SPSS中的相關性分析的功能計算定級指數與經營效益分值間的相關程度。

Chinese Research Hospital Association, No. Y2019FH-DTCC-SC3.

With good postoperative recovery, the postoperative CT film (performed on November 16, 2020,Figure 2C) was stored, and the four-cycle chemotherapy regimen was continued at the same dosage as that administered previously. Until February 27, 2022, the patient was examined quarterly for 12 mo (4 times), and he was in a good condition without disease progression. The timeline of this case report is indicated in Figure 3.

In a study of combined immunotherapy and trastuzumab treatment for HER2-positive gastric carcinoma[13], 25 patients received immunotherapy and targeted therapy as the initial treatment and chemotherapy in the second cycle, whereas 12 patients received immunotherapy, targeted therapy, and chemotherapy as the initial treatment. In the initial treatment, no significant difference was observed in PFS and 12-mo OS between the 25-patient and 12-patient groups. While in our case, the patient did not receive chemotherapy in the initial treatment; more specifically, the patient received Herceptin and toripalimab in the first cycle and chemotherapy in the second cycle. Previous studies have found no difference in survival between groups receiving chemotherapy and groups not receiving chemotherapy in the initial treatment. Our study suggested that, for HER2-positive gastric carcinoma patients, it is worthy to further evaluate whether the first-line “de-chemotherapy” can be carried out with a large cohort sample.

Nothing to disclose.

給排水工程管材的選擇需要根據給排水工程的實際情況，進行擇優選擇，按照不同的特性，選擇適合當地環境標準的管材。給排水管材的選用一般遵循以下原則：①管道的安全性與衛生性。根據環保健康與安全要求，選用給水管材必須滿足衛生環保要求。尤其是生活給水管道，選用管材必須符合國家現行有關產品標準的要求，確保運輸過程中的水質衛生情況。②管材的實用性。即選用的管材必須滿足使用要求，首先要求管道在運輸壓力及溫度環境下要具有足夠強的機械強度，其次管道內還具有良好耐腐蝕性。確保所選的材料能夠具有較強的環境適應性。③管材的經濟性。設計時應該選擇既經濟，又具有良好性能和安裝維修方面的管材。

The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).

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China

Rui Liu 0000-0003-1287-2589; Xia Wang 0000-0002-2935-0691; Zhi Ji 0000-0002-2935-0692; Ting Deng 0001-0002-2935-0694; Hong-Li Li 0000-0002-8476-0936; Yan-Hui Zhang 0002-0002-3546-0876; Yu-Chong Yang 0000-0002-2935-0698; Shao-Hua Ge 0001-0002-2935-7642; Le Zhang 0001-0002-2935-0699; Ming Bai 0000-0002-2935-0666; Tao Ning 0000-0002-2935-0654; Yi Ba 0000-0002-2935-0634.

2017年，彩云社區在進行居民情況調查時，了解到楊家的事。李敬益打算啃啃硬骨頭，牽頭調解試試看。他把楊家七個兄妹都找來，挨個了解了下他們的想法；再把老太太的兩個兄弟請來，“兩個舅舅一來，講了句公道話，‘都是一家人，現在就剩下你們媽媽了，也得考慮考慮她?！崩罹匆媛犕?，心里大概有了數，這一家人的目光總圍著商鋪轉，如果按著以往的思路往下走，只討論商鋪的歸屬，這矛盾怕是難解。得轉換個思路，綜合考慮、綜合盤算。

Fan JR

Wang TQ

貴州省積極創新水利投融資模式，建立健全水利投入穩定增長機制，全面落實好水利建設基金、提取土地出讓收益金12%用于農田水利建設、鼓勵信貸融資等各項政策，從公共財政、信貸融資、社會投入等多渠道籌集水利建設資金。預計全年完成水利投資185.52億元，比2012年增長8.5%，再次創下歷史新高。其中，完成中央投資72.52億元、地方投資73億元、社會投資40億元。

Fan JR