Treatment of gastric hepatoid adenocarcinoma with pembrolizumab and bevacizumab combination chemotherapy: A case report

INTRODUCTION

Gastric hepatoid adenocarcinoma (GHA) is a primary gastric cancer with the characteristics of adenocarcinoma and hepatocellular carcinoma-like differentiation. GHA is a rare and special subtype of gastric cancer with a clinical incidence rate that is less than or equal to 1%[1-3]. GHA is more common in men. Most patients have high serum AFP levels and are prone to lymph node and liver metastasis. The median overall survival time of GHA is 6-17 mo[4-6]. Some studies have confirmed that the prognosis of patients with GHA is worse than that of patients with common gastric cancer. However, there is currently no standard treatment for this disease.

We report a case of GHA who experienced general chemotherapy failure. Pembrolizumab and bevacizumab combination chemotherapy was successful. The overall survival (OS) was 16 mo, and the main adverse reaction was tolerable.

請注意，國務院的國資委只管第一類，即狹義的央企。換句話說，如果某駐京辦下屬的賓館要裁員，職工找到國務院國資委，對不起，這里幫不上你。

CASE PRESENTATION

Chief complaints

A 72-year-old male was admitted to our hospital in December 2019 with a 3-mo history of epigastric pain.

History of present illness

Three months before admission, the patient began to experience epigastric pain. He had no abdominal distention, diarrhea, nausea, vomiting,Because the symptoms persisted and tended to worsen, the patient visited our hospital for further evaluation.

History of past illness

According to the National Comprehensive Cancer Network guidelines, the patient received first-line treatment of 2 cycles of chemotherapy with oxaliplatin + teggio on December 17, 2019. The doses of oxaliplatin and teggio were 130 mg/m(Day 1) and 60 mg bid (Days 1-14), respectively. Then, reexamination of abdominal enhanced CT showed the following: (1) the gastric fundus and cardia were occupied, the abdominal cavity and retroperitoneal lymph node showed signs of metastasis, and the previously identified lesions were larger than before; and (2) the range of lesions in the right lobe of the liver was larger than before (Figure 3).

Personal and family history

No family history to note.

A gastroscopy biopsy confirmed a histopathological diagnosis of gastric hepatoid adenocarcinoma. Immunohistochemistry showed HER-2 (-), Ki-67 (+ > 75%), MSH6 (+ > 75%), MSH2 (+ > 75%), PMS2 (+ > 75%), MLH1 (+ > 75%), AFP (+), hepatocytes (+), GPC-3 (+), and SALL4 (+) (Figure 2). Gene detection was performed (2019-12-27, Baishibo, sample type: plasma and paraffin section, SP142), and programmed cell death-ligand 1 (PD-L1) protein expression in paraffin sections was positive. The percentage of positive tumor cells was 0%. The comprehensive positive score was + (5%). In a paraffin section, microsatellites were stable. The TMB values were 8.94 mutations/MB (high) in plasma and 3.81 mutations/MB (moderate) in paraffin sections, with quantiles of 82.36% and 41.9%, respectively. The TP53 Levels were 57.79% in paraffin sections and 11.98% in plasma.

Physical examination

Upon physical examination, the abdomen was flat and soft. There was tenderness in the upper abdomen without rebound pain or muscle tension. There was no mass in the abdomen, and there was no swelling of the liver or spleen.

(1)目標函數的建立。區域醫療衛生資源配置公平性，主要依照學術界對基尼系數的計算函數，本文將基尼系數引入醫療衛生資源分配的公平性中，可作如下假設：若一定比例的人口分配了相同比例的醫療衛生資源，則醫療衛生資源絕對平均，或一定比例的面積分配了相同比例的醫療衛生資源，則醫療衛生資源配置絕對公平。可見醫療衛生資源基尼系數的內涵與經濟領域的基尼系數意義基本一致。根據基尼系數的計算，其目標函數為[11]：

Laboratory examinations

Routine blood examination, blood coagulation function, urinalysis, stool analysis, liver chemistry tests, urea, creatinine, uric acid and electrocardiogram results were all within normal limits. His serum AFP was 339.6 μg/L on December 5, 2019.

Imaging examinations

An abdominal enhanced computed tomography (CT) scan revealed the following: (1) The gastric fundus and cardia were occupied malignant tumors and multiple lymph node metastases were found around the stomach; and (2) The right anterior lobe of the liver had a low density and was considered metastatic (Figure 1). PET/CT examination showed gastric cancer with perigastric lymph node and liver metastasis. No obvious abnormality was found in the rest of the abdomen.

Pathologic findings

再如學習“資本主義發展”時，從不同的史觀角度去分析它存有不同的影響。雖然它掠奪了許多地區的金銀、土地。但它卻推動了人類文明的發展、推動了世界的聯系。所以學生在對該知識進行學習時必須從“兩面”角度去思考，以辯證眼光去看待歷史，才能夠真正學習歷史。

FINAL DIAGNOSIS

The patient was diagnosed with GHA, with a classification of clinical stage IV.

TREATMENT

He had no history of other diseases.

The patient's family reported that the patient had diarrhea with fever again in March 2021. He was treated in a local hospital but died in April 2021. The cause of death was intestinal infection. The last telephone follow-up was June 18, 2021. The patient, whose progression-free survival (PFS) and OS were 14 mo and 16 mo, achieved remission after second-line treatment. The main adverse reaction of the treatment was tolerable. He died of intestinal infection rather than tumor progression.

Laboratory examinations showed that his inflammatory indices were high, leukocytes and neutrophils were slightly low, and other measures, such as thyroid function and the presence hepatitis B virus, were normal. However, the patient refused to allow examination of the stool routine, culture,, thus preventing the collection of etiological evidence. The possibility of intestinal infection was considered in the diagnosis. The patient was given parenteral nutrition, anti-infection therapy, an indwelling gastric tube for enteral nutrition and other supportive treatment. After the symptoms improved, the patient was discharged and returned to his hometown.

The combination of pembrolizumab and bevacizumab with chemotherapy is an effective and safe regimen for treating this GHA patient. However, the sample size of this study was very small. Further evaluation of this treatment in a larger cohort or a randomized controlled trial is needed.

例1～例4“勿”都修飾謂語，可見“勿”的用法在兩部文獻中無太多差別，例1和例2“勿”后的動詞“令”接賓語“煙”，“示”接賓語“人”，“先秦時期，禁止性否定副詞‘勿’后動詞、介詞一般不出現賓語。至遲到東漢，‘勿’后動詞或介詞已經完全不受是否接賓語的限制了。”[8] 相對而言“勿”在北方使用頻率更大。

40年來，中國鉀肥工業用埋頭攻關打破技術封鎖，用規模產能回應貿易壁壘、平抑市場價格，更讓“中國鉀”實現500萬噸的歷史突破，使中國這個曾經的貧鉀國家，向鉀鹽富集技術邁進，由技術開發、加工生產為主導向循環經濟、資源高效利用轉變，在全球鉀肥市場中雄踞一隅。

OUTCOME AND FOLLOW-UP

The following evaluation of curative effect is based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 standard. We selected liver metastases and the two perigastric malignant lymph nodes (indicated by the arrow in Figure 3) as target lesions, in which the maximum diameter of liver metastases and the minimum diameter of perigastric malignant lymph nodes were measured. The sum of the three was the measurable lesion length. See Table 1 for detailed data. Disease progression (PD) was evaluated. Due to failure of first-line chemotherapy, the effective probability of second-line chemotherapy by itself was not high. GHA has similar components to hepatocellular carcinoma. In recent years, drug treatments for liver cancer have been tried as treatments for GHA. After communicating with the patient and his family and obtaining their consent, we decided to try secondline chemotherapy with pembrolizumab and bevacizumab in February 2020. The doses of epirubicin, albumin binding paclitaxel, pembrolizumab and bevacizumab were 90 mg/m(Day 1), 260 mg/m(Day 1), 2 mg/kg (Day 2) and 7.5 mg/kg (Day 0). This was repeated every 3 wk. However, the patient developed 4 degrees of myelosuppression and agranulocytosis with fever and 1 degree of gastrointestinal reaction after the first cycle of the above treatment. He returned to normal soon after symptomatic treatment. Therefore, epirubicin was reduced to 80 mg/m, while other drug doses remained unchanged in cycles 2-4. The above side effects did not reoccur. The patient achieved remission after second-line treatment (Figure 3E3C; Figure 3F3D). After general surgery consultation, surgery was recommended. Therefore, we halted bevacizumab treatment in the 5th cycle (June 2020) and recommended that the patient undergo general surgery for surgical treatment after 3 wk. However, due to his advanced age, he did not follow the doctor's advice undergo surgery. In August 2020, he received pembrolizumab by itself for the last time. However, he received no further treatment and recuperated at home for personal reasons. However, in January 2021, he developed diarrhea with fever and could not eat normally. His body mass index dropped to 18. Thus, he returned to the hospital. PET/CT examination showed that the tumor was still stable (Figure 4).

DISCUSSION

The incidence rate of GHA is low. In addition, there is no standard treatment. Most of the treatment methods follow the principles of general gastric cancer. Surgery and chemotherapy are the main treatments. Molecular targeting therapy and immunotherapy are also being explored. D2 radical resection is the first choice for patients with early-stage GHA. For patients with isolated liver metastasis, palliative gastrectomy plus simultaneous resection of liver metastasis can be considered. Palliative gastrectomy plus local treatment of liver metastasis, such as hepatic artery chemoembolization or radiofrequency ablation, can also be considered. Chemotherapy is the main treatment for patients with advanced GHA that cannot be removed by surgery. Related studies have indicated that the first-line standard chemotherapy plan for GHA includes 5-FU and platinum-based chemotherapy, combined with simultaneous Taxol, irinotecan, methotrexate, mitomycin-C and other chemotherapy[3,7-8]. With the development of molecular detection technology, molecular targeted therapy has also been a topic of major interest in recent years. Trastuzumab combined with chemotherapy in the first-line treatment of HER2-positive common gastric cancer achieved positive results in a phase 3 Large-scale clinical study (ToGA study). Ranuciumab, which is a VEGFR2 antibody, has been approved as the first antiangiogenic drug for the treatment of advanced common gastric cancer[8]. In this case, the patient’s HER-2 status was negative; thus, his cancer was not suitable for anti-Her-2 treatment. In addition, because of drug accessibility, ramucirumab-targeted therapy was not carried out. SOX chemotherapy was carried out as the first-line treatment, but it failed. The selection of the second-line treatment was based on the following four considerations: (1) The patient was diagnosed with GHA, had eating difficulties (medication was inconvenient) and had similar components of hepatocellular carcinoma. However, chemotherapy alone was ineffective. According to the literature, multiple targeted antiangiogenic drugs, such as apatinib and sorafenib[9-10], can be used to treat clinical hepatoid adenocarcinoma; (2) IMbrave150, a phase 3 clinical trial of liver cancer[11], showed that the OS and PFS of atezolizumab + bevacizumab in unresectable HCC patients without previous systemic therapy were statistically and clinically significant and improved compared with those of sorafenib, with controllable safety; (3) PD-L1 protein expression was positive in this patient, with a TMB of 8.94 mutations/MB (high) in plasma and 3.81 mutations/MB in paraffin sections; and (4) Because of the accessibility of atezolizumab and the patient’s financial means, we tried a new kind of "T + A"-like combined chemotherapy: pembrolizumab + bevacizumab combined chemotherapy. Ultimately, the patient achieved an extended PFS. The main adverse reaction was hematological toxicity, which was tolerated. Unfortunately, the patient died of complications: intestinal infection, not tumor progression. His OS might have been longer.

Immunotherapy treatment of GHA is relatively understudied. However, a recent phase III randomized clinical trial, Keynote-062, showed that pembrolizumab was not inferior to chemotherapy for untreated advanced gastric/gastroesophageal junction cancer. In addition, fewer adverse events were observed. pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for OS and PFS endpoints[12]. However, the results of the Checkmate 649 study showed that for patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma who had not been treated in the past, nivolumab was the first PD-1 inhibitor that was clinically shown to be superior to chemotherapy alone in terms of OS and PFS, with controllable safety[13]. The first-line chemotherapy treatment failed in this patient. However, the second-line attempt of pembrolizumab + bevacizumab combined chemotherapy led to tumor remission, and the side effects were tolerable. Consistent with the results of the Checkmate 649 study, pembrolizumab + bevacizumab combined chemotherapy may be effective. However, in the Keynote-062 clinical trial, pembrolizumab + chemotherapy was not superior to chemotherapy alone for OS and PFS. Possible explanations are as follows: (1) The lack of a synergistic effect of anti-angiogenesis targeted drugs such as bevacizumab; and (2) first-line chemotherapy may increase antigen exposure, and as a result, the benefits of second-line immunotherapy. However, these possible explanations are only speculation; there is no current evidence.

Previous studies have shown that surgery, chemotherapy and targeted therapy can be used in patients with GHA. However, the application of immunotherapy in such patients has not been reported in the literature. In this case of GHA, we tried a new regimen of pembrolizumab and bevacizumab with chemotherapy, and the patient benefited. However, the sample size of this was very small. Further studies should evaluate this treatment in a larger cohort or a randomized controlled trial.

CONCLUSION

3.3 是整個操作作業過程中，機手要注意安全。對插秧機進行維護保養時，要在發動機熄火的情況下進行，以防發生事故。

毋庸置疑，在招投標中工程量大，存在難點，相關的造價工作人員需要進行工程量計算與審核，尤其是在當前科學技術的不斷發展下，工程量清單計價模式下，招標方與投標方需要對工程量進行反復計算，招標方還需要對工程量以及標的定額消耗的工程量進行計算，相關人員對其內容加以分析，制成表格，另外因為計算過程中人員比較多，工程量計算模式存在差異，所以工程量計算結果不同，近幾年在BIM技術的有效應用下，工程造價單位可以根據BIM技術進行信息量的檢索，編制出高水平的工程量清單，減少內容缺失或者計算失誤，這樣一來可以減少各類糾紛的發生。

FOOTNOTES

Liu M contributed to the design, analysis, and drafted the manuscript; Li X contributed to the analysis, and critically revised the manuscript; Luo C contributed to the analysis; Xie ZZ collected medical history information, and edited charts; and all authors read and approved the final manuscript.

Informed written consent was obtained from the patient for publication of this report and any accompanying images.

The authors declare that they have no conflict of interest.

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

應用Epidata 3.1統計軟件進行數據錄入，建立數據庫，采用SPSS 17.0統計軟件進行數據分析，采用描述性分析方法分析調查對象的一般人口社會學資料、對器官捐獻的態度；單因素分析采用方差分析或t檢驗，比較不同特征調查對象對器官捐獻態度的異同；多因素分析采用多元逐步回歸分析法，分析調查對象對器官捐獻不同態度的影響因素。

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China

骨傷手術患者因機體受到較大創傷,手術過程中可能會出現大量出血,需要進行大量輸血[1]。大量輸血指的是24小時內的輸血量約等于或大于患者的一個血容量[2]。研究顯示[3],大量輸血會導致器官功能障礙,再加上庫存血在保存過程中的保存損傷,會引發凝血功能障礙等嚴重并發癥,給患者的的健康甚至生命安全造成嚴重威脅。為了進一步對大量輸血對患者凝血功能造成的影響進行分析探討,筆者對我院2016年1月~2017年12月接受收的44例骨傷手術患者的臨床資料進行回顧性分析,現報道如下:

Mei Liu 0000-0002-8863-6577; Cheng Luo 0000-0001-9275-8772; Zong-Zhou Xie 0000-0002-1533-7189;Xun Li 0000-0002-1663-170X.

Ma YJ

A

Ma YJ