Successful multimodality treatment of metastatic gallbladder cancer: A case report and review of literature

lNTRODUCTlON

Gallbladder cancer is the most common malignant tumor in the biliary system, with a global average incidence of approximately 2.71/100000 and a high incidence in Chile, Japan and India[1,2]. Gallbladder cancer is characterized by its high aggressiveness and an extremely poor prognosis, and the five-year survival rates of stage I, IVA and IVB gallbladder cancer are only 50%, 12.4% and 2.5% respectively[3-5]. Radical surgery is the only way to cure gallbladder cancer. However, gallbladder cancer has an insidious onset and is difficult to diagnose at an early stage. In fact, some patients are already in the advanced stage when the diagnosis is made[6,7]. For unresectable or metastatic gallbladder cancer, the National Comprehensive Cancer Network guidelines for hepatobiliary cancers recommend chemotherapy, radiotherapy, immunotherapy and biliary drainage as palliative therapy to prolong patient survival[8]. Here, we report a patient with stage IVB gallbladder cancer who has survived for more than six years and is currently in disease-free survival after multidisciplinary treatment.

CASE PRESENTATlON

Chief complaints

In December 2014, a 73-year-old male presented to our hospital with right abdominal pain for 3 d.

History of present illness

Zhang B, Li S, and Liu ZY wrote and corrected the manuscript; Peiris KGK and Song LF reviewed and corrected the manuscript; Liu MC, Luo P, Shang D, and Bi W were the patient's surgeon; Shang D and Bi W supervised and edited the manuscript; all authors approved the final version of the manuscript.

History of past illness

The patient had no other significant medical history.

Personal and family history

The patient had no family history of cancer or hepatobiliary disease.

Physical examination

Physical examination indicated mild tenderness in the right upper quadrant of the abdomen and positive Murphy’s sign.

治療組有1例輕度上腹部不適，對照I組有1例上腹部不適，對照II組有1例輕度乏力，均為一過性，均繼續完成治療；所有患者均無因為不良反應情況而需要調整者，所有患者均無嚴重不良反應。無其他異常表現。

譯文： Some officials are not fulfilling their duties properly. They sidestep difficult problems and matters of public concern, argue and pass the buck, and tackle their responsibilities in a perfunctory manner…[2]467

Laboratory examinations

Radioactive seed implantation can provide continuous therapeutic doses in the tumor target area and rapidly decrease the distance of seeding. Thus, seed implantation can cause tumor cell death and delay tumor growth, and it results in only minor injuries to normal tissues[22,23]. Studies have shown that biliary stents combined with

I seed implantation could prolong stent patency and improve survival time for patients with cholangiocarcinoma[22,24]. Furthermore, studies[25,26] have shown that compared with transcatheter arterial chemoembolization (TACE) alone,

I seed implantation combined with TACE can better control the tumor and improve the survival time for liver cancer patients. The treatment of residual liver cancer near complex sites after TACE is challenging, but

I seed implantation is effective and safe for patients[27].

Imaging examinations

In December 2014, abdominal magnetic resonance imaging (MRI) indicated gallbladder cancer with a tumor size of approximately 3.2 cm × 4.1 cm, right liver metastasis with a tumor size of approximately 4.7 cm × 4.7 cm, left liver metastasis with a tumor size of approximately 3.6 cm × 4.2 cm, and peritoneum metastasis (Figure 1).

F-fluorodeoxyglucose positron emission tomography/computed tomography (

F-FDG-PET/CT) depicted gallbladder cancer (early SUVmax was 9.6, delayed SUVmax was 12.0) with multiple liver metastases (early SUVmax was 12.9, delayed SUVmax was 22.8), lymph node metastases (early SUVmax was 4.1, delayed SUVmax was 6.1), peritoneum metastasis and diaphragm metastasis (early SUVmax was 2.1, delayed SUVmax was 3.3) (Figure 2).

FlNAL DlAGNOSlS

Based on all the above examinations and the 8th edition of the American Joint Committee on Cancer[9],the patient was diagnosed with clinical T4N2M0 and stage IVB gallbladder cancer with multiple liver metastases, peritoneum metastasis, diaphragm metastasis and lymph node metastases (Figure 3).

TREATMENT

為滿足教學目標并保障教學效果，在藥理學教學中成功實施案例教學法，需要遵循如下基本原則：理論聯系實際原則，以基礎理論為導向，同時有機結合實際問題；重要性與典型性并存原則，強調選擇具有理論重要性和方法典型性的案例；針對性原則，既要針對專業知識，又要針對臨床實際問題。

We recommended that the patient first went to the oncology department to receive palliative therapy, as there were no specific indications for radical surgery. In March 2015, the patient began receiving chemotherapy (gemcitabine 1.4 g and oxaliplatin 150 milligrams every 21 d, seven cycles) and targeted therapy (cetuximab 400 milligrams every 21 d, continuing to this day). During chemotherapy and targeted therapy, the level of tumor markers gradually decreased but remained higher than the normal level (Figure 4). In August 2015, abdominal MRI after seven cycles of chemotherapy showed that the gallbladder was malformed and that the right liver metastasis was larger than the prior scan (Figure 5).In October 2015, the patient received iodine-125 (

I) seed implantation to treat gallbladder cancer, liver metastases, and lymph node metastases. The

I seed was implanted around the gallbladder under the guidance of CT. In January 2016, the patient began receiving immunotherapy (nivolumab 200 milligrams every 21 d, continuing to this day) and targeted therapy (apatinib 250 milligrams every day).Due to the side effects of hypertension, apatinib was in turn replaced with nintedanib and regorafenib.In March 2016,

F-FDG-PET/CT showed that

I seeds were around the gallbladder, but the gallbladder was not clearly visible. The left and right liver metastases still existed, and the hilar and peripancreatic lymph node metastases had disappeared (Figure 6).

In February 2018, abdominal CT and

F-FDG-PET/CT showed that the gallbladder had disappeared and that liver metastasis was limited to the left liver (Figure 7). We speculated that a series of adjuvant treatments led to the gradual disappearance of the gallbladder. Then the patient underwent surgery because the liver metastasis was limited to the left liver. During surgery, we detected a lesion in the left liver involving the diaphragm, and a hard mass could be palpated in the gallbladder region. Left hepatectomy with radical lymphadenectomy and partial diaphragmatic resection was subsequently conducted. The entire operation lasted approximately 3 h, and the blood loss was approximately 100 mL. The postoperative pathological examination confirmed moderate poorly differentiated cholangiocarcinoma in the left liver with invasion of the liver capsule and diaphragm, and the liver resection margin was negative (Figure 8). The postoperative immunohistochemical examination indicated ARGINASE-1 (-), CK19 (+), GPC-3 (partial +), hep-par (-), CEA (partial+), CK20 (-), and CK7 (+)(Figure 8). There were no postoperative complications, and the patient was discharged 15 d after surgery.

OUTCOME AND FOLLOW-UP

Our patient eventually underwent radical surgery after a series of palliative treatments.Chemotherapy, targeted therapy,

I seed implantation and immunotherapy certainly played an important role in facilitating radical surgery in this patient. However, the patient underwent a very long and complicated treatment process. It is difficult to identify the specific role of each treatment. More studies are needed to investigate this issue, and we look forward to future studies on multidisciplinary treatment for advanced gallbladder cancer.

DlSCUSSlON

The prognosis of advanced gallbladder cancer is extremely poor, and many clinicians and even experienced surgeons are uncertain and pessimistic about the treatment of advanced gallbladder cancer.A study from Kayahara

[10] found that surgical resection did not improve the prognosis for patients with stage IV gallbladder cancer. However, some studies have shown that surgical resection can provide survival benefits for patients with advanced gallbladder cancer[11,12]. With the development of adjuvant therapies, such as chemotherapy, radiotherapy, targeted therapy and immunotherapy, a study showed that preoperative adjuvant therapy could increase the resectability and survival time of advanced malignancies[13].

Gemcitabine plus oxaliplatin or gemcitabine plus cisplatin has been shown to significantly increase the survival time of patients with advanced biliary tract cancer (BTC) and is recommended as the firstline chemotherapy for advanced BTC[14-18]. A phase III randomized controlled trial on unresectable gallbladder cancer suggested that, compared with gemcitabine plus cisplatin, gemcitabine plus oxaliplatin could provide a survival improvement, and the survival improvement median overall survival (OS) was 9 mo in the gemcitabine plus oxaliplatin group and 8.3 mo in the gemcitabine plus cisplatin group (

= 0.057)[19].

Cetuximab is a targeted therapy against epithelial growth factor receptor. A phase II study[20]involving 30 patients with unresectable advanced BTC found that cetuximab and gemcitabine plus oxaliplatin had obvious antitumor activity, and nine patients underwent potential radical secondary resection after a major response to treatment. However, a randomized, open-label, noncomparative phase II trial[21] showed that, compared to chemotherapy alone, cetuximab and gemcitabine plus oxaliplatin in patients with advanced biliary tract tumors did not show a survival improvement or a survival advantage. Whether cetuximab can benefit patients with advanced BTC is still a topic that is under research, and we anticipate that a high-quality result will benefit the future of the medical and surgical fields.

根據食物的配料來分，可以分為味苦的，味甜的等。這與人的味覺是緊密結合的，酸甜苦辣咸，五味調和也是先民們不滿足于食物簡單的原滋原味而探求的吧！

Our patient firstly received chemotherapy with gemcitabine plus oxaliplatin and targeted therapy with cetuximab because there was no specific indication for radical surgery. The tumor markers levels of the patient gradually decreased during chemotherapy and targeted therapy, which suggested that chemotherapy and targeted therapy were beneficial for the patient. After seven cycles of chemotherapy,the patient received

I seed implantation and immunotherapy.

In December 2014, the laboratory examinations showed the following for tumor markers: Alphafetoprotein, 1.61 IU/mL (normal, 0-5.8 IU/mL); carcinoembryonic antigen (CEA), 115.8 ng/mL (normal,0-5 ng/mL); carbohydrate antigen19-9 (CA19-9), ＞ 1000 IU/mL (normal, 0-27 IU/mL); and CA12-5,112.3 IU/mL (normal, 0-35 IU/mL). The blood count, liver function and kidney function examinations of the patient were at normal levels.

Immunotherapy based on checkpoint blockers can block the inhibitory pathways of T-cell activation,thereby enabling tumor-reactive T cells to recognize tumor antigens and restore the antitumor immune response[28]. Immunotherapy has been indicated to benefit patients with advanced cancers such as hepatocellular carcinoma, nonsmall cell lung cancer and urothelial carcinoma, but the efficacy of immunotherapy for advanced BTC is still in the exploratory stage[29]. A nonrandomized, multicenter,open-label, phase I study[30] showed that, compared with nivolumab only, nivolumab and cisplatin plus gemcitabine could significantly increase OS from 5.2 mo to 15.4 mo and increase PFS from 1.4 mo to 4.2 mo for unresectable or recurrent BTC.

女性盆底功能障礙是一種臨床常見病，多發生于中老年女性，其主要臨床特點是尿頻、尿失禁、下腹部墜脹疼痛、盆底器官脫垂等[1] 。導致本病發生的因素較多，如年齡升高，體重增加，激素水平下降，子宮增大，分娩，孕次及產次，便秘等[2] 。既往治療本病以手術為主，但創傷性大，不易被女性所接受，物理方法、中醫療法則備受推崇。近年來筆者采用溫針灸治療女性盆底功能障礙，取得了理想的效果，現報道如下。

In October 2019, the patient came to our hospital for follow-up. The patient’s tumor markers had reduced to normal levels as follows: CEA, 2.23 ng/mL; CA19-9, 21.45 IU/mL; and CA12-5, 11.54 IU/mL. Additionally, abdominal CT showed no signs of tumor recurrence (Figure 9A). In March 2021,the patient’s tumor markers were still at normal levels, and abdominal CT showed no signs of tumor recurrence (Figure 9B).

CONCLUSlON

We reported a patient with advanced gallbladder cancer cured by multidisciplinary treatment, which was extremely rare and inspiring. Although the prognosis of metastatic gallbladder cancer remains extremely poor in the current medical field, the presented case highlights the importance of providing aggressive multidisciplinary treatment to appropriately selected patients with metastatic gallbladder cancer to achieve long-term survival.

小麥是主要的農作物，小麥產量是國家和政府關心問題所在，若要讓小麥得到高產，則應結合當地氣候和地理條件等多項種植技術。在此條件上，應根據小麥生長情況，做好預控病蟲害問題。相信伴隨著科技信息的快速發展，小麥種植和防治病蟲害可以有效解決。

FOOTNOTES

The patient suffered right abdominal pain for 3 d.

National Natural Science Foundation of China, No. 81873156 and No. 82000075; Liaoning Province Education Foundation, No. LZ2019051; and National Natural Science Foundation of Liaoning, No. 2020-BS-195.

The authors declare that they have no conflict of interest.

貓貓紅著臉搖頭：“沒有。”羅老師繼續微笑，繼續上課：“來，我們一起唱……”可是貓貓還是忍不住扭屁股吊腰。

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

2014年召開的全國職業教育會議強調探索和規范職業院校境外辦學，培育一批具有國際競爭力的職業技術院校，服務國家對外開放戰略。我國高職教育近十幾年來在教學引進上成效顯著，先后借鑒參考了德國的雙元制、澳大利亞的TAFE模式等先進的教學理念和方法，但在“走出去”上取得的成績乏善可陳。國內走出去的學生多，國外來的學生少；邀請的國外專家多，去國外講學的專家少；國際化的課程引進國內的多，具備中國特色的職教課程被國外引出的少……這樣的問題[9]與國家提出的走出去的戰略越來越不相適應。

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

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: http://creativecommons.org/Licenses/by-nc/4.0/

China

Biao Zhang 0000-0001-6305-838Χ; Shuang Li 0000-0002-3030-3075; Zhao-Yi Liu 0000-0002-7791-3620;Karieshinie Ghandalie Kalandika Peiris 0000-0003-4374-0845; Li-Fu Song 0000-0002-5909-8239; Mu-Cang Liu 0000-0002-1618-4479; Peng Luo 0000-0002-1444-7634; Dong Shang 0000-0002-4300-359Χ; Wei Bi 0000-0002-3516-5716.

Yan JP

在任何學科的學習中，只有進行比較，才能獲得一些有用的信息，這些信息既有積極的，也有負面的。在小學綜合實踐課中，有些學生通過與其他學生比較，發現了自己的優勢，獲得了存在感和自信心；也有的學生通過與其他學生比較，體驗到了失敗，感受到了挫敗感和畏懼感。這是學生與學生之間的橫向比較，容易產生負面情緒，所以這種橫向比較是不提倡的。

A

Yan JP

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