Combined targeted therapy and immunotherapy in anaplastic thyroid carcinoma with distant metastasis:A case report

lNTRODUCTlON

Anaplastic thyroid carcinoma (ATC) is an undifferentiated tumor which is derived from follicular epithelial cells of the thyroid. The annual incidence of ATC is 1-2/1000000 and accounts for 1%-2% of all thyroid carcinomas[3]. The prognosis of patients is associated with age, socioeconomic status, distant metastases, surgery, chemotherapy,

[4,5]. At present, there is no definite or standardized treatment for ATC in order to prolong the survival of patients. Treatments include surgery, radiation,chemotherapy, immunotherapy, and targeted therapy. Patients are often diagnosed at advanced stages of the disease and it is difficult to completely remove ATC by surgery[6]. As a result, the overall response rate is usually very low, so is the overall survival rate. Due to the poor prognosis and lack of treatment, molecular characterization of the tumor may provide more targets and provide patients with more therapeutic options[7]. We here summarize the clinical diagnosis and treatment of an ATC patient.The patient showed significant improvement in survival following targeted therapy and immunotherapy.

CASE PRESENTATlON

Chief complaints

A 65-year-old man was admitted to hospital due to hoarseness, cough and expectoration for 3 mo.

History of present illness

He was found to have a thyroid mass on physical examination.

Neck examination showed no abnormal sign.

最后必須要說明的是，實(shí)踐永在路上，糾偏永無止境，我們看重“實(shí)踐”這一概念，在這一大框架下重新理解“傳統(tǒng)”與“風(fēng)俗”，就意味著我們相信動(dòng)態(tài)變化、批評交流與自我反省。北師大民俗學(xué)的鄉(xiāng)村研究理論與路徑，也與它的研究對象一樣，始終處于這一過程之中。

History of past illness

The patient had no relevant medical history.

Personal and family history

There was no personal history of tobacco or alcohol consumption or any other family medical history.

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Physical examination

3.城鄉(xiāng)差距仍然是影響基本公共服務(wù)均等化供給的主要阻礙性因素。城鄉(xiāng)差距影響均等化指數(shù)的系數(shù)為正，說明城鄉(xiāng)差距使得公共服務(wù)均等化程度降低。

In this case report, it was confirmed that immunotherapy and/or targeted therapy against PD-1 may be an effective treatment strategy for ATC, which can prolong the survival of patients with this disease and provide more treatment possibilities. Finally, it is hoped that some treatment options can be better improved through immune combined targeted therapy to improve the survival rate of ATC.

Laboratory examinations

ATC has a high degree of malignancy and rapid progression, and its imaging diagnosis is difficult[9].The positive rate of fine needle aspiration cytology is not high, and confirmation of the diagnosis mostly relies on postoperative pathology[10]. The patient in this report developed hilar and mediastinal lymph node and adrenal metastases, and was treated with chemotherapy, palliative radiotherapy and targetedtherapy, but the disease was not controlled. He was subsequently treated with targeted therapy combined with immunotherapy. Nivolumab is a monoclonal antibody that can bind to the PD-1 receptor, which can block the interaction between PD-1 and PD-L1/PD-L2, alleviates inhibition of the PD-1 pathway-mediated immune response, and restores tumor-specific T cell immunity. This combination allows the tumor cells that are otherwise induced by T cells to be released, in order to reidentify the tumor cells and attack and kill them[11]. By targeted therapy, it means that appropriate anti-cancer drugs are used to precisely hit cancer cells, thereby killing tumor cells and preventing continued tumor growth[12]. The targeted anti-cancer drug can specifically select the carcinogenic site and combine with it to produce an effect

, inducing apoptosis of tumor cells, but does not affect the normal tissue cells around the tumor; thus, it will not damage the normal cells of the body[13].However, a single targeted therapy does have some limitations. Cancer cells can become resistant; the targets themselves change due to mutation, so that targeted therapy does not interact well with them[14]. Similarly, after long-term immunotherapy, tumor cells may undergo further variation, thereby evading the inhibition effect of immunotherapy. In addition, targeted therapies can also modulate immune responses. By analyzing the advantages and disadvantages of targeted drugs and immunotherapy, we have realized that these two therapies may have complementary effects in cancer treatment,and the combination of the two may increase the therapeutic effect[15]. In the present case, The resected tumor tissue was sent for immunohistochemical analysis and targeted next generation sequencing.However, only the RET gene was mutated. Treatment with Immunologicals may not have a significant therapeutic effect. So we used Cabozantinib. At that time, Nivolumab was relatively mature, more experiments were performed in other cancers, the safety was high, and furthermore, the subjective willingness of patients was strong, and the drugs were purchased and used on their own. the patient was treated with cabozantinib and nivolumab, and clinical benefit was seen over 30 mo. At present, the patient is alive and regularly followed up. In this patient, it was confirmed that immunotherapy and/or targeted therapy against PD-1 may be an effective treatment strategy for ATC, which can prolong survival of patients with ATC and may provide more treatment possibilities. Of course, there are still some issues to be resolved. While immunotherapy can relieve the disease and improve the patient survival, it will also cause immune-related adverse reactions. Therefore, to select a more appropriate treatment strategy according to individualized risk and benefit is important. However, it is expected that the survival rate of ATC can be improved by immune combined targeted therapy.

除了上機(jī)課在電腦前操作電腦進(jìn)行學(xué)習(xí)，還有什么方式可以輔助教學(xué)呢？伴隨信息化的深入發(fā)展，陸陸續(xù)續(xù)出現(xiàn)了多種移動(dòng)環(huán)境下即時(shí)互動(dòng)教學(xué)新模式。教師在移動(dòng)平臺上發(fā)送通知、分享資源、布置作業(yè)、批改作業(yè)、組織討論答疑、開展教學(xué)互動(dòng)。學(xué)生也可在手機(jī)上輕輕松松地完成作業(yè)，參與討論，而且即刻反饋，即刻點(diǎn)評。平時(shí)主要用于了解學(xué)生“計(jì)算機(jī)應(yīng)用基礎(chǔ)”的理論知識的掌握程度。在平臺上發(fā)布選擇題作業(yè)，學(xué)生利用課余時(shí)間登錄完成作業(yè)，系統(tǒng)即刻根據(jù)學(xué)生的完成情況給予評分，并對錯(cuò)誤進(jìn)行解析。同時(shí)，后臺生成數(shù)據(jù)，教師也可輕松獲得學(xué)生對知識點(diǎn)的掌握情況的數(shù)據(jù)分析。根據(jù)獲得的數(shù)據(jù)，教師就能夠在課堂上進(jìn)行更有針對性的復(fù)習(xí)與指導(dǎo)工作。

Imaging examinations

The patient's cerebellar and adrenal lesions were significantly reduced, and the corresponding symptoms also disappeared gradually. Clinical benefit was observed over 30 mo.

Ma DΧ wrote this paper; Shi P joined the surgery and revised the paper; Zhang C collect the information and follow up of the patient; Ding ΧP joined the targeted therapy and immunotherapy.

FlNAL DlAGNOSlS

The patient was diagnosed with ATC with brain and adrenal metastases.

TREATMENT

The patient received multiple cycles of chemotherapy after thyroidectomy. During this period, the patient received radiotherapy to the thyroid tumor bed and metastases, with a planned prescribed dose of 2.0 Gy/fraction × 28 fractions. After the appearance of brain metastases, He then received radiotherapy for cerebellar metastases at a prescribed dose of 3.0 Gy/fraction × 14 fractions. After recurrence of metastasis, nivolumab (240 mg every two weeks) was administered in combination with cabozantinib (40 mg) for two years. During the treatment, the patient experienced some immune-related adverse events (irAEs) and vascular endothelial growth factor receptor-tyrosine kinase inhibitor toxicity, mainly gastrointestinal toxicity and pneumonia, manifested as abdominal pain, diarrhea, cough and dyspnea, However, the patient developed arteriovenous thrombotic events, which were considered to be caused by cabozantinib, so the drug was discontinued. But the patient insisted on antiprogrammed death-1 (PD-1) therapy for two years, during which time, after symptomatic treatment with glucocorticoids, the grade of irAEs could be controlled below grade 1[8]. After re-follow-up, the dose of nivolumab was changed to 200 mg once every three weeks.The whole treatment process of patients is shown in Table 1.

OUTCOME AND FOLLOW-UP

He was found to have thyroid nodules on thyroid ultrasound. And underwent thyroidectomy.Pathological diagnosis of the resected tissue suggested the possibility of ATC (Figure 1). Ten days later,positron emission tomography-computed tomography (PET-CT) showed multiple metastases in the right hilar and mediastinal lymph nodes, and left adrenal metastases (Figure 2). One month later, CT reexamination showed that mediastinal lymph node and left adrenal metastases were larger than before(Figure 3A). During chemotherapy, repeated CT showed that the mediastinal lymph nodes were not significantly changed, and left adrenal metastases were larger (Figure 3B). Brain magnetic resonance imaging (MRI) showed a cerebellar mass, which was considered to be metastasis (Figure 3C). In these two years of combination therapy, the results of regular review of brain MRI are as follows (Figure 4).

DlSCUSSlON

Laboratory examination were unremarkable.

CONCLUSlON

古人云：“師者，傳道、授業(yè)、解惑也。”教師之所以受到全社會的尊重，除了因?yàn)槠涫种姓莆罩_啟知識寶庫的金鑰匙之外，最突出的特征是教師高尚的品質(zhì)情操，能夠感召學(xué)生。因此，陶冶情操，提高自身品德和心理素質(zhì)便成了教師實(shí)施綠色教育的重要一環(huán)。

FOOTNOTES

隨著互聯(lián)網(wǎng)的發(fā)展，傳統(tǒng)經(jīng)濟(jì)的發(fā)展模式逐漸被互聯(lián)網(wǎng)顛覆，傳統(tǒng)中小外貿(mào)公司的壟斷優(yōu)勢漸漸喪失，其生存發(fā)展陷入困境。不少國內(nèi)外學(xué)者開始關(guān)注“互聯(lián)網(wǎng)+”這個(gè)新經(jīng)濟(jì)形態(tài)及新形勢下中小外貿(mào)企業(yè)轉(zhuǎn)型升級問題，探討“互聯(lián)網(wǎng)+”背景下中小外貿(mào)企業(yè)發(fā)展跨境電子商務(wù)的轉(zhuǎn)型升級新路徑。

核桃栽植三年掛果，五年進(jìn)入豐產(chǎn)期，平均產(chǎn)干核桃為3000kg/ hm2，按照目前30元/kg計(jì)算，收入在90000元/ hm2左右，遠(yuǎn)高于種植一般農(nóng)作物。近兩年，核桃銷路很好，呈現(xiàn)供不應(yīng)求的局面，經(jīng)濟(jì)效益非常可觀，不少種植戶從核桃種植中嘗到了甜頭，種植積極性很高。

Informed consent was obtained from the patient for this case report and accompanying images.

All authors have no relevant conflicts of interest with the manuscript.

The authors adopted the guidelines of the CARE checklist (2016) during the preparation of this manuscript and have compared the modifications.

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

Dong-Χu Ma 0000-0001-5142-6667; Χiu-Ping Ding 0000-0002-0415-9321; Chi Zhang 0000-0001-5078-1536; Peng Shi 0000-0002-0187-7520.

Ma YJ

A

Ma YJ

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