Anti-programmed death 1 antibody in the treatment of coexistent Mycobacterium fortuitum and lung cancer: A case report

lNTRODUCTlON

Nontuberculous mycosis (NTM) is a lung disease characterized by exposure to mycobacteria other than

(

) and

. NTM has clinical manifestations similar to pulmonary tuberculosis (TB), and the number of patients with pulmonary NTM is increasing worldwide[1].

(

) accounts for 5.9% of all NTM cases[2]. Lung cancer is one of the most frequent malignant tumors, and it has a very high morbidity and mortality. Lung cancer and NTM lung disease share some common predisposing factors (

, smoking, atmosphere pollution), and coexistence of these two diseases is not uncommon. Diagnosis and treatment are more complex for patients with lung cancer and NTM. Immune checkpoint inhibitors (ICIs) have become generalized for use as anticancer therapeutics in many types of cancer. Many previous trials have reported that ICIs provide clinical benefits in patients with non-small cell lung cancer (NSCLC)[3,4].Although ICIs are often effective in NSCLC, unique adverse events are known to occur during treatment, including skin rash, hepatotoxicity, and endocrine disturbances; these events are termed immune-related adverse events. Among the several types of immune-related adverse events, cases of infectious diseases have been increasing steadily[5]. ICI immunotherapy can also cause TB and other infectious diseases as well as noninfectious immune-related complications. However, it remains unknown whether ICI immunotherapy can cause a recurrence of TB or NTM and whether ICI immunotherapy is an appropriate option for patients with both lung cancer and NTM. Here, we report a case with no recurrence of

following pembrolizumab treatment for unresectable stage IIIb NSCLC.

CASE PRESENTATlON

Chief complaints

Immunotherapy and immune-checkpoint inhibitors (programmed cell death protein 1 or PD-L1 inhibitors) administered as monotherapy or in combination with chemotherapy have recently exhibited breakthrough progress in the treatment of advanced NSCLC[8,9]. Programmed cell death protein 1 or PD-L1 inhibitors lead to the activation of cytotoxic T cells, which promotes immune-mediated cancer cell recognition and destruction. In theory, the increased immune response to foreign antigens (cancer cells or infection factors) can lead to a high inflammatory response at a site of persistent infection[10].However, existing clinical trials of immunosuppressive checkpoint inhibitors in advanced lung cancer generally exclude patients with active TB (NTM) infection. Therefore, little is known about the clinical use of immunosuppressive checkpoint inhibitors in these patients.

History of past illness

The patient had a history of coronary heart disease (12 years), hypertension (more than 10 years), and a 40-year history of smoking 40 cigarettes per day.

The patient continued to be treated with pembrolizumab (200 mg, every 3 wk). After 14 cycles, the lesion shrunk by 79%, there was no recurrence of

infection, and there were no intolerable adverse reactions. We next organized a multidisciplinary consultation in which doctors from a TB hospital indicated that the TB was stable and that anti-TB drugs could be reduced. Radiologists recommended that the patient be followed up by radical chest radiotherapy. At present, chest radiotherapy has been completed. Chest CT examination showed the lung cancer in a stable condition,and no recurrence of

infection was found. At the time of publication, progression-free survival reached more than 21 mo. We will continue to follow up the patient.

Physical examination

His left lung sounds were a bit quieter than normal.

However, in 2018, Ishii

[14] published a case report entitled “Improvement of

Pulmonary Disease after Nivolumab Administration in a Patient with Advanced Non-Small Cell Lung Cancer.” The patient in this report was initially diagnosed as stage IIIB, and there were no sensitive mutations. Therefore, there were no opportunities for surgical treatment or molecule-targeted treatments. Radiotherapy and chemotherapy could be administered until the

infection was better controlled.

Laboratory examinations

Carcinoembryonic antigen on July 2, 2019 was 29.86 ng/mL, and pathology diagnosis (

bronchoscopy, left upper lobe lung biopsy) identified poorly differentiated NSCLC. High-throughput sequencing revealed: ten-eleven translocation 2 p.E1318Exon7; tumor protein 53 c.672+2T ＞ C; and Bcell lymphoma 2-like protein 112903-bp deletion. Tumor mutational burden was 33.06 Muts/Mb.Microsatellite stability and programmed death-ligand 1 (PD-L1) expression of 55% (Figure 1).

Imaging examinations

A chest computed tomography (CT) scan showed a mass shadow in the left upper lung with uneven density, carcinoembryonic antigen was measured to be 23.99 ng/mL, and sputum smear results were positive for TB. A biopsy was performed

bronchoscope (left apex), which identified a few blood vessels and fibrous tissues that were accompanied by carbon dust deposition. Species identification found Mycobacteria in bronchoalveolar lavage fluid [

(+)]. The patient was administered anti-TB drugs (isoniazid, moxifloxacin, and clarithromycin). A positron emission tomography-CT on July 2, 2019 identified: (1) An irregular mass in the posterior segment of the left superior lobe tip (3.0 cm× 2.3 cm). The mass was hypermetabolic with obstructive atelectasis and inflammation; and (2) Multiple enlarged lymph nodes in the right supraclavicular fossa, the left hilum, and the mediastinum (anterior to the trachea, aortopulmonary window, and inferior tracheal protuberance), with abnormal metabolism(the largest enlarged lymph node was 2.1 cm in diameter).

MULTlDlSClPLlNARY EXPERT CONSULTATlON

The treatment of NTM is a very difficult and lengthy process. Although NTM has high resistance to anti-TB drugs, it is still commonly treated using anti-TB drugs such as isoniazid, rifampicin, ethambutol,pyrazinamide, and streptomycin. In addition to high drug resistance, treatment can be complicated by physical factors and other problems[6]. Active TB is often detected during traditional cytotoxic chemotherapy because chemotherapy can lead to immunosuppression. Patients with lung cancer complicated with TB are primarily male patients with smoking history, and the most common pathological tumor type in this group is adenocarcinoma[7]. Therefore, the opportunity to use molecular-targeted treatments is relatively small, and this means it is difficult to treat patients with both lung cancer and NTM.

企業(yè)之間是天然的競爭者，區(qū)塊鏈要求企業(yè)之間必須一起合作，這種競爭合作悖論是區(qū)塊鏈應(yīng)用規(guī)模化的最大阻礙。存在的問題不在于識(shí)別網(wǎng)絡(luò)，甚至不是最初的認(rèn)同，而是在于對(duì)系統(tǒng)、數(shù)據(jù)、投資等監(jiān)管決策的產(chǎn)生和管理達(dá)成共識(shí)。要克服這些問題常常需要贊助商(如監(jiān)管機(jī)構(gòu)或行業(yè)機(jī)構(gòu))來起帶頭作用。此外，必須確保對(duì)所有參與者的激勵(lì)是一致的，這在高度分散的市場中很難做到。

FlNAL DlAGNOSlS

The admitting diagnoses were: (1) Cancer of the left lung with a pathological diagnosis of poorly differentiated NSCLC, likely poorly differentiated adenocarcinoma, clinical stage IIIb (T3N3M0); and (2)

infection.

英語教學(xué)過程，并不是一個(gè)簡單的教師“教”和學(xué)生“學(xué)”的過程，教師要充分發(fā)揮自己的智慧，從學(xué)生的實(shí)際出發(fā)，改變傳統(tǒng)的教材觀，以“巧妙結(jié)合”、“相機(jī)補(bǔ)充”、“適時(shí)調(diào)整”等方式對(duì)教材進(jìn)行教學(xué)要求下的“活化”處理。從而用足教材，讓教學(xué)更有實(shí)效性；用厚教材，讓教學(xué)更有豐富性；用對(duì)教材，讓教學(xué)更有針對(duì)性。

TREATMENT

The National Comprehensive Cancer Network guidelines recommend that immunotherapy alone can be chosen as a first-line treatment for patients with PD-L1 expression ≥ 50%. After consulting with a TB specialist, the patient, and his family, we chose to proceed with pembrolizumab treatment (200 mg,intravenous infusion, every 3 wk). After two treatment cycles, a chest CT showed a new irregular subpleural mass in the anterior segment of the left upper lobe of the lung (Figure 2), a reduction in the mediastinal enlarged lymph node, and no other obvious changes. Next, an ultrasound-guided biopsy of the new tumor was performed. Pathological examination showed that a large number of carbon particles were deposited in the alveolar tissue with histiocyte reaction and multinucleated giant cell formation; some areas of fibrous tissue showed hyperplasia of collagen (Figure 3).

The chest CT and biopsy received consultation from a TB specialist, who diagnosed the patient with“pulmonary

infection,” thought to be caused by opportunistic infection. The mediastinal lymph nodes were smaller than those anterior, indicating that antitumor therapeutics were probably effective. The patient was receiving anti-TB treatment, and therefore the new subpleural mass in the anterior segment of the left superior lobe may have been induced by anti-TB therapy. The TB specialist suggested that anti-TB therapy be combined with continued antitumor treatment.

Black-Scholes模型定價(jià)基準(zhǔn)與漂移率以及期權(quán)價(jià)格不存在相關(guān)性，從而BS定價(jià)模型叫作風(fēng)險(xiǎn)中性定價(jià)，Black-Scholes模型的假設(shè)前提為無風(fēng)險(xiǎn)套利。

OUTCOME AND FOLLOW-UP

他們又回到以前的狀況。那個(gè)丟人的解決辦法行之無效，哥倆都經(jīng)不住誘惑，干了欺騙的勾當(dāng)。該隱的幽靈在游蕩——但是尼爾森兄弟之間的感情深厚無比——有誰說得清他們共同經(jīng)歷過的艱難危險(xiǎn)！——他們寧愿把激怒發(fā)泄在別人頭上。發(fā)泄在一個(gè)陌生人，在狗，在替他們帶來不和的胡利安娜身上。

DlSCUSSlON

After consulting with a TB specialist, the patient, and his family, we chose to proceed with pembrolizumab treatment.

A 61-year-old male patient visited a doctor in May 2019 and was admitted with intermittent chest pain for 4 mo, anorexia and fatigue for 1 mo, and chest tightness for 20 d.

In Japan, Fujita

[11] reported a lung cancer patient with pulmonary TB that developed into acute pulmonary TB after treatment with nivolumab. Kato

[12] published the first report of TB reactivation during durvalumab therapy after radical chemoradiotherapy for stage III NSCLC. A study by Fujita

[13] explained that “Immunotherapy with immune checkpoint inhibitors (ICIs), while ameliorating lung cancer, can cause infectious diseases, including TB, in addition to immune-related noninfectious complications.”

據(jù)不完全統(tǒng)計(jì)[8]在我國有10%的人有過耳鳴，其中5%患者就醫(yī)，2%患者會(huì)嚴(yán)重影響其生活、睡眠、精力集中、工作能力和社會(huì)活動(dòng)。針灸治療耳鳴可以溯源至兩千多年前的經(jīng)典醫(yī)籍《黃帝內(nèi)經(jīng)》[9]，《靈樞·邪氣藏府病形》曰：“十二經(jīng)脈……別氣走于耳而為聽。”《靈樞·厥病》曰：“耳鳴，取耳前動(dòng)脈。”《黃帝內(nèi)經(jīng)·靈樞注證發(fā)微》曰：“有耳鳴者，取耳中動(dòng)脈，即耳門穴，系手少陽三焦經(jīng)。依據(jù)經(jīng)脈所過循行的原則，刺激耳周穴位可促進(jìn)耳內(nèi)局部血液循環(huán)，調(diào)節(jié)大腦皮質(zhì)功能，更重要的是可以改善耳神經(jīng)的營養(yǎng)供給，從而達(dá)到消除癥狀的目的[10]。”

因畜禽的養(yǎng)殖方式，畜禽排泄物主要成分為：氮化合物，磷，鈣，粗纖維，未消化藥物等，禽畜品種不同、飼養(yǎng)方式不同、所選飼料不同，則畜禽排泄物的成分含量因此不同。這些成分隨著畜禽排便進(jìn)入空氣、水源與土壤中，為生態(tài)環(huán)境帶來污染。同時(shí)，在畜禽產(chǎn)品加工中，某些廢棄物如：蛋殼、毛發(fā)、下腳料、內(nèi)臟等并未被全部處理，也會(huì)有直接與排泄物一同丟棄的現(xiàn)象，為環(huán)境帶來污染。

In the absence of other anti-cancer strategies, pembrolizumab was chosen as a treatment after reviewing results of the immunological index detection, upon suggestion of a TB specialist, and after adequate communication with the patient and his family. After two treatment cycles, symptoms of

infection vanished completely. The patient’s physique was obviously improved, and tumor marker expression also decreased. However, imaging results showed an irregular soft tissue mass in the anterior segment of the left upper lobe after two cycles. The identification of this new mass was surprising, and it was initially unclear whether this was an indicator of lung cancer disease progression or

recurrence.

Improved physique, absence of

symptoms, and decreased tumor marker expression did not support disease progression or

recurrence. Therefore, we completed an ultrasoundguided biopsy of the new mass and consulted a TB expert. The expert suspected that this new lump was caused by opportunistic infection and may have been induced by anti-TB treatment. Although it has been reported that ICI treatment can lead to TB recurrence[15], the patient’s physical condition (anemia,hypoproteinemia, and fervescence all disappeared) had improved, and recurrence of NTM was not considered. We think this is caused by treatment (anti-TB treatment or antitumor therapy). Therefore, he recommended the continuation of antitumor therapy combined with anti-TB treatment. After treatment with pembrolizumab for 14 cycles, the patient continued to show improvements and also received radical radiation. At present, the radiotherapy has ended, and progression-free survival has exceeded 21 mo with no recurrence of

lung disease.

CONCLUSlON

Written informed consent has been provided by the patient’s next-of-kin to have the case details and any accompanying images published.

ACKNOWLEDGEMENTS

We owe thanks to the patient and his family. We thank the staff at Tianjin Medical University Cancer Institute and Hospital.

航空發(fā)動(dòng)機(jī)齒輪傳動(dòng)系統(tǒng)主要由傳動(dòng)軸、軸承和齒輪組成。軸承在高速轉(zhuǎn)動(dòng)過程中支承傳動(dòng)軸工作，傳動(dòng)軸上齒輪在嚙合傳動(dòng)過程中產(chǎn)生的各向分力經(jīng)軸傳遞到軸承處，由軸承支反力抵消。也就是說，軸承的負(fù)荷來自齒輪的嚙合傳動(dòng)，因此，進(jìn)行軸承受力計(jì)算就必須要輸入齒輪的受力。

FOOTNOTES

Zhang CC and Chen P composed the article.

We have observed that in cases of lung cancer complicated with

infection, opportunistic pathogen infection recurrence can be overcome, and immunotherapy is most beneficial when TB doctors and oncologists cooperate to closely observe dynamic changes in

and lung cancer.Treatment should be maintained with low dosage anti-TB drugs after general anti-TB chemotherapy for 1 year; this may prevent opportunistic pathogens infection recurrence during immunotherapy. While the results achieved in this case are indeed promising, the effectiveness of ICIs for treating

infection requires confirmation by further randomized clinical trials.

All the authors hereby declare that they do not have any competing interests with regard to the manuscript submitted here for review.

長江采砂管理工作是一項(xiàng)綜合性很強(qiáng)的工作，要做好水事糾紛調(diào)解、違法案件查處，執(zhí)法人員不僅要有豐富的法律知識(shí)，而且還要懂專業(yè)、政治素質(zhì)高、協(xié)調(diào)能力強(qiáng)，這也是提高執(zhí)法人員素質(zhì)中要亟待解決的問題。目前大家都有一個(gè)誤解，認(rèn)為執(zhí)法人員素質(zhì)不高，只是對(duì)法律、法規(guī)的學(xué)習(xí)不透徹。其實(shí)要辦理好一個(gè)水事案件，不僅僅需要法律、法規(guī)知識(shí)，還要在專業(yè)知識(shí)、政治素質(zhì)、人性化管理和綜合協(xié)調(diào)能力上下工夫。

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: https://creativecommons.org/Licenses/by-nc/4.0/

China

Cui-Cui Zhang 0000-0002-3187-9324; Peng Chen 0000-0003-3153-7591.

Ma YJ

Filipodia

Ma YJ

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