Pembrolizumab-induced Stevens-Johnson syndrome in advanced squamous cell carcinoma of the lung: A case report and review of literature

lNTRODUCTlON

Pembrolizumab is an anti-PD-1 (programmed death 1) humanized IgG4 monoclonal antibody that blocks the PD-1 receptor to enable T cell killing. Pembrolizumab, combined with chemotherapy, has shown improved efficacy in patients with advanced squamous cell carcinoma of the lung[1], with drugrelated adverse events reported in 64% of patients[2]. However, adverse events of grade 3 or higher were reported in less than 10% of patients and included cutaneous side-effect cases.

2.2 RT-PCR法檢測ABCG2的mRNA表達結果 因方差不齊，故使用Dunnett’s T3方法，四組之間兩兩比較差異有統(tǒng)計學意義(P<0.05)。與對照組相比，阿霉素組ABCG2 mRNA表達上升，苦參素組和聯(lián)合組ABCG2 mRNA表達下降。見表1。

CASE PRESENTATlON

Chief complaints

The patient was a 68-year-old female without a history of smoking. On October 1st, 2020, she was admitted due to repeated cough and breathlessness for 1 mo.

Immunotherapy, as a new treatment in the 2010s, has a definite effect on the treatment of advanced lung cancer. However, there remain many difficulties to be overcome in the treatment of serious adverse reactions related to immunotherapy. The combination of high-dose corticosteroid shock therapy, IVIG,cyclosporine, and best supportive care might reduce mortality in the treatment of SJS. The incidence of serious immune-related skin toxicity, such as SJS, is low, but the lethality is still very high. However,there is still a long way to go for immune-related adverse events, such as predictors for adverse events and ways to prevent them in advance. In future studies, we might focus more on the prediction,prevention, and treatment of irAEs, although immunotherapy is in full swing.

History of present illness

Systemic examinations, including chest computed tomography (CT), whole abdominal CT, brain magnetic resonance imaging (MRI), bone scintigraphy, and blood tests, were performed. The test results showed that the levels of tumor markers were clearly elevated, and CT indicated a lung mass in the right lobe, several bilateral nodules, multiple mediastinal lymph nodes, and a solitary liver metastasis.Squamous cell carcinoma of the lung was diagnosed through CT-guided percutaneous needle lung biopsy, and polymerase chain reaction (PCR) revealed no epidermal growth factor receptor, anaplastic lymphoma kinase, or receptor tyrosine kinase mutations. According to the American Joint Commission on Cancer 8edition staging system, she was clinically diagnosed with stage IVA lung squamous cell carcinoma (cT4N2M1b). According to the 2020 National Comprehensive Cancer Network guidelines,the combination of immunotherapy and chemotherapy is the best optional treatment for patients with advanced lung squamous cell carcinoma. On October 14, 2020, the patient was treated with one cycle of paclitaxel 270 mg d1 + cisplatin 120 mg d1 chemotherapy combined with pembrolizumab therapy. On November 4, 2021, which was nearly three weeks after one cycle of chemotherapy, the patient started with low fever, sore throat, and severe fatigue. Then, the patient was considered to be related to cold exposure. Penicillin treatment was used in the hospital nearby, but the patient's symptoms did not improve, which lasted for almost 5 d. On November 9, small papules and typical erythema,accompanied by severe itchiness and general discomfort, gradually appeared on the patient's skin and were mainly distributed in the anterior chest and face. Considering the severity of the patient's symptoms, the patient visited our hospital on November 12. The patient’s temperature was normal.The pain in her throat persisted. The physical examination of the patient showed that multiple erythematous papules could be detected on the patient’s head, neck, chest, and back (covering 30% of the total body skin) (Figure 1), most of which fused to form blisters. The patient reported that these papules felt mild itchiness but painful. Eyelid edema was obvious. There were some ulcers around the lip. The patient’s oral ulcers were too painful to allow her to eat anything.

History of past illness

There was no remarkable past medical history with no alcohol consumption or history of smoking.

Personal and family history

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Physical examination

Since the 21century, the introduction of immunotherapy treatments has dramatically revolutionized the treatment paradigm of non-small-cell lung cancer (NSCLC)[16]. However, immune checkpoint inhibition usually leads to systemic adverse reactions, which are immune-related adverse events,mainly encompassing rash, colitis, pneumonitis, hepatitis, and thyroiditis[17]. Dermatologic toxicities seem to be the most frequently reported adverse events. SJS is a rare and severe dermatologic toxicity with high mortality[4]. The first SJS case induced by pembrolizumab in NSCLC was reported in a Japanese case[14]. Our case report is the first Chinese case of pembrolizumab-associated SJS in NSCLC.

Laboratory examinations

She was admitted to our hospital, and the relevant blood tests after admission are shown in Table 1 below.

Imaging examinations

Chest and abdominal CT scans showed that the primary lung lesions and liver metastases were significantly reduced, and the overall response evaluation was PR according to RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).

FlNAL DlAGNOSlS

We arranged an urgent consultation with a dermatologist. According to the skin and mucous membrane performance of the patient during these days, the rapid development of the disease, and history of PD-1 inhibitor use, pembrolizumab-induced SJS was diagnosed.

TREATMENT

由文獻[4]關于剪力滯系數(shù)分析可知，箱梁截面總的剪力滯系數(shù)λ取決于偏心距，偏心距越小，箱梁截面總的剪力滯產(chǎn)生的剪力滯效應越接近于僅受到軸力作用的狀態(tài)。本文僅施加預應力時，偏心距較小，所以截面剪力滯系數(shù)更接近于僅受軸向荷載作用下的彎矩。與文獻[3]中所得出的跨中剪力滯系數(shù)相近，箱梁頂板的剪力滯系數(shù)峰值(正對腹板的上翼緣板處)均為1左右，進一步說明了本文的數(shù)值解是符合解析解的。

OUTCOME AND FOLLOW-UP

By referring to the opinions from the consultation, intravenous methylprednisolone 120 mg/d (2 mg/kg/d), gamma globulin 20 g/d, topical gentamicin, and diluted potassium permanganate were administered. Sepprayi 25 mg (recombinant human type II tumor necrosis factor receptor-antibody fusion protein, rhTNFR:Fc) was injected subcutaneously twice a week, and oral antihistamine was administered for pruritus. After a week of treatment, the dermatologic toxicities were gradually alleviated (Figure 4). Then, oral prednisone was gradually reduced, and topical drug administration continued. The treatment lasted for 3 mo, and the skin toxicity eventually disappeared (Figure 5). In terms of lung carcinoma, the pulmonary nodule was smaller than the baseline and remained stable during the 6-mo evaluation. In May 2021, the latest re-examination showed that although the patient didnot receive any antitumor treatment, the lesion remained stable.

DlSCUSSlON

A poor general condition, SCORTEN (severity-of-illness score for TEN) score of 4 points. Nikolsky’s sign was positive. Koebner phenomenon was negative. Erythematous papules could be detected on the patient’s head, neck, chest, and back (covering 30% of the total body skin) with mild itchy but painful symptoms. Eyelid edema was obvious. There were some ulcers around the lip. Her oral ulcers were too painful to allow her to eat anything. No other apparently positive signs were found.

At present, the exact mechanism of SJS remains undefined. The currently recognized theory is the T cell-mediated type IV delayed hypersensitivity reaction[18,19]. The drug triggering SJS binds the T cell receptor and MHC class I, and as a result, it leads to the massive replication of cytotoxic T cells, which directly kill keratinocytes, and the release of granulysin, which destroys cells in the skin and the mucous membrane[20]. Yun-Shiuan’s research showed that the blockade of PD-1/PD-L1 may contribute to the imbalance of the immune system, manifesting the enhancement of the T cell response and increasing the incidence of hypersensitivity[21]. During the treatment of SJS induced by ipilimumab and nivolumab in a melanoma patient[22], an increase in CD8+ T cells in the dermal epidermal junction and an increase in PD-L1 expression in keratinocytes were noted. Unfortunately, the biopsy analysis of our case has not been finished, and therefore, this viewpoint cannot be further confirmed. Overall, the mechanism of SJS caused by immunosuppressive drugs requires further research.

Cutaneous toxicities of immune checkpoint inhibitors might result in a longer PFS (progression-free survival) and a higher OS (overall survival) rate[23]. Bairavi and his colleagues demonstrated that NSCLC patients with one irAE and multisystem irAEs incrementally improved OS and PFS. Longer immune checkpoint inhibitor durations were an independent risk factor for the development of irAEs.In our case, it was rare that such severe AEs occurred after just one cycle of immunotherapy[24]. Susana also indicated that the median PFS was 9.49 mo in the group with irAEs1.99 mo in the group without irAEs (＜ 0.0001) in NSCLC treated with nivolumab[25]. In our case, the condition of the patient was stable for up to 6 mo just after one cycle of the treatment. Thus, we speculate that skin toxicities and delayed immunological effects both contributed to such a long progression-free survival time.

There is no standard treatment regimen for SJS[26], and multidisciplinary care, best supportive care,and corticosteroids are currently the most important components of its therapy[20]. By applying highdose corticosteroids early, we can rapidly arrest SJS, while the optimal cutoff time of corticosteroids remains controversial because of its adverse drug reaction[27]. From the author’s perspective, the appropriate duration of high-dose corticosteroids is within 4 wk. The combination of IVIG and steroids seems to bring better outcomes to patients with SJS[28].

Therefore, we immediately administered moderate- to high-potency topical steroids to treat the affected areas, oral antihistamines for pruritus and oral prednisone at 40 mg/d. After three days of treatment,the dermatologic toxicities were clearly aggravated. On November 18 (Figure 2), the rash began to spread to almost the entire body (covering more than 45% of the total body skin). The blisters were formed superficially in the epidermis with skin ulceration, and most of them had blood and fluid oozing. Part of the epidermis was peeled off from the surface of the body, exposing a moist, painful,flushed erosive surface. The oral ulcers continued to be aggravated. Both the itchiness and pain worsened, and the patient became severe (G3-4). At this point, we suspended immunotherapy,administered high potency topical steroids to the affected areas and prophylactically used antibiotics;additionally, we increased the prednisone dose to 100 mg. After three days of treatment, the cutaneous toxicities continued to worsen (Figure 3).

In addition to corticosteroids and IVIG, drugs that suppress the immune response or inflammatory factors are also being tried in the treatment of SJS. Over the last several years, several retrospective trials have advocated the benefits of cyclosporine in the treatment of SJS/TEN[29,30]. Cyclosporine inhibits the activation of CD4+ and CD8+ T cells in the early phase, subsequently inhibiting the secretion of granulysin, granzyme, and perforin[31]. Despite a lack of randomized control trials, cyclosporine has proven to have a mortality benefit in the treatment of SJS/TEN without a low risk of side effects. In our case, we did not use cyclosporine due to the lack of experience in the early phase of treatment for SJS. In the late phase, we used recombinant human tumor necrosis factor receptor type II-Fc fusion protein antibody as recommended by the dermatologist. The reason we used Sepprayi is that it can reduce the level of inflammatory factors, such as tumor necrosis factor-α (TNF-α), inhibiting the occurrence of hypersensitivity[32]. In our case, Sepprayi had a clear effect on the improvement of the patient's inflammatory response. However, more clinical practice and data support are needed due to limited trials.

CONCLUSlON

團結鄉(xiāng)鄉(xiāng)村旅游發(fā)展以及“美麗家園”建設是一個長期而艱巨的任務，在其后期的發(fā)展、建設過程中，仍需要進一步研究和實踐。將PPP模式運用到美麗鄉(xiāng)村旅游發(fā)展建設中，及對鄉(xiāng)村旅游相關從業(yè)人員進行培訓等，對促進云南鄉(xiāng)村旅游的發(fā)展有著積極的作用。

FOOTNOTES

Wu JY and Kang K designed the study and performed the experiments; Yi J, Yang B, and Wu JY performed the experiments, analyzed the data, and wrote the manuscript; Wu JY and Kang K contributed to this article equally.

Consent was obtained from the patient for publication of this report.

The authors declare that they have no competing interests.

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

Family and personal history were unremarkable. She had no significant medical history or drug allergy.

China

在高校之間，形成高校聯(lián)盟，共同進行符合企業(yè)需求的人才聯(lián)合定制培養(yǎng)，構建基于高校聯(lián)盟的協(xié)同共享平臺。建立人才聯(lián)合培養(yǎng)的靈活機制，組建各種跨學校的研究中心、實驗中心、教學中心，通過搭建多種形式的跨學科教育平臺，組織不同高校、不同學科的教師一起突破學科壁壘，組成跨學科研究小組和教學小組，開設全校性的公共跨學科課程，以整體組合的課程替代嚴格的學科分類課程，同時大力推進全校范圍內(nèi)的選課制，尤其是跨學科專業(yè)的選課制度，以學院為主體，按學科群開設大量的跨學科選修課，鼓勵學生跨學院跨專業(yè)選課，為學生帶來不同的學科視野和綜合化的知識結構，從而有效地促進人才培養(yǎng)。

具體到畢業(yè)設計的管理來說，面對新工科的要求，需要將畢業(yè)設計的總體目標分解成一系列任務，通過完成一系列的任務去實現(xiàn)社會崗位需求畢業(yè)生的人文素養(yǎng)、科技知識、實踐技能、職業(yè)能力、倫理價值和行為規(guī)范的新工科目標。從選題到完成答辯的整個教學進程都應該在傳統(tǒng)學科專業(yè)建設的基礎上，重新審視培養(yǎng)方案、管理模式、教學平臺建設的合理性,并提出對指導教師能力素質的新要求。

Jing-Yi Wu 0000-0003-1886-5697; Kai Kang 0000-0002-0429-0346; Jing Yi 0000-0001-8040-9516; Bin Yang 0000-0002-2249-2590.

Liu JH

A

實用性的核心是教師的直覺。教師應創(chuàng)建自己的課程內(nèi)容。根據(jù)實際，選擇合適的教學材料。教師自己構建課程內(nèi)容，選取既有知識性又有時代感的材料，拓寬學生視野，使學生獲得新的信息。

Liu JH