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An 81 year old male with Child-Pugh A cirrhosis and metastatic hepatocellular carcinoma (HCC) treated with 3-weekly atezolizumab and bevacizumab developed a pulmonary sarcoid-like reaction (SLR) after 5 months. Atezolizumab, an immune checkpoint inhibitor, was identified as the likely culprit. He was treated with prednisolone, resulting in improvement, and was successfully rechallenged with both atezolizumab and bevacizumab.

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BACKGROUND: Pembrolizumab is among the approved treatments for a variety of cancer types, including clear cell renal cell carcinoma (ccRCC). It has contributed to enhancing the prognosis of renal cell carcinoma. However, it is essential to be aware of the numerous potential immune-related side effects associated with its use. CASE PRESENTATION: A 69-year-old patient with a history of metastatic renal cell carcinoma has been undergoing treatment with Pembrolizumab, an immune checkpoint inhibitor. The medication has led to the development of a sarcoid-like reaction, initially misinterpreted as cancer recurrence and progression. Additionally, the patient has experienced new-onset hypothyroidism, which has been attributed to the immunotherapy. CONCLUSION: Clinicians, including oncologists, endocrinologists, and radiologists, should maintain a high level of suspicions and awareness regarding the potential adverse events associated with newly introduced immunotherapies like pembrolizumab. This knowledge is crucial for the accurate diagnosis and appropriate management of patients receiving these treatments.

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Immune-checkpoint inhibitors have profoundly changed cancer treatment, improving the prognosis of many oncologic patients. However, despite the good efficacy of these drugs, their mechanism of action, which involves the activation of the immune system, can lead to immune-related adverse events, which may affect almost all organs. Pulmonary adverse events are relatively common, and potentially life-threatening complications may occur. The diagnosis is challenging due to the wide and non-specific spectrum of clinical and radiological manifestations. The role of the radiologist is to recognize and diagnose pulmonary immune-related adverse events, possibly even in the early stages, to estimate their extent and guide patients' management.

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Background: Oncologists are prescribing checkpoint inhibitors with greater frequency, and an awareness of and ability to recognize immune-related adverse events (irAEs) is a key part of the safe administration of these drugs. Case Description: Herein, we report the case of a 26-year-old male diagnosed with de novo metastatic right-sided colon cancer to the liver, with tumor immunohistochemistry demonstrating loss of MSH2 and MSH6, and a pathogenic mutation in MSH2 identified on germline testing, consistent with Lynch Syndrome. The patient received first-line treatment with pembrolizumab. Following 7 months of immune checkpoint blockade (ICB), new pulmonary findings on routine imaging were felt to be concerning for disease progression, despite ongoing excellent clinical status, disease control in the liver, and stable tumor markers. An endobronchial biopsy of one of the mediastinal lymph nodes demonstrated granulomatous inflammation consistent histologically with sarcoidosis, and a diagnosis of sarcoid-like reaction (SLR) secondary to immunotherapy was established. Pembrolizumab was discontinued, and the patient continued active monitoring off of active therapy, with durable cancer control. After 8 months of watchful waiting, new hepatic lesions and increasing abdomino-pelvic lymphadenopathy were identified on imaging, concerning for progression of disease. Inguinal lymph node biopsy demonstrated findings consistent with ongoing SLR. The patient remains with durable cancer control, now 24 months since receipt of ICB. In addition, he remains asymptomatic of the SLR. Conclusions: This case highlights the propensity of SLRs to imitate progression of disease, and the importance of awareness of this adverse effect, to prompt appropriate investigation and management.

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Sarcoid Like Reaction (SLR) is a localized non-caseating epithelioid granulomatous reaction seen secondary to certain immunotherapies and malignancies. Invasive melanoma, while being associated with onset of sarcoidosis, has not shown to directly induce SLR in the literature. We present the case of a 68-year-old male with malignant melanoma, who was found to have SLR prior to starting immunotherapy, which worsened while on pembrolizumab. This case highlights the challenge of distinguishing between drug-induced SLR and melanoma-induced SLR, and the implications in terms of management.

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Sarcoid-like granulomatous inflammation (SLGI) is defined as the development of non-necrotizing epithelioid granulomas in patients who do not meet the criteria for systemic sarcoidosis. Its occurrence is known to be linked to diverse conditions, including malignancies, infections, the use of certain drugs and inorganic substances. To the best of our knowledge, the available literature to date lacks any description regarding SLGI in a paraganglioma. The present study describes the first case of SLGI in a carotid body paraganglioma (CBP). A 54-year-old female patient presented with anterior neck swelling for 27 years without any other symptoms. An ultrasonography revealed a multinodular goiter with retrosternal extension and a solid lesion on the right side of the neck measuring 40x30x22 mm, which was suggestive of a CBP. The patient underwent a total thyroidectomy, and the right-side cervical mass was resected via another longitudinal incision. A histopathological examination of the thyroid specimen revealed findings of a multinodular goiter. Sections from the right-side cervical mass confirmed the diagnosis of CBP accompanied by multiple, well-formed, small-medium sized, non-necrotizing epithelioid granulomas associated with multinucleated giant cells, indicative of SLGI. Non-necrotizing epithelioid cell granulomas (as with SLGIs), identical to those observed in sarcoidosis, may rarely be observed in patients who do not meet the criteria of systemic sarcoidosis; however, they have been observed in association with various neoplasms. It is thus crucial to distinguish them from actual sarcoidosis, as misdiagnoses may lead to severe consequences. The presence of SLGIs accompanying a paraganglioma is an extremely rare phenomenon. Due to this, it is difficult to conclude if it confers a better prognosis or not.

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BACKGROUND: The drug-induced sarcoidosis-like reaction (DISR) is a condition clinically and pathologically similar to sarcoidosis but is induced by certain drugs. A few cases of DISR associated with the use of TNF-α antagonists have been reported in the literature. CASE REPORT: A 49-year-old female patient with a diagnosis of Crohn's Disease under treatment with adalimumab presented with a 2-month-long ulcerated swelling in the left lower fornix. Histological analysis of the biopsy specimen revealed multiple non-caseating granulomas multinucleated cells and epithelioid macrophages surrounded by lymphocytes. The lesion is under symptomatic control with a topical corticosteroid, and the patient is being monitored for manifestation in other organs and systems. CONCLUSION: Lesions of DISR may occur isolated in the oral mucosa. Therefore, this complication must be considered in the differential diagnosis of oral granulomatous lesions in patients under treatment with anti-TNF-α drugs.

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We describe the case of a 54-year-old woman with triple-negative breast cancer whose baseline F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) showed hypermetabolic left breast primary, ipsilateral axillary lymphadenopathy, lung nodules, and mediastinal lymph nodes. Histopathological examination of tissue from mediastinal lymph nodes confirmed a diagnosis of sarcoid-like reaction. Chemotherapy may induce or cause a flare-up of malignancy-associated sarcoid-like reaction. However, in our patient's post-chemotherapy F-18 FDG PET/CT, there was reduction in size and uptake of the mediastinal lymph nodes along with partial response shown by the other lesions. We aim to describe this rare course of malignancy-associated sarcoid-like reaction and highlight the role of F-18 FDG PET-CT in such cases.

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BACKGROUND: Patients with breast cancer present with lymphadenopathy involving non-caseating epithelioid cell granulomas in the mediastinum or axilla, referred to as sarcoidosis or sarcoid-like reactions (SLRs). However, sarcoidosis/SLRs prevalence and clinical presentation remain unclear. This study aimed to determine the frequency and clinical presentation of sarcoidosis/SLRs among postoperative patients with breast cancer. METHODS: Among all patients who underwent surgery for early-stage breast cancer at St. Luke's International Hospital in Japan between 2010 and 2021, those who subsequently developed enlarged mediastinal lymph nodes and underwent bronchoscopy for suspected breast cancer recurrence were included. Patients were classified into sarcoidosis/SLR or metastatic breast cancer groups, and the clinical characteristics were compared. RESULTS: A total of 9,559 patients underwent breast cancer surgery; bronchoscopy was performed to diagnose enlarged mediastinal lymph nodes in 29 cases. Breast cancer recurrence was observed in 20 patients. Eight women with a median age of 49 years (range 38-75) and a median time from surgery to diagnosis of 4.0 years (range 0.2-10.8) were diagnosed with sarcoidosis/SLRs. Four of the eight patients underwent mammoplasty with silicone breast implants (SBIs), and two experienced postoperative recurrences of breast cancer before or after lymphadenopathy, which was considered inciting factors for SLRs. The remaining two cases could have developed sarcoidosis after breast cancer surgery with no underlying causes for SLR. CONCLUSIONS: Postoperative sarcoidosis/SLRs rarely occur in patients with breast cancer. An adjuvant action of SBI likely contributed to the progression of SLRs; few cases exhibited a causal relationship with breast cancer recurrence.

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A 56-year-old male underwent treatment for sarcoma with metastases to the lungs. Follow-up imaging revealed multiple pulmonary nodules and masses with a favorable response on positron emission tomography (PET) scanning showing enlarging mediastinal lymph nodes concerning for progression of the disease. To evaluate the lymphadenopathy, the patient underwent bronchoscopy with endobronchial ultrasound and transbronchial needle aspiration. The lymph nodes were negative for cytology but showed granulomatous inflammation. Granulomatous inflammation is a rare occurrence in patients with concurrent metastatic lesions and is exceedingly rare in cancers that have not originated in the thorax. This case report highlights the clinical significance of sarcoid-like reactions in the mediastinal lymph nodes and the need for further investigation.

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This case represents an impressive finding of a young male who developed cutaneous sarcoid-like reactions that arose secondarily to tattoo ink. Cutaneous manifestations of sarcoidosis can present themselves in various ways, be caused by different inducing factors, and may present themselves not only cutaneously but as one of the many findings of systemic sarcoidosis. A 24-year-old black gentleman presented to the dermatology clinic with a manifestation of papules in his tattoos that covered a majority of his body. The patient tried hypoallergenic tattoo ink to see if this would prevent the formation of these bumps; however, this only further provoked the production of these papules confined to tattooed areas. Skin findings revealed linear raised papules in a continuous fashion in areas where the patient had tattoo ink on his torso, bilateral arms and legs, and face. At presentation, he denied any constitutional, pulmonary, or ophthalmologic symptoms. Pathological findings revealed sarcoidal granulomatous dermatitis showing nodular non-necrotizing granulomatous inflammatory infiltrate involving the superficial and deep dermis. The patient was then evaluated by pulmonology to rule out any systemic findings of sarcoidosis, which showed a negative chest x-ray. The patient was started on oral prednisone and topical pimecrolimus cream, and when he returned for his one-month follow-up, there were minimal to no visible cutaneous lesions. Tattoo ink has been shown to cause a variety of cutaneous reactions such as infections, neoplasms, and inflammatory dermatoses such as eczema, lichen planus, psoriasis, vitiligo, and sarcoidosis. Cutaneous sarcoid-like reactions secondary to tattoo ink are rare findings; however, they must be taken seriously due to the risk of systemic sarcoidosis involvement both at initial presentation and in the future.

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Introduction Endobronchial ultrasound-guided fine-needle aspiration biopsy (EBUS-FNAB) is a minimally invasive method used to obtain cytological or histological specimens of masses and lymphadenopathies (LAP) adjacent to the trachea and bronchi. Granulomas, which represent a chronic inflammatory response and occur for a variety of reasons, like a 'sarcoid-like reaction', cause LAPs. In this study, it was aimed to evaluate the long-term follow-up results of granulomatous lymphadenitis diagnosed with EBUS-FNAB and to investigate whether granulomatous lymphadenopathies were precursors of malignancies that occurred during the follow-up period. Material and methods The medical records of 123 patients who underwent EBUS-FNAB and were diagnosed with granulomatous lymphadenitis were retrospectively reviewed. Age, gender, acid-fast bacilli (ARB) staining, tuberculosis culture and tuberculosis polymerase chain reaction (PCR) culture results were examined by FNAB, and the procedure indications of all patients diagnosed with granulomatous lymphadenitis were recorded. The long-term health records of 52 patients could not be accessed. Data were collected from 71 patients. The progression, regression or stable conditions of LAPs in the long-term radiological follow-up of at least two years and the treatment conditions of diagnosis after biopsy were examined. Results One hundred twenty-three patients were included in the study. Rapid onset evaluation (ROSE) was performed in 93 (75.6%) patients. In 62 (66.6%) of the 93 patients, the smear results were consistent with granulomatous reaction at baseline. Malignancy was present in seven patients (5.6%) at the time of the procedure. In two patients (1.62%), tuberculous lymphadenitis was diagnosed by a positive tuberculosis culture. The long-term follow-up results were not obtained in 52 (42.7%) patients included in the study. At the long-term follow-up of six patients' LAPs with known malignancies, three of them regressed, one of them progressed, and two of them remained stable after chemoradiotherapy. Methylprednisolone treatment was started in eight patients with the diagnosis of sarcoidosis. While LAP remained stable in five patients, regression was observed in three patients. Idiopathic LAPs remained stable in 24 of 55 patients who received no treatment and regressed spontaneously in 31 of them. One of the patients was diagnosed with lymphoma, and the other patient was diagnosed with primary lung cancer in the long-term follow-up. Conclusion In cases where tuberculosis is suspected, not only cytomorphology but also microbiological confirmation is important. Granulomatous lymphadenitis can be detected both in the disease course of patients with a history of malignancy and as a precursor to undiagnosed malignancy. So the diagnosis of granulomatous lymphadenitis is a clinicopathological diagnosis that must be followed up in patients without symptoms or other findings.

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BACKGROUND: The association between sarcoidosis and autoimmunity has been reported for years. However, the significance of autoantibodies in the pathophysiology and clinical management of sarcoidosis is not well understood. No autoantibodies that can be used as serologic biomarkers to diagnose the disease, monitor the state of the disease, and predict the prognosis of patients are established. METHODS: We performed a comprehensive analysis of serum autoantibodies and analyzed their associations with clinical features of sarcoidosis. RESULTS: Patients with systemic autoimmune rheumatic diseases-associated autoantibodies had a higher prevalence of advanced radiographic stage and consolidations in high-resolution computed tomography than patients without autoantibodies (p < .05). Age, sex, clinical history, pulmonary function tests, serum angiotensin-converting enzyme levels, rheumatoid factor, and the number of involved organs were not significantly different between the two groups. CONCLUSIONS: There may be an association between autoantibodies and more advanced pulmonary lesions in patients with sarcoidosis. Further investigations are needed to establish the significance of autoantibodies.

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Background: Coronavirus disease (COVID-19)-associated acute pericarditis has recently received much attention owing to its high frequency associated with pericardial tamponade (PT), showing unfavorable prognosis. However, early diagnosis and treatment remain challenging in cases of non-specific signs and symptoms. Case presentation: A 64-year-old man was admitted to our hospital for acute osteomyelitis of the toes and was properly treated with antimicrobial agents. Three days after admission, the patient developed mild COVID-19 without pneumonia, for which early anti-COVID-19 agents were initiated. Nevertheless, the patient developed hemorrhagic PT due to acute pericarditis 2 weeks later, which was confirmed by cardiac magnetic resonance, requiring an urgent pericardiocentesis. Although cytological analysis of the hemorrhagic pericardial fluid strongly suggested adenocarcinoma, the atypical cells were eventually proven to be mesothelial cells with reactive atypia. Furthermore, lymph nodes swelling with abnormal 2-[18F]-fluoro-2-deoxy-D-glucose accumulation on imaging were suggestive of malignancy. However, biopsy examination revealed multiple non-caseating granulomas in the lymph node, unlikely due to malignancy. Eventually, the temporal association of the preceding COVID-19 with the occurrence of subacute PT without other identifiable cause led to a final diagnosis of COVID-19-associated acute pericarditis. With anti-inflammatory and corticosteroids treatment, the patient's symptoms involving the pericardial structure and function were completely resolved along with improvements in size of the affected lymphadenopathies. Conclusions: We encountered a unique case of COVID-19-associated acute pericarditis exhibiting hemorrhagic PT. This case underscores the residual risk of delayed pericardial involvement even in patients with mild COVID-19 who receive early treatment, and the recognition that COVID-19 may cause various cytomorphological and histological features. Additionally, the importance of considering this rare entity as a cause of hemorrhagic pericardial effusions should be highlighted.

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BACKGROUND: Sarcoidosis is a systemic inflammatory disease that is characterized by non-caseating epithelioid-cell granulomas upon histology. However, similar histological findings may also be seen with certain infections. Thus, differentiation from infection is pivotal to ensure appropriate treatment. Here, we present a case of a disseminated infection with Mycobacterium genavense owing to an interleukin 12 receptor subunit beta 1 (IL-12Rß1) associated immunodeficiency in a previously healthy female who was initially misdiagnosed with sarcoidosis. M. genavense is a nontuberculous mycobacterium which can cause lymphadenopathy, gastrointestinal and bone marrow infiltration in immunocompromised patients. With this case report we aim to highlight that an infection with M. genavense on the ground of a genetic defect of mycobacterial immune control may represent a rare differential diagnosis of sarcoidosis. CASE PRESENTATION: A 31-year-old female was referred to our hospital with progressive lymphadenopathy, hepatosplenomegaly, pancytopenia and systemic inflammation. She had previously been evaluated for generalized lymphadenopathy in another hospital. At that time, lymph node biopsies had revealed sarcoid-like lesions and a systemic corticosteroid treatment was initiated based on a putative diagnosis of sarcoidosis. When her condition worsened, she was transferred to our university clinic, where the diagnosis of disseminated M. genavense infection owing to an inborn interferonopathy was made. Her family history revealed that her brother had also suffered from IL-12Rß1 deficiency and had died from a systemic infection with M. genavense at the age of 21. The patient received antimycobacterial treatment combined with subcutaneous type I interferon, which eventually led to a gradual improvement over the next months. CONCLUSIONS: Differentiating between sarcoidosis and sarcoid-like lesions secondary to infections may be challenging, especially when pathogens are difficult to detect or not expected in an apparently immunocompetent patient. Patients with IL-12Rß1-associated immunodeficiency may be asymptomatic until adulthood, and disseminated M. genavense infection on the grounds of an IL-12Rß1-associated immunodeficiency may represent a rare differential diagnosis of sarcoidosis.

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Dupilumab is a new monoclonal antibody inhibiting IL-4 and IL-13 signaling transduction through the blockage of the α-subunit of the IL-4 receptor. It is used to treat type 2 inflammatory disorders including atopic dermatitis, asthma, and chronic rhinosinusitis. Here we describe the case of a 79-year-old male presenting with visual hallucinations, disorientation, cognitive decline, and behavioral changes, evolving over 3 weeks. He had been under treatment with dupilumab for atopic dermatitis for the previous 4 months. Radiology and CSF analysis showed a granulomatous meningoencephalitis suspicious of sarcoidosis. Underlying infectious and antibody-mediated causes for meningoencephalitis were ruled out. Pausing Dupilumab and steroids (i.v. and oral) led to rapid clinical improvement. Inhibition of IL-4 and IL-13, key players in the differentiation and activation of Th2 cells, may shift the Th1/Th2- ratio toward an excessive Th1-mediated response, granuloma formation, and drug-induced (neuro)sarcoidosis reaction. Attention should be raised to this side effect.

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The use of immune-checkpoint inhibitor (ICI) therapy has significantly improved patient outcomes in a wide variety of cancers and has become a cornerstone in the treatment of renal cell carcinoma. However, ICI treatment has the potential to cause a variety of immune-related adverse events (irAEs) that can affect any tissue or organ. This report describes the diagnostic dilemma of a patient with both RCC and diffuse large B-cell lymphoma who developed acute onset of fever and diffuse lymphadenopathy following treatment with combined ipilimumab and nivolumab. While diagnostic considerations included worsening lymphoma, hyperprogression of RCC, sarcoid-like reaction from immunotherapy, and fungal infection, his lymphadenopathy eventually resolved with treatment for histoplasmosis and discontinuation of immunotherapy. Despite only receiving two doses of immunotherapy, he has not required additional systemic therapy for RCC. This case demonstrates both the effectiveness of ICI therapy and the need for multidisciplinary approach to potential irAEs.

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Sarcoidosis is a heterogeneous disease, which can affect virtually every body organ, even though lungs and intra thoracic lymph nodes are almost universally affected. The presence of noncaseating granulomas is the histopathological hallmark of the disease, and clinical picture depends on the organs affected. Data about interaction between sarcoidosis and comorbidities, such as cardiovascular and pulmonary diseases, autoimmune disorders, malignancy and drug-related adverse events are limited. Several lung conditions can be associated with sarcoidosis, such as pulmonary hypertension and fibrosis, making it difficult sometimes the differentiation between complications and distinctive pathologies. Their coexistence may complicate the diagnosis of sarcoidosis and contribute to the highly variable and unpredictable natural history, particularly if several diseases are recognised. A thorough assessment of specific disorders that can be associated with sarcoidosis should always be carried out, and future studies will need to evaluate sarcoidosis not only as a single disorder, but also in the light of possible concomitant conditions.Key messagesComorbidities in sarcoidosis are common, especially cardiovascular and pulmonary diseases.In the diagnostic workup, a distinction must be made between sarcoidosis-related complaints and complaints caused by other separate disorders. It can be very difficult to distinguish between complications of sarcoidosis and other concomitant conditions.The coexistence of multiple conditions may complicate the diagnosis of sarcoidosis, affect its natural course and response to treatment.

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Immune checkpoint inhibitor (ICI) treatment has dramatically revolutionized the landscape of therapeutic approaches in multiple cancers, particularly, non-small-cell lung cancer (NSCLC). With the increasing use of programmed death-1 (PD-1) inhibitors in the clinic, the emerging toxicity profile presents a novel learning curve for clinicians. Here we report the first case of an NSCLC patient displaying sarcoid/granulomatous-like reaction (SLR, also known as GLR) in the liver during an anti-PD-1 therapy which showed efficacious response of complete regression. Also, this is the first report describing the SLR induced by toripalimab, a novel PD-1 inhibitor. Given this kind of hepatic findings can be easily mistaken as metastasis, even resulting in premature use of second-line treatments. In particular, we briefly review the clinical features of all those cases reporting sarcoidosis and SLRs manifested on different organs during anti-PD-(L)1 therapy. We anticipate that these clinical cases would help to alert the attention of clinicians that SLRs, as a rare immune-related adverse event (irAE), is manageable and that histopathological analysis is necessary before interpreting it as disease progression.

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Immune checkpoint inhibitor-induced sarcoid-like reactions and tertiary lymphoid structures (TLSs) are increasingly recognized but rarely reported in the same patient. We report a patient with lung adenocarcinoma who displayed sarcoid-like reactions in intrathoracic lymph nodes and tertiary lymphoid structures in surgical tumor after neoadjuvant therapy with nivolumab plus ipilimumab. Pathological examination revealed 50% residual tumor cells after treatment, and the CT evaluation of the primary tumor showed a stable disease. The patient experienced a recurrence eight months after surgery. To identify immune correlates of the limited response to immunotherapy, we conducted genomic and transcriptional assays, multiplex immunoassay, and multiplex immunohistochemistry on the pre- and post-immunotherapy tumor, lymph node, and plasma samples. TP53 R181C, KRAS G12C and SMAD4 R361H were identified as driver mutations of the tumor. In addition to abundant infiltrated lymphocytes, immunotherapy induced high levels of inhibitory components in post-treatment tissue samples, especially the FOXP3+ regulatory T cells in tumor and PD-L1 expression in the lymph node. Despite abundant TLSs in the post-treatment tumor, most TLSs were immature. Moreover, increasing levels of circulating checkpoint proteins BTLA, TIM-3, LAG-3, PD-1, PD-L1, and CTLA4 were observed during immunotherapy. Collectively, our observations revealed that high levels of immunosuppressive molecules in tumor, lymph nodes and/or in peripheral blood might indicate poor outcomes after immunotherapy, even in the setting of a patient with concurrent sarcoid-like reactions and tertiary lymphoid structures.

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