Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade. The indications for these agents continue to expand across malignancies and disease settings, thus reshaping many of the previous standard-of-care approaches and bringing new hope to patients. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), which are often distinctly different from the classical chemotherapy-related toxicities. Owing to the growing use of ICIs in oncology, clinicians will increasingly be confronted with common but also rare irAEs; hence, awareness needs to be raised regarding the clinical presentation, diagnosis and management of these toxicities. In this Review, we provide an overview of the various types of irAEs that have emerged to date. We discuss the epidemiology of these events and their kinetics, risk factors, subtypes and pathophysiology, as well as new insights regarding screening and surveillance strategies. We also highlight the most important aspects of the management of irAEs.

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Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance.

自身免疫性垂体炎是一种罕见的内分泌疾病,多发生于妊娠或产后.其发病机制不明,临床表现多变,主要包括垂体压迫、腺垂体功能减退症、尿崩症和高催乳素血症等相关症状.治疗目的主要是减小垂体肿块的大小和(或)替代有缺陷的内分泌功能.多数患者需要长期使用激素替代治疗。

Autoimmune hypophysitis

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions.

In recent years the use of immunomodulating therapy to treat various cancers has been on the rise. Three checkpoint inhibitors have been approved by the Food and Drug Administration (ipilimumab, pembrolizumab and nivolumab). The use of these drugs comes with serious adverse events related to excessive immune activation, collectively known as immune-related adverse events (irAEs). We conducted a system-based review of 139 case reports/case series that have described these adverse events between January 2016 and April 2018, found in the PubMed database. There was a broad spectrum of presentations, doses and checkpoint inhibitors used. The most common check point inhibitor observed in our literature review was nivolumab. The most common adverse effects encountered were colitis (14/139), hepatitis (11/139), adrenocorticotropic hormone insufficiency (12/139), hypothyroidism (7/139), type 1 diabetes (22/139), acute kidney injury (16/139) and myocarditis (10/139). The treatment most commonly consisted of cessation of the immune checkpoint inhibitor, initiation of steroids and supportive therapy. This approach provided a complete resolution in a majority of cases; however, there were many that developed long-term adverse events with deaths reported in a few cases. The endocrine system was the mostly commonly affected with the development of type 1 diabetes mellitus or diabetic ketoacidosis being the most frequently reported adverse events. While immunomodulating therapy is a significant advance in the management of various malignancies, it is capable of serious adverse effects. Because the majority of the cases developed pancreatic dysfunction within five cycles of therapy, in addition to the evaluation of other systems, pancreatic function should be closely monitored to minimize adverse impact on patients.

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Adverse Effects of Immune Checkpoint Inhibitors (Programmed Death-1 Inhibitors and Cytotoxic T-Lymphocyte-Associated Protein-4 Inhibitors): Results of a Retrospective Study.

Cancer treatment strategies based on immune stimulation have recently entered the clinical arena, with unprecedented success. Immune checkpoint inhibitors (ICIs) work by indiscriminately promoting immune responses, which target tumour-associated antigens or tumour-specific mutations. However, the augmented immune response, most notably the T cell response, can cause either direct neurotoxicity or, more commonly, indirect neurotoxic effects through systemic or local inflammatory mechanisms or autoimmune mechanisms. Consequently, patients treated with ICIs are susceptible to CNS disease, including paraneoplastic neurological syndromes, encephalitis, multiple sclerosis and hypophysitis. In this Opinion article, we introduce the mechanisms of action of ICIs and review their adverse effects on the CNS. We highlight the importance of early detection of these neurotoxic effects, which should be distinguished from brain metastasis, and the need for early detection of neurotoxicity. It is crucial that physicians are well informed of these neurological adverse effects, given the anticipated increase in the use of immunotherapies to treat cancer.

Inflammatory CNS disease caused by immune checkpoint inhibitors: status and perspectives

The anti-programmed cell death-1 monoclonal antibody (mab), nivolumab has recently been approved for the treatment of unresectable or metastatic malignant melanoma and non-small-cell lung cancers in Japan. Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 mab for malignant melanoma that was approved earlier than nivolumab in Western countries, is known to frequently cause endocrine immune-related adverse events such as hypophysitis and thyroid dysfunction. We herein report a patient with advanced melanoma who appeared to develop hypophysitis as a consequence of the inhibition of PD-1 by nivolumab. One week after the 6th administration of nivolumab, the patient developed progressive fatigue and appetite loss. Laboratory data on admission for the 7th administration of nivolumab showed eosinophilia and hyponatremia. Since ACTH and cortisol levels were low, nivolumab was discontinued and a large dose of hydrocortisone (100 mg/d) was promptly administered intravenously. A magnetic resonance imaging scan revealed the mild enlargement of the anterior pituitary gland and thickening of the stalk with homogenous contrast. A detailed assessment of anterior pituitary functions with hypothalamic hormone challenges showed that hormonal secretions other than ACTH and TSH were normal. With a replacement dose of hydrocortisone (20 mg/d), the 7th administration of nivolumab was completed without exacerbating the patient's general condition. The present report provides the first detailed endocrinological presentation of nivolumab-induced hypophysitis showing the enlargement of the pituitary gland and stalk in a malignant melanoma patient in Japan. Oncologists and endocrinologists need to be familiar with potentially life-threatening hypophysitis induced by immune-checkpoint inhibitors.

https://www.jstage.jst.go.jp/article/endocrj/advpub/0/advpub_EJ16-0161/_pdf

Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma.

The aim of the current study was to evaluate the utility of F-18-fluoro-2-deoxy-d-glucose (F-18 FDG) positron emission tomography/computed tomography (PET/CT) in assessing patients diagnosed with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) with inflammation of the head and neck glands. We reviewed the records of 17 patients (16 men and 1 woman) with IgG4-RD exhibiting inflammation of the head and neck glands (lacrimal or salivary glands; LSG) who were diagnosed by excisional biopsy of the LSG. F-18 FDG PET/CT images were retrospectively evaluated for locations of high FDG accumulation, and the maximum standardized uptake value (SUVmax) of each lesion was calculated. In 15 of 17 patients (88 %), FDG accumulation was observed in organs outside of the biopsied LSG. High FDG accumulation was most frequently seen in the lymph node (71 %), followed by the non-biopsied LSG (41 %). FDG accumulation was also found in other typically affected organs including the prostate and retroperitoneum (18 %), kidney and lung (12 %), and pancreas (1 %). FDG accumulation was most commonly observed in two lesions outside of the biopsied site (41 %). Detection of the multi-organ involvement before treatment is important for patients with IgG4-RD. F-18 FDG PET/CT is an effective tool for assessing the location of extra-LSG lesions in patients with IgG4-RD with LSG inflammation.

Role of F-18 FDG PET/CT in assessing IgG4-related disease with inflammation of head and neck glands.

Bone scintigraphy (bone scan) is useful in detecting metastatic bone lesions through visual assessment of hot spots. A semi-quantitative analysis method that evaluates bone scan images has been eagerly anticipated. BONENAVI is software that enables automatic assessment of bone scan index (BSI). BSI is useful for stratifying cancer patients and monitoring their therapeutic response. The purpose of this study was to evaluate the BONENAVI reading in determining BSI and hot spots at different time intervals after radioisotope injection. We evaluated 32 patients, including 22 males and 10 females. Ten patients had breast cancer, 20 patients had prostate cancer, and 2 had malignant pheochromocytoma. Patients were injected with 740 MBq of 99mTc-methylene diphosphonate and bone scintigraphy was performed at 2, 4, and 6 h after injection on each patient. The BSI and the number of hot spots were obtained from BONENAVI software. Bone scan images were also visually assessed to exclude false positives due to artifacts. Analyses were performed in all lesions, selected true lesions, segment based and cancer type based. Non-parametric statistical analyses for pairwise multiple group comparison were performed using Friedman test followed with post hoc analysis. The BSIs and the number of hot spots were significantly increased with time, with significant differences between each of time points (P < 0.001). Analysis of regional BSI (rBSI) and hot spot number changes of selected 15 true lesions also showed similar increase (P < 0.001). In general, the pelvic segment was the most prone to rBSI changes and the chest segment was the most prone to hot spot number changes. Visual assessment showed that BONENAVI diagnosed some typical artifacts as metastases (hot spots). BONENAVI reading of BSIs and hot spot numbers was highly affected by acquisition time. In serial or follow-up examinations (in particular, for monitoring therapeutic efficacy), acquisition time should be fixed for each patient. Cautious interpretation should be made on segments with high physiological uptake. BONENAVI reading was prone to misinterpretation of artifacts. Visual assessment is necessary to rule out this possibility.

Evaluation of bone scan index change over time on automated calculation in bone scintigraphy.

This meta-analysis aims to compare the diagnostic performance of l-3-18F-α-methyl tyrosine (18F-FAMT) positron emission tomography (PET) and 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) PET for malignancy detection. The workflow of this study follows Cochrane Collaboration Guidelines of a systematic review of diagnostic test accuracy studies. An electronic search was performed for clinical diagnostic studies directly comparing 18F-FAMT and 18F-FDG PET for malignant tumors. Study quality, the risks of bias and sources of variation among studies were assessed using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) assessment tool. A separate meta-analysis was performed for diagnostic performance based on visual assessment and diagnostic cut-off values. Whenever possible, a bivariate random-effect model was used for analysis and pooling of diagnostic measures across studies. Electronic search revealed 56 peer-reviewed basic science investigations and clinical studies. Six eligible studies (272 patients) of various type of cancer were meta-analyzed. The 18F-FAMT diagnostic accuracy for malignancy was higher than 18F-FDG based on both visual assessment (diagnostic odd ratio (DOR): 8.90, 95% confidence interval (CI) [2.4, 32.5]) vs 4.63, 95% CI [1.8, 12.2], area under curve (AUC): 77.4% vs 72.8%) and diagnostic cut-off (DOR: 13.83, 95% CI [6.3, 30.6] vs 7.85, 95% CI [3.7, 16.8], AUC: 85.6% vs 80.2%), respectively. While the average sensitivity and specificity of 18F-FAMT and 18F-FDG based on visual assessment were similar, 18F-FAMT was significantly more specific than 18F-FDG (p < 0.05) based on diagnostic cut-off values. 18F-FAMT is more specific for malignancy than 18F-FDG, while their sensitivity is comparable. 18F-FAMT PET is equal to 18F-FDG PET in diagnostic performance for malignancy detection in several cancer types.

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The diagnostic performance of 18F-FAMT PET and 18F-FDG PET for malignancy detection: a meta-analysis

18F- or 131I-labeled (4-fluoro-3-iodobenzyl)guanidine (FIBG) has been a promising yet unattainable derivative of radioiodine-labeled meta-iodobenzylguanidine (MIBG), because of the complex radiofluorination method. In this study, we proposed a 2-step radiosynthetic method to obtain 18F-FIBG and evaluated the diagnostic and therapeutic potential of 18F-FIBG and 131I-FIBG in a pheochromocytoma model (PC-12). Methods:18F-FIBG was prepared from a (mesityl)(aryl)iodonium salt precursor in the presence of a copper catalyst. Biodistribution studies, PET imaging, and a therapeutic study were performed on the PC-12 xenograft mice with either 18F- or 131I-FIBG. The association between the therapeutic effect and the tumor uptake of pretherapy 18F-FIBG PET was also evaluated. Results: The copper-mediated radiofluorination method readily yielded 18F-FIBG, as well as its regioisomer, 18F-IFBG. The isolated 18F-FIBG showed a higher accumulation in the PC-12 xenograft tumor than in any other tissue. The high tumor uptake of 18F-FIBG allowed clear tumor visualization in the PET images as early as 1 h after injection, with an excellent tumor-to-background ratio. A biodistribution study with 131I-FIBG revealed its higher and prolonged retention in the tumor in comparison with 125I-MIBG. As a result, a therapeutic dose of 131I-FIBG delayed tumor growth significantly more than did 131I-MIBG. The tumor uptake of 18F-FIBG was proportional to the therapeutic effect of 131I-FIBG. Conclusion: These results suggest the potential usefulness of FIBG as a diagnostic and therapeutic agent for the management of norepinephrine transporter (NET)-expressing tumors.

https://jnm.snmjournals.org/content/jnumed/59/5/815.full.pdf

Tetsuya Higuchi

Papers

Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma.

Role of F-18 FDG PET/CT in assessing IgG4-related disease with inflammation of head and neck glands.

Evaluation of bone scan index change over time on automated calculation in bone scintigraphy.

The diagnostic performance of 18F-FAMT PET and 18F-FDG PET for malignancy detection: a meta-analysis

Radiolabeled (4-Fluoro-3-iodobenzyl)guanidine improves imaging and targeted radionuclide therapy of norepinephrine transporter-expressing tumors