Hypereosinophilia is a predictive biomarker of immune checkpoint inhibitor-induced hypopituitarism in patients with renal cell carcinoma.

BACKGROUND: This study aimed to evaluate whether hypereosinophilia is a clinical biomarker of immune checkpoint inhibitor-induced hypopituitarism in patients with renal cell carcinoma treated with nivolumab plus ipilimumab. METHODS: This was a retrospective cohort study conducted at Jichi Medical University Saitama Medical Center between January 2018 and December 2020. In total, 12 patients with renal cell carcinoma who presented with immune checkpoint inhibitor-induced hypopituitarism were enrolled in this study. The clinical parameters and symptoms at baseline, last visit, and onset of hypopituitarism were analyzed. RESULTS: The median period from the initial treatment with immune checkpoint inhibitors to the onset of hypopituitarism was 82.5 (range: 56-196) days. Most patients developed hypopituitarism within 6 months. One patient presented with hypophysitis and 11 patients presented with isolated adrenocorticotropic hormone deficiency. The major symptoms noted at onset were fatigue (66.7%) and loss of appetite (41.7%). None of the patients had symptoms during the last visit. However, four developed hypereosinophilia. Eosinophil fraction (%) and eosinophil count (/µL) increased during the last visit and at the onset of hypopituitarism, respectively. The serum sodium and plasma glucose levels were similar. CONCLUSIONS: The eosinophil count increased before the onset of hypopituitarism. Thus, hypereosinophilia can be an early predictor of hypopituitarism.

Hypophysitis from immune checkpoint inhibitors: challenges in diagnosis and management.

PURPOSE OF REVIEW: This review will summarize the most recent and pertinent evidence regarding immune checkpoint inhibitor (ICI)-induced hypophysitis to describe diagnostic and management algorithm with the help of a case report. RECENT FINDINGS: Hypophysitis is the most common endocrine adverse event from CTLA-4 inhibitors and much less with PD-1/PD-L1 inhibitors. Its pathophysiology appears to be lymphocytic, predominantly affecting the anterior pituitary. The utility of high-dose glucocorticoids for treatment has been questioned, as they do not influence recovery of hypopituitarism and may reduce survival. A survival benefit with hypophysitis has been suggested. SUMMARY: The nonspecific nature of symptoms underlies the importance of clinical and hormonal monitoring especially in the first 6 months of CTLA-4 inhibitor cancer therapy. Adrenal insufficiency can be a diagnostic and management challenge, which persists in most cases; hence, a multidisciplinary team of oncologists and endocrinologists is essential for providing high-quality care to these patients. High-dose glucocorticoids should be reserved for mass effect or optic chiasm impingement. The ICI may need to be temporarily withheld but not discontinued. A survival advantage in cancer patients that develop ICI-induced hypophysitis may be a silver lining, especially as ICIs are being investigated for advanced endocrine malignancies.

Insights into non-classic and emerging causes of hypopituitarism.

Hypopituitarism is defined as one or more partial or complete pituitary hormone deficiencies, which are related to the anterior and/or posterior gland and can have an onset in childhood or adulthood. The most common aetiology is a sellar or suprasellar lesion, often an adenoma, which causes hypopituitarism due to tumour mass effects, or the effects of surgery and/or radiation therapy. However, other clinical conditions, such as traumatic brain injury, and autoimmune and inflammatory diseases, can result in hypopituitarism, and there are also genetic causes of hypopituitarism. Furthermore, the use of immune checkpoint inhibitors to treat cancer is increasing the risk of hypopituitarism, with a pattern of hormone defects that is different from the classic patterns and depends on mechanisms that are specific for each drug. Moreover, autoantibody production against the pituitary and hypothalamus has been demonstrated in studies investigating the development or worsening of some cases of hypopituitarism. Finally, evidence suggests that posterior pituitary damage can affect oxytocin secretion. The aim of this Review is to summarize current knowledge on non-classic and emerging causes of hypopituitarism, so as to help clinicians improve early identification, avoid life-threatening events and improve the clinical care and quality of life of patients at risk of hypopituitarism.

Progression of Hypopituitarism and Hypothyroidism after Treatment with Pembrolizumab in a Patient with Adrenal Metastasis from Non-small-cell Lung Cancer.

Pembrolizumab, or anti-programmed death receptor 1 antibody, is an immune checkpoint inhibitor that can cause immune-related adverse events. We herein report for the first time the progression of hypopituitarism and hypothyroidism after treatment with pembrolizumab in a patient with adrenal metastasis of non-small-cell lung cancer. Severe primary hypothyroidism occurred three weeks after the first administration of pembrolizumab. Four months after the discontinuation of pembrolizumab, isolated adrenocorticotropic hormone (ACTH) deficiency was noted. Corticotropin-releasing hormone and rapid ACTH tests performed repeatedly showed that the patient's pituitary and adrenal function had been gradually deteriorating. It is important to diagnose adrenal insufficiency without delay in order to prevent adrenal crisis.

Treatment-triggered onset and diagnosis of Sheehan syndrome in a multiple myeloma patient.

BACKGROUND: Sheehan syndrome refers to a series of clinical symptoms resulting from avascular necrosis of anterior pituitary due to various reasons. CASE: We report a case of multiple myeloma patient after one cycle of chemotherapy consisting of bortezomib and dexamethasone diagnosis of Sheehan syndrome with obstinate diarrhea, low blood glucose, and coma symptom, especially, the fluorodeoxyglucose positron emission tomography (FDG-PET) and brain magnetic resonance imaging (MRI) revealed that the manifestations in the saddle area were in accordance with empty sella syndrome. A single administration with lenalidomide was given for both consolidative and maintenance treatment, and satisfactory efficacy was achieved. With the patient now remaining in satisfactory medical condition, the success of this therapy has been shown. CONCLUSIONS: This is the first report showing a patient with combined multiple myeloma and rarely seen Sheehan syndrome, in which lenalidomide was given for treatment, and satisfactory efficacy was achieved.

Hypophysitis and other autoimmune complications related to immune checkpoints inhibitors´ treatment: Spectrum of imaging appearances.

OBJECTIVES: Immune checkpoints inhibitors (ICI) represent a new therapy option for the treatment of several advanced tumors. However, this therapy has been linked to a spectrum of ICI related autoimmune (AI) adverse events. Some may be life threatening and their diagnosis is tricky. The aim of our study was to describe various imaging appearances of ICI related secondary hypophysitis and other coincidental AI diseases. MATERIAL AND METHODS: We included 28 patients (19 females, 9 men, mean aged 58±13 years), who were consecutively treated mostly for advanced stage melanoma by different ICI. All their CT/MRI records and clinical data were reviewed. RESULTS: We found 5 (18%) cases of endocrinology proven secondary hypophysitis; 2 cases of panhypopituitarism and 3 cases of central hypocortisolism. Four cases were MRI positive, 1 case was MRI negative. Three cases were accompanied by other AI diseases: 1 by hemorrhagic colitis and mesenterial lymphadenitis, 1 by AI pancreatitis and 1 by pneumonitis. On MRI pituitary gland was swollen in 3 cases, twice enhanced non-homogenously, once homogenously; infundibular enlargement was present in 2 cases. Those 3 cases reacted to glucocorticoid therapy by hypophyseal shrinkage. In 1 case of MRI positive hypophysitis, the pituitary gland was not enlarged, slightly nonhomogeneous with peripheral contour enhancement; no reaction to glucocorticoids was mentioned. CONCLUSION: Secondary hypophysitis is probably more common ICI related adverse event than reported in the literature. Its MRI appearance is variable. Most of our cases were in coincidence with other AI ICI related events that affected their clinical manifestations.

[Opioid Induced Pituitary Dysfunction].

A 77-year-old woman with a history of anal squamous cell carcinoma was admitted because of malaise, diarrhea and nausea, in addition to back pain related to a verte- bral compression fracture. During the course of treatment, opioid therapy was initiated, following which the patient became progressively hypotensive and hyponatraemic and respiratory drive progressively decreased. Serum levels of cortisol, TSH and LH were decreased and prolactin slightly elevated, but a Synacthen test and brain MRI turned out normal, suggesting a diagnosis of opioid-induced pituitary dysfunction. The patient was given glucocorticoid replacement therapy with good results. Here we present a case of this serious but less well recognised side-effect of opioids.

Risk of cumulative toxicity after complete melanoma response with pembrolizumab.

Pembrolizumab is an approved first-line systemic therapy for unresectable metastatic melanoma. Despite the achievement of complete and durable responses in a small subgroup of patients, it is standard practice that pembrolizumab therapy continues beyond complete response. Nevertheless, the incidence of immune-related toxicities gradually increases with continuing pembrolizumab therapy. We report a case highlighting the occurrence of serious induced immune-related adverse events, which were attributed to pembrolizumab in a patient with metastatic melanoma who obtained a complete response (CR) after receiving pembrolizumab for a total of 6.5 months. Although mild pembrolizumab-related toxicity persists, the patient remains disease-free 5.5 months after discontinuation of pembrolizumab. Accordingly, we believe that cessation of pembrolizumab should be considered in patients who achieve a CR because of the ongoing risk of toxicity with extended pembrolizumab administration.

The chronic syndromes after previous treatment of pituitary tumours.

Ultimately, almost all patients who are appropriately treated for pituitary tumours enter a chronic phase with control or cure of hormonal excess, adequate treatment of pituitary insufficiency and relief of mass effects. This phase is associated with improvement of initial signs and symptoms, but also with the persistent consequences of the initial disease and associated treatments. Pituitary insufficiency is a common denominator in many of these patients, and is associated with a reduction in quality of life, despite adequate endocrine substitution. Hypothalamic dysfunction can be present in patients previously treated for visual impairments caused by large suprasellar adenomas, or craniopharyngiomas. In addition to hypopituitarism, these patients can have multisystem morbidities caused by altered hypothalamic function, including weight gain and disturbed regulation of sleep-wake cycles. Mortality can also be affected. Patients cured of Cushing disease or acromegaly have chronic multisystem morbidities (in the case of Cushing disease, also affecting mortality) caused by irreversible effects of the previous excesses of cortisol in Cushing disease and growth hormone and insulin-like growth factor 1 in acromegaly. In addition to early diagnosis and treatment of pituitary tumours, research should focus on the amenability of these chronic post-treatment syndromes to therapeutic intervention, to improve quality of life and clinical outcomes.

Ipilimumab-induced hypophysitis in melanoma patients: an Australian case series.

BACKGROUND: Ipilimumab (Yervoy; Bristol-Myers Squibb) is a novel fully humanised monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4, an immune checkpoint molecule, to augment anti-tumour T-cell responses. It is associated with significant immune-related side-effects including hypophysitis. AIM: We reviewed the clinical and biochemical characteristics of 10 patients with ipilimumab-induced hypophysitis (IH), and developed guidelines for the early detection and management of IH based on our experiences at three major teaching hospitals in Sydney. METHODS: All patients were evaluated at the Crown Princess Mary Cancer Centre and Department of Endocrinology, Westmead Hospital, Department of Endocrinology, Royal Prince Alfred Hospital, the Melanoma Institute Australia and Macarthur Cancer Therapy Centre, Campbelltown Hospital from 2010 to 2014. Relevant data were extracted by review of medical records. Main outcome measures included clinical features, hormone profile and radiological findings associated with IH, and presence of pituitary recovery. RESULTS: Ten patients were identified with IH. In four patients who underwent monitoring of plasma cortisol, there was a fall in levels in the weeks prior to presentation. The pituitary-adrenal and pituitary-thyroid axes were affected in the majority of patients, with the need for physiological hormone replacement. Imaging abnormalities were identified in five of 10 patients, and resolved without high-dose glucocorticoid therapy. To date, all patients remain on levothyroxine and hydrocortisone replacement, where appropriate. CONCLUSIONS: There is significant morbidity associated with development of IH. We suggest guidelines to assist with early recognition and therapeutic intervention.

Ipilimumab-induced hypophysitis: review of the literature.

PURPOSE: Ipilimumab is a human monoclonal antibody against cytotoxic T-lymphocyte antigen 4 available as an immunotherapy mainly for advanced melanoma. It induces an activation of T cells, resulting in an immune-mediated anti-tumor response and also immune-related adverse events, including hypophysitis. The aim of this review is to identify and discuss features concerning ipilimumab-induced hypophysitis (IIH). DESIGN: A MEDLINE research of all years of publication of IIH was conducted. We gathered information regarding clinical, radiologic and laboratory features of 71 cases recorded in the literature. RESULTS: In our review, IIH was more frequent among older and male patients. Fatigue and headache were the most frequent initial clinical manifestations of IIH and enlargement of the pituitary gland at MRI was present in the majority of patients. Those who received more than 3 cycles of ipilimumab had more fatigue (p = 0.04) and arthritis (p = 0.04). Adrenal insufficiency was more prevalent in men (p = 0.007). Glucocorticoid therapy and hormone replacement were required in most patients and pituitary function recovery was uncommon. Low prolactin at diagnosis tended to predict permanent pituitary dysfunction (p = 0.07). CONCLUSION: Hypopituitarism as a consequence of IIH, if not promptly recognized, can lead to potentially fatal events, such as adrenal insufficiency. IIH can be easily managed with glucocorticoids and hormonal replacement; therefore, physicians should be familiar with the key aspects of this condition. More studies to develop screening protocols and therapeutic intervention algorithms should be performed to decrease morbidity related to IIH.

Swinging for the Fences: Long-Term Survival With Ipilimumab in Metastatic Melanoma.

A 40-year-old man with stage III melanoma arising from his left shoulder underwent wide local excision, sentinel lymph node biopsy, and lymph node dissection. Nine months after receiving adjuvant biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2 (IL-2), and interferon alfa as part of a clinical trial, he developed headaches and right-hand weakness and was found to have a 2-cm left parietal CNS metastasis. A comprehensive staging workup identified multiple nonspecific subcentimeter pulmonary nodules. The brain mass was resected and confirmed to be metastatic melanoma; the surgical bed was treated with stereotactic radiosurgery. He was monitored off therapy, but 5 months later, he developed a second left parietal CNS metastasis and enlarging lung nodules. The new brain lesion was treated with stereotactic radiosurgery, and he began systemic therapy with ipilimumab on a clinical trial. After the third dose, he presented with headache, nausea, and vomiting; a brain magnetic resonance imaging scan showed left anterior temporal enhancement, possibly representing new disease. His symptoms improved with a course of corticosteroids. Restaging of the chest showed a mixed response among the pulmonary nodules. After tapering off corticosteroids, he received the fourth dose of ipilimumab, which was complicated by grade 3 transaminitis and hypophysitis with documented hypothyroidism and adrenal insufficiency. They were managed with corticosteroids and thyroid and adrenal hormone replacement. Restaging scans showed further disease regression except for new confluent enhancing nodules and edema in the left temporal lobe. Craniotomy and resection of this area showed only necrotic tissue with no viable melanoma cells. Nine years after treatment with ipilimumab, he is alive and shows no evidence of melanoma on the basis of annual computed tomography scans of the chest, abdomen, and pelvis and magnetic resonance imaging scans of the brain. He has full neurologic function but still requires hormone replacement for persistent hypopituitarism.