Le Min

Background: Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with hypophysitis being a serious endocrine toxicity that often requires hormone replacement and poses a risk of adrenal crisis. Biomarkers for predicting ICI-induced hypophysitis are lacking. Methods: This retrospective, single-center cohort study used the Research Patient Data Registry (RPDR) to identify adults with breast cancer, lung cancer, renal cell carcinoma, or melanoma who received PD-1 inhibitor monotherapy (pembrolizumab or nivolumab) between January 1, 2000, and May 29, 2024. The final cohort included 82 patients with available tumor genomic profiling data, including 26 who developed hypophysitis and 56 matched PD-1 inhibitor-treated controls who did not develop hypophysitis. Tumor mutational burden (TMB) and tumor gene mutation profiles were compared between groups. Results: Genomic analysis showed that the hypophysitis group had a higher overall tumor mutational burden (6.02 vs. 5.19 mut/Mb, P = 0.002). Furthermore, we identified significantly high rate of mutations in the genes BABAM1 (18.2% vs. 0%, P = 0.014), KDM5C (18.2% vs. 0%, P = 0.014), CDH4 (19.2% vs. 1.8%, P = 0.018), and TAL1 (19.2% vs. 1.8%, P = 0.018) in the hypophysitis group. In contrast, PAXIP1 mutations were more common in the non-hypophysitis group (19.6% vs. 0%, P = 0.037), suggesting a potential protective role. Conclusions: This exploratory study identifies a tumor genomic profile associated with PD-1 inhibitor-related hypophysitis. Higher TMB and enrichment of selected tumor mutations may reflect a tumor immunogenicity state that predisposes to pituitary autoimmunity under PD-1 blockade. These findings provide a hypothesis-generating genomic framework for future studies of endocrine irAE risk stratification.

Context: Acromegaly, caused by excess GH and IGF-1 due to pituitary adenomas, often necessitates first-generation somatostatin receptor ligands (fgSRLs) therapy when surgery fails. However, responses to fgSRLs therapy vary widely. Objective: To develop a machine learning (ML)-based calculator that predicts individual responses to fgSRLs therapy, enabling evidence-based acromegaly management. Design: A retrospective study (January 2010-July 2024) utilizing the Research Patient Data Registry to evaluate 10 ML algorithms and create a predictive calculator. Setting: Single-center study conducted at Mass General Brigham-affiliated hospitals. Patients: One hundred eleven acromegaly patients met inclusion criteria, classified as fgSRLs-responsive (n = 64) or fgSRLs-resistant (n = 47). Interventions: IGF-1 trajectories were analyzed using linear mixed-effects modeling. Ten ML algorithms were assessed to predict fgSRLs resistance. SHapley Additive exPlanations (SHAP) analysis identified key predictors for the development of a web-based clinical calculator. Main Outcome Measures: Model performance was primarily evaluated using area under the receiver operating characteristic curve (AUROC), along with accuracy, precision, recall, specificity, F1 score, and decision curve analysis (DCA). Results: The CatBoost model exhibited optimal performance based on AUROC 0.896 (95% confidence interval: 0.751-0.990), with accuracy 82.4%, precision 86.7%, specificity 88.2%, and F1 score 81.2%. Key predictors of fgSRLs resistance identified via SHAP analysis included pre-fgSRLs treatment GH, Knosp grade, pre-fgSRLs treatment IGF-1 index, T2-weighted magnetic resonance imaging density, and comorbidity burden. The model demonstrated excellent calibration (Brier score 0.131) and clinical utility via DCA. A web-based calculator was developed for clinical use. Conclusion: The CatBoost-based calculator effectively predicts fgSRLs treatment response in acromegaly patients. Prospective validation is required before clinical implementation.

Background: Bone-target agents (BTAs), including denosumab (DMAb), are one of the bone metastasis treatments that should continue indefinitely. However, BTAs may be interrupted in some cases. In osteoporosis, DMAb withdrawal causes a rebound effect characterized by an increased bone turnover with spine fractures and hypercalcemia; evidence of the DMAb withdrawal effect in oncology is lacking. Methods: This study aimed to identify the DMAb withdrawal effect amongst lung cancer patients treated with DMAb for bone metastases between January 2020 and December 2021. Patients who discontinued DMAb were included. Encounter notes, radiological and laboratory findings were comprehensively reviewed. Results: Thirty patients were included with a median follow-up of 21 months (interquartile range [IQR], 10-30) after DMAb discontinuation. Bisphosphonates were administered before starting DMAb in 7 patients (23.3%) and after DMAb withdrawal in 4 cases (13.3%). Three cases of DMAb withdrawal-related hypercalcemia and 3 cases of spine fractures following DMAb cessation were identified in 5 patients (16.7%), all of them were females and the median age was 65 years old (IQR, 65-70). No statistical difference in DMAb duration or number of injections was found in patients developing DMAb withdrawal-related spine fractures or hypercalcemia compared with others (binary logistic regression, p=0.688 and p=0.938, respectively). Conclusions: Patients with bony-metastatic lung cancer, especially post-menopausal women, are at risk of fractures and calcium abnormalities after DMAb discontinuation, suggesting that DMAb withdrawal effect may also be present in the oncological setting. A close follow-up and careful monitoring during and after discontinuation of DMAb is necessary.

The estimated prevalence of pituitary lesions is 10% to 38.5% in radiologic studies. However, how frequently these incidental lesions should be monitored by serial pituitary magnetic resonance imaging (MRI) remains unclear. To evaluate changes in pituitary microadenomas over time. Retrospective, longitudinal cohort study. Mass General Brigham, Boston, Massachusetts. Evidence of pituitary microadenoma from MRI. Dimensions of pituitary microadenomas. During the study period (from 2003 to 2021), 414 patients with pituitary microadenomas were identified. Of the 177 patients who had more than 1 MRI, 78 had no change in the size of the microadenoma over time, 49 had an increase in size, 34 had a decrease in size, and 16 had both an increase and decrease in size. By linear mixed model analysis, the estimated slope was 0.016 mm/y (95% CI, -0.037 to 0.069). In the subgroup analysis, pituitary adenomas with a baseline size of 4 mm or less tended to increase in size. The estimated slope was 0.09 mm/y (CI, 0.020 to 0.161). In contrast, in the subgroup with baseline tumor size greater than 4 mm, the size tended to decrease. The estimated slope was -0.063 mm/y (CI, -0.141 to 0.015). Retrospective cohort, some patients were lost to follow-up for unknown reasons, and data were limited to local large institutions. During the study period, approximately two thirds of the microadenomas remained unchanged or decreased in size. The growth, if any, was slow. These findings suggest that less frequent pituitary MRI surveillance for patients with incidental pituitary microadenomas may be safe. None.

Background It is unclear whether diabetes and glycemic control affects the outcomes of breast cancer, especially among those with metastatic disease. This study aims to determine the impact of diabetes and hyperglycemia on cancer progression and mortality in individuals with metastatic breast cancer (MBC). Methods Patients with a diagnosis of MBC between 2010 and 2021 were identified using the MBC database at 2 academic institutions. We evaluated the effects of diabetes and glycemic control on overall survival (OS) and time to next treatment (TTNT). Results We compared 244 patients with diabetes (median age 57.6 years) to 244 patients without diabetes (matched for age, sex, ethnicity, and receptor subtype). OS at 5 years [diabetes: 54% (95% CI 47-62%) vs controls: 56% (95% CI 49-63%), P = 0.65] and TTNT at 1 year [diabetes: 43% (95% CI 36-50%) vs controls: 44% (95% CI 36-51%), P = 0.33] were similar between groups. A subgroup analysis comparing those with good glycemic control and those with poor glycemic control among patients with specific receptor subtype profiles showed no differences in OS at 5 years or TTNT at 1 year. In an 8-year landmark subgroup analysis, there was worse OS among individuals with diabetes compared to controls, and OS was found to be better among those with good glycemic control compared to those with poor control. Conclusions Diabetes was not associated with increased mortality in individuals with MBC at 5 years. However, diabetes and hyperglycemia were associated with worse OS among a cohort of longer-term survivors. These findings suggest that individualized diabetes and glycemic goals should be considered in patients with MBC.

Autoimmune diabetes is a rare but severe endocrine toxicity induced by immune checkpoint inhibitor (ICI) treatment. It is unclear if ICI causes selective islet toxicity or non-selective pancreas toxicity. We analyzed 11 patients treated with ICI who developed ICI-related autoimmune diabetes. Eight patients had lipase and/or amylase tested on the same day of diagnosis of autoimmune diabetes. Among them, 75% (6/8) had normal lipase and 100% (6/6) had normal amylase. There was no correlation between glucose level at onset and biochemical pancreatitis. We characterized the clinical features of ICI-induced autoimmune diabetes. Fifty-five percent (6/11) of patients tested positive for GAD65 autoantibodies, and 55% (6/11) developed diabetic ketoacidosis at manifestation of hyperglycemia. In all 11 patients, C-peptide levels were low in the presence of hyperglycemia. ICI-induced thyroiditis was found in 64% (7/11), of which 36% (4/11) were newly diagnosed with thyroiditis while the remaining 27% (3/11) had pre-existing hypothyroidism followed by ICI-induced thyroiditis. Additionally, 27% (3/11), developed ICI-induced hypophysitis. Thyroiditis and autoimmune diabetes coexisted in all patients with ICI-induced hypophysitis. The median time from ICI treatment to the onset of autoimmune diabetes was 11 weeks. Our data suggest that few patients had coexistent ICI-induced autoimmune diabetes and pancreatitis, suggesting ICI mainly caused selective islet toxicity.

Thyroid disorders have emerged as one of the most common immune-related adverse events (irAE), yet optimum management and biomarkers to predict vulnerable individuals remain to be explored. High-dose glucocorticoid (HDG) therapy is routinely recommended for irAEs. However, systematic analysis of the impact of glucocorticoid therapy on the outcome of immune-checkpoint inhibitor (ICI)–induced thyroid disorders is lacking. We analyzed 151 patients with or without ICI-related thyroid disorders. We divided the patients with ICI-related thyroid disorders into two subgroups: those with and without HDG treatment. Our results showed no significant differences between HDG and no HDG groups in terms of the median duration of thyrotoxicosis: 28 (range, 7–85) and 42 (range, 14–273) days, the median time to conversion from thyrotoxicosis to hypothyroidism: 39 days (range, 14–169) and 42 days (range, 14–315) days, the median time to onset of hypothyroidism: 63 (range, 21–190) and 63 (range, 14–489) days, and the median maintenance dose of levothyroxine: 1.5 (range, 0.4–2.3) μg/kg/day, and 1.3 (range, 0.3–2.5) μg/kg/day. The median pretreatment TSH was 2.3 (range, 0.3–5.2) mIU/L and 1.7 (range, 0.5–4.5) mIU/L in patients with and without ICI-related thyroid disorders, respectively. Baseline TSH was significantly higher in patients who developed ICI-related thyroid disorders (P = 0.05). Subgroup analysis revealed significantly higher baseline TSH in male but not in female patients with ICI-induced thyroid dysfunction. Our results show that HDG treatment did not improve the outcome of ICI-related thyroid disorders.

Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.