Andrew L. Lin

Context: Patients with Cushing syndrome (CS) often experience impaired quality of life (QoL) and mood despite biochemical control. The relationship between late-night salivary cortisol (LNSC) and psychological outcomes remains poorly characterized. Objective: Assess QoL and mood outcomes in biochemically controlled CS patients based on circadian rhythm restoration. Design: Cross-sectional. Setting: Tertiary-care center. Participants: Ninety treated, biochemically controlled patients with CS (84 Cushing disease (CD); 6 adrenal CS), stratified into three groups: normal LNSC (Group A), abnormal LNSC (Group B), on long-term GC replacement (Group C). Main Outcome Measures: Hospital Anxiety and Depression Scale (HADS), CushingQoL questionnaire, Nottingham Health Profile (NHP). Results: Group A had lower HADS-Anxiety (4 vs 7, A vs B; p=0.006) and (HADS-Depression 2.5 vs 6 vs 9, A vs B; p=0.006, A vs C; p<0.001). QoL was better in group A vs C in psychosocial (67.5 vs 39.5; p<0.001) and physical (63.9 vs 44.3; p=0.005) domains. Group A had better Emotional Reaction (0 vs 24; p=0.002), A vs B; Energy Level (0 vs 63; p=0.001) and Sleep (13 vs 56; p<0.001), A vs C. In multivariable analyses excluding group C, LNSC normalization was consistently associated with better outcomes in all HADS domains, CushingQoL psychosocial, NHP Emotional Reaction, Social Isolation, Physical Abilities and Home Relationships. Group B had the highest diabetes rate. Among patients with surgically remitted CD, 18.6% had abnormal LNSC, characterizing a previously unrecognized clinical phenotype. Conclusions: In biochemically controlled CS, LNSC normalization correlates with QoL, mood, and metabolic outcomes, and could represent a therapeutic target.

Background: Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety management strategies require further characterization. Patients and Methods: The safety profile of repotrectinib (treatment-emergent/related adverse events [TEAEs/TRAEs]) was established in patients who initiated treatment at the recommended dose (160 mg daily [QD] for 14 days, then 160 mg twice daily [BID]) across all cohorts of the global, multicenter phase 1/2 TRIDENT-1 study. AE management strategies were outlined. Results: In 472 patients, the most common TRAEs (dizziness [58%] and dysgeusia [50%]) were likely TRK inhibition-related. Median relative dose intensity was 90%; 14% (n = 66/472) of patients did not increase their initial QD dose to BID (mostly due to CNS AEs). Rates of dizziness (median onset, 7 days) were similar in patients with/without baseline brain metastases. Dose modifications downgraded severity or resolved dizziness in 78% of patients; 58% of patients had pharmacologic intervention without dose modification. Dizziness was downgraded/resolved in 62% (n = 120/195) of patients who did not receive dose modification or pharmacologic intervention. Treatment-related cognitive impairment and weight gain occurred in 19% and 12% of patients, respectively. Treatment-emergent withdrawal pain occurred in 14% of patients (median resolution time, 2.1 weeks). Dose interruption and reduction from TRAEs occurred in 39% and 38% of patients, respectively; 10% reported later re-escalation back to 160 mg BID. Conclusion: Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.

PURPOSE: A subset of brainstem gliomas harbor an isocitrate dehydrogenase 1/2 ( IDH1/2 ) mutation, which has important prognostic and treatment implications. We evaluated the radiographic features and the sensitivity of magnetic resonance spectroscopy (MRS) and cerebrospinal fluid cell-free DNA (CSF cfDNA) sequencing at detecting IDH1/2 mutations in a cohort of these tumors. METHODS: We identified IDH-mutant brainstem gliomas by retrospective chart review. IDH1/2 mutation was established by biopsy, CSF cfDNA sequencing, and/or the presence of a 2-hydroxyglutarate (2HG) peak by 3-Tesla MRS. RESULTS: Twenty-one patients with IDH-mutant brainstem gliomas were identified, 57% male with a median age of 26 (6-59) years. All tumors involved the pons and/or abutted the brachium pontis. Although 18 (86%) of 21 were nonenhancing, only one of 21 demonstrated T2-FLAIR mismatch. An IDH1/2 mutation was identified by biopsy in 17 and by CSF cfDNA sequencing in three; in the final patient, an IDH1/2 mutation was inferred by the presence of a 2HG peak. The sensitivity of MRS at identifying 2HG in patients with confirmed IDH1/2 mutations was 64.3% (95% CI, 35.1 to 87.2), which increased to 85.7% (95% CI, 42.1 to 99.6) when the study was performed before treatment. The 2HG peak was absent in all four patients with a repeat MRS after completion of radiation. IDH1/2 mutation was identified in four of seven patients who underwent sequencing of CSF cfDNA. In this cohort, median progression-free survival and overall survival were 57.6 and 90.4 months, respectively. An objective response to radiotherapy was observed in 76%. CONCLUSION: IDH-mutant brainstem gliomas have a characteristic clinical and radiographic phenotype. MRS is more sensitive than CSF cfDNA sequencing for noninvasively identifying the presence of an IDH1/2 mutation when performed before radiotherapy.

Context: Cushing’s syndrome (CS) impairs quality of life (QoL) and mood. Prospective real-life data on posttreatment recovery and predictors of improvement are limited. Objectives: Evaluate changes in QoL, depression, and anxiety in patients with CS, before and after biochemical control, and identify predictors of clinically meaningful improvement. Design and Setting: Prospective observational study at a tertiary center. Patients: Sixty-seven patients with endogenous CS (60 pituitary, 7 adrenal) were assessed with active disease and again after achieving biochemical control through surgery and/or medication. Outcomes: Patient-reported outcomes included CushingQoL, Beck Depression Inventory-II (BDI-II), and State-Trait Anxiety Inventory (STAI). Results: Mean and longest follow-up was 2.3 and 11.5 years, respectively. Treatment led to improvements in mean scores across all domains (QoL: +18.2 ± 20.9, BDI-II: −6.8 ± 8.6, STAI-State: −9.6 ± 12.5, STAI-Trait: −8.6 ± 12.6; all P < .001). However, a minimal important difference was achieved in 64.6% for QoL, 67.9% for BDI-II, and 53.2% and 52.8% for STAI subscales. After multivariable analysis, QoL improvements were predicted by lower baseline body mass index, pretreatment symptoms 6 months, and normal follow-up late-night salivary cortisol (LNSC). Depression improvements were predicted by symptoms 6 months postoperative hydrocortisone. Depression improved more gradually than QoL and anxiety. Conclusion: Although effective treatment improves mood and QoL in CS, clinically meaningful recovery is variable and incomplete for some patients. Our findings highlight the need to limit diagnostic delay and provide comprehensive posttreatment care that includes normalization of cortisol circadian rhythm.

Several tumor predisposition syndromes have been linked to the development of gliomas and glioneuronal tumors (glioma/GNT). For many pathogenic germline variants, the prevalence and clinical significance remain unclear. Germline variants and copy-number variants affecting 76–90 well-established cancer predisposing genes were identified in 2,187 patients with gliomas/GNT, who underwent prospective sequencing of their tumor and a matched normal sample. A germline pathogenic or likely pathogenic (P/LP) mutation was identified in 11% (250/2187, 95% CI 10.1–12.8%). Affected high- and moderate-penetrance genes included BRCA2 (n = 11; 0.5%), TP53 (n = 8; 0.4%), NF1 (n = 8; 0.4%), CHEK2 (n = 21, 0.9% excluding common variant I157T), and the mismatch repair (MMR) genes (n = 22, 1.0%). Biallelic inactivation was identified in 8/8 tumors with a germline NF1 mutation, 7/8 tumors with a germline TP53 alteration, and 10/19 tumors with a heterozygous germline MMR defect. Gliomas/GNT with biallelic inactivation of an MMR gene were characterized by hypermutation, microsatellite instability, and a distinct clinical phenotype. Assessment of zygosity identifies biallelic inactivation of DNA double-strand break repair alterations in a minority of tumors, including BRCA2-deficient gliomas with increased genomic scarring attributable to homologous recombination deficiency, and refutes the contribution of the most common P/LP germline variants. Irrespective of gene, tumors with biallelic inactivation were diagnosed at a younger age than tumors without a germline variant (p = 3.5 × 10^–6) and tumors with a monoallelic alteration (p = 0.00014). In conclusion, germline sequencing identifies a P/LP variant in a high proportion of patients with glioma/GNT. Biallelic inactivation was common in younger patients with germline variants and patients with neurofibromatosis type 1/Li-Fraumeni, but was only present in half of the patients with Lynch syndrome.

Pituitary tumours, originating from endocrine cells of the anterior pituitary, are quite common, and in most cases well-controlled by surgery or medical treatment. However, a small subset of pituitary tumours presents with multiple local recurrences or tumour progression despite combined surgical, medical or radiotherapeutic treatment. These are known as aggressive pituitary tumours (APT); also called aggressive pituitary neuroendocrine tumours (PitNETs); or, in the rare case of metastases, pituitary carcinomas (PC) or metastatic PitNETs. Early identification of APT is challenging but is of major clinical importance as they are associated with an increased morbidity and mortality even in the absence of metastases. Here, we provide a revision of the first international, interdisciplinary European Society of Endocrinology (ESE) clinical practice guideline on APTs and PC (2018). Since publication of the 2018 guideline, results from the second ESE survey on APT and PC were published, and more data on APT treatment, including temozolomide, immune checkpoint inhibitors and bevacizumab, emerged. These data are reviewed in this guideline and translated into a practical algorithm to guide APT and PC management. Furthermore, standardized reporting of imaging and histopathological investigations of these tumours is proposed, and the role of molecular analysis is discussed. Last, a section is dedicated to special circumstances such as APT in pregnancy.

Context: Pituitary neuroendocrine tumors (PitNETs) that progress following surgery and radiotherapy are in need of additional treatment options. Responses to immune checkpoint inhibitors (ICIs) have been described; however, the feasibility of ICI therapy and biomarkers of response have not been formally assessed. Objective: To evaluate the activity of ICI as a treatment for PitNETs. Methods: We performed a single-center, prospective, phase 2 trial investigating the activity of ipilimumab and nivolumab in patients with PitNETs. The primary endpoint was objective response using the iRANO response criteria. We then explored genetic biomarkers of response to ICIs in 13 patients with PitNETs who were treated with ICIs, on or outside of the trial. Results: Ten patients with a PitNET were enrolled, including 5 corticotroph, 4 lactotroph, and 1 somatotroph tumor, of which 9/10 (4 metastatic and 5 nonmetastatic) patients were evaluable for the primary endpoint. While no objective responses were observed, tumor shrinkage was seen in 2/9 patients. In a biomarker discovery cohort, comprising 7 tumors treated on trial and 6 tumors treated off trial, temozolomide hypermutation, and mismatch repair deficiency (MMRd) were associated with immunological response. In 3 tumors sequenced pre- and post-ICI treatment, we identified evidence of immunoediting, characterized by loss of MMRd and/or a decrease in tumor mutational burden. Conclusion: This study demonstrates the safety and feasibility of ICI treatment in aggressive PitNETs. We also identified MMRd and temozolomide hypermutation as potential biomarkers of response to ICI. Overall, our data suggest that ICIs might provide an additional treatment option for PitNET; this should be evaluated more broadly in future studies.

Purpose: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). Patients and Methods: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy. Results: Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8–9.2] with 1-year PFS at 23.7% (95% CI, 12.4%–45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3–14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses. Conclusions: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up.