Citations

Summary: Giant cell tumor of bone (GCTB) typically presents in the epiphysis of long bones and occurs in the skull in less than 1% of cases. When GCTB is diagnosed in the skull, it is primarily seen in the temporal and sphenoid bones. GCTB is an osteoclastic stromal tumor that is locally aggressive and tends to recur. We present a case of a 43-year-old woman with slowly progressive, left-sided proptosis, eyelid swelling, photophobia, epiphora, and pressure sensation. Computed tomography and magnetic resonance imaging revealed an enhancing tumor in the left inferior orbit with infiltration into the maxillary sinus roof. Histological examination was conclusive for a giant cell tumor of the maxillary bone presenting as an inferior orbital mass. Gross total surgical resection was performed via an inferior anterior orbitotomy, and the patient had resolution of symptoms without recurrence in her postoperative course to date. This report contributes to the scarce literature available on this type of tumor of skull bones, specifically presenting the first case in the maxillary bone of the floor of the orbit.

Achieving health equity in populations with congenital heart disease (CHD) requires recognizing existing disparities throughout the lifespan that negatively and disproportionately impact specific groups of individuals. These disparities occur at individual, institutional, or system levels and often result in increased morbidity and mortality for marginalized or racially minoritized populations (population subgroups (e.g., ethnic, racial, social, religious) with differential power compared to those deemed to hold the majority power in the population). Creating actionable strategies and solutions to address these health disparities in patients with CHD requires critically examining multilevel factors and health policies that continue to drive health inequities, including varying social determinants of health (SDOH), systemic inequities, and structural racism. In this comprehensive review article, we focus on health equity solutions and health policy considerations for minoritized and marginalized populations with CHD throughout their lifespan in the United States. We review unique challenges that these populations may face and strategies for mitigating disparities in lifelong CHD care. We assess ways to deliver culturally competent CHD care and to help lower-health-literacy populations navigate CHD care. Finally, we review system-level health policies that impact reimbursement and research funding, as well as institutional policies that impact leadership diversity and representation in the workforce.

This commentary is a call to action for a concerted commitment and effort to transform clinical trials and enable people with cancer to participate in clinical trials closer to home. Three key strategies are identified to address major barriers: confront challenges with the interpretation of US Food and Drug Administration Form 1572 requirements (Statement of Investigator); broaden acceptance of local laboratories and imaging centers; and invest in the creation of effective, sustainable partnerships between research centers and local providers.

Abstract Context Patients with nonfunctioning adrenal adenomas (NFA) and mild autonomous cortisol secretion (MACS) demonstrate an increased risk of chronic kidney disease (CKD); however, factors associated with CKD are unknown. Objective We aimed to identify the factors associated with CKD and assess the effect of adrenalectomy on kidney function in patients with NFA or MACS. Methods A single-center cohort study of patients with NFA and MACS, 1999 to 2020, was conducted. MACS was diagnosed based on post dexamethasone suppression test (DST) cortisol greater than or equal to 1.8 mcg/dL. Age, sex, dysglycemia, hypertension, therapy with statin, angiotensin-converting enzyme inhibitor, or angiotensin II receptor blocker were included in the multivariable analysis. Outcomes included estimated glomerular filtration rate (eGFR) at the time of diagnosis with MACS or NFA and postadrenalectomy delta eGFR. Results Of 972 patients, 429 (44%) had MACS and 543 (56%) had NFA. At the time of diagnosis, patients with MACS had lower eGFR (median 79.6 vs 83.8 mL/min/1.73 m2; P < .001) than patients with NFA. In a multivariable analysis, factors associated with lower eGFR were older age, hypertension, and higher DST. In 204 patients (MACS: 155, 76% and NFA: 49, 24%) treated with adrenalectomy, postadrenalectomy eGFR improved in both groups starting at 18 months up to 3.5 years of follow-up. Factors associated with increased eGFR were younger age, lower preadrenalectomy eGFR, and longer follow-up period. Conclusion DST cortisol is an independent risk factor for lower eGFR in patients with adrenal adenomas. Patients with both MACS and NFA demonstrate an increase in eGFR post adrenalectomy, especially younger patients with lower eGFR pre adrenalectomy.

Abstract Estrogen-secreting adrenocortical carcinoma (ACC) is exceedingly rare, representing 1% to 2% of all ACCs. We present a case of a 65-year-old man diagnosed with an estrogen-secreting, 4.3-cm right adrenal mass discovered during work-up for bilateral gynecomastia. Gynecomastia and hyperestrogenism resolved after laparoscopic adrenalectomy, and pathology was reported as adrenocortical adenoma. However, 5 years later, he again developed bilateral gynecomastia because of recurrent hyperestrogenism. Imaging revealed multiple metastases in the abdomen. Urine steroid profiling demonstrated increased androgen precursors, androgen metabolites, and glucocorticoid precursors. Ultrasound-guided biopsy of one of the metastases confirmed ACC. Initial therapy included debulking surgery with removal of metastatic lesions. Mitotane therapy was initiated 4 weeks later along with hydrocortisone for anticipated mitotane-induced adrenal insufficiency. Histopathology from the adrenalectomy specimen 5 years earlier was rereviewed and confirmed ACC. Estrogen-secreting adrenal tumors are exceedingly rare, and the majority are malignant. This case underlines the importance of making an initial accurate diagnosis of adrenal malignancy that allows better surgical planning and appropriate monitoring. Indeterminate imaging characteristics of the adrenal mass, as well as the presentation with estrogen excess, suggested an elevated risk for ACC. Initial pathology-based misdiagnosis illustrates the need for an expert adrenal pathologist to review these rare tumors.

Purpose: The discovery of MAPK/ERK pathway mutations has led to the approval of MEK-inhibitor (MEKi) cobimetinib in histiocytic neoplasms. However, the pivotal clinical trial that led to the approval of cobimetinib included only 4 patients with Langerhans cell histiocytosis (LCH). Therefore, there is a need to define outcomes with MEKi therapy in patients with LCH. We undertook a multi-center collaboration through the Adult LCH Working Group for the Histiocyte Society to address this gap in knowledge. Methods: Adults with LCH who received MEKi therapy were included from five institutions. Objective response rate (ORR) was evaluated using PET/CT criteria, and CT/MRI if PET scan was not available; response categories were categorized into complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Progression-free (PFS) and overall survival (OS) were calculated from the time of targeted therapy initiation. Risk organ disease was defined as liver, spleen, or bone marrow involvement. Results: 25 adults with LCH were included in this study; median age at MEKi initiation 43y (range, 18-85). Most common systems involved at diagnosis were bone (52%), pituitary (44%), and lung (36%). Risk organ involvement was observed in 7 (28%, 6 liver, 1 liver and spleen) and 2 (8%) patients had intra-axial CNS involvement. Median lines of prior therapy received were 2 (range: 1-5), and 4 (16%) patients received MEKi in first-line. MAPK/ERK pathway status was assessed via target capture next generation sequencing (NGS) in 22 (96%) cases. Amongst those who underwent NGS, alterations identified included: BRAF V600E (2/22, 9%), BRAF deletions (11/22 50%), MAP2K1 or MEK mutations (4/22, 18%), and MAPK1 or ERK2 (n=1, 5%). Overall, 5 patients also received BRAF inhibitors (4 patients as first therapy prior to MEKi and 1 concomitantly due to BRAF V600E positive melanoma). Specific MEKi agents utilized included cobimetinib (n=13) and trametinib (n=12). Among the response evaluable patients (n=23), ORR to MEKi treatment was 78% (9 CR, 9 PR, 4 SD, 1 PD). Among the 7 patients with liver involvement, responses were seen in 2 (29%) cases. ORR did not significantly differ according to mutation status among those with NGS data (78% MAPK mutated vs. 100% unmutated; p=1.0). In this subcohort, all of the 4 cases that did not respond to MEKi had liver involvement; 3 had BRAF deletions (2 SD and 1 PD), and one had MAPK1 mutation (SD). Median follow-up duration after MEKi initiation in the entire cohort was 18 months (95% CI 6 - 30). The median PFS and OS were not reached; 2-year PFS and OS were 78.1% and 79.9%, respectively (Figure 1A). The median PFS was much shorter in those with liver involvement (7 months [95% CI 0 - 14]) compared with those without liver disease (not reached [95% CI 19-not reached] P=0.047; Figure 1B). PFS did not differ significantly between MAPK pathway mutated and unmutated patients (p=0.34) Adverse events (AEs) were reported in 36% (n=9) and most commonly included rash (n=5) and fatigue (n=3). Four patients experienced grade 3-4 AEs including rash, fatigue, and thrombocytopenia. Common causes of MEKi discontinuation included AEs (n=3), progression (n=2), and drug holiday (n=2). At last follow-up, 5 patients died and 18 remained on MEKi. Death was attributable to LCH (n=3), concomitant malignancy (n=1), or unknown causes (n=1). Conclusions: In our multi-institutional study of adults with LCH, we found MEKi therapy to be highly efficacious. However, liver involvement correlated with a lack of response and worse PFS, while mutational status did not. Future studies are needed to evaluate optimum treatment for high-risk subgroups of LCH like liver disease.

Introduction The treatment of Erdheim-Chester disease (ECD) has been revolutionized by the discovery of MAPK/ERK pathway mutations, most common being BRAF-V600E (50%). The US-FDA approved single-agent vemurafenib for BRAF-V600-mutated ECD in 2017 based on a phase II trial that included 22 patients with ECD and 4 with Langerhans cell histiocytosis (LCH), resulting in 100% overall response rate (ORR) by FDG-PET criteria (Diamond et al. JAMA Onc 2018). However, adverse events (AEs) to vemurafenib led to treatment interruption and/or dose modification in all patients, and drug discontinuation in 8 (31%) patients. Long-term outcomes and tolerability of BRAF-inhibitor (BRAFi) monotherapy in real world setting are unknown. In this study, we aimed to address these questions utilizing a large cohort of patients with ECD. Methods Registry-based ( NCT03329274) study of patients with ECD who received BRAFi (vemurafenib or dabrafenib) as any line of treatment. The registry captures detailed longitudinal clinical, treatment, and outcomes data through medical record abstraction. For this study, we focused on the events of discontinuation, dose reductions, and AEs to BRAFi therapy. Time-to-event analyses were conducted using Kaplan-Meier method from the date of initiation of BRAFi. Primary endpoint of the study was event-free survival (EFS), defined as time to progression of disease, discontinuation or alteration of therapy due to any cause (including addition of a MEK inhibitor), or death. Secondary endpoints included progression-free survival (PFS), defined as time to progression of disease or death, and overall survival (OS). Results We included 64 patients with ECD (including 7 with mixed ECD/LCH) in this study. Median age at diagnosis was 56y (range, 26-77) and at initiation of BRAFi was 57y (range, 26-77). Of these, 59 (92%) were BRAF-V600E, 2 (3.1%) were BRAF-wildtype, 1 had BRAF-V471F, 1 had BRAF-PICALM fusion, and 1 had unknown BRAF status. The distribution of organ involvement was bone (91%), neurologic (78%), brain parenchyma (62%), cardiovascular (58%), retroperitoneum (58%), skin (25%), and pulmonary (19%). BRAFi therapy was used as first-line in 38 (59.3%) and as subsequent line in the rest (median 1, range 1-7). The most common initial BRAFi used was vemurafenib (80%) followed by dabrafenib (20%). The median starting dose of vemurafenib was 720 mg bid (range 480-960) and end dose was 480mg bid (range, 240-480). The median start dose of dabrafenib was 100mg bid (range 50-150) and end dose was 50mg bid (range 50-100). Initial dose reduction of BRAFi was required due to AEs in 28 of 52 cases (54%) with final dose data available, encompassing cutaneous (43%), generalized symptoms or fatigue (18%), >1 system affected (14%), lab abnormalities (11%), musculoskeletal (7%), and other (7%) toxicities. Of 60 patients with response data, a response was seen in 51 patients or 85% (42 partial response, 9 complete response, 8 stable disease, and 1 progressive disease). The median follow-up duration was 3.9 years (range 0.2-8.8). Single-agent BRAFi therapy was discontinued in 38 (59%) patients who received it initially (vemurafenib 63% vs. dabrafenib 46%, p=0.28). Reasons for discontinuation included AEs (n=20, 53%), addition of MEK-inhibitor (18%) for reducing cutaneous toxicities (n=5) or augment CNS response (n=2), disease progression (n=4, 11%), death (n=3, 8%), or others (n=4, 11%). 17 patients were rechallenged with a BRAFi after initial discontinuation, and 6 (35%) discontinued it again. The median EFS for the entire cohort from first BRAFi treatment was 2.99y (95% CI 1.6-4.8) and from second BRAFi was 2.82y (95% CI 1.19- not reached). The median PFS and OS were not reached, and 4 patients died at last follow-up (3 from ECD). Conclusions Almost 5 years after the FDA approval of vemurafenib for ECD, our real-world study from long-term follow-up of a large cohort of patients highlights high response rates, but at the cost of adverse events leading to dose reductions and treatment discontinuation in a large subset. Our results also highlight the entity of disease progression on BRAFi therapy. Our results underscore the importance of developing therapies that are efficacious and well-tolerated in this incurable disease.

Abstract Objective Overnight metyrapone test (OMT) is a dynamic test used to diagnose secondary adrenal insufficiency (SAI). Data on OMT use and its safety are scarce. We aimed to describe the indications and safety of outpatient OMT and compare OMT to the cosyntropin stimulation test (CST). Design Single‐centre retrospective study of adult patients undergoing OMT between 1 April 2018 and 27 January 2023. Measurements OMT‐related adverse events, post‐OMT diagnosis of SAI, and OMT comparison to CST. Results OMT was performed in 114 patients (81, 71% women) at a median age of 48 (interquartile range 37–58). The pretest probability for SAI was low in 52 (46%) patients, moderate in 48 (42%) patients and high in 14 (12%) patients. Adverse events were reported in 7 (6.1%) patients and were mild except for one hospitalization. No baseline or OMT‐related factors were associated with the development of adverse events. Prevalence of the OMT‐based SAI diagnosis was 26 (23%) and 47 (46%) using 11‐deoxycortisol cutoff <7 and <10 mcg/dL, respectively. Higher pretest probability was associated with the OMT‐based diagnosis of SAI. Post‐OMT 11‐deoxycortisol cutoff of 10 mcg/dL was used most to diagnose SAI. Compared to the OMT‐based diagnosis of SAI (11‐deoxycortisol cutoff of 10 mcg/dL), the specificity of CST was 100%, but the sensitivity was only 52%. Conclusions OMT was well tolerated and used in patients with low and moderate pretest probability for SAI. CST can erroneously exclude patients with SAI. Thus, OMT should be considered in selected patients with normal CST.