The size and location of the primary tumor were significant clinical risk factors for metastasis and decreased overall survival duration. These findings delineate the follow-up and treatment for these tumors.

BackgroundAlterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations.Patients and methodsPotent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly.ResultsLOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein −/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved.ConclusionsThese results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

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Purpose. Because parathyroid carcinoma is rare, clear consensus is not available regarding the optimal management of patients with this condition. Treatment strategies generally derive from clinical and anecdotal experiences. We report our experience with this entity.Methods. We included all patients with parathyroid carcinoma seen at The University of Texas M. D. Anderson Cancer Center since January 1, 1980. The medical records and pathology specimens were reviewed and verified in all cases.

Objective Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis. Herein, we describe the clinical features and outcomes for a large series of ACC patients. Design and Methods Retrospective review of ACC patients seen at The University of Texas MD Anderson Cancer Center from 1998 through 2011. Results 330 patients with median age at diagnosis of 48.5 years; 12 (3.6%) patients were under 18 years. Hormonally functioning tumors represented 41.8% (n=138) of all cases. Surgical resection for the primary tumor was done in 275 (83.3%) patients [45 at MD Anderson (16.4%)]. For those who had surgical resection, the median local-recurrence-free time was 1.04 years. Factors associated with local recurrence included positive surgical margins (P= 0.007) and advanced disease stage (P=0.026). Median overall survival time for all patients was 3.21 years. Median survival times were 24.1, 6.08, 3.47, and 0.89 years for stages I, II, III, and IV, respectively. In multivariable analysis, older age, functioning tumors, and higher disease stage remained significant prognostic factors associated with poor survival. Conclusion ACC prognosis remains poor with the use of currently available treatments. Older age, functioning tumors, and incomplete resections are clinical factors associated with poor survival. Surgical expertise is important to achieve complete resections and to improve outcome.

IrT manifests as an early onset of thyrotoxicosis, which is largely asymptomatic, followed by rapid transition to hypothyroidism requiring long-term levothyroxine substitution. The evolution of irT is more rapid with combination ICI. Frequent monitoring of thyroid function tests during ICI is warranted. Future guidelines need to recognize this entity and incorporate their management.

IMPORTANCE Anaplastic thyroid carcinoma (ATC) historically has a 4-month median overall survival (OS) from time of diagnosis, with disease-specific mortality approaching 100%. The association between recent major advancements in treatment and OS has yet to be evaluated. OBJECTIVE To evaluate rates of OS in patients with ATC over the last 2 decades.

BACKGROUND:Cushing syndrome (CS) secondary to ectopic adrenocorticotropic hormone (ACTH) secretion (EAS) has been described in association with a variety of tumors. The current experience with this syndrome was based on a few case series and individual case reports. Limited data were available about the tumors associated with CS‐EAS in a cancer center setting. In this report, the authors have described their experience with CS‐EAS at The University of Texas MD Anderson Cancer Center to further enhance the current understanding and management of this syndrome.METHODS:This was a retrospective review of 43 patients with CS‐EAS who were diagnosed between 1979 and 2009 at The University of Texas MD Anderson Cancer Center.RESULTS:Different neuroendocrine tumors were associated with CS‐EAS. Twenty‐one patients (48.9%) had tumors located in the chest cavity, with bronchial carcinoid and small cell lung cancer representing the 2 most common causes. The ACTH source remained occult in 4 patients (9.3%) despite extensive workup. Clinical presentation varied, and the classic features of CS were not evident in some patients. Death occurred in 27 patients (62.8%), and the median overall survival was 32.2 months. Major morbidities included new‐onset or worsening hyperglycemia (77%), symptomatic venous thromboembolism (14%), and infections (23%).CONCLUSIONS:In patients with CS‐EAS who attended a comprehensive cancer center, tumors originating in the chest cavity were the leading tumors associated with this syndrome. The authors suspect that CS‐EAS is under reported because of the atypical presentation in some patients. Thus, they suggest careful evaluation of patients with neuroendocrine tumors to avoid missing coexisting CS‐EAS. Cancer 2011;. © 2011 American Cancer Society.