Mimi I. Hu

Medical management of postsurgical hypoparathyroidism.

OBJECTIVE To provide a clinical update on the management of hypoparathyroidism with focus on postsurgical hypoparathyroidism. METHODS Using PubMed, English-language literature was searched related to management of hypoparathyroidism after thyroid and parathyroid surgery. We discuss the incidence, pathophysiology, differential diagnosis, early diagnosis, and treatment of transient and permanent hypoparathyroidism. RESULTS Hypoparathyroidism is a well-recognized complication after thyroid and parathyroid surgery. Transient hypoparathyroidism occurs in 10% of patients who undergo total thyroidectomy. Less than half of patients who develop transient hypoparathyroidism after thyroid surgery develop permanent hypoparathyroidism. Postsurgical hypocalcemia resulting from inadequate parathyroid hormone (PTH) secretion could cause neurologic complications and respiratory compromise. Calcium supplements and vitamin D analogues effectively treat hypocalcemia associated with postsurgical hypoparathyroidism. Measurement of PTH after thyroid and parathyroid surgery allows early identification of patients likely to require calcium supplements and vitamin D analogue therapy. Early identification and appropriate management of postsurgical hypoparathyroidism prevent hypocalcemia-related complications and allow patients to be discharged from the hospital earlier. Patients who develop permanent hypoparathyroidism should receive appropriate follow-up care to monitor for long-term complications related to supplemental therapy. PTH replacement therapy is currently being evaluated for the treatment of transient and permanent hypoparathyroidism. CONCLUSIONS A multidisciplinary approach involving an endocrinologist and surgeon is imperative to reduce the morbidity associated with hypoparathyroidism after thyroid and parathyroid surgery. Supplemental therapy with calcium and vitamin D analogues is standard. New drugs currently in clinical trials offer promising treatment options.

Efficacy and Tolerability of Vemurafenib in Patients with BRAFV600E -Positive Papillary Thyroid Cancer: M.D. Anderson Cancer Center Off Label Experience

CONTEXT Vemurafenib, a selective BRAF inhibitor, appears to have promising clinical activity in patients with papillary thyroid cancer (PTC) harboring the BRAF(V600E) mutation. OBJECTIVE To determine the efficacy and safety of vemurafenib when used outside of a clinical trial. DESIGN A retrospective review at MD Anderson Cancer Center. METHODS The best responses were evaluated using RECIST v1.1. A single radiologist reviewed all images. Adverse events (AEs) were evaluated using CTCAE v.4.0. RESULTS We identified 17 patients with advanced PTC harboring the BRAF(V600E) mutation who were treated with vemurafenib outside of a clinical trial. Median age at diagnosis was 63 years, and 53% were male. At vemurafenib start, 3 (18%) patients had disease confined to the neck, and 14 (72%) had distant metastases. Tyrosine kinase inhibitors had been previously administered to 4 (24%) patients. Two (12%) patients discontinued vemurafenib because of AEs before restaging. Best response: partial response (PR) in 7/15 (47%) and stable disease (SD) in 8/15(53%) patients. The rate of durable response (PR plus SD ≥ 6 months) was 67%. Median time to treatment failure was 13 months. There was no association between change in thyroglobulin and tumor size. Drug discontinuation, drug interruptions, and dose reductions were needed in 5 (29%), 13 (76%), and 10 (59%) patients, respectively. Most common AEs were fatigue (71%), weight loss (71%), anorexia (65%), arthralgias (59%), hair loss (59%), rash (59%), hand-foot syndrome (53%), calluses (47%), diarrhea (47%), fever (41%), dry mouth (35%), nausea (35%), and verrucous keratosis (35%). Grade ≥ 3 AEs were present in 8 (47%) patients. CONCLUSIONS Vemurafenib is a potentially effective and well-tolerated treatment strategy in patients with advanced PTC harboring the BRAF(V600E) mutation. Our results are similar to those reported in a phase II clinical trial and support the potential role of vemurafenib in this patient population.

Cushing's syndrome secondary to ectopic ACTH secretion: The University of Texas MD Anderson Cancer Center Experience

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.

Cushing syndrome secondary to ectopic adrenocorticotropic hormone secretion: the University of Texas MD Anderson Cancer Center Experience.

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.

Role of Salvage Targeted Therapy in Differentiated Thyroid Cancer Patients Who Failed First-Line Sorafenib

CONTEXT Sorafenib, a tyrosine kinase inhibitor, is a common first-line therapy for advanced differentiated thyroid cancer (DTC). However, responses are not durable and drug toxicity remains a problem. OBJECTIVE The objective of the study was to determine the efficacy of salvage therapy after first-line sorafenib failure. DESIGN This was a retrospective review at M. D. Anderson Cancer Center from January 2005 to May 2013. PATIENTS The study included patients with metastatic DTC who received salvage therapy after their initial sorafenib failure (group 2). PATIENTS who received first-line sorafenib only (group 1) were evaluated for comparison of overall survival (OS). OUTCOME MEASURES Progression-free survival, best response, and median OS were measured. RESULTS Sixty-four patients with metastatic, radioactive iodine refractory DTC were included; 35 were in group 1 and 25 were in group 2, and the groups were well balanced. Median OS of all 64 patients receiving first line sorafenib was 37 months; median OS was significantly longer with salvage therapy compared with sorafenib alone (58 vs 28 months, P = .013). In group 2, 17 patients were evaluable for best response, although two patients had toxicity with sorafenib, which was discontinued before restaging. Best responses with first-line sorafenib were partial response in 2 of 15 (13%), stable disease in 10 of 15 (67%), and progressive disease in 3 of 15 (20%) patients. With salvage therapy, partial responses were seen in 7 of 17 (41%) and stable disease in 10 of 17 (59%) patients. Median progression-free survival was 7.4 months with first-line sorafenib and 11.4 months with salvage therapy. Salvage therapy included sunitinib (n = 4), pazopanib (n = 3), cabozantinib (n = 4), lenvatinib (n = 3), and vemurafenib (n = 3). CONCLUSIONS Other targeted agents are effective salvage treatments after sorafenib failure, despite similar mechanisms of action, and should be offered to patients who are able to receive salvage therapy.

Calcitonin Gene Family of Peptides

Publisher Summary The calcitonin (CT) gene family of peptides belong to a complex series of ligands, receptors, and coreceptors that regulate a broad spectrum of physiological functions that include skeletal remodeling, blood pressure control, neural transmission in both the central and peripheral nervous system, cardiovascular development, and development of the lymphatic system. This system, modified by evolutionary pressure, is present in a broad spectrum of species, is expressed very early in development and has important roles in normal mammalian development. This chapter focuses primarily on the role of the calcitonin and calcitonin gene-related family of peptides in bone, also providing an overview of current progress associated with the entire family. CT maintains bone mineral in emergency situations (i.e., to combat hypercalcemia) and plays a role in the conservation of body calcium stores in certain physiological but stressful states (i.e., growth, pregnancy, and lactation). However, it is clear from the growing body of literature that the CT gene family of peptides, as a whole, has many important physiological and pathological functions. Further investigations into this broad family of peptides are likely to provide great insight into the physiology of the human in healthy and disease states.

The Characterization of Pheochromocytoma and Its Impact on Overall Survival in Multiple Endocrine Neoplasia Type 2

CONTEXT Pheochromocytoma (PHEO) occurs in 50% of patients with multiple endocrine neoplasia type 2 (MEN2). It is unknown if the presence of PHEO is associated with more aggressive medullary thyroid cancer (MTC). OBJECTIVE To present our experience with MEN2 PHEO and evaluate whether PHEO impacts MTC overall survival in patients with RET codon 634 mutations. DESIGN We performed a retrospective chart review of MEN2 patients at MD Anderson Cancer Center from 1960 through 2012. PATIENTS The study group comprised 85 patients (group 1) with MEN2-associated PHEO. Of these, 59 patients (subgroup 1) with RET codon 634 mutations were compared to 48 patients (group 2) with RET codon 634 mutations, but without MEN2-associated PHEO. MAIN OUTCOME MEASURES Of 85 patients with MEN2 and PHEO, 70 had MEN2A and 15 had MEN2B. Median age at PHEO diagnosis was 32 years. The initial manifestation of MEN2 was MTC in 60% of patients, synchronous MTC and PHEO in 34%, and PHEO in 6% of patients. Of patients, 72% had bilateral PHEO, and most tumors were synchronous (82%). Subgroup analysis of MEN2 patients with and without PHEO, who were carriers of RET codon 634, the most common mutation with PHEO, showed no significant differences in the stage of MTC at initial diagnosis. The median follow-up time for patients with PHEO was 249 months and without PHEO was 67 months (P < .01). Survival analyses among RET 634 carriers did not show shorter survival for patients with PHEO. The median survival time for patients with PHEO was 499 months and without PHEO was 444 months (P < .05). CONCLUSIONS PHEO in MEN2 patients are usually bilateral and unlikely to be metastatic. Subgroup analysis of patients with RET 634 mutations with and without PHEO showed that PHEO was not associated with a more advanced stage of MTC at diagnosis or a shorter survival.

Skeletal sequelae of cancer and cancer treatment.

IntroductionSurvivors of cancer may experience lingering adverse skeletal effects such as osteoporosis and osteomalacia. Skeletal disorders are often associated with advancing age, but these effects can be exacerbated by exposure to cancer and its treatment. This review will explore the cancer and cancer treatment-related causes of skeletal disorders.MethodsWe performed a comprehensive search, using various Internet-based medical search engines such as PubMed, Medline Plus, Scopus, and Google Scholar, for published articles on the skeletal effects of cancer and cancer therapies.ResultsOne-hundred-forty-two publications, including journal articles, books, and book chapters, met the inclusion criteria. They included case reports, literature reviews, systematic analyses, and cohort reports. Skeletal effects resulting from cancer and cancer therapies, including hypogonadism, androgen deprivation therapy, estrogen suppression, glucocorticoids/corticosteroids, methotrexate, megestrol acetate, platinum compounds, cyclophosphamide, doxorubicin, interferon-alpha, valproic acid, cyclosporine, vitamin A, NSAIDS, estramustine, ifosfamide, radiotherapy, and combined chemotherapeutic regimens, were identified and described. Skeletal effects of hyperparathyroidism, vitamin D deficiency, gastrectomy, hypophosphatemia, and hyperprolactinemia resulting from cancer therapies were also described.Discussion/ConclusionsThe publications researched during this review both highlight and emphasize the association between cancer therapies, including chemotherapy and radiotherapy, and skeletal dysfunction.Implications for cancer survivorsThese studies confirm that cancer survivors experience a more rapid acceleration of bone loss than their age-matched peers who were never diagnosed with cancer. Further studies are needed to better address the skeletal needs of cancer survivors.

Medullary Thyroid Cancer in the Era of Tyrosine Kinase Inhibitors: To Treat or Not to Treat—and With Which Drug—Those Are the Questions

CONTEXT Medullary thyroid cancer (MTC) is a rare form of thyroid cancer comprising approximately 4% of all thyroid cancers. The majority of patients have a relatively good prognosis; however, a subgroup of patients will require systemic therapy. Large phase III randomized trials led to the approval of two drugs--vandetanib and cabozantinib--for progressive or symptomatic MTC. The decision regarding which drug to initiate first is not entirely clear and is a common concern amongst treating physicians. EVIDENCE ACQUISITION AND SYNTHESIS A review of the literature in English was conducted, and data were summarized and integrated into a decision matrix. CONCLUSIONS The decision regarding which drug to initiate first for progressive MTC should be based on a careful review of the medical history, physical examination findings, medication list, electrocardiogram, laboratory results, and tumor characteristics. It is necessary to consider the relative contraindications when choosing which drug to initiate first.

Association of Vitamin D Levels With Outcome in Patients With Melanoma After Adjustment For C-Reactive Protein

PURPOSE To evaluate for an association between 25-hydroxyvitamin D levels (vitamin D) and outcome measures in patients with melanoma after evaluation is controlled for systemic inflammatory response (SIR) on the basis of simultaneous C-reactive protein (CRP) measurement. MATERIALS AND METHODS Plasma samples from 1,042 prospectively observed patients with melanoma were assayed for vitamin D and CRP. The associations of demographics and CRP with vitamin D were determined, followed by a determination of the association between vitamin D and stage and outcome measures from the date of blood draw. The vitamin D level was considered sufficient if it was 30 to 100 ng/mL. Kaplan-Meier and Cox regression analyses were performed. RESULTS The median vitamin D level was 25.0 ng/mL. The median follow-up time was 7.1 years. A lower vitamin D was associated with the blood draw during fall/winter months (P < .001), older age (P = .001), increased CRP (P < .001), increased tumor thickness (P < .001), ulcerated tumor (P = .0105), and advanced melanoma stage (P = .0024). On univariate analysis, lower vitamin D was associated with poorer overall (OS; P < .001), melanoma-specific survival (MSS; P = .0025), and disease-free survival (DFS; P = .0466). The effect of vitamin D on these outcome measures persisted after adjustment for CRP and other covariates. Multivariable hazards ratios per unit decrease of vitamin D were 1.02 for OS (95% CI, 1.01 to 1.04; P = .0051), 1.02 for MSS (95% CI, 1.00 to 1.04; P = .048), and 1.02 for DFS (95% CI, 1.00 to 1.04; P = .0427). CONCLUSION Lower vitamin D levels in patients with melanoma were associated with poorer outcomes. Although lower vitamin D was strongly associated with higher CRP, the associations of lower vitamin D with poorer OS, MSS, and DFS were independent of this association. Investigation of mechanisms responsible for these associations may be of value to patients with melanoma.