Notch3 as a novel therapeutic target in metastatic medullary thyroid cancer.

BACKGROUND: Medullary thyroid cancer portends poor survival once liver metastasis occurs. We hypothesize that Notch3 overexpression in medullary thyroid cancer liver metastasis will decrease proliferation and growth of the tumor. METHODS: TT cells were modified genetically to overexpress Notch3 in the presence of doxycycline, creating the TT-Notch3 cell line. Mice were injected intrasplenically with either TT-Notch3 or control vector TT-TRE cells. Each cell line had 3 treatment groups: control with 12 weeks of standard chow, early DOX with doxycycline chow at day 0 and for 70 days thereafter, and late DOX with doxycycline chow at 8 weeks. Each animal underwent micro-computed tomography to evaluate for tumor formation and tumor quantification was performed. Animals were killed at 12 weeks, and the harvested liver was stained with Ki-67, hematoxylin and eosin, and Notch3. RESULTS: Induction of Notch3 did not prevent formation of medullary thyroid cancer liver metastases as all mice in the early DOX group developed tumors. However, induction of Notch after medullary thyroid cancer liver tumor formation decreased tumor size, as seen on micro-computed tomography scans (late DOX group). This translated to a 37-fold decrease in tumor volume (P = .001). Notch3 overexpression also resulted in decreased Ki-67 index (P = .038). Moreover, Notch3 induction led to increased areas of neutrophil infiltration and necrosis on hematoxylin and eosin staining of the tumors CONCLUSION: Notch3 overexpression demonstrates an antiproliferative effect on established metastatic medullary thyroid cancer liver tumors and is a potential therapeutic target in treatment.

Neuroendocrine Tumor-Targeted Upconversion Nanoparticle-Based Micelles for Simultaneous NIR-Controlled Combination Chemotherapy and Photodynamic Therapy, and Fluorescence Imaging.

Although neuroendocrine tumors (NETs) are slow growing, they are frequently metastatic at the time of discovery and no longer amenable to curative surgery, emphasizing the need for the development of other treatments. In this study, multifunctional upconversion nanoparticle (UCNP)-based theranostic micelles are developed for NET-targeted and near-infrared (NIR)-controlled combination chemotherapy and photodynamic therapy (PDT), and bioimaging. The theranostic micelle is formed by individual UCNP functionalized with light-sensitive amphiphilic block copolymers poly(4,5-dimethoxy-2-nitrobenzyl methacrylate)-polyethylene glycol (PNBMA-PEG) and Rose Bengal (RB) photosensitizers. A hydrophobic anticancer drug, AB3, is loaded into the micelles. The NIR-activated UCNPs emit multiple luminescence bands, including UV, 540 nm, and 650 nm. The UV peaks overlap with the absorption peak of photocleavable hydrophobic PNBMA segments, triggering a rapid drug release due to the NIR-induced hydrophobic-to-hydrophilic transition of the micelle core and thus enabling NIR-controlled chemotherapy. RB molecules are activated via luminescence resonance energy transfer to generate 1O2 for NIR-induced PDT. Meanwhile, the 650 nm emission allows for efficient fluorescence imaging. KE108, a true pansomatostatin nonapeptide, as an NET-targeting ligand, drastically increases the tumoral uptake of the micelles. Intravenously injected AB3-loaded UCNP-based micelles conjugated with RB and KE108-enabling NET-targeted combination chemotherapy and PDT-induce the best antitumor efficacy.

Optimizing Outpatient Pain Management After Thyroid and Parathyroid Surgery: A Two-Institution Experience.

BACKGROUND: Thyroidectomy and parathyroidectomy are the most commonly performed endocrine operations, and are increasingly being completed on a same-day basis; however, few data exist regarding the outpatient postoperative pain requirement of these patients. We aimed to describe the outpatient narcotic medication needs for patients undergoing thyroid and parathyroid surgery, and to identify predictors of higher requirement. METHOD: We examined patients undergoing thyroid and parathyroid surgery at two large academic institutions from 1 January-30 May 2014. Prospective data were collected on pain scores and the oral morphine equivalents (OMEQs) taken by these patients by their postoperative visit. RESULTS: Overall, 313 adult patients underwent thyroidectomy or parathyroidectomy during the study period; 83% of patients took ten or fewer OMEQs, and 93% took 20 or fewer OMEQs. Patients who took more than ten OMEQs were younger (p < 0.001) and reported significantly higher overall mean pain scores at their postoperative visit (p < 0.001) than patients who took fewer than ten OMEQs. A multivariate model was constructed on pre- and intraoperative factors that may predict use of more than ten OMEQs postoperatively. Age <45 years (p = 0.002), previous narcotic use (p = 0.037), and whether parathyroid or thyroid surgery was performed (p = 0.003) independently predicted the use of more than ten OMEQs after surgery. A subgroup analysis was then performed on thyroidectomy-only patients. CONCLUSION: Overall, 93% of patients undergoing thyroidectomy and parathyroidectomy require 20 or fewer OMEQs by their postoperative visit. We therefore recommend these patients be discharged with 20 OMEQs, both to minimize waste and increase patient safety.

The changing pattern of diagnosing primary hyperparathyroidism in young patients.

BACKGROUND: Primary hyperparathyroidism (PHPT) is increasing in adults but rarely reported in young patients where routine blood work is obtained more judiciously. We aim to determine how PHPT is currently being diagnosed in young patients and examine surgical outcomes. METHOD: We retrospectively analyzed PHPT patients 24 years of age or less who underwent parathyroidectomy from 2001 to 2014. Patients were divided into 2 time periods: 2001 to 2007 (A) and 2008 to 2014 (B). Incidentally, diagnosed patients lacked objective symptoms of PHPT and had no family history. RESULTS: Forty young patients met inclusion criteria: 16 in group A and 24 in group B. Those in group A compared with group B had similar mean age, preoperative calcium, and parathyroid hormone (P > .05). Incidental diagnosis was more common in the contemporary group (42% vs 25%, P = .001). CONCLUSIONS: Current diagnosis of PHPT in young patients is increasingly incidental. This trend may be attributed to the more liberal use of labs in younger patients.

How long should we follow patients after apparently curative parathyroidectomy?

BACKGROUND: Little is known about the long-term recurrence risk for primary hyperparathyroidism after immediately "curative" parathyroidectomy. This study aimed to evaluate the risk of recurrent hyperparathyroidism in the 10 years after operation. METHOD: We retrospectively identified patients with sporadic primary hyperparathyroidism undergoing initial parathyroidectomy between November 1, 2000 and June 30, 2005. Recurrence was defined as serum calcium >10.2 mg/dL after 6 months from operation. Kaplan-Meier estimates and Cox proportional hazards were used to evaluate disease-free survival and predictors of recurrence. RESULTS: We evaluated 196 patients with a 14.8% 10-year recurrence rate. Median time to recurrence was 6.3 years (interquartile range 3.4-10.8 years), and 34.5% of all recurrences were identified >10 years after operation. There was no difference in recurrence between open and minimally invasive operation (P = .448). Double adenomas (P = .006), intraoperative parathyroid hormone drop <70% (P = .015), and young age (P = .032) were predictive of disease recurrence. Multivariable analysis demonstrated that older age was protective against recurrence (hazard ratio 0.97, 95% confidence interval 0.94-0.99, P = .034), while double adenomas (hazard ratio 3.52, 95% confidence interval 1.23-10.08, P = .019) were an independent predictor for recurrence. CONCLUSION: The long-term recurrence rate for sporadic primary hyperparathyroidism after "curative" parathyroidectomy is likely greater than reported. With over one-third of our institutional recurrences at >10 years after the initial operation, long-term follow-up is essential.

Parathyroidectomy is underused in patients with tertiary hyperparathyroidism after renal transplantation.

BACKGROUND: Parathyroidectomy (PTX) is the only curative treatment for tertiary hyperparathyroidism (3HPT). With the introduction of calcimimetics (cinacalcet), PTX can sometimes be delayed or avoided. The purpose of this study was to determine the current incidence of utilization of PTX in patients with posttransplant 3HPT with the advent of cinacalcet. METHODS: We evaluated renal transplant patients between January 1, 2004, and June 30, 2012, with a minimum of 24 months follow-up who had persistent allograft function. Patients with an increased serum level of parathyroid hormone (PTH) at 1 year after successful renal transplantation with normocalcemia or hypercalcemia were defined as having 3HPT. A multivariate logistic regression model was constructed to determine factors associated with undergoing PTX. RESULTS: We identified 618 patients with 3HPT, only 41 (6.6%) of whom underwent PTX. Patients with higher levels of serum calcium (P < .001) and PTH (P = .002) posttransplant were more likely to be referred for PTX. Importantly, those who underwent PTX had serum calcium and PTH values distributed more closely to the normal range on most recent follow-up. PTX was not associated with rejection (P = .400) or with worsened allograft function (P = .163). CONCLUSION: PTX seems to be underused in patients with 3HPT at our institution. PTX is associated with high cure rates, improved serum calcium and PTH levels, and is not associated with rejection.

How Well Does Renal Transplantation Cure Hyperparathyroidism?

BACKGROUND: Most patients with end-stage renal disease will develop hyperparathyroidism (HPT). Transplantation reportedly resolves HPT in most cases. Currently, guidelines recommend a watchful waiting approach to HPT for the first 12 months after the transplantation to allow maximal allograft function. The purpose of our study is to examine the incidence and impact of HPT, defined as an elevated parathyroid hormone (PTH) level, after renal transplantation in a contemporary cohort. METHODS: Primary kidney transplantation was performed on 1609 patients from January 1, 2004, to June 6, 2012. Patients were stratified by timing of achieving normal serum PTH levels, and a multivariate logistic regression was constructed to determine predictive variables. Kaplan-Meier analysis was then performed on overall graft survival based on PTH normalization. RESULTS: Four hundred eighty-eight (30.3%) patients achieved normal PTH within 1 year posttransplant. Four hundred twenty-seven (26.6%) attained normal PTH between 1 and 2 years, with the remaining 694 (43.1%) categorized as having HPT. Patients achieving normal PTH within 12 months of transplantation had a significantly longer median graft survival (7.33 years) compared with those patients who normalized between 12 and 24 months (4.92 years, P < 0.001), and those with HPT (5.13 years, P < 0.001). Comparing normalization of PTH by 2 years to HPT patients, obesity (P < 0.001), months on dialysis (P < 0.001), and delayed graft failure (P = 0.006) were predictive of nonnormalization. Overall, allograft survival analysis revealed a survival advantage for patients who normalize PTH within 24 months of transplantation (P = 0.038). CONCLUSIONS: Renal transplant resolves HPT in 56.9% of patients at 2 years. Resolution within the first year portends longer graft survival. Therefore, earlier intervention for HPT should be considered.

Do additional imaging studies change operative management in patients undergoing adrenalectomy?

BACKGROUND: The purpose of this study is to determine the incidence of a secondary imaging modality (SIM) in the workup of adrenal masses and the usefulness of this additional imaging in changing surgical management. METHODS: A retrospective analysis of our adrenalectomy database was performed on adult patients who underwent ≥1 imaging study before surgery. A multivariate logistic regression model was then constructed to identify patient factors that predisposed SIM. RESULTS: From February 2001 to August 2014, 264 cases met inclusion criteria, of which 98 (37%) were identified to have SIM. Patients with cancer (P = .001), incidentaloma (P = .002), and pheochromocytoma (P < .0001) were more likely to undergo additional imaging. MRI was the most commonly obtained SIM. In addition, 90 of the 98 cases (92%) met indications for adrenalectomy with primary imaging study and biochemical screening alone. Of the remaining 8 cases, in only 4 instances (4%) did SIM modify surgical decision making. CONCLUSION: The high incidence of unnecessary additional imaging performed in patients undergoing adrenalectomy is counterproductive to efforts toward cost-conscious, high-quality health care. Patients with adrenal tumors would benefit from early surgical referral to allow the surgeon to help guide clinical decision making and to avoid the use of excessive imaging.