Thyroid-stimulating hormone receptor (TSHR) as a target for imaging differentiated thyroid cancer.

BACKGROUND: Of the half a million cases of thyroid cancer diagnosed annually, 95% are differentiated thyroid cancers. Although clinical guidelines recommend surgical resection followed by radioactive iodine ablation, loss of sodium-iodine symporter expression causes up to 20% of differentiated thyroid cancers to become radioactive iodine refractory. For patients with radioactive iodine refractory disease, there is an urgent need for new diagnostic and therapeutic approaches. We evaluated the thyroid-stimulating hormone receptor as a potential target for imaging of differentiated thyroid cancer. METHODS: We immunostained tissue microarrays containing 52 Hurthle cell carcinomas to confirm thyroid-stimulating hormone receptor expression. We radiolabeled chelator deferoxamine conjugated to recombinant human thyroid-stimulating hormone analog superagonist TR1402 with 89Zr (t1/2 = 78.4 h, ß+ =22.7%) to produce [89Zr]Zr-TR1402. We performed in vitro uptake assays in high-thyroid-stimulating hormone receptor and low-thyroid-stimulating hormone receptor-expressing THJ529T and FTC133 thyroid cancer cell lines. We performed in vivo positron emission tomography/computed tomography and biodistribution studies in male athymic nude mice bearing thyroid-stimulating hormone receptor-positive THJ529T tumors. RESULTS: Immunohistochemical analysis revealed 62% of patients (27 primary and 5 recurrent) were thyroid-stimulating hormone receptor membranous immunostain positive. In vitro uptake of 1nM [89Zr]Zr-TR1402 was 38 ± 17% bound/mg in thyroid-stimulating hormone receptor-positive THJ529T thyroid cancer cell lines compared to 3.2 ± 0.5 in the low-expressing cell line (P < .01), with a similar difference seen in FTC133 cell lines (P < .0001). In vivo and biodistribution studies showed uptake of [89Zr]Zr-TR1402 in thyroid-stimulating hormone receptor-expressing tumors, with a mean percentage of injected dose/g of 1.9 ± 0.4 at 3 days post-injection. CONCLUSION: Our observation of thyroid-stimulating hormone receptor expression in tissue microarrays and [89Zr]Zr-TR1402 accumulation in thyroid-stimulating hormone receptor-positive thyroid cancer cells and tumors suggests thyroid-stimulating hormone receptor is a promising target for imaging of differentiated thyroid cancer.

Somatostatin Receptor Type 2 and Thyroid-Stimulating Hormone Receptor Expression in Oncocytic Thyroid Neoplasms: Implications for Prognosis and Treatment.

Somatostatin receptor type 2 (SSTR2) and thyroid-stimulating hormone receptor (TSHR) display variable expression in primary thyroid tumors and have been implicated as theranostic targets. This study was designed to explore the differential expression of SSTR2 and TSHR in oncocytic (Hurthle cell) carcinoma (OC) vs oncocytic adenoma (OA). We performed a retrospective review for oncocytic neoplasms treated at our institution from 2012 to 2019. Formalin-fixed paraffin-embedded tissue blocks were used for tissue microarray construction. Tissue microarray blocks were cut into 5-µm sections and stained with anti-SSTR2 and anti-TSHR antibodies. Immunostains were analyzed by 3 independent pathologists. χ2 and logistic regression analysis were used to analyze clinical and pathologic variables. Sixty-seven specimens were analyzed with 15 OA and 52 OC. The mean age was 57 years, 61.2% were women, and 70% were White. SSTR2 positivity was noted in 2 OA (13%) and 15 OC (28%; 10 primary, 4 recurrent, and 1 metastatic) (P = .22). TSHR positivity was noted in 11 OA (73%) and 32 OC (62%; 31 primary and 1 metastatic) (P = .40). Those who presented with or developed clinical recurrence/metastasis were more likely to be SSTR2-positive (50% vs 21%; P = .04) and TSHR-negative (64.3% vs 28.9%; P = .02) than primary OC patients. Widely invasive OC was more likely to be SSTR2-positive compared to all other OC subtypes (minimally invasive and angioinvasive) (P = .003). For all patients with OC, TSHR positivity was inversely correlated with SSTR2 positivity (odds ratio, 0.12; CI, 0.03-0.43; P = .006). This relationship was not seen in the patients with OA (odds ratio, 0.30; CI, 0.01-9.14; P = .440). Our results show that recurrent/metastatic OC was more likely to be SSTR2-positive and TSHR-negative than primary OC. Patients with OC displayed a significant inverse relationship between SSTR2 and TSHR expression that was not seen in patients with OA. This may be a key relationship that can be used to prognosticate and treat OCs.

Implementation of solutions to reduce opioid-induced oversedation and respiratory depression.

PURPOSE: The implementation of interventions to mitigate the causes of opioid-induced oversedation and respiratory depression (OSRD) is reported. SUMMARY: A single-site retrospective review of eligible rescue naloxone cases was conducted to identify the causes of opioid-induced OSRD in a hospital as well as to identify risk factors. A survey was used to assess potential opioid knowledge deficits among hospitalist prescribers. Based on the findings of the case reviews and results of the opioid knowledge assessments, a series of interventions to address noted deficiencies was implemented over the ensuing months, including enhanced monitoring for sedation, improved clinical decision support in the electronic medical record (EMR), and various adjustments to dosing for high-risk patients. The primary endpoint of our analysis was naloxone use for documented cases of opioid-induced OSRD to determine the effectiveness of the interventions. A mean of 16 OSRD events occurred per quarter before intervention implementation. An average of five risk factors (range, two to six) was found among OSRD cases, most commonly age of >60, obesity, and comorbidities of the kidneys and lungs. Deficiencies of clinical care were found in four inter-related domains: knowledge deficits, inadequate monitoring, failure to leverage the EMR, and cultural issues regarding pain assessments and sedation management. CONCLUSION: Implementation of solution bundles that utilized an EMR to create meaningful clinical decision support and cultural changes related to pain goals and communication about sedation level at an acute care hospital resulted in a fivefold reduction in OSRD events that has been sustained for two years.

Improving hospital performance in the treatment of febrile neutropenia.

PURPOSE: Febrile neutropenia (FN) remains a common and dangerous complication of cancer treatment. Guidelines from the Infectious Disease Society of America urge initiating antibiotics within 2 h of presentation. We reviewed our institution's performance to identify areas of needed improvement and to design performance improvement steps. METHODS: FN management was deconstructed into discrete tasks. Experienced practitioners estimated appropriate time allowance for each task. Cycle time analysis data on a baseline cohort (baseline group) identified causes and loci of delay. Based on these data, new processes to bypass roadblocks for timely therapy were introduced. Performance monitoring continued as these changes were implemented (the transitional group) and for 20 months thereafter (the post-intervention group). RESULTS: Sixty-nine episodes of FN were identified. Ten distinct improvement steps were implemented. Median time to antibiotics was reduced from 252 min, to 188 min and 118 min for the baseline, transitional, and post-intervention groups, respectively (p = 0.0002 for the baseline vs. the post-intervention group comparison). Variability was reduced with the inter-quartile range falling from 174 min (baseline) to 65 min (post-intervention). Despite improvement, there were persisting episodes of delays, due to competing priorities from other patients or decisions to postpone infusion of antibiotics until patients had been admitted. Standardized order sets eliminated improper antibiotic choices as a source of error. CONCLUSIONS: Improvements in the management of FN can be accomplished and sustained by the focused study of performance of individual tasks, the design of streamlined processes by practitioners, and the ongoing review of performance with feedback to clinical departments.

Experimental reduction of food quality is not compensated with increased food intake in high-Arctic muskoxen (Ovibos moschatus).

A total of four barren adult female muskoxen (Ovibos moschatus) were used over a period of 2 years for the purpose of the present study. During the first year, the natural changes in appetite (ad libitum intake of standard pelleted reindeer feed) and body mass were determined in two of the animals. During the second year, the effect of reduced food quality on ad libitum food intake was tested in all four animals in July when the appetite had been found to be at a high. We found that the experimentally reduced food quality was not compensated with increased food intake in these large high-Arctic herbivores.

Immobilization of muskoxen (Ovibos moschatus) with etorphine and xylazine.

One hundred and thirty three "wild" muskoxen, 81 of which of known body mass, were successfully immobilized using etorphine (M99), and xylazine (Rompun®), delivered by use of a dart gun. A dose of 0.05 mg/kg M99, supplemented by 0.15 mg/kg Rompun was found to be very effective. This dose is much higher than currently recommended e.g. by Handbook of Wildlife Chemical Immobilization.