Neuropsychological complications of hypoprolactinemia.

Prolactin (PRL) is primarily produced by the pituitary lactotrophic cells and while initially named for its role in lactation, PRL has several other biological roles including immunomodulation, osmotic balance, angiogenesis, calcium metabolism, and appetite regulation. Most of the PRL-related literature has traditionally focused on hyperprolactinemia, whereas hypoprolactinemia has received little attention. There is evidence to suggest that PRL receptors are widely distributed within the central nervous system including the limbic system. Furthermore, PRL has been shown to play key role in the stress regulation pathway. Recent data also suggest that hypoprolactinemia may be associated with increased sexual dysfunction, anxiety, and depression. In this paper we discuss the current understanding regarding the neuropsychological impact of hypoprolactinemia and highlight the need for adequately defining hypoprolactinemia as an entity and consideration for future replacement therapies.

Rare distant metastases to pancreas, liver, and lung as initial presentation of mixed tall cell and columnar cell variants of papillary thyroid cancer.

Summary: The most common sites of distant metastases of papillary thyroid carcinoma (PTC) are lung and bone. Widespread distant metastases of PTC are rare and associated with poor overall prognosis. Metastases to sites such as liver and pancreas are extremely rare, and literature is sparse on overall survival. In this report, we present a 57-year-old man whose initial presentation of PTC was with pancreatic, liver, and lung metastases, and subsequently developed metastases to bone and brain. He underwent a total thyroidectomy, neck dissection, and tracheal resection. Pathology revealed a predominant columnar cell variant PTC with focal areas of tall cell variant, and genomic sequencing showed both PIK3CA and BRAF gene mutations. Radioactive iodine ablation with I-131 did not show any uptake in metastatic sites and he had progression of the metastases within 6 months. Therefore, therapy with lenvatinib was initiated for radioactive iodine refractory disease. Our patient has tolerated the lenvatinib well, and all his sites of metastases decreased in size. His liver and pancreatic lesions took longer to respond but showed response 6 months after initiation of lenvatinib, and he remains on full dose lenvatinib 18 months into treatment. Learning points: Papillary thyroid carcinoma (PTC) usually metastasizes to lung and bone but can rarely occur in many other sites. Patients with distant metastases have significantly worse long-term prognosis. Lenvatinib can be an effective treatment of radioactive iodine refractory PTC with rare sites of distant metastases. Lenvatinib can be an effective treatment of PTC with BRAF V600E and PIK3CA mutation.

Rate of malignancy for thyroid nodules with AUS/FLUS cytopathology in a tertiary care center - a retrospective cohort study.

BACKGROUND: Thyroid nodules are stratified through fine-needle aspiration (FNA) and are often categorized using The Bethesda System for Reporting Thyroid Cytopathology, which estimates the risk of malignancy for six cytopathological categories. The atypia of undetermined significance (AUS) and follicular lesion of undetermined significance (FLUS) categories have varying malignancy rates reported in the literature which can range from 6 to 72.9%. Due to this heterogeneity, we assessed the malignancy rate and effectiveness of repeat FNA (rFNA) for AUS/FLUS thyroid cytopathology at our institution. METHODS: Electronic health records of patients with AUS/FLUS thyroid cytopathology on FNA at our center since the implementation of the Bethesda System on May 1, 2014-December 31, 2019 were retrospectively reviewed. Patient demographics, treatment pathway, and pathology results were collected. The treatment pathway of the nodules, the rFNA results, and the malignant histopathology results were reported. Malignancy rates were calculated as an upper and lower limit estimate. RESULTS: This study described 182 AUS/FLUS thyroid nodules from 177 patients. In total, 24 thyroid nodules were deemed malignant upon histopathology, yielding a final malignancy rate of 13.2-25.3%. All of the malignancies were variants of papillary thyroid carcinoma. The malignancy rate of the nodules which underwent resection without rFNA (21.5%) was lower than the malignancy rate of the nodules which underwent resection after rFNA (43.8%). 45.5% of the rFNA results were re-classified into more definitive categories. CONCLUSION: The malignancy rate of AUS/FLUS thyroid cytopathology at our center is in line with the risk of malignancy stated by the 2017 Bethesda System. However, our malignancy rate is lower than some other Canadian centers and approximately half of our rFNAs were re-classified, highlighting the importance of establishing center-specific malignancy and rFNA re-classification rates to guide treatment decisions.

Insulinoma presenting as hypoglycemia during lactose tolerance testing: a case report.

BACKGROUND: Insulinoma is a rare functioning pancreatic endocrine tumor, typically presenting as a sporadic solitary lesion causing hypoglycemia. While these tumors can lead to marked autonomic and neuroglycopenic symptoms, the diagnosis is often delayed. CASE PRESENTATION: We present a case of a 60-year-old Caucasian man presenting with a 1-year history of progressive episodic confusion and an unexpected finding of symptomatic hypoglycemia during a lactose tolerance test. Further inquiry revealed an 8-year history of more subtle episodic neuroglycopenic symptoms preceding his presentation. After additional biochemical testing suggested a diagnosis of insulinoma, abdominal imaging was performed and revealed a 1.2-cm tumor in the tail of the pancreas. Following laparoscopic resection of the tumor, the patient had complete resolution of his symptoms and maintained normal glucose levels. CONCLUSIONS: The clinical presentation of functioning pancreatic neuroendocrine tumors can be subtle and nonspecific. As such, clinicians should remain vigilant for insulinoma when symptomatic hypoglycemia is present. To our knowledge, this is the first report of an insulinoma found after hypoglycemia was detected during lactose tolerance testing.

Ischemic stroke and intracerebral hemorrhage: the latest evidence on mortality, readmissions and hospital costs from Scotland.

BACKGROUND AND PURPOSE: Stroke is the third leading cause of death in the UK, yet little information exists on current treatment patterns, outcomes and costs. This study assessed survival, readmissions and total hospital costs over 12 months in patients with first-ever intracerebral hemorrhage (ICH) or ischemic stroke (IS) in Scotland. METHODS: Hospital-based retrospective inception cohort design using data from the Hospital Record Linkage System in the National Health Service in Scotland. Survival, readmissions and total hospital costs were evaluated in all patients admitted to hospital for ICH or IS from April 1, 2004, to March 31, 2005. RESULTS: A total of 1,016 patients with ICH and 4,295 with IS were identified. The average age was 67.6 years (SD 14.5) for ICH and 70.4 years (SD 12.7) for IS at stroke onset. In-hospital mortality was 45.2% (95% confidence interval, CI, 41.0-49.3) for ICH and 15.6% (95% CI, 14.4-16.7) for IS, while 52.5% (95% CI, 48.0-56.9) and 27.2% (95% CI, 25.7-28.8), respectively, were dead at 1 year after stroke onset. The cumulative 1-year risk of rehospitalization for stroke and severe cardiac events was 15.0 and 1.0% in the ICH cohort, respectively, and 10.8 and 1.5% in the IS cohort. The average length of initial hospital stay was 38.4 days for ICH and 39.3 days for IS. The average total hospital costs over 12 months were GBP 13,960 (SD 21,487) for ICH and GBP 14,051 (SD 17,850) for IS. CONCLUSION: Individuals experiencing an ICH continue to exhibit a much worse prognosis than IS, and both forms of stroke continue to imply significant hospital costs to the National Health Service in Scotland.

Outcomes and costs of blunt trauma in England and Wales.

BACKGROUND: Trauma represents an important public health concern in the United Kingdom, yet the acute costs of blunt trauma injury have not been documented and analysed in detail. Knowledge of the overall costs of trauma care, and the drivers of these costs, is a prerequisite for a cost-conscious approach to improvement in standards of trauma care, including evaluation of the cost-effectiveness of new healthcare technologies. METHODS: Using the Trauma Audit Research Network database, we examined patient records for persons aged 18 years and older hospitalised for blunt trauma between January 2000 and December 2005. Patients were stratified by the Injury Severity Score (ISS). RESULTS: A total of 35,564 patients were identified; 60% with an ISS of 0 to 9, 17% with an ISS of 10 to 16, 12% with an ISS of 17 to 25, and 11% with an ISS of 26 to 75. The median age was 46 years and 63% of patients were men. Falls were the most common cause of injury (50%), followed by road traffic collisions (33%). Twenty-nine percent of patients were admitted to critical care for a median length of stay of 4 days. The median total hospital length of stay was 9 days, and 69% of patients underwent at least one surgical procedure. Seven percent of the patients died before discharge, with the highest proportion of deaths among those in the ISS 26-75 group (32%). The mean hospital cost per person was 9,530 pounds sterling (+/- 11,872). Costs varied significantly by Glasgow Coma Score, ISS, age, cause of injury, type of injury, hospital mortality, grade and specialty of doctor seen in the accident and emergency department, and year of admission. CONCLUSION: The acute treatment costs of blunt trauma in England and Wales vary significantly by injury severity and survival, and public health initiatives that aim to reduce both the incidence and severity of blunt trauma are likely to produce significant savings in acute trauma care. The largest component of acute hospital cost is determined by the length of stay, and measures designed to reduce length of admissions are likely to be the most effective in reducing the costs of blunt trauma care.

Cost per successfully treated patient for vortioxetine versus duloxetine in adults with major depressive disorder: an analysis of the complete symptoms of depression and functional outcome.

OBJECTIVE: To determine the cost-effectiveness of vortioxetine vs duloxetine in adults with moderate-to-severe major depressive disorder (MDD) in Norway using a definition of a successfully treated patient (STP) that incorporates improvement in both mood symptoms and functional capacity. METHODS: Using the population of patients who completed the 8-week CONNECT study, the cost-effectiveness of vortioxetine (n = 168) (10-20 mg/day) vs duloxetine (n = 176) (60 mg/day) was investigated for the treatment of adults in Norway with moderate-to-severe MDD and self-reported cognitive dysfunction over an 8-week treatment period. Cost-effectiveness was assessed in terms of cost per STP, defined as improvement in mood symptoms (≥50% decrease from baseline in Montgomery-Åsberg Depression Rating Scale total score) and change in UCSD [University of California San Diego] performance-based skills assessment [UPSA] score of ≥7. The base case analysis utilized pharmacy retail price (apotek utsalgspris (AUP)) for branded vortioxetine (Brintellix) and branded duloxetine (Cymbalta). RESULTS: After 8 weeks of antidepressant therapy, there were more STPs with vortioxetine than with duloxetine (27.4% vs 22.5%, respectively). The mean number needed to treat for each STP was 3.6 for vortioxetine and 4.4 for duloxetine, resulting in a lower mean cost per STP for vortioxetine (NOK [Norwegian Kroner] 3264) than for duloxetine (NOK 3310) and an incremental cost per STP of NOK 3051. The use of a more challenging change in the UPSA score from baseline (≥9) resulted in a mean cost per STP of NOK 3822 for vortioxetine compared with NOK 3983 for duloxetine and an incremental cost per STP of NOK 3181. CONCLUSIONS: Vortioxetine may be a cost-effective alternative to duloxetine, owing to its superior ability to improve functional capacity. The dual-response STP concept introduced here represents a more comprehensive analysis of the cost-effectiveness of antidepressants.

The effect of time of day testing and utility of 30 and 60 minute cortisol values in the 250 mcg ACTH stimulation test.

BACKGROUND: Despite widespread use of the 250-mcg Cosyntropin test (ACTH test) for the diagnosis of adrenal insufficiency (AI), the effect of time of day and the utility of performing both 30- and 60-min serum cortisol values remains unclear. METHODS: We conducted a retrospective cohort study of all ACTH testing at the Halifax Neuropituitary Program, Nova Scotia, Canada between January 2006 and April 2016. Data were collected on age, gender, medication history, serum cortisol levels at 0, 30 and 60 min after ACTH administration, as well as time of and indication for testing. RESULTS: There were 336 tests performed, divided by time of day (0800-1000 h, 1001-1200 h, and after 1200 h). There were no differences in mean cortisol levels at 30 (574.5, 559, 534 nmol/L, respectively; p = 0.25) and 60 min (642, 623, 619 nmol/L, respectively; p = 0.63) between groups. When comparing 30- vs. 60-min values using a cut-off of ≥500 nmol/L, 45 patients (13.4%) failed to reach the cut-off at 30 min but met the cut-off at 60 min. Conversely, only 2 patients (0.6%) who met the cut-off at 30 min failed to reach it at 60 min. CONCLUSION: We found that outcomes from ACTH testing are not affected by time of day. Furthermore, using a 30-min cortisol level in isolation results in more than one in seven patients having a false positive diagnosis of AI; a 60-min value of ≥500 nmol/L alone may be sufficient to diagnose AI in >99% of cases.

Cost-utility of somatropin (rDNA origin) in the treatment of growth hormone deficiency in children.

OBJECTIVE: The objective of this study was to generate estimates of cost-effectiveness/utility of somatropin (rDNA origin) in the treatment of growth hormone deficiency (GHD) in children. METHODS: A decision-analytic model of the epidemiology and treatment of GHD in children was developed. Treatment of GHD was assessed in two hypothetical cohorts compared to no treatment--treatment with somatropin 0.030 mg/kg/day from ages 5 to 16 years, and treatment from ages 3 to 18 years. Costs (stated in 2005 US$) included those related to drug acquisition, endocrinologist consultations, and primary care office visits. Estimates of patient weight by age and sex were derived from published literature, as was the proportion of patients achieving normal height through somatropin treatment and pre/post-treatment patient utilities. Cost-effectiveness/utility was estimated over patients' expected lifetimes, and was stated alternatively as discounted (3% per annum) US dollars per normal height year (NHY) gained, and cost per quality adjusted life-year (QALY) gained. Multivariate sensitivity analyses were conducted to ensure robustness of the model. RESULTS: The cost-effectiveness and cost-utility of treating children from ages 5 to 16 years with somatropin was estimated at approximately $8,900 per NHY gained and $37,000 per QALY gained, respectively. Corresponding ratios pertaining to treatment of children from ages 3 to 18 years were $9,300 per NHY gained and $42,600 per QALY gained. Findings were relatively insensitive to variation in most model parameters. CONCLUSIONS: For both age cohorts, the cost-effectiveness/utility of somatropin in the treatment of GHD compares favorably to well-accepted threshold values. The use of somatropin represents reasonable value for money for the treatment of GHD in children.

Pharmacoeconomic analysis of recombinant factor VIIa versus APCC in the treatment of minor-to-moderate bleeds in hemophilia patients with inhibitors.

OBJECTIVE: To compare the cost-effectiveness of three treatment regimens using recombinant activated Factor VII (rFVIIa), NovoSeven, and activated prothrombin-complex concentrate (APCC), FEIBA VH, for home treatment of minor-to-moderate bleeds in hemophilia patients with inhibitors. METHODS: A literature-based, decision-analytic model was developed to compare three treatment regimens. The regimens consisting of first-, second-, and third-line treatments were: rFVIIa-rFVIIa-rFVIIa; APCC-rFVIIa-rFVIIa; and APCC-APCC-rFVIIa. Patients not responding to first-line treatment were administered second-line treatment, and those failing second-line received third-line treatment. Using literature and expert opinion, the model structure and base-case inputs were adapted to the US from a previously published analysis. The percentage of evaluable bleeds controlled with rFVIIa and APCC were obtained from published literature. Drug costs (2005 US$) based on average wholesale price were included in the base-case model. Univariate and probabilistic sensitivity analyses (second-order Monte Carlo simulation) were conducted by varying the efficacy, re-bleeding rates, patient weight, and dosing to ascertain robustness of the model. RESULTS: In the base-case analysis, the average cost per resolved bleed using rFVIIa as first-, second-, and third-line treatment was $28 076. Using APCC as first-line and rFVIIa as second- and third-line treatment resulted in an average cost per resolved bleed of $30 883, whereas the regimen using APCC as first- and second-line, and rFVIIa as third-line treatment was the most expensive, with an average cost per resolved bleed of $32 150. Cost offsets occurred for the rFVIIa-only regimen through avoidance of second and third lines of treatment. In probabilistic sensitivity analyses, the rFVIIa-only strategy was the least expensive strategy more than 68% of the time. CONCLUSIONS: The management of minor-to-moderate bleeds extends beyond the initial line of treatment, and should include the economic impact of re-bleeding and failures over multiple lines of treatment. In the majority of cases, the rFVIIa-only regimen appears to be a less expensive treatment option in inhibitor patients with minor-to-moderate bleeds over three lines of treatment.

Cost-effectiveness analysis of solifenacin versus oxybutynin immediate-release in the treatment of patients with overactive bladder in the United Kingdom.

OBJECTIVE: To carry out a cost-utility analysis comparing initial treatment with solifenacin 5 mg/day vs oxybutynin immediate-release (IR) 15 mg/day for the treatment of patients with overactive bladder (OAB) from the perspective of the U.K. National Health Service (NHS). METHODS: A Markov model with six health states was developed to follow a cohort of OAB patients treated with either solifenacin or oxybutynin during a 1-year period. Costs and utilities were accumulated as patients transited through the health states in the model and a drop-out state. Some of the solifenacin patients were titrated from 5 mg to 10 mg/day at 8 weeks. A proportion of drop-out patients were assumed to continue treatment with tolterodine ER. Utility values were obtained from a Swedish study and pad use was based on a multinational clinical trial. Adherence rates for individual treatments were derived from a U.K. database study. For pad use and utility values, the drop-out state was split between those patients who were no longer receiving treatment and those on second-line therapy. Patients on second-line therapy who drop-out were referred for a specialist visit. Results were expressed in terms of incremental cost-utility ratios. RESULTS: Total annual costs for solifenacin and oxybutynin were £504.30 and £364.19, respectively. First-line drug use represents 49% and 4% of costs and pad use represent 23% and 40% of costs for solifenacin and oxybutynin, respectively. Differences between cumulative utilities were small but were greater for solifenacin (0.7020 vs. 0.6907). The baseline incremental cost-effectiveness ratio was £12,309/QALY. CONCLUSION: Under the baseline assumptions, solifenacin would appear to be cost-effective with an incremental cost-utility of less than £20,000/QALY. However, small differences in utility between the alternatives and the large number of drop-outs means that the results are sensitive to small adjustments in the values of utilities assigned to the drop-out state.

Valuing lives and life years: anomalies, implications, and an alternative.

Many government interventions seek to reduce the risk of death. The value of preventing a fatality (VPF) is the monetary amount associated with each statistical death that an intervention can be expected to prevent. The VPF has been estimated using a preference-based approach, either by observing market behaviour (revealed preferences) or by asking hypothetical questions that seek to replicate the market (stated preferences). The VPF has been shown to differ across and within these methods. In theory, the VPF should vary according to factors such as baseline and background risk, but, in practice, the estimates vary more by theoretically irrelevant factors, such as the starting point in stated preference studies. This variation makes it difficult to choose one unique VPF. The theoretically irrelevant factors also affect the estimates of the monetary value of a statistical life year and the value of a quality-adjusted life year. In light of such problems, it may be fruitful to focus more research efforts on generating the VPF using an approach based on the subjective well-being associated with different states of the world.