Metastatic HER2 lacrimal/salivary gland duct adenocarcinoma.

In this report, we present a case of a patient with a 30-year history of orbital asymmetry who presented with metastatic human epidermal growth factor receptor 2 (HER2) positive lacrimal/salivary gland ductal adenocarcinoma. The patient was treated with chemoradiotherapy and trastuzumab. Tumours of lacrimal gland origin are rare, and unfortunately can frequently present in late stage. There are no current guidelines on the optimal treatment of metastatic lacrimal gland tumours, in particular those with HER2 amplified malignancy. This case highlights a unique presentation of a rare disease, and the potential for targeted therapy.

Growth hormone replacement may influence the biological action of thyroid hormone on liver and bone tissue.

OBJECTIVE: Growth hormone (GH) replacement alters the peripheral interconversion of thyroxine (T4) and triiodothyronine (T3). However, little is known about the clinical impact of these alterations. We aimed to compare changes observed in the serum T3:T4 ratio with known biological markers of thyroid hormone action derived from different peripheral tissues. DESIGN: We prospectively studied twenty GH deficient men before and after GH replacement in a tertiary referral endocrine center. Serum biochemical measurements included insulin like growth factor-1 (IGF-1), thyroid hormones (free & total T3, free & total T4 and reverse T3) and TSH. Changes in thyroid hormone concentration were compared to alterations in hepatic and bone biomarkers of thyroid hormone action. RESULTS: GH replacement provoked a decline in serum free T4 concentration (-1.09 ± 1.99 pmol/L; p = 0.02) and an increase in free T3 (+0.34 ± 0.15 pmol/L; p = 0.03); therefore, the free T3:free T4 ratio increased from 0.40 ± 0.02 to 0.47 ± 0.02 (p = 0.002). Sex hormone binding globulin (SHBG) level was unchanged. However, a decline in serum ferritin (-26.6 ± 8.5 ng/mL; p = 0.005) correlated with a fall in freeT4. Alterations in lipid profile, including a rise in large HDL sub-fractions and Lp (a) (+2.1 ± 21.1 nmol/L; p = 0.002) did not correlate with thyroid hormone levels. Significant increases were recorded in serum bone turnover markers - procollagen type 1 amino-terminal propeptide +57.4%; p = 0.0009, osteocalcin +48.6%; p = 0.0007; c-terminal telopeptides of type 1 collagen +73.7%; p = 0.002. Changes in bone formation markers occurred in parallel with fluctuations in thyroid hormone. CONCLUSION: GH-induced alterations in the thyroid axis are associated with complex, tissue specific effects on thyroid hormone action. Modulation of bone turnover markers suggests that GH may improve the biological action of thyroid hormone on bone.

A Nonadaptive Combinatorial Group Testing Strategy to Facilitate Health Care Worker Screening during the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Outbreak.

Routine testing for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in health care workers (HCWs) is critical. Group testing strategies to increase capacity facilitate mass population testing but do not prioritize turnaround time, an important consideration for HCW screening. We propose a nonadaptive combinatorial (NAC) group testing strategy to increase throughput while facilitating rapid turnaround. NAC matrices were constructed for sample sizes of 700, 350, and 250. Matrix performance was tested by simulation under different SARS-CoV-2 prevalence scenarios of 0.1% to 10%. NAC matrices were compared versus Dorfman sequential (DS) group testing approaches. NAC matrices performed well at low prevalence levels, with an average of 97% of samples resolved after a single round of testing via the n = 700 matrix at a prevalence of 1%. In simulations of low to medium (0.1% to 3%) prevalence, all NAC matrices were superior to the DS strategy, measured by fewer repeated tests required. At very high prevalence levels (10%), the DS matrix was marginally superior, although both group testing approaches performed poorly at high prevalence levels. This strategy maximizes the proportion of samples resolved after a single round of testing, allowing prompt return of results to HCWs. This methodology may allow laboratories to adapt their testing scheme based on required throughput and the current population prevalence, facilitating a data-driven testing strategy.

Refusal of viral testing during the SARS-CoV-2 pandemic.

Widespread testing for the respiratory syndrome coronavirus-2 (SARS-CoV-2) will represent an important part of any strategy designed to safely reopen societies from lockdown. Healthcare settings have the potential to become reservoirs of infectivity, and therefore many hospital trusts are beginning to carry out routine screening of staff and patients. This could promote the effective cohorting of patients and reduce the rate of nosocomial infection. However, for various reasons, some individuals may refuse this testing. Here we highlight this as an emergent ethicolegal issue which we expect to become increasingly relevant as testing becomes ubiquitous. We explore this position from an ethical and legal perspective, determining whether refusal of testing is acceptable under UK law. Individual patients refusing testing could undermine a hospital's testing strategy; therefore clinicians and policy makers must prospectively determine the best course of action if this were to occur.

Spurious HbA1c results in patients with diabetes treated with dapsone.

SUMMARY: Measurement of glycated haemoglobin (HbA1c) has been utilised in assessing long-term control of blood glucose in patients with diabetes, as well as diagnosing diabetes and identifying patients at increased risk of developing diabetes in the future. HbA1c reflects the level of blood glucose to which the erythrocyte has been exposed during its lifespan, and there are a number of clinical situations affecting the erythrocyte life span in which HbA1c values may be spuriously high or low and therefore not reflective of the true level of glucose control. In the present case series, we describe the particulars of three patients with diabetes who had spuriously low HbA1c levels as a result of dapsone usage. Furthermore, we discuss the limitations of HbA1c testing and the mechanisms by which it may be affected by dapsone in particular. LEARNING POINTS: Various conditions and medications can result in falsely low HbA1c. Dapsone can lead to falsely low HbA1c by inducing haemolysis and by forming methaemoglobin. Capillary glucose measurement, urine glucose measurements and fructosamine levels should be used as alternatives to HbA1c for monitoring glycaemic control if it was falsely low or high.

A review of the propriety of thyroid ultrasound referrals and their follow-up burden.

PURPOSE: The overdiagnosis of thyroid nodules and indolent thyroid cancers represents an increasing burden on health services, with thyroid ultrasound (US) imaging often representing the initial entry point into the thyroid nodule diagnostic pathway. The aim of this study was to retrospectively review thyroid US referrals to a single Irish hospital to determine if the stated indications for imaging had been appropriate, to review the results of the scans, and to assess the follow-up required in each case. METHODS: Patient demographics, scan indications, results, and outcomes were retrospectively reviewed for all patients undergoing thyroid ultrasound from 2012 to 2016. Data were analyzed using GraphPad Prism and expressed in mean ± standard deviation. RESULTS: In total, 318 patients (mean age 53 ± 15 years, 85% female) had at least one ultrasound. Most US scans were performed for appropriate indications in order to follow up known thyroid nodular disease and/or malignancy (34.3%), to assess new thyroid goiters or discrete neck lumps (33.3%), and to follow up incidental findings from other imaging modalities (12.6%). However, scans were also requested (in the absence of any palpable goiter or mass) for choking/neck pain/swallowing complaints (12.3%), hypo/hyperthyroidism (6.6%), and miscellaneous reasons (0.6%) that were deemed either potentially or likely inappropriate. Of these scans, approximately half of the identified nodule(s) were deemed unlikely to be related to the stated symptoms, but which subsequently required follow-up imaging ± biopsy. No cases of malignancy were identified. CONCLUSIONS: In our center, a significant percentage of thyroid US scans along with their subsequent follow-up were potentially avoidable.

A case of pembrolizumab-induced severe DKA and hypothyroidism in a patient with metastatic melanoma.

Immune checkpoint inhibitors (ICIs) have revolutionised cancer therapy and improved outcomes for patients with advanced disease. Pembrolizumab, a monoclonal antibody that acts as a programmed cell death 1 (PD-1(PDCD1)) inhibitor, has been approved for the treatment of advanced melanoma and other solid tumours. Immune-related adverse events (irAEs) including endocrinopathies have been well described with this and other PD-1 inhibitors. While hypothyroidism and hyperthyroidism, and less commonly hypophysitis, are the most common endocrinopathies occurring in patients treated with pembrolizumab, the incidence of type 1 diabetes mellitus (T1DM) was low in clinical trials. We report a case of pembrolizumab-induced primary hypothyroidism and T1DM presenting with severe diabetic ketoacidosis (DKA). A 52-year-old male patient was treated with pembrolizumab for metastatic melanoma. He presented to the emergency department with a 1-day history of nausea and vomiting 2 weeks after his seventh dose of pembrolizumab, having complained of polyuria and polydipsia for 2 months before presentation. He had been diagnosed with thyroid peroxidase (TPO) antibody-negative hypothyroidism, requiring thyroxine replacement, shortly after his fifth dose. Testing revealed a severe DKA (pH: 6.99, glucose: 38.6 mmol/L, capillary ketones: 4.9 and anion gap: 34.7). He was treated in the intensive care unit as per the institutional protocol, and subsequently transitioned to subcutaneous basal-bolus insulin. After his diabetes and thyroid stabilised, pembrolizumab was recommenced to treat his advanced melanoma given his excellent response. This case highlights the importance of blood glucose monitoring as an integral part of cancer treatment protocols composed of pembrolizumab and other ICIs. Learning points: The incidence of T1DM with pembrolizumab treatment is being increasingly recognised and reported, and DKA is a common initial presentation. Physicians should counsel patients about this potential irAE and educate them about the symptoms of hyperglycaemia and DKA. The ESMO guidelines recommend regular monitoring of blood glucose in patients treated with ICIs, a recommendation needs to be incorporated into cancer treatment protocols for pembrolizumab and other ICIs in order to detect hyperglycaemia early and prevent DKA.

A case of diencephalic syndrome presenting with isolated lipodystrophy.

Diencephalic syndrome is a disorder characterized by severe emaciation during childhood. The rarity of the disorder coupled with nonspecific symptomology means that there is often a protracted diagnostic journey. Here, we report a child who was referred to a clinical genetics service for investigation of lipodystrophy and failure to thrive. A broad range of genetic differential diagnoses were considered and investigated before a mass lesion was identified in the hypothalamus, confirming diencephalic syndrome. In the context of this case, we consider the relevant differentials and appropriate workup of a child with lipodystrophy presenting to a genetics service. This report also highlights the importance of considering diencephalic syndrome in cases such as this.

Marked hyperandrogenicity in a 60-year-old woman.

Markedly elevated androgen levels can lead to clinical virilization in females. Clinical features of virilization in a female patient, in association with biochemical hyperandrogenism, should prompt a search for an androgen-producing tumor, especially of ovarian or adrenal origin. We herein report the case of a 60-year-old woman of Pakistani origin who presented with the incidental finding of male pattern baldness and hirsutism. Her serum testosterone level was markedly elevated at 21 nmol/L (normal range: 0.4-1.7 nmol/L), while her DHEAS level was normal, indicating a likely ovarian source of her elevated testosterone. Subsequently, a CT abdomen-pelvis was performed, which revealed a bulky right ovary, confirmed on MRI of the pelvis as an enlarged right ovary, measuring 2.9 × 2.2 cm transaxially. A laparoscopic bilateral salpingo-oophorectomy was performed, and histopathological examination and immunohistochemistry confirmed the diagnosis of a Leydig cell tumor, a rare tumor accounting for 0.1% of ovarian tumors. Surgical resection led to normalization of testosterone levels. LEARNING POINTS: Hirsutism in postmenopausal women should trigger suspicion of androgen-secreting tumorExtremely elevated testosterone level plus normal DHEAS level point toward ovarian sourceLeydig cell tumor is extremely rare cause of hyperandrogenicity.

The effect of growth hormone replacement on the thyroid axis in patients with hypopituitarism: in vivo and ex vivo studies.

OBJECTIVE: Alterations in the hypothalamic-pituitary-thyroid axis have been reported following growth hormone (GH) replacement. The aim was to examine the relationship between changes in serum concentration of thyroid hormones and deiodinase activity in subcutaneous adipose tissue, before and after GH replacement. DESIGN: A prospective, observational study of patients receiving GH replacement as part of routine clinical care. PATIENTS: Twenty adult hypopituitary men. MEASUREMENTS: Serum TSH, thyroid hormones - free and total thyroxine (T4) and triiodothyronine (T3) and reverse T3, thyroglobulin and thyroid-binding globulin (TBG) levels were measured before and after GH substitution. Changes in serum hormone levels were compared to the activity of deiodinase isoenzymes (DIO1, DIO2 and DIO3) in subcutaneous adipose tissue. RESULTS: The mean daily dose of growth hormone (GH) was 0·34 ± 0·11 mg (range 0·15-0·5 mg). Following GH replacement, mean free T4 levels declined (-1·09 ± 1·99 pmol/l, P = 0·02). Reverse T3 levels also fell (-3·44 ± 1·42 ng/dl, P = 0·03) and free T3 levels increased significantly (+0·34 ± 0·15 pmol/l, P = 0·03). In subcutaneous fat, DIO2 enzyme activity declined; DIO1 and DIO3 activities remained unchanged following GH substitution. Serum TSH, thyroglobulin and TBG levels were unaltered by GH therapy. CONCLUSIONS: In vitro analysis of subcutaneous adipose tissue from hypopituitary human subjects demonstrates that GH replacement is associated with significant changes in deiodinase isoenzyme activity. However, the observed variation in enzyme activity does not explain the changes in the circulating concentration of thyroid hormones induced by GH replacement. It is possible that deiodinase isoenzymes are differentially regulated by GH in other tissues including liver and muscle.

The importance of night-time systolic blood pressure in diabetic patients: Dublin Outcome Study.

OBJECTIVE: Diabetic patients exhibit a higher cardiovascular risk compared to people without diabetes. The use of ambulatory blood pressure monitoring (ABPM) is gaining popularity in this population. Night-time SBP has consistently been shown to be a potent predictor of cardiovascular risk in the normal population. We studied the predictive value of night-time ABPM in a cohort of diabetic patients. RESEARCH DESIGN AND METHODS: At baseline, when not on antihypertensive medication, 11 291 patients (5326 men, mean age 54.6 years) underwent ABPM. Using a computerized national registry of death, mortality outcome was ascertained. Among 859 diabetic patients with a mean follow-up of 5.3 years, there were 74 deaths. RESULTS: Compared to people without diabetes, those with diabetes had daytime and night-time SBP of 146.4 vs. 145.1 (P = NS) and 131.2 vs. 126.4  mmHg (P < 0.0001), respectively. As a consequence, more diabetic patients had a non-dipping night-time SBP profile (47.4 vs. 35.5%; P =  < 0.0001). In a Cox proportional-hazards model, night-time SBP was an independent predictor of cardiovascular mortality in diabetic patients after adjustment for sex, age, smoking history, previous cardiovascular events, BMI and daytime SBP. The resultant hazard ratio for a 10-mmHg increase in night-time SBP for total cardiovascular, stroke and cardiac mortality was 1.32 (1.12-1.69), 1.95 (1.18-3.20) and 1.24 (0.99-1.56), respectively. CONCLUSION: Night-time SBP is a significant predictor of cardiovascular mortality in patients with diabetes.

Endothelial progenitor cells and cardiovascular disease.

Endothelial Progenitor Cells (EPCs) are bone-marrow derived stem cells that are postulated to contribute to post-natal vasculogenesis and to repair of damaged endothelium by incorporation into the vessel wall, secretion of paracrine hormones and stimulation of angiogenesis. Since the first description of the putative EPCs in 1997, and the role of these cells in neovascularisation of mouse and rabbit ischaemic limbs was originally described, there has been an explosion of research into the role of EPCs in human cardiovascular disease. There is now a large body of direct and indirect evidence to support an important role for EPCs in cardiovascular disease processes. This book chapter explores the following: 1. Correlation between EPCs and other cardiovascular risk markers 2. EPCs in patients with established cardiovascular disease 3. Reversible defects in EPC number and function in patients with an increased cardiovascular risk 4. Statins and EPC biology 5. The effect on EPCs of other interventions known to reduce cardiovascular risk - EPCs and treatment of diabetes, hypertension, subclinical hypothyroidism 6. Beneficial effects of EPC-based therapies animal models of ischaemia 7. Human Studies of EPC-based therapies A lower level of circulating EPCs and reduced EPC function in vitro are associated with an increased cardiovascular risk. The accumulated evidence suggests that a balance between the damaging effects of conventional cardiovascular risk factors and the ability of circulating EPCs to affect endothelial repair determines this cardiovascular risk.

Endothelial progenitor cells in mothers of low-birthweight infants: a link between defective placental vascularization and increased cardiovascular risk?

CONTEXT: Offspring birthweight is inversely associated with future maternal cardiovascular mortality, a relationship that has yet to be fully elucidated. Endothelial progenitor cells (EPCs) are thought to play a key role in vasculogenesis, and EPC numbers reflect cardiovascular risk. OBJECTIVE: Our objective was to ascertain whether EPC number or function was reduced in mothers of low-birthweight infants. DESIGN AND SETTING: This was a prospective cohort study in a general antenatal department of a university maternity hospital. PARTICIPANTS: Twenty-three mothers of small for gestational age (SGA) infants (birthweight < 10th centile) and 23 mothers of appropriate for gestational age (AGA) infants (birthweight ≥ 10th centile) were recruited. MAIN OUTCOME MEASURES: Maternal EPC number and function, conventional cardiovascular risk markers, and cord blood adiponectin were measured. RESULTS: Median EPC count was lower (294 vs. 367, P = 0.005) and EPC migration was reduced (0.91 vs. 1.59, P < 0.001) in SGA compared with AGA infants, with no difference in EPC adhesion (0.221 vs. 0.284 fluorescence units, P = 0.257). Maternal triglyceride levels were higher in SGA than AGA infants (0.98 vs. 0.78 mmol/liter, P = 0.006), but there was no difference in cholesterol, glucose, insulin, glycosylated hemoglobin, adiponectin, or blood pressure. There was a moderate monotone (increasing) relationship between birthweight and umbilical cord blood adiponectin (r = 0.475, P = 0.005). CONCLUSION: Giving birth to an SGA infant was associated with lower maternal EPC number and reduced migratory function. Cord blood adiponectin was significantly correlated with birthweight.