Occult metastatic thyroid cancer diagnosed during breast cancer axillary sentinel node biopsy.

SUMMARY: In most developed countries, breast carcinoma is the most common malignancy in women and while thyroid cancer is less common, its incidence is almost three to five times greater in women than in men. Since 1966, studies have demonstrated an association between thyroid and breast cancer and despite these studies, the mechanism/s by which they are related, remains unclear. We present a case of a 56-year-old lady who initially presented in 2014 with a screen detected left breast carcinoma but was subsequently found to have occult metastatic thyroid cancer to the axilla, diagnosed from a sentinel node biopsy from the primary breast procedure. The patient underwent a left mastectomy, left axillary dissection and total thyroidectomy followed by three courses of radioactive iodine ablation. Despite this, her thyroglobulin level continued to increase, which was secondary to a metastatic thyroid cancer parasternal metastasis. Breast and thyroid cancer presents metachronously or synchronously more often than by chance. With improving mortality in primary cancers, such as breast and differentiated thyroid cancer, it is likely that as clinicians, we will continue to encounter this association in practice. LEARNING POINTS: There has been a long-standing observation of an association between breast and thyroid cancer although the exact mechanism of this association remains unclear. Our patient presented with thyroid cancer with an incidental diagnosis from a sentinel node biopsy during her primary breast operation for breast cancer and was also found to have a parasternal distant bony metastasis. Thyroid axillary metastases are generally rare. The interesting nature in which this patient's metastatic thyroid carcinoma behaved more like a breast carcinoma highlights a correlation between these two cancers. With improving mortality in these primary cancers, clinicians are likely to encounter this association in clinical practice. Systemic therapy for metastatic breast and thyroid cancers differ and therefore a clear diagnosis of metastasis is crucial.

A novel CASR mutation (p.Glu757Lys) causing autosomal dominant hypocalcaemia type 1

Autosomal dominant hypocalcaemia type 1 (ADH1) is a rare familial disorder characterised by low serum calcium and low or inappropriately normal serum PTH. It is caused by activating CASR mutations, which produces a left-shift in the set point for extracellular calcium. We describe an Australian family with a novel heterozygous missense mutation in CASR causing ADH1. Mild neuromuscular symptoms (paraesthesia, carpopedal spasm) were present in most affected individuals and required treatment with calcium and calcitriol. Basal ganglia calcification was present in three out of four affected family members. This case highlights the importance of correctly identifying genetic causes of hypocalcaemia to allow for proper management and screening of family members. Learning points: •• ADH1 is a rare cause of hypoparathyroidism due to activating CASR mutations and is the mirror image of familial hypocalciuric hypercalcaemia. •• In patients with ADH1, symptoms of hypocalcaemia may be mild or absent. Basal ganglia calcification may be present in over a third of patients. •• CASR mutation analysis is required for diagnostic confirmation and to facilitate proper management, screening and genetic counselling of affected family members. •• Treatment with calcium and activated vitamin D analogues should be reserved for symptomatic individuals due to the risk of exacerbating hypercalciuria and its associated complications.

ABCB1 and ABCC1 single-nucleotide polymorphisms in patients treated with clozapine.

Clozapine (CZ) has superior efficacy to other antipsychotic agents in the treatment of schizophrenia and has been extensively used in clinical practice. ATP-binding cassette (ABC) transporter proteins are responsible for the distribution of various molecules as well as drugs across extracellular and intracellular membranes, including the blood-brain barrier. Genetic variations in these proteins can account for differences in treatment response. We investigated the influence of ABCB1 rs1045642 and ABCC1 rs212090 single-nucleotide polymorphisms (SNPs) on CZ serum level, clinical outcome, and changes in body mass index (BMI) in the first year of CZ treatment. These polymorphisms influenced baseline BMI in males (p=0.009 and 0.054, B1 and C1, respectively), changes in BMI in males after 3 (p=0.026, ABCB1) and 12 months (p=0.022, ABCC1) of CZ treatment, and level of diastolic pressure (p=0.002 and 0.051, respectively). The combination of ABCB1 + ABCC1 homozygote SNPs was associated with increased CZ and norclozapine serum levels (p=0.054 and 0.010, respectively). ABC transporter SNPs could be potential biomarkers for CZ-induced weight gain and cardiovascular complications. Further pharmacogenetic research is warranted to help clinicians with their treatment decision, including concomitant use of drugs and prevention of side effects.

CYP2C19*17 protects against metabolic complications of clozapine treatment.

OBJECTIVES: Clozapine (CZ) is the most effective drug for managing treatment-resistant schizophrenic disorders. Its use has been limited due to adverse effects, which include weight gain and new-onset diabetes, but the incidence of these varies between patients. METHODS: We investigated 187 Clozapine Clinic patients (of whom 137 consented for genotyping) for the presence of CYP2C19*17 and its association with CZ and norclozapine (NCZ) levels, and clinical outcomes. RESULTS: Thirty-nine percent of genotyped patients were carriers of the CYP2C 19*17 polymorphism. This group demonstrated significantly higher NCZ serum levels, and significantly lower fasting glucose (5.66 ± 1.19 vs 6.72 ± 3.01 mmol/l, P = 0.009) and Hb1Ac (35.36 ± 4.78 vs 49.40 ± 20.60 mmol/mol, P = 0.006) levels compared to non-carriers of this polymorphism. CZ-treated patients with CYP2C19*17/*17 had a significantly lower prevalence of diabetes as well as a higher likelihood of clinical improvement of their schizophrenia, compared to those without this polymorphism (P = 0.012 and P = 0.031, respectively). CONCLUSIONS: Our data suggest that CYP2C19*17 ultra-rapid-metaboliser status is a protective factor against the development of diabetes during clozapine treatment, and increases the likelihood of improvement in schizophrenia. The role of NCZ in treatment response and side effects, including metabolic syndrome, warrants further pharmacogenetic, pharmacokinetic and pharmacodynamic studies.

Coordinated care versus standard care in hospital admissions of people with chronic illness: a randomised controlled trial.

OBJECTIVE: To determine whether Care Navigation (CN), a nurse-led hospital-based coordinated care intervention, reduced the use of hospital services and improved quality of life for patients with chronic illness. DESIGN: Randomised controlled trial; participants were allocated to CN or standard care. PARTICIPANTS AND SETTING: Patients with chronic illness presenting to the emergency department of Nepean Hospital, Sydney, New South Wales. High-risk status for an unplanned admission was defined as i) three or more unplanned hospital admissions in 12 months for patients aged ≥ 70 or at least one admission for cardiac or respiratory disease in patients aged 16-69 years; or ii) judged by a CN nurse to be high risk and likely to benefit. MAIN OUTCOME MEASURES: Numbers of re-presentations or readmissions, quality of life, time to re-presentation, readmission or death, length of stay, and access to hospital and community health services. RESULTS: 500 participants were randomised between May 2010 and February 2011; 359 by previous unplanned admission and 141 by clinical impression. The CN group received more community health services (rate ratio, 1.94; 95% CI, 1.35-2.81; P < 0.001) than participants receiving standard care; however, this did not result in statistically significant differences in number of re-presentations (rate ratio, 0.83; 95% CI, 0.68-1.01; P = 0.07), number of readmissions (rate ratio, 0.85; 95% CI, 0.70-1.04; P = 0.11), quality of life at 24 months (mean difference, 0; 95% CI, - 0.10 to 0.09, P = 0.93), or other measures. CONCLUSIONS: CN did not improve quality of life or reduce unplanned hospital presentations or admissions despite community health services almost doubling. Future service development should explore potential benefits of linking navigated intrahospital care to ongoing, proactive care planning and delivery in the community. TRIAL REGISTRATION: ACTRN12609000554268.

Demographic and clinical predictors of unplanned hospital utilisation among chronically ill patients: a prospective cohort study.

BACKGROUND: In urban Australia, patients with serious and continuing illnesses make frequent use of hospital emergency department (ED) services. However, the risk factors for hospital utilisation among the broad population of people with chronic illness are not well known. The aim of this study was to assess the predictors of hospital utilisation (either inpatient admissions or ED visits) in a cohort of 308 patients with chronic illness. METHODS: We studied patients with serious and continuing chronic illnesses presenting to an ED in a large periurban hospital in western Sydney, Australia, between 2010 and 2013. ED presentations and hospital admissions were observed over two years. Multivariate negative-binomial regression analyses were used to identify risk factors for the number of presentations to hospital. RESULTS: The main risk factors for hospital utilisation were having a live-in carer, and a history of hospital utilisation. Having a live-in carer was associated with an increase in number of ED presentations by 88% (RR 1.88; 95% CI 1.41-2.51), and of admissions by 116% (RR 2.16; 95% CI 1.61-2.92). Seventy-seven percent of hospital utilisation in the cohort was attributable to carer status. Each additional ED presentation that a person had in the 12 months prior to the study led to an increased risk of an ED presentation in the follow-up period by 6% (RR = 1.06, 95% CI = 1.03-1.08). Between 20% and 25% of variability in hospital utilisation in the cohort was attributable to the number of hospital admissions or ED presentations in the previous 12 months. CONCLUSIONS: Patients with a live-in carer and with a history of hospital utilisation are at high risk for future hospital use.

Implementation and effectiveness of 'care navigation', coordinated management for people with complex chronic illness: rationale and methods of a randomised controlled trial.

BACKGROUND: Chronic illness is a significant driver of the global burden of disease and associated health care costs. People living with severe chronic illness are heavy users of acute hospital services; better coordination of their care could potentially improve health outcomes while reducing hospital use. The Care Navigation trial will evaluate an in-hospital coordinated care intervention on health service use and quality of life in chronically ill patients. METHODS/DESIGN: A randomised controlled trial in 500 chronically ill patients presenting to the emergency department of a hospital in Western Sydney, Australia. Participants have three or more hospital admissions within a previous 12 month period and either aged ≥70 years; or aged ≥45 years and of Aboriginal or Torres Strait Islander descent; or aged ≥ 16 with a diagnosis of a respiratory or cardiology related illness. Patients are randomised to either the coordinated care program (Care Navigation), or to usual care. The Care Navigation program consists of dedicated nurses who conduct patient risk assessments, oversee patient nursing while in hospital, and guide development of a care plan for the management of chronic illness after being discharged from hospital. These nurses also book community appointments and liaise with general practitioners. The main outcome variables are the number of emergency department re-presentations and hospital readmissions, and quality of life during a 24 month follow-up. Secondary outcomes are length of hospital stay, mortality, time to first hospital re-admission, time to first emergency department re-presentation, patient satisfaction, adherence to prescribed medications, amount and type of in-hospital referrals made for consultations and diagnostic testing, and the number and type of community health referrals. A process evaluation and economic analysis will be conducted alongside the randomised trial. DISCUSSION: A trial of in-hospital care coordination may support recent evidence that engaging primary health services in care plans linked to multidisciplinary team support improves patient outcomes and reduces costs to the health system. This will inform local, national and international health policy. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12609000554268.

Seasonal reduction in vitamin D level persists into spring in NSW Australia: implications for monitoring and replacement therapy.

CONTEXT: Seasonal variation in 25-hydroxyvitamin D [25OHD] status and its relationship to gender, age, socioeconomic and geographic determinants in Australians has not been described in large biomedical sampling cohorts. OBJECTIVES: To analyse 25OHD levels in all primary tests undertaken consecutively in a 2-year period to determine the prevalence of 25OHD deficiency and its relation to patient setting, gender, age, season, urban or rural residency, socioeconomic status, latitude and longitude. DESIGN: We assessed 24 819 ambulatory and inpatient samples taken from the largest reference laboratory in NSW, Australia between 01 July 2008 and 30 July 2010. MAIN OUTCOME MEASURES: Serum 25OHD was measured using chemiluminescent immunoassay. Vitamin D deficiency was defined as 25OHD <50 nm. RESULTS: Median 25OHD was 54 nm ranging from 63 nm in summer to 44 nm in spring and was lowest in inpatient women (49 nm) and highest in ambulatory men (64 nm). Mean 25OHD peaked in January (67 nm) and reached a nadir in August/September (39 nm). During summer, 36% subjects overall had a level below 50 nm, increasing to 58% in spring. The highest prevalence of deficiency occurred in female inpatients (42% in summer and 62% in spring). Factors associated with lower 25OHD included being tested in spring, an inpatient, female, aged 20-39 or >79 years, socioeconomically disadvantaged and from a major city. CONCLUSION: This cross-sectional study demonstrates the extent and duration of 25OHD deficiency is greater than expected, and particular individuals are at higher risk. Our findings imply that supplementation guidelines need to be modified and strengthened.

Postsurgical pathology reporting of thyroid cancer in New South Wales, Australia.

BACKGROUND: Clear, accurate, and complete reporting of postsurgical pathology is crucial for the correct evaluation and management of thyroid cancer patients. This study aimed to describe the completeness, as defined by international guidelines, of pathology reporting in a cohort of newly diagnosed thyroid cancer patients in New South Wales (NSW) and to identify factors associated with the completeness of reports. METHODS: Postsurgical pathology reports, held by the NSW Central Cancer Registry, for 448 thyroid cancer patients were reviewed. Presence or absence of recommended key features (tumor histology type, maximum dimension, focality, completeness of excision, extrathyroidal extension, lymphovascular invasion, and lymph node involvement) was recorded. Associations between the number of key items reported and several patient characteristics were investigated. RESULTS: For 285 (63.6%) patients one or more key pathological features were missing, with 177 (39.5%) missing one only, 88 (19.6%) missing two, and 20 (4.5%) missing three or more. Extrathyroidal extension was the most poorly reported key feature, being present in only 228 (50.9%) reports [95% confidence interval 46.2, 55.6]. Pathology reports were less complete for patients with small tumor size (p<0.001) or localized spread (p<0.001). Synoptic reports were significantly more complete than narrative-style reports (98.3% vs. 27.1%, p<0.001). CONCLUSIONS: Postsurgical pathology reporting of differentiated thyroid cancer in NSW was found to be far from complete, with 64% of reports missing information on at least one feature that is considered internationally to be a critical factor in the prognosis and treatment of thyroid cancer patients. Synoptic reporting reduces the number of key features missing from pathology reports.

Pathways to the diagnosis of thyroid cancer in New South Wales: a population-based cross-sectional study.

BACKGROUND: Over the past few decades, an increase in the incidence of thyroid cancer has been recorded in many countries around the world including Australia. Heightened medical surveillance and increased technological sensitivity could be contributing to greater detection of asymptomatic disease. OBJECTIVES: To describe the pathways to diagnosis of thyroid cancer for a cohort of newly diagnosed patients in New South Wales (NSW), Australia, and compare these pathways by age, sex, place of residence, ethnic background, medical insurance status, and disease characteristics. METHODS: A total of 452 newly diagnosed cases of thyroid cancer were recruited through the population-based NSW Central Cancer Registry. Participants completed a questionnaire and diary of doctor visits and investigations that led to their diagnosis. Tumor characteristics were obtained from pathology reports. RESULTS: Forty percent of patients initially presented to their doctor with a lump or symptom specific to thyroid cancer and 60% had their cancer detected incidentally during a medical encounter. Men were more likely than women to be diagnosed after imaging for another health concern versus reporting a thyroid lump or symptom (p = 0.001). Thyroid cancer diagnosis after imaging for another health concern increased with age (p = 0.023), and larger tumors were less likely to be diagnosed after treatment for a benign thyroid disease (p = 0.040). CONCLUSION: As the majority of participants had incidental diagnoses, the reported incidence of thyroid cancer is likely to be influenced by diagnostic technology and medical surveillance practices. This, however, probably only partly explains the observed rise in the incidence of thyroid cancer in NSW.

Warfarin toxicity and individual variability-clinical case.

Warfarin is a widely used anticoagulant in the treatment and prevention of thrombosis, in the treatment for chronic atrial fibrillation, mechanical valves, pulmonary embolism, and dilated cardiomyopathy. It is tasteless and colorless, was used as a poison, and is still marketed as a pesticide against rats and mice. Several long-acting warfarin derivatives-superwarfarin anticoagulants-such as brodifacoum, diphenadione, chlorophacinone, bromadiolone, are used as pesticides and can produce profound and prolonged anticoagulation. Several factors increase the risk of warfarin toxicity. However, polymorphisms in cytochrome P450 genes and drug interactions account for most of the risk for toxicity complications. Each person is unique in their degree of susceptibility to toxic agents. The toxicity interpretation and the health risk of most toxic substances are a subject of uncertainty. Genetically determined low metabolic capacity in an individual can dramatically alter the toxin and metabolite levels from those normally expected, which is crucial for drugs with a narrow therapeutic index, like warfarin. Personalized approaches in interpretation have the potential to remove some of the scientific uncertainties in toxicity cases.

Effect of prehospital triage on revascularization times, left ventricular function, and survival in patients with ST-elevation myocardial infarction.

Shorter reperfusion times lead to better outcomes in patients with ST-elevation myocardial infarction (STEMI). We assessed the efficacy of prehospital triage with bypass of community hospitals and early activation of the cardiac catheterization team on revascularization times, left ventricular (LV) ejection fraction, and survival. Patients with STEMI (624) were divided into 3 groups determined by site of triage: ambulance field triage (163), interventional center emergency department (202), and 3 community hospital emergency departments (259). Compared with community hospital and interventional center triages, ambulance field triage resulted in a significant median decrease in door-to-balloon times of 68 and 27 minutes, respectively (p <0.001). LV ejection fraction was highest in the field triage group (52 +/- 13%) compared with the interventional center (49 +/- 12%) and community hospital (48 +/- 12%, p = 0.017) groups. Thirty-day mortality was lowest in the ambulance field group (3%) compared with the interventional facility (11%) and community hospital (4%, p = 0.007) groups. There was a significant difference in long-term survival with up to 30-month follow-up among the 3 triage groups (p = 0.041). With time-dependent Cox regression modeling the difference in survival was significant only during the first week after STEMI (p = 0.020). Every extra minute of symptom onset to reperfusion time was associated with a relative risk of long-term mortality of 1.003 (95% confidence interval 1.000 to 1.006, p = 0.027). In conclusion, field triage of patient with STEMI decreased revascularization times, which preserved LV function, and improved early survival.

Implementing and sustaining transformational change in health care: lessons learnt about clinical process redesign.

*Clinical process redesign has enabled significant improvements in the delivery of health care services in emergency departments and elective surgery programs in New South Wales and at Flinders Medical Centre in South Australia, with tangible benefits for patients and staff. *The principles used in clinical process redesign are not new; they have been applied in other industries with significant gains for many years, but have only recently been introduced into health care systems. *Through experience with clinical process redesign, we have learnt much about the factors critical to the success of implementing and sustaining this process in the health care setting. *The key elements for success are leadership by senior executives, clinical leadership, team-based problem solving, a focus on the patient journey, access to data, ambitious targets, strong performance management, and a process for maintaining improvement.

Iodine status in pregnant women and their newborns: are our babies at risk of iodine deficiency?

OBJECTIVES: To determine whether pregnant women and their newborns show evidence of iodine deficiency, and to examine the correlation between maternal urine iodine concentration (UIC) and newborn thyroid-stimulating hormone (TSH) level. DESIGN: A cross-sectional study. SETTING: Hospital antenatal care services (March-May 2004) and private obstetrician clinics (June 2004) in the Central Coast area of New South Wales. PARTICIPANTS: 815 pregnant women (> or = 28 weeks' gestation) and 824 newborns. MAIN OUTCOME MEASURES: World Health Organization/International Council for the Control of Iodine Deficiency Disorders criteria for assessing severity of iodine deficiency (recommended levels: < 20% of urine samples in a population with UIC < 50 microg/L; and < 3% of newborns with whole-blood TSH level > 5 mIU/L). RESULTS: The median UIC for pregnant women was 85 microg/L, indicating mild iodine deficiency. Almost 17% of pregnant women had a UIC < 50 microg/L, and 18 newborns (2.2%) had TSH values > 5 mIU/L. There was no statistically significant linear correlation between neonatal whole-blood TSH level and maternal UIC (r = - 0.03; P = 0.4). Mothers with a UIC < 50 microg/L were 2.6 times (relative risk = 2.65; 95% CI, 1.49-4.73; P = 0.01) more likely to have a baby with a TSH level > 5 mIU/L. CONCLUSION: The pregnant women surveyed were mildly iodine deficient. TSH values for their newborns were mostly within acceptable limits. Ongoing surveillance of the iodine status of NSW communities to establish trends over time is recommended.