Screening for anaplastic lymphoma kinase (ALK) gene rearrangements in non-small-cell lung cancer in New Zealand.

BACKGROUND: Lung cancer is a major cause of death in New Zealand. In recent years, targeted therapies have improved outcomes. AIM: To determine the uptake of anaplastic lymphoma kinase (ALK) testing, and the prevalence, demographic profile and outcomes of ALK-positive non-small-cell lung cancer (NSCLC), in New Zealand, where no national ALK-testing guidelines or subsidised ALK tyrosine kinase inhibitor (TKI) therapies are available. METHODS: A population-based observational study reviewed databases to identify patients presenting with non-squamous NSCLC over 6.5 years in northern New Zealand. We report the proportion tested for ALK gene rearrangements and the results. NSCLC samples tested by fluorescence in situ hybridisation were retested by next generation sequencing and ALK immunohistochemistry. A survival analysis compared ALK-positive patients treated or not treated with ALK TKI therapy. RESULTS: From a total of 3130 patients diagnosed with non-squamous NSCLC, 407 (13%) were tested for ALK gene rearrangements, and patient selection was variable and inequitable. Among those tested, 34 (8.4%) had ALK-positive NSCLC. ALK-positive disease was more prevalent in younger versus older patients, non-smokers versus smokers and in Maori, Pacific or Asian ethnic groups than in New Zealand Europeans. Fluorescence in situ hybridisation, ALK immunohistochemistry and next generation sequencing showed broad concordance for detecting ALK-positive disease under local testing conditions. Among patients with ALK-positive metastatic NSCLC, those treated with ALK TKI survived markedly longer than those not treated with ALK TKI (median overall survival 5.12 vs 0.55 years). CONCLUSION: Lung cancer outcomes in New Zealand may be improved by providing national guidelines and funding policy for ALK testing and access to subsidised ALK TKI therapy.

Lung cancer mutation testing: a clinical retesting study of agreement between a real-time PCR and a mass spectrometry test.

To investigate the clinical validity and utility of tests for detecting Epidermal Growth Factor Receptor (EGFR) gene mutations in non-squamous non-small cell lung cancer patients, tumour DNA extracts from 532 patients previously tested by the cobas EGFR Mutation Test (RT-PCR test) were retested by the Sequenom/Agena Biosciences MassArray OncoFocus mass spectrometry test (MS test). Valid results from both tests were available from 470 patients (88%) for agreement analysis. Survival data were obtained for 513 patients (96%) and 77 patients (14%) were treated with EGFR tyrosine kinase inhibitors (TKIs). Agreement analysis revealed moderately high positive (79.8%), negative (96.9%) and overall percentage agreement (93.2%) for the detection of EGFR mutations. However, EGFR mutations were detected by one test and not by the other test in 32 patients (7%). Retesting of discordant samples revealed false-positive and false-negative results generated by both tests. Despite this, treatment and survival outcomes correlated with the results of the RT-PCR and MS tests. In conclusion, this study provides evidence of the clinical validity and utility of the RT-PCR and MS tests for detection of EGFR mutations that predict prognosis and benefit from EGFR-TKI treatment. However, their false-positive and false-negative test results may have important clinical consequences.

EGFR Mutation Testing of non-squamous NSCLC: Impact and Uptake during Implementation of Testing Guidelines in a Population-Based Registry Cohort from Northern New Zealand.

BACKGROUND: Since 2013, clinical practice guidelines recommend EGFR mutation testing of non-squamous NSCLC to select advanced-stage patients for first-line treatment using EGFR-TKIs. OBJECTIVE: We aimed to determine population-based trends in the real-world uptake and impact in routine practice of these recently updated testing guidelines. PATIENTS AND METHODS: A population-based observational study was conducted of notifications to the New Zealand Cancer Registry of patients eligible for EGFR testing diagnosed in northern New Zealand between January 2010 and April 2014. The main study variable was EGFR mutation testing. Main outcome measures (overall survival and dispensing of EGFR-TKIs) were extracted from prospectively archived electronic databases until October 2015. RESULTS: The population-based cohort of 1857 patients had an average age of 70 years. Most had adenocarcinoma and metastatic disease at diagnosis. EGFR testing was undertaken in 500 patients (27%) with mutations detected in 109 patients (22%). EGFR testing increased during the period of study from <5% to 67% of patients (P < 0.0001). Full uptake of testing by all eligible patients was limited by a lack of availability of specimens for testing and variable testing referral practices. The proportion of patients treated with EGFR-TKIs decreased during the same time period, both among untested patients (from 12.2% to 2.8% (P < 0.0001)) and in the population as a whole (from 13.7% to 10.6% (P < 0.05)). EGFR testing was associated with prolonged overall survival (Adjusted HR = 0.76 (95% CI, 0.65-0.89) Log-rank P < 0.0001) due at least in part to the much longer overall survival achieved by mutation-positive patients, of whom 79% received EGFR-TKIs. Compared to untested EGFR-TKI-treated patients, mutation-positive EGFR-TKI-treated patients received EGFR-TKIs for longer, and survived longer both from the start of EGFR-TKI treatment and date of their diagnosis. CONCLUSIONS: In this real world setting, high uptake of EGFR testing was achieved and associated with major changes in EGFR-TKI prescribing and improved health outcomes. Modifiable factors determined testing uptake. Study registration ACTRN12615000998549.

Cardiomyopathy as presenting sign of glycogenin-1 deficiency-report of three cases and review of the literature.

We describe a new type of cardiomyopathy caused by a mutation in the glycogenin-1 gene (GYG1). Three unrelated male patients aged 34 to 52 years with cardiomyopathy and abnormal glycogen storage on endomyocardial biopsy were homozygous for the missense mutation p.Asp102His in GYG1. The mutated glycogenin-1 protein was expressed in cardiac tissue but had lost its ability to autoglucosylate as demonstrated by an in vitro assay and western blot analysis. It was therefore unable to form the primer for normal glycogen synthesis. Two of the patients showed similar patterns of heart dilatation, reduced ejection fraction and extensive late gadolinium enhancement on cardiac magnetic resonance imaging. These two patients were severely affected, necessitating cardiac transplantation. The cardiomyocyte storage material was characterized by large inclusions of periodic acid and Schiff positive material that was partly resistant to alpha-amylase treatment consistent with polyglucosan. The storage material had, unlike normal glycogen, a partly fibrillar structure by electron microscopy. None of the patients showed signs or symptoms of muscle weakness but a skeletal muscle biopsy in one case revealed muscle fibres with abnormal glycogen storage. Glycogenin-1 deficiency is known as a rare cause of skeletal muscle glycogen storage disease, usually without cardiomyopathy. We demonstrate that it may also be the cause of severe cardiomyopathy and cardiac failure without skeletal muscle weakness. GYG1 should be included in cardiomyopathy gene panels.

Assessing the amount of unscheduled screening ("contamination") in the control arm of the UK "Age" Trial.

UNLABELLED: The UK Age Trial of mammographic screening from age 40 has reported a nonsignificant 17% reduction in breast cancer mortality calculated on an "intention to treat" basis. High levels of ad hoc screening in the control arm could potentially have diluted the estimated effect. OBJECTIVES: To estimate the level of unscheduled mammography in the control arm of the UK Age Trial. METHODS: Data were obtained from questionnaires sent to a random sample of 3,706 women at five centers in the control arm of this trial. Questions included in the Office for National Statistics Omnibus Surveys about the timing of and reasons for any breast screening provided comparable data. The overall response rate was 58.8%. RESULTS: Overall, 24.9% (95% confidence interval, 23.0-26.8) of Age Trial controls responding reported ever having had a mammogram, 18.2% reported a mammogram for symptomatic reasons, and 8.4% reported unscheduled mammography. Overall, 4.0% and 1.8% of women reported symptomatic and unscheduled mammography, respectively, within the previous 12 months. Results from the Omnibus surveys were similar, 14.2% of women reported previous mammography for symptomatic reasons or follow-up after breast cancer and 6.8% reported unscheduled mammography. CONCLUSIONS: The level of contamination due to mammographic screening in the control arm of the Age Trial was low and will have had a minimal effect on the estimated reduction in mortality from breast cancer. IMPACT: Estimating the extent of screening in the control arm in randomized trials of screening is important to inform interpretation of the results.

Pulmonary embolization by chorionic villi causing maternal death after a car crash.

Throughout the last century, there has been a marked decline in obstetric maternal deaths, resulting in an increase in the proportion of nonobstetric deaths among pregnant women. Trauma, in particular, has become a leading cause of maternal death. We report the case of a 20-year-old primigravid woman who was involved in a motor vehicle crash at 36 weeks gestation. The woman developed abruptio placentae, followed by disseminated intravascular coagulation, adult respiratory distress syndrome, and shock, and died the day after the crash. Widespread pulmonary embolization by chorionic villi was identified at autopsy. This report discusses traumatic maternal deaths, with emphasis on the differences in injury pattern observed in pregnant trauma victims in comparison with other adults. It is important that the pathologist be aware of these problems so that an accurate cause of death can be identified in cases of maternal death after trauma. Also discussed is the relationship between trauma and placental abruption and the mechanism of death in the patient. To the authors' knowledge, this is the first reported case of extensive embolism of chorionic villi to the lungs after trauma.

Cardiac sarcoidosis: an elusive diagnosis.

The diagnosis of sarcoidosis of the heart can be elusive, and is seldom established in life. We report the case of a 43-year-old man who underwent heart transplantation for presumed idiopathic dilated cardiomyopathy. Endomyocardial biopsy before transplantation showed only a mild infiltrate of lymphocytes. Histology of his explanted heart revealed extensive noncaseating granulomas and scarring, typical of sarcoidosis. A diagnosis of sarcoidosis had been made several years before by mediastinoscopic biopsy, after routine chest X-ray revealed mediastinal lymphadenopathy. Aside from the cardiac manifestations, the patient had no other symptoms of this disease. We discuss the inherent difficulties in the diagnosis of this rare but important condition, its varying presentations relating to the underlying pathology, as well as treatment options, including the role of transplantation.