Canadian anaplastic lymphoma kinase study: a model for multicenter standardization and optimization of ALK testing in lung cancer.

INTRODUCTION: Fluorescence in situ hybridization (FISH) is currently the standard for diagnosing anaplastic lymphoma kinase (ALK)-rearranged (ALK+) lung cancers for ALK inhibitor therapies. ALK immunohistochemistry (IHC) may serve as a screening and alternative diagnostic method. The Canadian ALK (CALK) study was initiated to implement a multicenter optimization and standardization of laboratory developed ALK IHC and FISH tests across 14 hospitals. METHODS: Twenty-eight lung adenocarcinomas with known ALK status were used as blinded study samples. Thirteen laboratories performed IHC using locally developed staining protocols for 5A4, ALK1, or D5F3 antibodies; results were assessed by H-score. Twelve centers conducted FISH using protocols based on Vysis' ALK break-apart FISH kit. Initial IHC results were used to optimize local IHC protocols, followed by a repeat IHC study to assess the results of standardization. Three laboratories conducted a prospective parallel IHC and FISH analysis on 411 consecutive clinical samples using post-validation optimized assays. RESULTS: Among study samples, FISH demonstrated 22 consensus ALK+ and six ALK wild type tumors. Preoptimization IHC scores from 12 centers with 5A4 and the percent abnormal cells by FISH from 12 centers showed intraclass correlation coefficients of 0.83 and 0.68, respectively. IHC optimization improved the intraclass correlation coefficients to 0.94. Factors affecting FISH scoring and outliers were identified. Post-optimization concurrent IHC/FISH testing in 373 informative cases revealed 100% sensitivity and specificity for IHC versus FISH. CONCLUSIONS: Multicenter standardization study may accelerate the implementation of ALK testing protocols across a country/region. Our data support the use of an appropriately validated IHC assay to screen for ALK+ lung cancers.

Clinically detectable copy number variations in a Canadian catchment population of schizophrenia.

Copy number variation (CNV) is a highly topical area of research in schizophrenia, but the clinical relevance is uncertain and the translation to clinical practice is under-studied. There is a paucity of research involving truly community-based samples of schizophrenia and widely available laboratory techniques. Our objective was to determine the prevalence of clinically detectable CNVs in a community sample of schizophrenia, while mimicking typical clinical practice conditions. We used a brief clinical screening protocol for developmental features in adults with schizophrenia for identifying individuals with 22q11.2 deletions and karyotypically detectable chromosomal anomalies in 204 consecutive patients with schizophrenia from a single Canadian catchment area. Twenty-seven (13.2%) subjects met clinical criteria for a possible syndrome, and 26 of these individuals received clinical genetic testing. Five of these, representing 2.5% of the total sample (95% CI: 0.3%-4.6%), including two of ten patients with mental retardation, had clinically detectable anomalies: two 22q11.2 deletions (1.0%), one 47, XYY, and two other novel CNVs--an 8p23.3-p23.1 deletion and a de novo 19p13.3-p13.2 duplication. The results support the utility of screening and genetic testing to identify genetic syndromes in adults with schizophrenia in clinical practice. Identifying large, rare CNVs (particularly 22q11.2 deletions) can lead to significant changes in management, follow-up, and genetic counselling that are helpful to the patient, family, and clinicians.

Postal survey of physicians and laboratories: practices and perceptions of molecular oncology testing.

BACKGROUND: Molecular oncology testing (MOT) to detect genomic alterations underlying cancer holds promise for improved cancer care. Yet knowledge limitations regarding the delivery of testing services may constrain the translation of scientific advancements into effective health care. METHODS: We conducted a cross-sectional, self-administered, postal survey of active cancer physicians in Ontario, Canada (N = 611) likely to order MOT, and cancer laboratories (N = 99) likely to refer (i.e., referring laboratories) or conduct (i.e., testing laboratories) MOT in 2006, to assess respondents' perceptions of the importance and accessibility of MOT and their preparedness to provide it. RESULTS: 54% of physicians, 63% of testing laboratories and 60% of referring laboratories responded. Most perceived MOT to be important for treatment, diagnosis or prognosis now, and in 5 years (61% - 100%). Yet only 45% of physicians, 59% of testing labs and 53% of referring labs agreed that patients in their region were receiving MOT that is indicated as a standard of care. Physicians and laboratories perceived various barriers to providing MOT, including, among 70% of physicians, a lack of clear guidelines regarding clinical indications, and among laboratories, a lack of funding (73% - 100%). Testing laboratories were confident of their ability to determine whether and which MOT was indicated (77% and 82% respectively), and perceived that key elements of formal and continuing education were helpful (75% - 100%). By contrast, minorities of physicians were confident of their ability to assess whether and which MOT was indicated (46% and 34% respectively), and while majorities considered various continuing educational resources helpful (68% - 75%), only minorities considered key elements of formal education helpful in preparing for MOT (17% - 43%). CONCLUSION: Physicians and laboratory professionals were enthusiastic about the value of MOT for cancer care but most did not believe patients were gaining adequate access to clinically necessary testing. Further, our results suggest that many were ill equipped as individual stakeholders, or as a coordinated system of referral and interpretation, to provide MOT. These challenges should inspire educational, training and other interventions to ensure that developments in molecular oncology can result in optimal cancer care.

A male phenotype with Aicardi syndrome.

Aicardi syndrome is a rare neurodevelopmental condition that occurs almost exclusively in women. We report a second male phenotype and 47,XXY karyotype with a typical presentation of the Aicardi syndrome including a midline arachnoid cyst.

Boy with 47,XXY,del(15)(q11.2q13) karyotype and Prader-Willi syndrome: a new case and review of the literature.

We report on a 10-year-old boy with a 47,XXY,del(15)(q11.2q13) karyotype and a Prader-Willi syndrome phenotype. His medical history and physical examination conformed to all of the major clinical criteria for Prader-Willi syndrome, but his height was taller than expected based on his hand and foot sizes. The deleted chromosome 15 was paternal in origin and molecular analysis showed maternal origin for the additional X chromosome. These findings suggest that the presence of these two disorders was coincidental in our patient. This supports the findings in the two other 47,XXY and Prader-Willi cases for which parent of origin studies have been published. Given the information from the literature and presented herein, we suggest that genetic counseling for cases of PWS and 47,XXY should address these two conditions separately.