Pathologist-initiated reflex testing for biomarkers in non-small-cell lung cancer: expert consensus on the rationale and considerations for implementation.

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

Consensus recommendations for optimizing biomarker testing to identify and treat advanced EGFR-mutated non-small-cell lung cancer.

The advent of personalized therapy for non-small-cell lung carcinoma (nsclc) has improved patient outcomes. Selection of appropriate targeted therapy for patients with nsclc now involves testing for multiple biomarkers, including EGFR. EGFR mutation status is required to optimally treat patients with nsclc, and thus timely and accurate biomarker testing is necessary. However, in Canada, there are currently no standardized processes or methods in place to ensure consistent testing implementation. That lack creates challenges in ensuring that all appropriate biomarkers are tested for each patient and that the medical oncologist receives the results for making informed treatment decisions in a timely way. An expert multidisciplinary working group was convened to create consensus recommendations about biomarker testing in advanced nsclc in Canada, with a primary focus on EGFR testing. Recognizing that there are biomarkers beyond EGFR that require timely identification, the expert multidisciplinary working group considered EGFR testing in the broader context of integration into complex lung biomarker testing. Primarily, the panel of experts recommends that all patients with nonsquamous nsclc, regardless of stage, should undergo comprehensive reflex biomarker testing at diagnosis with targeted next-generation sequencing. The panel also considered the EGFR testing algorithm and the challenges associated with the pre-analytic, analytic, and post-analytic elements of testing. Strategies for funding testing by reducing silos of single biomarker testing for EGFR and for optimally implementing the recommendations presented here and educating oncology professionals about them are also discussed.

Comprehensive genomic profiling for non-small-cell lung cancer: health and budget impact.

Background: Single-gene tests and hotspot panels targeting specific subsets of biomarkers constitute the Canadian genomic testing landscape for non-small-cell lung cancer (nsclc). However, newer testing options such as comprehensive genomic profiling (cgp) offer improved detection rates and identification of multiple classes of genomic alterations in a single assay, minimizing tissue requirements and turnaround time. The objective of the present analysis was to assess the health and budget impacts of adopting cgp testing for nsclc in Canada. Methods: This study assessed the impact of funding the cgp tests FoundationOne CDx and FoundationOne Liquid (Foundation Medicine, Cambridge, MA, U.S.A.) over a 3-year time horizon using a Canadian societal perspective for Ontario. Conventional testing strategies were summarized into two reference scenarios: a series of single-gene tests only, and reflex single-gene testing followed by a hotspot panel for negative results. Four adoption scenarios for cgp testing were considered: replacing all single-gene and hotspot panel testing, replacing hotspot panel testing only, use after negative single-gene and hotspot testing, and use of FoundationOne Liquid in individuals with insufficient tissue for conventional testing. Results: When cgp testing was assumed to replace all conventional testing with 50% uptake, the budget impact per person per year ranged from $0.71 to $0.87, depending on the reference scenario, with a 3-year gain of 680.9 life-years and 3831 working days over the full cohort. Conclusions: Given the present testing landscape for patients with nsclc in Canada, listing cgp testing could optimize the selection of appropriately targeted treatments, and thus add life-years and productivity for this population, with a minimal budget impact.

Management of EGFR-mutated non-small-cell lung cancer: practical implications from a clinical and pathology perspective.

Starting in the early 2000s, non-small-cell lung cancer (nsclc) subtypes have evolved from being histologically described to molecularly defined. Management of lung adenocarcinomas now generally requires multiple molecular tests at baseline to define the optimal treatment strategy. More recently, second biopsies performed at progression in patients treated with tyrosine kinase inhibitors (tkis) have further defined the continued use of molecularly targeted therapy. In the present article, we focus on one molecular subtype: EGFR-mutated nsclc. For that patient population, multiple lines of tki therapy are now available either clinically or in clinical trials. Each line of treatment is guided by the specific mutations (for example, L858R, T790M, C797S) identified in EGFR. We first describe the various mechanisms of acquired resistance to EGFR tki treatment. We then focus on strategies that clinicians and pathologists can both use during tissue acquisition and handling to optimize patient results. We also discuss future directions for the molecular characterization of lung cancers with driver mutations, including liquid biopsies. Finally, we provide an algorithm to guide treating physicians managing patients with EGFR-mutated nsclc. The same framework can also be applied to other molecularly defined nsclc subgroups as resistance patterns are elucidated and additional lines of treatment are developed.

Response to angiotensin blockade with irbesartan in a patient with metastatic colorectal cancer.

BACKGROUND: A patient suffering from metastatic colorectal cancer, treatment-related toxicity and resistance to standard chemotherapy and radiation was assessed as part of a personalized oncogenomics initiative to derive potential alternative therapeutic strategies. PATIENTS AND METHODS: Whole-genome and transcriptome sequencing was used to interrogate a metastatic tumor refractory to standard treatments of a patient with mismatch repair-deficient metastatic colorectal cancer. RESULTS: Integrative genomic analysis indicated overexpression of the AP-1 transcriptional complex suggesting experimental therapeutic rationales, including blockade of the renin-angiotensin system. This led to the repurposing of the angiotensin II receptor antagonist, irbesartan, as an anticancer therapy, resulting in the patient experiencing a dramatic and durable response. CONCLUSIONS: This case highlights the utility of comprehensive integrative genomic profiling and bioinformatics analysis to provide hypothetical rationales for personalized treatment options.

Personalized oncogenomics in the management of gastrointestinal carcinomas-early experiences from a pilot study.

BACKGROUND: Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting. Whole-genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways. METHODS: We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency. Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary, to explore treatment response to bevacizumab in a colorectal cancer, and to characterize an appendiceal adenocarcinoma. RESULTS: In the first case, genomic profiling revealed an IDH1 somatic mutation, supporting the diagnosis of cholangiocarcinoma in a malignancy of unknown origin, and further guided therapy by identifying epidermal growth factor receptor amplification. In the second case, a BRAF V600E mutation and wild-type KRAS profile justified the use of targeted therapies to treat a colonic adenocarcinoma. The third case was an appendiceal adenocarcinoma defined by a p53 inactivation; Ras/raf/mek, Akt/mtor, Wnt, and notch pathway activation; and overexpression of ret, erbb2 (her2), erbb3, met, and cell cycle regulators. SUMMARY: We show that whole-genome and transcriptome sequencing can be achieved within clinically effective timelines, yielding clinically useful and actionable information.

Relationship of thyroid transcription factor 1 to EGFR status in non-small-cell lung cancer.

BACKGROUND: Activating mutations of the epidermal growth factor receptor (EGFR) gene are known to drive a proportion of non-small-cell lung cancers. Identification of lung cancers harbouring such mutations can lead to effective treatment using one of the agents that targets and blocks egfr-mediated signalling. METHODS: All specimens received at the BC Cancer Agency (Vancouver) for EGFR testing were prospectively identified and catalogued, together with clinical information and EGFR status, over a 14-month period. RESULTS: Specimens from 586 patients were received for EGFR testing, and EGFR status was reported for 509 patients. No relationship between specimen type or site of origin and EGFR test failure rate was identified. Concurrent immunohistochemical (ihc) status for thyroid transcription factor 1 (ttf1) was available for 309 patients. The negative predictive value of ttf1-negative status by ihc was 94.2% for predicting negative EGFR status. CONCLUSIONS: In patients with limited tissue available for testing, a surrogate for EGFR status would aid in timely management. Immunohistochemistry for ttf1 is readily available and correlates highly with EGFR status. In conjunction with genetic assays, ttf1 could be used to optimize an EGFR testing strategy.

Handwriting: A neglected cornerstone of literacy.

This paper discusses the necessity for teaching children to have readable automatic handwriting. As demonstrated by a search of the literature, educational institutions in both the United States and Great Britain display a lack of concern about the importance of handwriting in school curricula. Researchers display a similar lack of concern as evidenced by the scarcity of major research studies on handwriting. They appear to be unaware of the benefits of effective early teaching. Often the choice of what to teach, how to teach, and when to teach is left up to the discretion of individual teachers, who typically have been given inadequate preparation for teaching handwriting. The decision of whether to begin with manuscript or cursive seems based on custom and opinion instead of any solid empirical evidence. The special needs of left-handed children and dyslexic children are seldom addressed. Yet, these children need to be taught handwriting meticulously. More attention needs to be focused on how all children can acquire the essential skill of legible serviceable handwriting.

The structured flexibility of Orton-Gillingham.

This paper discusses a philosophic basis for Orton-Gillingham teaching and attempts to demonstrate how certain of the features of such multisensory teaching act to remediate language problems exhibited by many dyslexic students. The common basis of the array of programs coming from both Orton and Gillingham is addressed. Some individual strengths and minor differences between Orton and Gillingham variations are examined.

Prediction of outcome in depressive illness by the Newcastle Diagnosis Scale. Its relationship with the unipolar/bipolar and DSM-III systems.

The Newcastle scores of a group of 64 and subsample of 52 severely depressed inpatients were not normally distributed. Evidence for discontinuity in these distributions was adduced from the contrast in outcome between the endogenous and neurotic patients thus defined, the endogenous consistently doing better than the neurotic group. The unipolar/bipolar system failed to predict different results for endogenous and neurotic patients unless unipolar was subdivided into endogenous and neurotic subgroups. The DSM-III criteria for major depression and melancholia failed to identify subgroups of differing prognoses.

Study of the effect of estradiol on gonadotrophin levels in untreated male-to-female transsexuals.

This project was an attempt to test Dörner's theory that aspects of gender identity and sexual behavior depend on a defect in a normal imprinting mechanism of testicular testosterone (T) on the male hypothalamus. It has been suggested that such an action by T is incomplete in male-to-female transsexuals and that in this disorder the hypothalamus retains a cyclic pattern of gonadotrophin secretion and a positive feedback response to estrogens, such as is seen in the normal female. Five untreated male-to-female transsexuals and five normal male controls were each given 2 mg IM of estradiol, and T, estradiol, LH, and FSH globulin was measured serially over the following five days. No significant differences were found in the gonadotrophin or any of the other hormone responses in the transsexuals compared to normal controls. If there is a defect in imprinting of the hypothalamus in transsexual men, it does not seem to affect the basal levels of gonadotrophins or the pattern of their response to estrogen, at least in the intact male.

Thyroid function screening in psychiatric in-patients.

During a two-year biochemical screening for thyroid disease amongst 191 psychiatric admissions, 38 (20 per cent) had an abnormal result, 5 were hyperthyroid and 7 hypothyroid. Thyroid dysfunction was associated with female sex and affective psychosis, but not with age. During the three weeks before admission the patients with an abnormal result had been prescribed significantly more phenothiazines, antiparkinsonian drugs and lithium than the patients with normal thyroid function. Almost half of those with abnormal function were physically ill on admission. Despite these findings we concluded that in most patients thyroid dysfunction was not a major determinant of the psychiatric disturbance.

The hemogram and the diagnosis of alcoholism.

Alcoholics had higher MCV and MCH and lower RBC than did controls.

Thiamine and pyridoxine lack newly-admitted psychiatric patients.

One hundred and fifty four patients admitted to a general hospital psychiatric unit with a history of poor diet were examined. Serum pyruvate was estimated in all, red cell transketolase in 74 and red cell aspartate transaminase in 66. Significantly more of the 58 abnormally low thiamine patients than of the normal thiamine group showed clinical signs of malnutrition or were diagnosed as chronic alcoholics, drug addicts, schizophrenics or endogenous depressives. Significantly more endogenous depressives than other patients had a raised aspartate transaminase activity coefficient (pyridoxine lack.) While most low thiamine findings are probably manifestations of malnutrition pyridoxine lack may have some aetiological significance in endogenous depression.

Serum folic acid and B12 in 272 psychiatric in-patients.

Serum folate and B12 estimations were carried out on 272 admissions to a psychiatric unit during 1972 and 1973. 21.3% had serum folate below 2 ng/ml and 26.1% serum B12 below 150 pg/ml. The organic psychosis patients had a significantly lower mean B12 than the others, and were over-represented among the low B12 group. Low B12 status was also associated with low RBC and WBC. Low folate status was linked with depression, malnutrition, physical illness and low Hb, RBC and WBC. There were more chronic alcoholics than others with serum folate greater than 4-9 ng/ml, low RBC and macrocytosis. The presence of one or more haematological abnormalities (macrocytosis, low Hb, low RBC or low WBC) predicted low folate in 76%, and low B12 in 79%, but these were also found in 40% of the normal folate and 41% of the normal B12 patients. Macrocytosis may prove to be a reliable sign of alcoholic abuse.

Comparison of antipsychotic depot injections in the maintenance treatment of schizophrenia.

122 Schizophrenic patients treated with injections of fluphenazine ethanate, 97 with fluphenazine decanoate and 199 with flupenthixol decanoate were followed up for mean times of 41, 33 and 21 months respectively. Their progress was compared by examining reasons for discontinuing injections and outcome in three separate groups defined according to first preparation given; relating the events causing patients to discontinue injections or be readmitted to patient-months spent on each drug; and analysing reasons for inter-drug transfers 43 per cent, 24 per cent and 23 per cent respectively of these three groups of patients discontinued the injections. Severe extrapyramidal effects were most frequent with fluphenazine ethanate, intermediate with fluphenazine decanote, and least frequent frequent with flupenthixol. Lack of cooperation was rather more frequent with flupenthixol than with the other drugs. Severe depression occurred with all three. More patients on fluphenazine injections were transferred for any reason to flupenthixol than vice-versa. A case of 'irreversible' movement disorder was seen with each preparation. It is suggested that current maintenance doses of flupenthixol decanoate are too low.