MET IHC Is a Poor Screen for MET Amplification or MET Exon 14 Mutations in Lung Adenocarcinomas: Data from a Tri-Institutional Cohort of the Lung Cancer Mutation Consortium

IntroductionMNNG HOS Transforming gene (MET) amplification and MET exon 14 (METex14) alterations in lung cancers affect sensitivity to MET proto-oncogene, receptor tyrosine kinase (MET [also known by the alias hepatocyte growth factor receptor]) inhibitors. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and immunohistochemistry (IHC) have been used to evaluate MET dependency. Here, we have determined the association of MET IHC with METex14 mutations and MET amplification.MethodsWe collected data on a tri-institutional cohort from the Lung Cancer Mutation Consortium. All patients had metastatic lung adenocarcinomas and no prior targeted therapies. MET IHC positivity was defined by an H-score of 200 or higher using SP44 antibody. MET amplification was defined by copy number fold change of 1.8x or more with use of NGS or a MET-to–centromere of chromosome 7 ratio greater than 2.2 with use of FISH.ResultsWe tested tissue from 181 patients for MET IHC, MET amplification, and METex14 mutations. Overall, 71 of 181 patients (39%) were MET IHC–positive, three of 181 (2%) were MET-amplified, and two of 181 (1%) harbored METex14 mutations. Of the MET-amplified cases, two were FISH positive with MET-to–centromere of chromosome 7 ratios of 3.1 and 3.3, one case was NGS positive with a fold change of 4.4x, and one of the three cases was MET IHC–positive. Of the 71 IHC-positive cases, one (1%) was MET-amplified and two (3%) were METex14-mutated. Of the MET IHC–negative cases, two of 110 (2%) were MET-amplified.ConclusionsIn this study, nearly all MET IHC–positive cases were negative for MET amplification or METex14 mutations. MET IHC can also miss patients with MET amplification. The limited number of MET-amplified cases in this cohort makes it challenging to demonstrate an association between MET IHC and MET amplification. Nevertheless, IHC appears to be an inefficient screen for these genomic changes. MET amplification or METex14 mutations can best be detected by FISH and a multiplex NGS panel.     

Amnestic MCI Patients’ Perspectives toward Disclosure of Amyloid PET Results in a Research Context

Background

Researchers currently are not obligated to share individual research results (IRR) with participants. This non-disclosure policy has been challenged on the basis of participants’ rights to be aware and in control of their personal medical information. Here, we determined how patients view disclosure of research PET results of brain amyloid and why they believe it is advantageous or disadvantageous to disclose.

Method

As a part of a larger diagnostic trial, we conducted semi-structured interviews with patients with amnestic Mild Cognitive Impairment (aMCI). Participants had the option to receive their brain amyloid PET scan result (i.e., their IRR). Interviews were conducted before they received their IRR.

Results

A total of 38 aMCI patients (100% of study participants) wanted to know their IRR. The two most frequently mentioned reasons for choosing IRR disclosure were to better understand their brain health status and to be better able to make informed decisions about future personal arrangements (e.g., inheritance tax, moving into a smaller house, end-of-life decisions, etc.). Emotional risk was mentioned as the primary disadvantage of knowing one’s IRR. On the other hand, non-disclosure was considered to be emotionally difficult also, as patients would be uncertain about their future health condition.

Conclusions

Many patients diagnosed clinically with aMCI want to know their brain amyloid test results, even though this knowledge may be disadvantageous to them. Knowing what is going on with their health and the ability to make informed decisions about their future were the two principal advantages mentioned for obtaining their amyloid PET results. Because of the overwhelming consensus of aMCI patients was to disclose their brain amyloid PET scan results, researchers should strongly consider releasing this information to research subjects.

     

Variation in care for surgical patients with colorectal cancer: protocol adherence in 12 European hospitals

Purpose

Surgical care for patients with colorectal cancer has become increasingly standardized. The Enhanced Recovery After Surgery (ERAS) protocol is a widely accepted structured care method to improve postoperative outcomes of patients after surgery. Despite growing evidence of effectiveness, adherence to the protocol remains challenging in practice. This study was designed to assess the adherence rate in daily practice and examine the relationship between the importance of interventions and adherence rate.

Methods

This international observational, cross-sectional multicenter study was performed in 12 hospitals in four European countries. Patients were included from January 1, 2014. Data was retrospectively collected from the patient record by the local study coordinator.

Results

A total of 230 patients were included in the study. Protocol adherence was analyzed for both the individual interventions and on patient level. The interventions with the highest adherence were antibiotic prophylaxis (95%), thromboprophylaxis (87%), and measuring body weight at admission (87%). Interventions with the lowest adherence were early mobilization—walking and sitting (9 and 6%, respectively). The adherence ranged between 16 and 75%, with an average of 44%.

Conclusion

Our results show that the average protocol adherence in clinical practice is 44%. The variation on patient and hospital level is considerable. Only in one patient the adherence rate was >70%. In total, 30% of patients received 50% or more of the key interventions. A solid implementation strategy seems to be needed to improve the uptake of the ERAS pathway. The importance-performance matrix can help in prioritizing the areas for improvement.

     

Estimating local and global measures of association for bivariate interval censored data with a smooth estimate of the density

Measures of association for bivariate interval censored data have not yet been studied extensively. Betensky and Finkelstein (Statist. Med. 1999; 18:3101-3109) proposed to calculate Kendall's coefficient of concordance using a multiple imputation technique, but their method becomes computer intensive for moderate to large data sets. We suggest a different approach consisting of two steps. Firstly, a bivariate smooth estimate of the density of log-event times is determined. The smoothing technique is based on a mixture of Gaussian densities fixed on a grid with weights determined by a penalized likelihood approach. Secondly, given the smooth approximation several local and global measures of association can be estimated readily. The performance of our method is illustrated by an extensive simulation study and is applied to tooth emergence data of permanent teeth measured on 4468 children from the Signal-Tandmobiel study.     

Metal concentrations, sperm motility, and RNA/DNA ratio in two echinoderm species from a highly contaminated fjord (the Sørfjord, Norway)

The present study evaluated the effects of field metal contamination on sperm motility and the RNA/DNA ratio in echinoderms. Populations of Asterias rubens and Echinus acutus that occur naturally along a contamination gradient of sediments by cadmium, copper, lead, and zinc in a Norwegian fjord (the S?rfjord) were studied. Sperm motility, a measure of sperm quality, was quantified using a computer-assisted sperm analysis system. The RNA/DNA ratio, a measure of protein synthesis, was assessed by a one-dye (ethidium bromide)/one-enzyme (RNase), 96-well microplate fluorometric assay. Although both species accumulate metals at high concentrations, neither sperm motility parameters in A. rubens nor the RNA/DNA ratio in both species were affected. The S?rfjord is still one of the most metal-contaminated marine sites in Europe, but even so, populations of A. rubens and E. acutus are able to endure under these conditions.     

Validation of a Type 2 Diabetes Screening Tool in Rural Honduras

OBJECTIVE

To validate a low-cost tool for identifying diabetic patients in rural areas of Latin America.

RESEARCH DESIGN AND METHODS

A regression equation incorporating postprandial time and a random plasma glucose was used to screen 800 adults in Honduras. Patients with a probability of diabetes of ≥20% were asked to return for a fasting plasma glucose (FPG). A random fifth of those with a screener-based probability of diabetes <20% were also asked to return for follow-up. The gold standard was an FPG ≥126 mg/dl.

RESULTS

The screener had very good test characteristics (area under the receiver operating characteristic curve = 0.89). Using the screening criterion of ≥0.42, the equation had a sensitivity of 74.1% and specificity of 97.2%.

CONCLUSIONS

This screener is a valid measure of diabetes risk in Honduras and could be used to identify diabetic patients in poor clinics in Latin America.As the global prevalence of diabetes increases, developing countries will experience 80% of the burden (1). A recent study (2) found that 7.8% of adults in the capital city of Honduras had diabetes and 42% of them were unaware of their condition.There is little consensus about the most cost-effective means of screening for diabetes in developing countries (3). The oral glucose tolerance test is difficult to implement, and laboratory-based A1C testing is unavailable in many areas (4). Screening tools have been developed that combine risk factor information into an overall estimate of patients'' probability of disease (4–8). Models limited to information about patient demographics, BMI, and blood pressure often show only moderate test specificity. In contrast, a screening algorithm that incorporates random plasma glucose test results and postprandial time has shown excellent predictive accuracy (4,5). Additional validation is important to ensure that the instrument has adequate sensitivity and specificity in Latin America, given differences in diet, body structure, and other risk factors in the region. The purpose of the current study was to validate this diabetes-screening tool among patients seeking medical care in Honduras.     

Availability of behavioral health treatment for women in prison

OBJECTIVES: This study examined whether women with behavioral health needs are more likely to receive treatment for these problems in prison or in the community and to what extent prison disrupts or establishes involvement in treatment for these women. METHODS: Data were collected in August 2004 as part of a population survey of female inmates in the only state correctional facility for women in New Jersey. RESULTS: A total of 908 women were surveyed. Fifty-six percent of the women surveyed reported needing behavioral health treatment before incarceration, but only 62 percent of this group reported receiving such treatment in the community. The rate at which treatment matched need within this population before incarceration varied by type of treatment needed: it was the highest (58 percent) for women who needed treatment for mental health problems, lower (52 percent) for those who needed substance abuse treatment, and lowest (44 percent) for those who needed treatment for comorbid mental health and substance abuse problems. In comparison, the rate of match between need for and receipt of treatment in prison was higher for all three types of behavioral health treatment (78 percent, 57 percent, and 65 percent, respectively). Additionally, the findings suggest that prison did not disrupt the type of behavioral health treatment that inmates had previously received in the community. CONCLUSIONS: At least in New Jersey, prison appears to improve access to behavioral health treatment among female inmates. Although this conclusion is consistent with the rehabilitation goals of incarceration, it also suggests that some women may have been able to avoid prison if treatment had been provided in the community, especially for substance-related problems.     

Artemin has potent neurotrophic actions on injured C-fibres

In this study, we have investigated the effects of artemin (ARTN), one of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, on C-fibres following nerve injury in the adult rat. GDNF family receptor alpha (GFRalpha) 3, the ligand binding domain of the ARTN receptor, is expressed in 34% of dorsal root ganglion (DRG) cells, predominantly in the peptidergic population of C-fibres and in a proportion of the isolectin B4 (IB4)-binding population. Interestingly, only 30% of GFRalpha3-expressing DRG cells co-expressed RET (the signal transducing domain). In agreement with previous studies, treatment with ARTN prevented many of the nerve injury-induced changes in the histochemistry of both the peptidergic and the IB4-binding populations of small, but not large, diameter DRG cells. In addition, ARTN treatment maintained C-fibre conduction velocity, and C-fibre evoked substance P release within the dorsal horn following nerve injury. ARTN was also protective following capsaicin treatment, which produces selective C-fibre injury. Given the potent neurotrophic actions of ARTN on C-fibres, it may therefore provide potential for the treatment of nerve injury, particularly in the maintenance of small fibre function.     

A genotypic assay for the amplification and sequencing of integrase from diverse HIV-1 group M subtypes

Recently, the Food and Drug Administration (FDA) of the USA approved the first integrase inhibitor for inclusion in treatment regimens of HIV-1 patients failing their current regimens with multi-drug resistant strains. However, treatment failure has been observed during integrase inhibitor-containing therapy. Several mutational pathways have been described with signature mutations at integrase positions 66, 92, 148 and 155. Therefore, a genotypic assay for the amplification and sequencing of HIV-1 integrase was developed. The assay displayed a detection limit of 10 HIV-1 III(B) RNA copies/ml plasma. As the HIV-1 pandemic is characterised by a large genetic diversity, the new assay was evaluated on a panel of 74 genetically divergent samples belonging to the following genetic forms A, B, C, D, F, G, J, CRF01-AE, CRF02-AG, CRFF03-AB, CRF12-BF and CRF13-cpx. Their viral load ranged from 178 until >500,000 RNA copies/ml. The amplification and sequencing was successful for 70 samples (a success rate of 95%). The four failures were most probably due to low viral load or poor quality of RNA and not to subtype issues. Some of the sequences obtained from integrase inhibitor-na?ve patients displayed polymorphisms at integrase positions associated with resistance: 74IV, 138D, 151I, 157Q and 163AE. The relevance of these polymorphisms in the absence of the signature mutations remains unclear.     

Sequence analysis of bluetongue virus serotype 8 from the Netherlands 2006 and comparison to other European strains

During 2006 the first outbreak of bluetongue ever recorded in northern Europe started in Belgium and the Netherlands, spreading to Luxemburg, Germany and north-east France. The virus overwintered (2006-2007) reappearing during May-June 2007 with greatly increased severity in affected areas, spreading further into Germany and France, reaching Denmark, Switzerland, the Czech Republic and the UK. Infected animals were also imported into Poland, Italy, Spain and the UK. An initial isolate from the Netherlands (NET2006/04) was identified as BTV-8 by RT-PCR assays targeting genome segment 2. The full genome of NET2006/04 was sequenced and compared to selected European isolates, South African vaccine strains and other BTV-8 strains, indicating that it originated in sub-Saharan Africa. Although NET2006/04 showed high levels of nucleotide identity with other 'western' BTV strains, it represents a new introduction and was not derived from the BTV-8 vaccine, although its route of entry into Europe has not been established.