Research Spotlight

Schulz-Heik, R. J., J. H. Poole, M. N. Dahdah, C. Sullivan, M. M. Adamson, E. S. Date, R. Salerno, K. Schwab and O. Harris (2017). “Service needs and barriers to care five or more years after moderate to severe tbi among veterans.” Brain Inj: 1-7.

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PRIMARY OBJECTIVE: The objective of this paper is to identify the most frequent service needs, factors associated with needs, and barriers to care among Veterans and service members five or more years after moderate to severe traumatic brain injury (TBI). RESEARCH DESIGN: Survey administered via telephone 5-16 years after injury (median eight years) and subsequent acute inpatient rehabilitation at a regional Veterans Affairs (VA) medical centre. METHODS AND PROCEDURES: Participants were 119 Veterans and military personnel, aged 23-70 (median 35), 90% male. Demographics, injury characteristics, service needs, whether needs were addressed, barriers to care, health and general functioning were assessed. MAIN OUTCOMES AND RESULTS: The most frequent needs were for help with memory, information about available services and managing stress. Obtaining information about services was the most consistently un-addressed need; managing stress was the most consistently addressed need. Cognitive and psychiatric symptoms and alienation from community were associated with needs going un-addressed. Participants treated after an expansion of TBI services at the study site reported fewer un-addressed needs. Not knowing where to get help was the most common barrier to care. CONCLUSION: Repeated outreach, assessment of needs and education about available services are needed throughout Veterans’ lifespan after moderate to severe TBI.

Asadollahi, R., M. Zweier, L. Gogoll, R. Schiffmann, H. Sticht, K. Steindl and A. Rauch (2017). “Genotype-phenotype evaluation of med13l defects in the light of a novel truncating and a recurrent missense mutation.” Eur J Med Genet: 2017 Jun [Epub ahead of print].

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A decade after the designation of MED13L as a gene and its link to intellectual disability (ID) and dextro-looped transposition of great arteries in 2003, we previously described a recognizable syndrome due to MED13L haploinsufficiency. Subsequent reports of 22 further patients diagnosed by genome-wide testing further delineated the syndrome with expansion of the phenotypic spectrum and showed reduced penetrance for congenital heart defects. We now report two novel patients identified by whole exome sequencing, one with a de novo MED13L truncating mutation and the other with a de novo missense mutation. The first patient indicates some facial resemblance to Kleefstra syndrome as a novel differential diagnosis, and the second patient shows, for the first time, recurrence of a MED13L missense mutation (p.(Asp860Gly)). Notably, our in silico modelling predicted this missense mutation to decrease the stability of an alpha-helix and thereby affecting the MED13L secondary structure, while the majority of published missense mutations remain variants of uncertain significance. Review of the reported patients with MED13L haploinsufficiency indicates moderate to severe ID and facial anomalies in all patients, as well as severe speech delay and muscular hypotonia in the majority. Further common signs include abnormal MRI findings of myelination defects and abnormal corpus callosum, ataxia and coordination problems, autistic features, seizures/abnormal EEG, or congenital heart defects, present in about 20-50% of the patients. With reference to facial anomalies, the majority of patients were reported to show broad/prominent forehead, low set ears, bitemporal narrowing, upslanting palpebral fissures, depressed/flat nasal bridge, bulbous nose, and abnormal chin, but macroglossia and horizontal eyebrows were also observed in approximately 30%. The latter are especially important in the differential diagnosis of 1p36 deletion and Kleefstra syndromes, while the more common facial gestalt shows some resemblance to 22q11.2 deletion syndrome. Despite the fact that MED13L was found to be one of the most common ID genes in the Deciphering Developmental Disorders Study, further detailed patient descriptions are needed to explore the full clinical spectrum, potential genotype-phenotype correlations, as well as the role of missense mutations and potential mutational hotspots along the gene.

Agarwal, A., A. Gopinath, M. T. Tetzlaff and V. G. Prieto (2017). “Phosphohistone-h3 and ki67: Useful markers in differentiating dermatofibroma from dermatofibrosarcoma protuberans and atypical fibrohistiocytic lesions.” Am J Dermatopathol 39(7): 504-507.

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Dermatofibromas (DF) are common, benign, skin tumors, usually easily differentiated from dermatofibrosarcoma protuberans (DFSP) by the presence of a relative low cellularity, lesser degree of infiltration of subcutaneous tissue, and immunohistochemical pattern (eg, FXIIIa in DF and CD34 in DFSP). Atypical fibrohistiocytic lesions (AFL) have features intermediate to DF and DFSP (trunk location, storiform pattern, infiltration of the subcutaneous tissue, and focal expression of both CD34 and Factor XIIIa). It is unclear if mitotic counts/degree of proliferation is helpful to distinguish DF from DFSP. To study the mitotic rate and proliferation index in DF, AFL/DFSP, anti-ki67, and anti-PHH3 were performed on 10 cases of DF (including 4 cellular DF), 10 standard DFSP, and 2 AFL. The proliferation index and mitotic figures were counted per square millimeter in a “hotspot” (in a fashion similar to mitotic counts in melanoma). All cases of DF showed much higher Ki67 proliferation index (P = 0.0001) along with increased mitotic figures both on H&E and with anti-PHH3 (P = 0.0001) when compared to AFL/DFSP. Our data indicate that DF has a higher proliferation index and mitotic counts when compared to superficial/peripheral portion of AFL and DFSP. This finding may be helpful in the differential diagnosis among these fibrohistiocytic lesions.

Chung, J. R., B. Flannery, R. K. Zimmerman, M. P. Nowalk, M. L. Jackson, L. A. Jackson, J. G. Petrie, E. T. Martin, A. S. Monto, H. Q. McLean, E. A. Belongia, M. Gaglani and A. M. Fry (2017). “Prior season vaccination and risk of influenza during the 2014-2015 season in the U.S.” J Infect Dis: 2017 Jun [Epub ahead of print].

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The US Flu VE Network conducts annual studies of VE using the test-negative study design that is also used in Canada. In the Canadian study, current and prior-season vaccination status is based on a combination of patient self-report and sentinel practitioner documentation. In the US Flu VE Network, current season vaccination status is also based on a combination of patient self-report and electronic immunization records; however, prior-season vaccination is based on immunization records only. Misclassification of vaccine history may result from inaccurate self-report or incomplete immunization records. One study that compared self-reported influenza vaccination to an immunization registry found that patients overreported vaccination by approximately 10% [5]; recall of prior seasons’ vaccination may be less accurate. To minimize misclassification of vaccination history in 2 prior seasons, we considered documented doses only among patients aged ≥9 years with medical records available for at least 2 years prior to enrollment, and excluded patients who reported 2014–2015 influenza vaccination that was not documented. After adjusting for age and other potential confounding variables, we found no statistically significant association between vaccination in 3 consecutive seasons and A(H3N2)-related illness during 2014–2015 (Table 1). However, we observed the highest point estimate among persons vaccinated in 2014–2015 only. A sensitivity analysis restricted to the main genetic group (clade 3C.2a) of antigenically drifted A(H3N2) and influenza negatives resulted in similar estimates (data not shown). Although the higher point estimate for vaccination only in 2014–2015 is consistent with potential negative interference from prior vaccination [1], our results do not support evidence of increased likelihood of influenza due to A(H3N2) viruses among repeatedly vaccinated individuals compared to those unvaccinated in 3 consecutive seasons.

Cortes, J., H. S. Rugo, A. Awada, C. Twelves, E. A. Perez, S. A. Im, P. Gomez-Pardo, L. S. Schwartzberg, V. Dieras, D. A. Yardley, D. A. Potter, A. Mailliez, A. Moreno-Aspitia, J. S. Ahn, C. Zhao, U. Hoch, M. Tagliaferri, A. L. Hannah and J. O’Shaughnessy (2017). “Prolonged survival in patients with breast cancer and a history of brain metastases: Results of a preplanned subgroup analysis from the randomized phase iii beacon trial.” Breast Cancer Res Treat.

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PURPOSE: Conventional chemotherapy has limited activity in patients with breast cancer and brain metastases (BCBM). Etirinotecan pegol (EP), a novel long-acting topoisomerase-1 inhibitor, was designed using advanced polymer technology to preferentially accumulate in tumor tissue including brain metastases, providing sustained cytotoxic SN38 levels. METHODS: The phase 3 BEACON trial enrolled 852 women with heavily pretreated locally recurrent or metastatic breast cancer between 2011 and 2013. BEACON compared EP with treatment of physician’s choice (TPC; eribulin, vinorelbine, gemcitabine, nab-paclitaxel, paclitaxel, ixabepilone, or docetaxel) in patients previously treated with anthracycline, taxane, and capecitabine, including those with treated, stable brain metastases. The primary endpoint, overall survival (OS), was assessed in a pre-defined subgroup of BCBM patients; an exploratory post hoc analysis adjusting for the diagnosis-specific graded prognostic assessment (GPA) index was also conducted. RESULTS: In the trial, 67 BCBM patients were randomized (EP, n = 36; TPC, n = 31). Treatment subgroups were balanced for baseline characteristics and GPA indices. EP was associated with a significant reduction in the risk of death (HR 0.51; P < 0.01) versus TPC; median OS was 10.0 and 4.8 months, respectively. Improvement in OS was observed in both poorer and better GPA prognostic groups. Survival rates at 12 months were 44.4% for EP versus 19.4% for TPC. Consistent with the overall BEACON population, fewer patients on EP experienced grade >/=3 toxicity (50 vs. 70%). CONCLUSIONS: The significant improvement in survival in BCBM patients provides encouraging data for EP in this difficult-to-treat subgroup of patients. A phase three trial of EP in BCBM patients is underway.