Research Spotlight

Posted July 15th 2017

Health-related quality of life results from the phase III CheckMate 067 study.

Charles L. Cowey M.D.

Charles L. Cowey M.D.

Schadendorf, D., J. Larkin, J. Wolchok, F. S. Hodi, V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J. J. Grob, C. L. Cowey, C. Lao, J. Wagstaff, M. K. Callahan, M. A. Postow, M. Smylie, P. F. Ferrucci, R. Dummer, A. Hill, F. Taylor, J. Sabater, D. Walker, S. Kotapati, A. Abernethy and G. V. Long (2017). “Health-related quality of life results from the phase iii checkmate 067 study.” Eur J Cancer 82: 80-91.

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BACKGROUND: Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067. PATIENTS AND METHODS: HRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated. RESULTS: Nivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause. CONCLUSION: These results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting.


Posted July 15th 2017

Observations from our evaluation of bodyweight changes after initiation of a biologic therapy in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).

Alan M. Menter M.D.

Alan M. Menter M.D.

Shear, N. H., R. Alhusayen, A. Fernandez-Obregon, A. B. Kimball, A. Menter, J. J. Wu, K. Goyal, H. Patel, R. Lin and A. W. Armstrong (2017). “Observations from our evaluation of body weight changes after initiation of a biologic therapy in psolar.” J Eur Acad Dermatol Venereol: 2017 Jun [Epub ahead of print].

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PSOLAR is a global, prospective, observational study designed to evaluate long-term safety and clinical outcomes for over 12,000 psoriasis patients who are receiving, or are eligible to receive, biologic and/or conventional systemic agents. Data from the registry may also be used to test hypotheses for topics of interest to dermatologists.1 While PSOLAR has produced many viable analyses of safety and efficacy outcomes, including overall safety, serious infections, comparative effectiveness, and persistence of treatment,2-5 a recently tested hypothesis related to treatment effect on body weight did not generate interpretable results. Our observations may be relevant for future research in this area.


Posted July 15th 2017

Service needs and barriers to care five or more years after moderate to severe TBI among Veterans.

Marie Dahdah Ph.D.

Marie Dahdah Ph.D.

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.


Posted July 15th 2017

Genotype-phenotype evaluation of MED13L defects in the light of a novel truncating and a recurrent missense mutation.

Raphael Schiffmann M.D.

Raphael Schiffmann M.D.

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.


Posted July 15th 2017

Phosphohistone-H3 and Ki67: Useful Markers in Differentiating Dermatofibroma From Dermatofibrosarcoma Protuberans and Atypical Fibrohistiocytic Lesions.

Atin Agarwal M.D.

Atin Agarwal M.D.

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.