Research Spotlight

Askar, M., A. Madbouly, L. Zhrebker, A. Willis, S. Kennedy, K. Padros, M. B. Rodriguez, C. Bach, B. Spriewald, R. Ameen, S. A. Shemmari, K. Tarassi, A. Tsirogianni, N. Hamdy, G. Mossallam, G. Honger, R. Spinnler, G. Fischer, I. Fae, R. Charlton, A. Dunk, T. A. Vayntrub, M. Halagan, K. Osoegawa and M. Fernandez-Vina (2019). “HLA Haplotypes In 250 Families: The Baylor Laboratory Results And A Perspective On A Core NGS Testing Model For The 17(th) International HLA And Immunogenetics Workshop.” Hum Immunol 80(11): 897-905.

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Since their inception, the International HLA & Immunogenetics Workshops (IHIW) served as a collaborative platform for exchange of specimens, reference materials, experiences and best practices. In this report we present a subset of the results of human leukocyte antigen (HLA) haplotypes in families tested by next generation sequencing (NGS) under the 17th IHIW. We characterized 961 haplotypes in 921 subjects belonging to 250 families from 8 countries (Argentina, Austria, Egypt, Jamaica, Germany, Greece, Kuwait, and Switzerland). These samples were tested in a single core laboratory in a high throughput fashion using 6 different reagents/software platforms. Families tested included patients evaluated clinically as transplant recipients (kidney and hematopoietic cell transplant) and their respective family members. We identified 486 HLA alleles at the following loci HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, -DPA1, -DPB1 (77, 115, 68, 69, 10, 6, 4, 44, 31, 20 and 42 alleles, respectively). We also identified nine novel alleles with polymorphisms in coding regions. This approach of testing samples from multiple laboratories across the world in different stages of technology implementation in a single core laboratory may be useful for future international workshops. Although data presented may not be reflective of allele and haplotype frequencies in the countries to which the families belong, they represent an extensive collection of 3rd and 4th field resolution level 11-locus haplotype associations of 486 alleles identified in families from 8 countries.

Armstrong, T. W., M. L. C. Williamson, T. R. Elliott, W. T. Jackson, N. T. Kearns and T. Ryan (2019). “Psychological distress among persons with upper extremity limb loss.” Br J Health Psychol 24(4): 746-763.

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OBJECTIVE: We examined predictors of clinically significant levels of psychological distress among individuals with upper limb loss (ULL). DESIGN: A multisite, cross-sectional study completed at six prosthetic rehabilitation centres throughout the United States. METHODS: Oral administration of a brief assessment battery to 307 participants with ULL including demographic variables, injury information, screening instruments for PTSD and depression, pain interference, and activity restriction measures. Hierarchical multinomial logit models were conducted. Outcome groups were created using recommended cut-off scores on brief screening measures of depression and PTSD. Final models were assessed including relative risk ratios and marginal effects. RESULTS: Over half of the sample screened positive for depression, PTSD, or both. Eight individuals exceeded the recommended cut-off score indicative of PTSD only (2.6%), and 106 participants (34.5%) screened positive for depression only. Moreover, 64 participants (20.8%) reported co-occurring PTSD and depression. Subsequent models revealed women and ethnic minority participants were more likely to have clinically significant levels of depression and PTSD. Greater restriction in activity and increased pain interference also predicted psychological distress. CONCLUSIONS: These findings indicate a significant number of individuals with ULL experience clinically significant levels of psychological distress, and routine clinical assessment of depression and PTSD is warranted. Women and individuals from ethnic minorities may be particularly at risk, regardless of the severity and cause of ULL. Restrictions in preferred and goal-directed activities and persistent pain are also contributing factors. Psychological interventions that address these issues are indicated. Statement of contribution What is already known on this subject? Research investigating psychological reactions and adjustment after limb loss has primarily focused on lower limb loss. Little research has investigated psychological adjustment or distress following upper extremity loss. Lower extremity limb loss is more likely to be from a disease process while upper extremity limb loss is more likely to be due to traumatic injuries. Upper extremity limb loss possesses a qualitatively different experience as upper limb amputation is more readily apparent to others, impacts activities of daily living, and limits instrumental function in social and non-verbal communication. What does this study add? A significant percentage of individuals with upper limb loss report significant levels of depression, PTSD, and mixed depression and PTSD. Moreover, women and minority clients were more likely to report clinically significant levels of depression and mixed PTSD and depression. Activity restriction and pain interference’s contributions in the final model helped to elucidate the clinical picture of psychological distress for persons with upper extremity limb loss. Greater activity restriction and limitations from pain interference increased the likelihood of reporting clinically significant levels of psychological distress.

Amin, S. D., K. B. Homan, M. Assar, M. Lee and C. D. Housewright (2019). “Hyfrecation and Interference With Implantable Cardiac Devices.” Dermatol Surg Oct 24. [Epub ahead of print].

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BACKGROUND: Mohs micrographic surgery, excisional surgery, and electrodessication and curettage (ED&C) are common dermatologic procedures that often use electrodessication through hyfrecators to achieve hemostasis. According to in vitro studies, electrodessication is considered safe in patients with implanted cardiac devices. To the authors’ knowledge, there are no in vivo data to support this claim. OBJECTIVE: In this study, the authors aim to describe the outcomes of hyfrecation during dermatologic procedures in patients with pacemakers and implantable cardiac devices. METHODS: Retrospective chart review was completed from March 2014 to April 2018 at a single center. Forty-five patients met criteria of having a cardiac device and having undergone an electrosurgery procedure using the Conmed 2000 Hyfrecator (Utica, NY). Adverse perioperative and postoperative outcomes, as well as device malfunction, were evaluated. RESULTS: No adverse perioperative effects were reported. Device reports were examined for inappropriate firing of the defibrillator, loss of capture, temporary inhibition of pacing, battery drainage, pacing at an elevated or erratic rate, failure to deliver antitachycardia, reversion to asynchronous pacing, induction of arrhythmias, or tissue damage at lead tissue, but no such issues were found. CONCLUSION: The lack of complications associated with cardiac devices with hyfrecation is reassuring. However, prospective and larger retrospective studies are warranted.

Abramson, V. G., M. Oliveira, A. Cervantes, H. Wildiers, M. R. Patel, T. M. Bauer, P. L. Bedard, C. Becerra, S. Richey, M. C. Wei, E. Reyner, J. Bond, N. Cui, T. R. Wilson, H. M. Moore, C. Saura and I. E. Krop (2019). “A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer.” Breast Cancer Res Treat 178(1): 121-133.

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PURPOSE: This open-label, phase Ib, dose-escalation, and dose-expansion study (NCT01862081) evaluated taselisib with a taxane in locally advanced or metastatic breast cancer (BC) and/or non-small cell lung cancer (NSCLC). METHODS: Patients received taselisib (2-6 mg tablet or 3-6 mg capsule) plus docetaxel or paclitaxel. Primary endpoints were safety, dose-limiting toxicities, maximum tolerated dose, and identification of a recommended phase II dose. Secondary endpoints included pharmacokinetics and antitumor activity assessment. RESULTS: Eighty patients (BC: 72; NSCLC: 7; BC/NSCLC: 1) were enrolled (docetaxel-receiving arms: 21; paclitaxel-receiving arms: 59). Grade >/= 3 adverse events (AEs), serious AEs, and AEs leading to death were reported in 90.5%, 42.9%, and 14.3% of patients, respectively (docetaxel-receiving arms), and 78.9%, 40.4%, and 3.5% of patients, respectively (paclitaxel-receiving arms). Eight patients experienced dose-limiting toxicities. The maximum tolerated dose was exceeded with 3 mg taselisib (capsule) for 21 consecutive days plus 75 mg/m(2) docetaxel and not exceeded with 6 mg taselisib (tablet) for 5 days on/2 days off plus 80 mg/m(2) paclitaxel. Objective response rates and clinical benefit rates were 35.0% and 45.0%, respectively (docetaxel-receiving arms), and 20.4% and 27.8%, respectively (paclitaxel-receiving arms). Exposure for paclitaxel or docetaxel plus taselisib was consistent with the single agents. CONCLUSIONS: Taselisib in combination with a taxane has a challenging safety profile. Despite evidence of antitumor activity, the benefit-risk profile was deemed not advantageous. Further development is not planned.

Larkin, J., V. Chiarion-Sileni, R. Gonzalez, J. J. Grob, P. Rutkowski, C. D. Lao, C. L. Cowey, D. Schadendorf, J. Wagstaff, R. Dummer, P. F. Ferrucci, M. Smylie, D. Hogg, A. Hill, I. Marquez-Rodas, J. Haanen, M. Guidoboni, M. Maio, P. Schoffski, M. S. Carlino, C. Lebbe, G. McArthur, P. A. Ascierto, G. A. Daniels, G. V. Long, L. Bastholt, J. I. Rizzo, A. Balogh, A. Moshyk, F. S. Hodi and J. D. Wolchok (2019). “Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.” New England Journal of Medicine Sep 28. [Epub ahead of print].

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BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).