Cell-free DNA from nail clippings as source of normal control for genomic studies in hematologic malignancies.

Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.

Enhanced clinical assessment of hematologic malignancies through routine paired tumor and normal sequencing.

Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.

A predictive model for intrathecal opioid dose escalation for chronic non-cancer pain.

BACKGROUND: Tolerance is defined as a phenomenon in which exposure to a drug results in a decrease of an effect or the requirement of a higher dose to maintain an effect. The fear of a patient developing opioid tolerance contributes regularly to the stigmatization and withholding of intrathecal opioid therapy for chronic pain of non-cancer origin. OBJECTIVES: The aim of this study was to describe the intrathecal opioid dose escalation throughout the years in chronic non-cancer pain patients. A secondary objective was the development of an intrathecal opioid dose predictive model. STUDY DESIGN: Retrospective assessment of medical records. SETTING: Department of Pain Management, Russells Hall Hospital, Dudley, United Kingdom. METHODS: Medical records were reviewed and pump refill notes screened from the date of implant through November 2010 for 31 patients undertaking continuous intrathecal opioid therapy. All the patients included had undertaken a minimum of 6 years of intrathecal therapy when the data were collected. RESULTS: Significant increases in the intrathecal morphine dose were verified between follow-up at one year and all subsequent observations, F (2.075, 62.238) = 13.858, 0 < 0.001, but ceased to be significant from year 3 onwards, indicating stability of the morphine dose, F (3, 90) = 2.516, P = 0.63. A model that accounts for 76% of the variability of morphine doses at year 6 based on year 2 assessment combined with duration of pain prior to initiation of intrathecal therapy was developed: year 6 dose = -0.509 + (1.296 x [year 2 dose]) + (0.061 x [duration of pain]). LIMITATIONS: Retrospective study. CONCLUSION: The opioid dose escalation observed throughout the years was modest and not significant following year 3 of therapy. The model developed has the potential to assist the physician in the identification of a need for alternative treatment strategies. Furthermore, since many of the pump replacements are performed prior to year 6, it can also assist in the informed decision of the benefits and risks of the maintenance of this therapy.