[NEW ANALGESIC PROTOCOL FOR THE TREATMENT OF PAIN AND ANXIETY IN PEDIATRIC BURN PATIENTS - DEVELOPMENT, IMPLEMENTATION AND FIRST RESULTS].

INTRODUCTION: Burns are one of the most common and painful injuries among babies and children. The pain endured during and in between treatment can be minimized with sedation. These sedations, however, are not without side effects and risks. Given the potential complications, we devised a Burn Analgesic Treatment Protocol that incorporates safe analgesia during burn treatment and throughout the day, thus minimizing the necessity for sedations. AIMS: Assessment of the effectiveness of the analgesic protocol by quantification of overall number of sedations needed for burn treatment and by assessment of the overall experience of the treating medical team exposed to burn care before and after implementation of the protocol. METHODS: A retrospective analysis of analgesic treatment regimens among admitted pediatric burn patients both before and after the implementation of our analgesic protocol was performed. Furthermore, questionnaires were given to the nurses of the treating medical team in order to better assess overall experience with the new analgesic protocol. RESULTS: A total of 87 patients were treated with the new analgesic protocol and 46 patients served as the control group. A significantly lower number of sedations were performed in the group treated with the new protocol compared to the control group (18% vs 30%, p=0.057). The questionnaires filled out by the treating nurses revealed an average score of 4.5 (between 1 - 5), indicating high satisfaction with the protocol. CONCLUSIONS: Our new analgesic protocol allows for highly effective treatment of burn wounds while minimizing the necessity for sedations, thus increasing overall patient safety and reducing potential complications.

Preclinical characterization of INCB053914, a novel pan-PIM kinase inhibitor, alone and in combination with anticancer agents, in models of hematologic malignancies.

The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intracellular signaling networks important in tumorigenesis, including the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors. This supports the therapeutic potential of pan-PIM kinase inhibitors, especially in combination with other anticancer agents chosen based on their role in overlapping signaling networks. Reported here is a preclinical characterization of INCB053914, a novel, potent, and selective adenosine triphosphate-competitive pan-PIM kinase inhibitor. In vitro, INCB053914 inhibited proliferation and the phosphorylation of downstream substrates in cell lines from multiple hematologic malignancies. Effects were confirmed in primary bone marrow blasts from patients with acute myeloid leukemia treated ex vivo and in blood samples from patients receiving INCB053914 in an ongoing phase 1 dose-escalation study. In vivo, single-agent INCB053914 inhibited Bcl-2-associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts. Additive or synergistic inhibition of tumor growth was observed when INCB053914 was combined with selective PI3Kδ inhibition, selective JAK1 or JAK1/2 inhibition, or cytarabine. Based on these data, pan-PIM kinase inhibitors, including INCB053914, may have therapeutic utility in hematologic malignancies when combined with other inhibitors of oncogenic kinases or standard chemotherapeutics.

Cephalometric evaluation of upper lip symmetry after functional unilateral cleft lip repair with the Kernahan and Bauer technique and primary cleft rhinoplasty.

BACKGROUND: Cleft lip repair with the Millard technique has undergone many modifications throughout the years, yet analysis of the successes of these various methods is still lacking. OBJECTIVES: To make a quantitative evaluation of the outcomes obtained after unilateral cleft lip surgical repair using the Kernahan and Bauer technique with primary rhinoplasty. METHODS: Five anatomical parameters for evaluating upper lip and nostril symmetry were compared between the cleft and the normal side at least 1 year post-surgery in 23 children who underwent unilateral cleft lip repair with this particular technique. RESULTS: Surgical success (defined as a 10% or less deviation between the cleft and contralateral side) was achieved for four of the five parameters: distance between oral commissure and peak of Cupid's bow, nasal sill width, distance between peak and lowest point of Cupid's bow, and vertical distance between the highest point of the philtral column and lowest point of the upper lip. Surgical success was not achieved for the last parameter: length of philtral column. CONCLUSIONS: Unilateral cleft lip repair using the Kernahan and Bauer technique with primary cleft rhinoplasty is mostly successful when aiming to achieve symmetry between the cleft and the normal side of the upper lip. Success was elusive in achieving symmetry between the philtral columns despite an overall average difference of only 1.2 mm.

Combined inhibition of Janus kinase 1/2 for the treatment of JAK2V617F-driven neoplasms: selective effects on mutant cells and improvements in measures of disease severity.

PURPOSE: Deregulation of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is a hallmark for the Philadelphia chromosome-negative myeloproliferative diseases polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We tested the efficacy of a selective JAK1/2 inhibitor in cellular and in vivo models of JAK2-driven malignancy. EXPERIMENTAL DESIGN: A novel inhibitor of JAK1/2 was characterized using kinase assays. Cellular effects of this compound were measured in cell lines bearing the JAK2V617F or JAK1V658F mutation, and its antiproliferative activity against primary polycythemiavera patient cells was determined using clonogenic assays. Antineoplastic activity in vivo was determined using a JAK2V617F-driven xenograft model, and effects of the compound on survival, organomegaly, body weight, and disease-associated inflammatory markers were measured. RESULTS: INCB16562 potently inhibited proliferation of cell lines and primary cells from PV patients carrying the JAK2V617F or JAK1V658F mutation by blocking JAK-STAT signaling and inducing apoptosis. In vivo, INCB16562 reduced malignant cell burden, reversed splenomegaly and normalized splenic architecture, improved body weight gains, and extended survival in a model of JAK2V617F-driven hematologic malignancy. Moreover, these mice suffered from markedly elevated levels of inflammatory cytokines, similar to advanced myeloproliferative disease patients, which was reversed upon treatment. CONCLUSIONS: These data showed that administration of the dual JAK1/2 inhibitor INCB16562 reduces malignant cell burden, normalizes spleen size and architecture, suppresses inflammatory cytokines, improves weight gain, and extends survival in a rodent model of JAK2V617F-driven hematologic malignancy. Thus, selective inhibitors of JAK1 and JAK2 represent a novel therapy for the patients with myeloproliferative diseases and other neoplasms associated with JAK dysregulation.