RAS/BRAF mutational status in familial non‑medullary thyroid carcinomas: A retrospective study

There are contrasting views on whether familial non‑medullary thyroid carcinomas (FNMTCs) are characterized by aggressive behavior, and limited evidence exists on the prognostic value of BRAF and RAS mutations in these tumors. Thus, in the present study, clinicopathological features were analyzed in 386 non‑medullary thyroid carcinomas (NMTCs), subdivided in 82 familial and 304 sporadic cases. Furthermore, the RAS and BRAF mutational statuses were investigated in a subgroup of 34 FNMTCs to address their clinical and biological significance. The results demonstrated that, compared with sporadic NMTCs, FNMTCs are characterized by significantly higher rates of multicentricity and bilaterality and are more frequently associated with chronic autoimmune thyroiditis. Notably, a statistically significant difference in the rates of multicentricity was observed by subgrouping familial tumors according to the number of relatives involved; those with ≥3 affected relatives were more likely to be multicentric. Furthermore, the FNMTC cohort exhibited higher rates of tumors >4 cm in size with extrathyroidal or lymph node involvement. However, no significant difference was observed. Similarly, no differences were observed with respect to the age of onset or the patient outcome. The mutational profiling exhibited a rate of 58.8% for BRAF V600E mutations in familial tumors, which is at the upper limit of the mutational frequency observed in historical series of sporadic thyroid cancer. A high rate of NRAS mutations (17.6%) was also observed, mostly in the follicular variant histotype. Notably, compared with BRAF/RAS‑wild type FNMTCs, the familial carcinomas bearing BRAF or NRAS mutations exhibited slightly higher rates of bilaterality and multicentricity, in addition to increased frequency of locally advanced stage or lymph node involvement. The present data support the theory that FNMTCs are characterized by clinicopathological features that resemble a more aggressive phenotype and suggest that RAS/BRAF mutational analysis deserves to be further evaluated as a tool for the identification of FNMTCs with a potentially unfavorable prognosis

Case report: biallelic DNMT3A mutations in acute myeloid leukemia

DNMT3A gene mutations, detected in 20-25% of de novo acute myeloid leukemia (AML) patients, are typically heterozygous. Biallelic variants are uncommon, affecting ~3% of cases and identifying a worse prognosis. Indeed, two concomitant DNMT3A mutations were recently associated with shorter event-free survival and overall survival in AML. We present an AML case bearing an unusual DNMT3A molecular status, strongly affecting its function and strangely impacting the global genomic methylation profile. A 56-year-old Caucasian male with a diagnosis of AML not otherwise specified (NOS) presented a complex DNMT3A molecular profile consisting of four different somatic variants mapping on different alleles (in trans). 3D modelling analysis predicted the effect of the DNMT3A mutational status, showing that all the investigated mutations decreased or abolished DNMT3A activity. Although unexpected, DNMT3A’s severe loss of function resulted in a global genomic hypermethylation in genes generally involved in cell differentiation. The mechanisms through which DNMT3A contributes to AML remain elusive. We present a unique AML case bearing multiple biallelic DNMT3A variants abolishing its activity and resulting in an unexpected global hypermethylation. The unusual DNMT3A behavior described requires a reflection on its role in AML development and persistence, highlighting the heterogeneity of its deregulation

Management of a humeral shaft non-union after a Gustilo III C fracture

A 25-year-old man was admitted to our Department with an open humeral shaft fracture (Gustilo III C); two large wounds were noticed with ulnar artery and median nerve completely dissected. Initial primary treatment included irrigation, debridement and fracture stabilization with a monolateral external fixator followed by vascular and nerve repair and wound closure. At 6 months follow up the patient was able to use his arm without any painful stimuli and a CT scan showed the presence of postero-medial callus formation. Consequently, the external fixator was removed and the patient was discharged to physiotherapy. After 7 months, the patient presented with severe pain and functional impairment with no history of trauma. X rays showed recent re-fracture on a background of oligotrophic nonunion. Revision surgery included debridement of the non-union bone edges, reaming of the medullary canal and insertion of a humeral nail. Six months later osseous healing was noted with complete restoration of shoulder and elbow movement and partial recovery of the median nerve. (C) 2015 Elsevier Ltd. All rights reserved

A comparative retrospective study of locking plate fixation versus a dedicated external fixator of 3- and 4-part proximal humerus fractures: Results after 5 years

Introduction: Fractures of the proximal humerus (PHF) represent a common injury among orthopedic department; especially for three- and four-part fractures no consensus about the best treatment is still achieved. The aim of our study was to compare clinical and radiological outcomes in patients alternatively treated with plates and screws or external fixation system for a type III-IV proximal humerus fracture. Material and methods: Sixty-nine patients went surgery for type III-IV PHF between January 2011 and January 2014. According to the Neer classification, fractures were classified as type III in 50 cases (72,46%) and type IV in 19 cases (24,56%). 45 patients were treated with plates (65%) and 24 external fixators (35%). The patients’ mean age was 62 years (range, 31–87 y). At five years, 60 patients (86,9%) were assessed using the visual analog scale (VAS) pain score, Constant Score (CS), the range of motion, and radiological evaluation. The CS at five years was the primary outcome measure. Results were evaluated and compared with the contralateral unaffected side to avoid bias related to different ages. Results: At the final follow up, we found no clinical differences when comparing the two procedures. Moreover, when age was considered as a variable, a significative difference of the CS was observed in the group of patients younger than 65 years treated with a plate (Plate Group Mean: 79; SD: +/- 15. Ex Fi Mean: 58; SD:+/- 4. P = 0,008). In the group of patients older than 65 years, the two procedures did not show significative differences in outcomes (Plate Group Mean: 69; SD: +/- 15. Ex Fi Mean: 63; SD:+/- 7. P = 0,032). External fixation procedure was overall associated with a reduction in blood loss, surgical time, length of hospital stay. Conclusion: Percutaneous techniques have a long tradition in PHF treatment; the introduction of dedicated external fixation system has the advantage to improve the stability and allow early rehabilitation when compared to the classical pinning technique. In our experience, the indication elderly patients with osteoporosis and comorbidities may benefit by this type of mini-invasive surgery with low soft tissue damages

Single-Cell Sequencing: Ariadne's Thread in the Maze of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a haematological neoplasm resulting from the accumulation of genetic and epigenetic alterations. Patients' prognoses vary with AML genetic heterogeneity, which hampers successful treatments. Single-cell approaches have provided new insights of the clonal architecture of AML, revealing the mutational history from diagnosis, during treatment and to relapse. In this review, we imagine single-cell technologies as the Ariadne's thread that will guide us out of the AML maze, provide a precise identikit of the leukemic cell at single-cell resolution and explore genomic, transcriptomic, epigenetic and proteomic levels

Single-Cell Sequencing: Ariadne’s Thread in the Maze of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a haematological neoplasm resulting from the accumulation of genetic and epigenetic alterations. Patients’ prognoses vary with AML genetic heterogeneity, which hampers successful treatments. Single-cell approaches have provided new insights of the clonal architecture of AML, revealing the mutational history from diagnosis, during treatment and to relapse. In this review, we imagine single-cell technologies as the Ariadne’s thread that will guide us out of the AML maze, provide a precise identikit of the leukemic cell at single-cell resolution and explore genomic, transcriptomic, epigenetic and proteomic levels

Exploring the Potential of Eltrombopag: Room for More?

Since its introduction in clinical practice, eltrombopag (ELT) has demonstrated efficacy in heterogeneous clinical contexts, encompassing both benign and malignant diseases, thus leading researchers to make a more in-depth study of its mechanism of action. As a result, a growing body of evidence demonstrates that ELT displays many effects ranging from native thrombopoietin agonism to immunomodulation, anti-inflammatory, and metabolic properties. These features collectively explain ELT effectiveness in a broad spectrum of indications; moreover, they suggest that ELT could be effective in different, challenging clinical scenarios. We reviewed the extended ELT mechanism of action in various diseases, with the aim of further exploring its full potential and hypothesize new, fascinating indications

JAK2 V617f in chronic myeloid leukemia: driving force or passive bystander?

Objectives BCR-ABL1 and JAK2 V617F coexistence in myeloproliferative neoplasms has been described as concomitant or sequential events. Despite this, we present a unique case of chronic myeloid leukemia (CML) not referable to either of the known scenarios. Methods BCR-ABL1 molecular monitoring was performed by real-time quantitative PCR (RQ-PCR). At the time of molecular relapse, a targeted next-generation sequencing analysis with a customized panel of 26 genes commonly mutated in myeloid diseases was performed. To investigate the kinetics of the JAK2 variant and its association with the BCR-ABL1 rearrangement, RQ-PCR was performed at different time points during the patient's follow-up. Results While negative at CML diagnosis, the JAK2 mutation was first detected 9 years later (VAF: 7.2%). The mutational burden of JAK2 remained stable in multiple determinations, with minor fluctuations independent of BCR-ABL1 kinetics. At the last available time point, the patient was in deep molecular response (MR4), the JAK2 mutational burden was 7%, and no clinical-laboratory findings of Ph-MPN were detectable. Discussion In the presented case, the JAK2variantoccurring during the course of the disease seems to stay in the shadows of CML, just as a bystander. The impact of this event (that may be considered suggestive of clonal hematopoiesis of indeterminate potential) on the disease outcome, even if seemingly irrelevant, has still to be explored

IRF4 Gene Expression on the Trail of Molecular Response: Looking at Chronic Myeloid Leukemia from Another Perspective

IntroductionInterferon regulatory factor 4 (IRF4) is a transcriptional factor with a key role in the modulation of inflammation and immune surveillance. The IRF4 gene is downregulated in Philadelphia-negative myeloproliferative neoplasms, and its expression is associated with prognosis and response to treatment. MethodsWe evaluated the IRF4 expression kinetics during tyrosine kinase inhibitor (TKI) treatment in a cohort of 116 chronic myeloid leukemia (CML) patients to elucidate its role in the disease course. ResultsA relationship between the IRF4 expression and the disease burden was observed at various disease stages. A correlation analysis between the International Scale (IS) and IRF4 values confirmed this close association. A significant increase is detected after 3 months of TKI treatment. Patients achieving early molecular response (EMR) had higher IRF4 values at both diagnosis and after 3 months of therapy as compared to those failing the EMR target. Patients achieving treatment-free remission (TFR) did not show IRF4 fluctuations during monitoring, while a decreased IRF4 expression emerged at the time of molecular relapse.ConclusionOur data seem to confirm the relevance of IRF4 in the pathogenesis of CML, suggesting a pivotal role at the disease onset and a predictive value during the CML course

Hybrid external fixation in the treatment of tibial pilon fractures: A retrospective analysis of 162 fractures

Objectives: To determine the efficacy of hybrid external fixation in the treatment of tibial pilon fractures.Design: Retrospective, multicentre study.Patients/Participants: Adult patients with tibial pilon fractures treated with hybrid external fixation.Intervention: Fracture reduction with ligamentotaxis and fixation with XCaliber hybrid external fixator.Main outcome measurements: Fracture union, complications, functional outcome (Mazur Ankle Score).Results: Union was obtained in 159 fractures at an average of 125 days; there were three delayed unions and three non-unions. The most frequent complication was superficial pin-track infections (48), all of which responded to local wound care and antibiotics. There were no deep infections and no DVT. Only one fracture had loss of reduction that required frame revision. The overall functional scores were 91 (excellent) for AO/OTA type A fractures, 89 (good) for type B fractures, and 75 (satisfactory) for type C fractures.Conclusions: Hybrid external fixation is an effective method of stabilising tibial pilon fractures, particularly those with marked comminution. The minimally-invasive technique and stable fixation enable early mobilisation, with good functional results and minimal complications. Level of evidence: Level IV Case series. (C) 2016 Elsevier Ltd. All rights reserved