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Introduction Nonunions remain a significant burden in orthopedics, often afflicting young males of working age. Positive findings have been published using bone marrow aspirate concentrate (BMAC) and platelet-rich fibrin (PRF) for the treatment augmentation of lower limb nonunions. The aim of this study was to investigate if the treatment augmentation with BMAC and PRF can also accelerate the healing of nonunions of the upper limb. Materials and methods Sixty-eight patients (45 men, 23 women) affected by 75 nonunions of long bones of the upper limb were treated and divided into two groups. The first series was treated with standard surgery alone (group A); afterwards, the second series benefited from standard surgery with the addition of BMAC and PRF applied on lyophilized bone chips. Nonunions were classified radiographically according to the Weber–Cech method and prognostically using the Calori and Moghaddam scores. All patients were radiographically assessed at 1.5, 3, 6, 12, and 24 months of follow-up. Results Baseline demographic characteristics did not present differences between groups. No differences were documented in terms of complications (two in group A and three in group B). Significant differences were instead documented in terms of healing time. The first healing signs were observed 1.5 months after surgery in 90.7% of patients in group B and 34.4% of group A (p p p = 0.001). Conclusion This study showed the benefits of restoring both mechanical and biological aspects when addressing nonunions of the long bones of the upper limb. In particular, the association of BMAC and PRF to lyophilized bone chips was safe and able to accelerate healing time. These good results were confirmed for humerus, radius, and ulna sites, as well as for challenging atrophic nonunions of the upper limb.

The role of monocytes/macrophages in the development and progression of chronic lymphocytic leukemia (CLL) is poorly understood. Transcriptomic analyses show that monocytes/macrophages and leukemic cells cross talk during CLL progression. Macrophage depletion impairs CLL engraftment, drastically reduces leukemic growth, and favorably impacts mouse survival. Targeting of macrophages by either CSF1R signaling blockade or clodrolip-mediated cell killing has marked inhibitory effects on established leukemia also. Macrophage killing induces leukemic cell death mainly via the TNF pathway and reprograms the tumor microenvironment toward an antitumoral phenotype. CSF1R inhibition reduces leukemic cell load, especially in the bone marrow, and increases circulating CD20(+) leukemic cells. Accordingly, co-targeting TAMs and CD20-expressing leukemic cells provides a survivalbenefit in the mice. These results establish the important role of macrophages in CLL and suggest therapeutic strategies based on interfering with leukemia-macrophage interactions.

Background Radial head fractures make up approximately 3% of all fractures and they are the most common elbow fracture in adults. Replacement through arthroplasty is the recommended treatment in the context of unstable elbow injury and comminuted radial head fracture. The midterm clinical, functional, and radiographic results in patients treated with anatomic radial head arthroplasty for a Mason type III radial head fracture are presented. Material and methods We performed a retrospective search of our facility's prospective trauma database to identify all skeletally mature patients who were treated by primary radial head replacement or open reduction and internal fixation following an acute radial head fracture. Inclusion criteria were Mason type III fractures and anatomic radial head arthroplasty (RHA). All the patients included were evaluated using a standard postoperative protocol including clinical and radiographic evaluation at 1, 3 and 12 months of follow-up. All the patients were reviewed clinically at an average of 30 months’ follow-up. Results Forty-one subjects (32 Mason type III and 9 Mason IV fractures) were treated with anatomic RHA (Acumed, Hillsboro, OR, USA). Of these, two patients (1 Mason type III and 1 Mason type IV) were excluded from the analysis because severe cognitive impairment. Moreover, we decided to exclude the subjects with a Mason type IV fracture to obtain a more homogeneous sample. Therefore, 31 patients with a Mason type III fracture were included in this study. Based on the Mayo Elbow Performance Score, excellent results were obtained in 24 (77%) patients, good in 3 (10%) and fair in 4 (13%) patients. Heterotopic ossification was reported in 8 patients (26% of cases). The final elbow flexion-extension range of motion was of 112°, with a mean flexion of 125°. The final forearm rotational range of motion was 134° with a mean pronation of 68° and a mean supination of 66°. Discussion Anatomic radial head replacement leads to a good functional recovery, even in the presence of severe instability, such as coronoid fractures and LUCL injury. However, patients should be informed of the high number of adverse events (mainly heterotopic ossification) following this treatment. Level of evidence Therapeutic IV.

Distal humeral malunions are uncommon injuries, often associated with limited elbow motion, pain, instability, weakness, and sometimes ulnar neuritis. The complex anatomy of the elbow joint makes this condition one of the most complex elbow injuries to treat. Four patients were treated by the same surgeon between 2011 and 2013 using a double-locking precontoured plating system for malunited intra-articular or extra-articular fractures of the distal end of the humerus. At a mean 3 years of follow-up, a significant improvement in the elbow motion and functional outcome, evaluated with the Mayo Elbow Performance Index and the Disability of the Arm, Shoulder, and Hand, were observed. Articular reduction obtained after the surgery was maintained in all patients without evidence of avascular necrosis. No other complications (i.e., infection, nervous iatrogenic lesions) were reported. Corrective osteotomy using double-locking precontoured plating system preceded by preoperative planning using a CT scan allowed an improvement in the functional outcome and elbow motion, without complications.

Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R-like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR/ILR family which inhibits other family members. To test the hypothesis that TLR and/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed E mu-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression. (Blood. 2011;118(3):660-669) "Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R-like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR\/ILR family which inhibits other family members. To test the hypothesis that TLR and\/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed E mu-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression. (Blood. 2011;118(3):660-669)"

The function of the intracellular protein hematopoietic cell-specific Lyn substrate-1 (HS1) in B lymphocytes is poorly defined. To investigate its role in migration, trafficking, and homing of leukemic B lymphocytes we have used B cells from HS1(-/-) mice, the HS1-silenced human chronic lymphocytic leukemia (CLL) MEC1 cell line and primary leukemic B cells from patients with CLL. We have used both in vitro and in vivo models and found that the lack of expression of HS1 causes several important functional effects. In vitro, we observed an impaired cytoskeletal remodeling that resulted in diminished cell migration, abnormal cell adhesion, and increased homotypic aggregation. In vivo, immunodeficient Rag2(-/-)gamma(-/-)(c) mice injected with HS1-silenced CLL B cells showed a decreased organ infiltration with the notable exception of the bone marrow (BM). The leukemic-prone E mu-TCL1 transgenic mice crossed with HS1-deficient mice were compared with E mu-TCL1 mice and showed an earlier disease onset and a reduced survival. These findings show that HS1 is a central regulator of cytoskeleton remodeling that controls lymphocyte trafficking and homing and significantly influences the tissue invasion and infiltration in CLL. (Blood. 2010;116(18):3537-3546) The function of the intracellular protein hematopoietic cell-specific Lyn substrate-1 (HS1) in B lymphocytes is poorly defined. To investigate its role in migration, trafficking, and homing of leukemic B lymphocytes we have used B cells from HS1(-/-) mice, the HS1-silenced human chronic lymphocytic leukemia (CLL) MEC1 cell line and primary leukemic B cells from patients with CLL. We have used both in vitro and in vivo models and found that the lack of expression of HS1 causes several important functional effects. In vitro, we observed an impaired cytoskeletal remodeling that resulted in diminished cell migration, abnormal cell adhesion, and increased homotypic aggregation. In vivo, immunodeficient Rag2(-/-)gamma(-/-)(c) mice injected with HS1-silenced CLL B cells showed a decreased organ infiltration with the notable exception of the bone marrow (BM). The leukemic-prone E mu-TCL1 transgenic mice crossed with HS1-deficient mice were compared with E mu-TCL1 mice and showed an earlier disease onset and a reduced survival. These findings show that HS1 is a central regulator of cytoskeleton remodeling that controls lymphocyte trafficking and homing and significantly influences the tissue invasion and infiltration in CLL. (Blood. 2010;116(18):3537-3546)

Easily reproducible animal models that allow for study of the biology of chronic lymphocytic leukemia (CLL) and to test new therapeutic agents have been very difficult to establish. We have developed a novel transplantable xenograft murine model of CLL by engrafting the CLL cell line MEC1 into Rag2(-/-)gamma(-/-)(c) mice. These mice lack B, T, and natural killer (NK) cells, and, in contrast to nude mice that retain NK cells, appear to be optimal recipient for MEC1 cells, which were successfully transplanted through either subcutaneous or intravenous routes. The result is a novel in vivo model that has systemic involvement, develops very rapidly, allows the measurement of tumor burden, and has 100% engraftment efficiency. This model closely resembles aggressive human CLL and could be very useful for evaluating both the biologic basis of CLL growth and dissemination as well as the efficacy of new therapeutic agents. (Blood. 2010;115:1605-1609) Easily reproducible animal models that allow for study of the biology of chronic lymphocytic leukemia (CLL) and to test new therapeutic agents have been very difficult to establish. We have developed a novel transplantable xenograft murine model of CLL by engrafting the CLL cell line MEC1 into Rag2(-/-)gamma(-/-)(c) mice. These mice lack B, T, and natural killer (NK) cells, and, in contrast to nude mice that retain NK cells, appear to be optimal recipient for MEC1 cells, which were successfully transplanted through either subcutaneous or intravenous routes. The result is a novel in vivo model that has systemic involvement, develops very rapidly, allows the measurement of tumor burden, and has 100% engraftment efficiency. This model closely resembles aggressive human CLL and could be very useful for evaluating both the biologic basis of CLL growth and dissemination as well as the efficacy of new therapeutic agents. (Blood. 2010;115:1605-1609)