Tumor suppressor TNFAIP3 (A20) is frequently deleted in Sézary syndrome.

Despite recent therapeutic improvements, the prognosis for patients suffering from Sézary syndrome (SS), a disseminated form of cutaneous T-cell lymphomas, is still poor. We identified bi- and monoallelic deletions of the tumor necrosis factor-α-induced protein 3 gene (TNFAIP3; A20) in a high proportion of SS patients as well as biallelic A20 deletion in the SS-derived cell line SeAx. Furthermore, we demonstrate that inhibition of A20 activates the NF-κB pathway thereby increasing the proliferation of normal T lymphocytes. On the other hand, the reconstitution of A20 expression slowed down the cell cycle in SeAx cells. Recently A20 inactivation has been reported in various B-cell lymphomas. In this study, we show that A20 is also a putative tumor suppressor in the T-cell malignancy-SS.

Inhibition of BCL11B expression leads to apoptosis of malignant but not normal mature T cells.

The B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11B gene (BCL11B) encodes a Krüppel-like zinc-finger protein, which plays a crucial role in thymopoiesis and has been associated with hematopoietic malignancies. It was hypothesized that BCL11B may act as a tumor-suppressor gene, but its precise function has not yet been elucidated. Here, we demonstrate that the survival of human T-cell leukemia and lymphoma cell lines is critically dependent on Bcl11b. Suppression of Bcl11b by RNA interference selectively induced apoptosis in transformed T cells whereas normal mature T cells remained unaffected. The apoptosis was effected by simultaneous activation of death receptor-mediated and intrinsic apoptotic pathways, most likely as a result of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) upregulation and suppression of the Bcl-xL antiapoptotic protein. Our data indicate an antiapoptotic function of Bcl11b. The resistance of normal mature T lymphocytes to Bcl11b suppression-induced apoptosis and restricted expression pattern make it an attractive therapeutic target in T-cell malignancies.

Smokers with airway obstruction are more likely to quit smoking.

BACKGROUND: Chronic obstructive pulmonary disease (COPD), usually caused by tobacco smoking, is one of the leading causes of morbidity and mortality. Smoking cessation at an early stage of the disease usually stops further progression. A study was undertaken to determine if diagnosis of airway obstruction was associated with subsequent success in smoking cessation, as advised by a physician. METHODS: 4494 current smokers (57.4% men) with a history of at least 10 pack-years of smoking were recruited from 100 000 subjects screened by spirometric testing for signs of airway obstruction. At the time of screening all received simple smoking cessation advice. 1177 (26.2%) subjects had airway obstruction and were told that they had COPD and that smoking cessation would halt rapid progression of their lung disease. No pharmacological treatment was proposed. After 1 year all subjects were invited for a follow up visit. Smoking status was assessed by history and validated by exhaled carbon monoxide level. RESULTS: Nearly 70% attended a follow up visit (n = 3077): 61% were men, mean (SD) age was 52 (10) years, mean (SD) tobacco exposure 30 (17) pack-years, and 33.3% had airway obstruction during the baseline examination. The validated smoking cessation rate in those with airway obstruction was 16.3% compared with 12.0% in those with normal spirometric parameters (p = 0.0003). After correction for age, sex, nicotine dependence, number of cigarettes smoked daily, and lung function, success in smoking cessation was predicted by lower lung function, lower nicotine dependence, and lower tobacco exposure. CONCLUSIONS: Simple smoking cessation advice combined with spirometric testing resulted in good 1 year cessation rates, especially in subjects with airway obstruction.

Disruption of the BCL11B gene through inv(14)(q11.2q32.31) results in the expression of BCL11B-TRDC fusion transcripts and is associated with the absence of wild-type BCL11B transcripts in T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is associated with chromosomal aberrations characterized by juxtaposition of proto-oncogenes to T-cell receptor gene loci (TCR), resulting in the deregulated transcription of these proto-oncogenes. Here, we describe the molecular characterization of a novel chromosomal aberration, inv(14)(q11.2q32.31), in a T-ALL sample, involving the recently described BCL11B gene and the TCRD locus. The inversion joined the 5' part of BCL11B, including exons 1-3, to the TRDD3 gene segment of the TCRD locus, whereas the reciprocal breakpoint fused the TRDV1 gene segment to the fourth exon of BCL11B. The TRDV1-BCL11B joining region was 1344 bp long and contained fragments derived from 20q11.22, 3p21.33 and from 11p12, indicating the complex character of this aberration. A strong expression of in-frame transcripts with truncated BCL11B and TCRD constant region (TRDC) were observed, but in contrast to normal T cells and other T-ALL samples, no wild-type BCL11B transcripts were detected in the T-ALL sample. Screening of 37 other T-ALLs revealed one additional case with expression of the BCL11B-TRDC fusion transcript. As BCL11B appears to play a key role in T-cell differentiation, BCL11B disruption and disturbed expression may contribute to the development of T-cell malignancies in man.

Isolated fractures of the atlas in adults.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment options in the management of isolated fractures of the atlas are based on the specific atlas fracture type. It is recommended that isolated fractures of the atlas with an intact transverse atlantal ligament be treated with cervical immobilization alone. It is recommended that isolated fractures of the atlas with disruption of the transverse atlantal ligament be treated with either cervical immobilization alone or surgical fixation and fusion.

Isolated fractures of the axis in adults.

UNLABELLED: FRACTURES OF THE ODONTOID: STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: Type II odontoid fractures in patients 50 years and older should be considered for surgical stabilization and fusion. OPTIONS: Type I, Type II, and Type III fractures may be managed initially with external cervical immobilization. Type II and Type III odontoid fractures should be considered for surgical fixation in cases of dens displacement of 5 mm or more, comminution of the odontoid fracture (Type IIA), and/or inability to achieve or maintain fracture alignment with external immobilization. TRAUMATIC SPONDYLOLISTHESIS OF THE AXIS (HANGMAN'S FRACTURE): STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Traumatic spondylolisthesis of the axis may be managed initially with external immobilization in most cases. Surgical stabilization should be considered in cases of severe angulation of C2 on C3 (Francis Grade II and IV, Effendi Type II), disruption of the C2--C3 disc space (Francis Grade V, Effendi Type III), or inability to establish or maintain alignment with external immobilization. FRACTURES OF THE AXIS BODY (MISCELLANEOUS FRACTURES): STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: External immobilization is recommended for treatment of isolated fractures of the axis body.

Management of combination fractures of the atlas and axis in adults.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment of atlas-axis combination fractures based primarily on the specific characteristics of the axis fracture is recommended. External immobilization of most C1--C2 combination fractures is recommended. C1--Type II odontoid combination fractures with an atlantodens interval of 5 mm or more and C1--hangman's combination fractures with C2--C3 angulation of 11 degrees or more should be considered for surgical stabilization and fusion. In some cases, the surgical technique must be modified as a result of loss of the integrity of the ring of the atlas.

Os odontoideum.

STANDARDS: There is insufficient evidence to support diagnostic standards. GUIDELINES: There is insufficient evidence to support diagnostic guidelines. OPTIONS: Plain x-rays of the cervical spine (anteroposterior, open-mouth odontoid, and lateral) and plain dynamic lateral x-rays performed in flexion and extension are recommended. Tomography (computed or plain) and/or magnetic resonance imaging of the craniocervical junction may be considered. STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Patients with os odontoideum, either with or without C1--C2 instability, who have neither symptoms nor neurological signs may be managed with clinical and radiographic surveillance. Patients with os odontoideum, particularly with neurological symptoms and/or signs, and C1--C2 instability may be managed with posterior C1--C2 internal fixation and fusion. Postoperative halo immobilization as an adjunct to posterior internal fixation and fusion is recommended unless successful C1--C2 transarticular screw fixation and fusion can be accomplished. Occipitocervical fusion with or without C1 laminectomy may be considered in patients with os odontoideum who have irreducible cervicomedullary compression and/or evidence of associated occipitoatlantal instability. Transoral decompression may be considered in patients with os odontoideum who have irreducible ventral cervicomedullary compression.

Treatment of subaxial cervical spinal injuries.

UNLABELLED: SUBAXIAL CERVICAL FACET DISLOCATION INJURIES: STANDARDS: There is insufficient evidence to recommend treatment standards. GUIDELINES: There is insufficient evidence to recommend treatment guidelines. OPTIONS: Closed or open reduction of subaxial cervical facet dislocation injuries is recommended. Treatment of subaxial cervical facet dislocation injuries with rigid external immobilization, anterior arthrodesis with plate fixation, or posterior arthrodesis with plate or rod or interlaminar clamp fixation is recommended. Treatment of subaxial cervical facet dislocation injuries with prolonged bedrest in traction is recommended if more contemporary treatment options are not available. SUBAXIAL CERVICAL INJURIES EXCLUDING FACET DISLOCATION INJURIES: STANDARDS: There is insufficient evidence to recommend treatment standards. GUIDELINES: There is insufficient evidence to recommend treatment guidelines. OPTIONS: Closed or open reduction of subluxations or displaced subaxial cervical spinal fractures is recommended. Treatment of subaxial cervical spinal injuries with external immobilization, anterior arthrodesis with plate fixation, or posterior arthrodesis with plate or rod fixation is recommended.

Management of acute central cervical spinal cord injuries.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Intensive care unit (or other monitored setting) management of patients with acute central cervical spinal cord injuries, particularly patients with severe neurological deficits, is recommended. Medical management, including cardiac, hemodynamic, and respiratory monitoring, and maintenance of mean arterial blood pressure at 85 to 90 mmHg for the first week after injury to improve spinal cord perfusion is recommended. Early reduction of fracture-dislocation injuries is recommended. Surgical decompression of the compressed spinal cord, particularly if the compression is focal and anterior, is recommended.

Management of vertebral artery injuries after nonpenetrating cervical trauma.

STANDARDS: There is insufficient evidence to support diagnostic standards. GUIDELINES: There is insufficient evidence to support diagnostic guidelines. OPTIONS: Conventional angiography or magnetic resonance angiography is recommended for the diagnosis of vertebral artery injury after nonpenetrating cervical trauma in patients who have complete cervical spinal cord injuries, fracture through the foramen transversarium, facet dislocation, and/or vertebral subluxation. STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Anticoagulation with intravenous heparin is recommended for patients with vertebral artery injury who have evidence of posterior circulation stroke. Either observation or treatment with anticoagulation in patients with vertebral artery injuries and evidence of posterior circulation ischemia is recommended. Observation in patients with vertebral artery injuries and no evidence of posterior circulation ischemia is recommended.

Cervical spine immobilization before admission to the hospital.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: All trauma patients with a cervical spinal column injury or with a mechanism of injury having the potential to cause cervical spine injury should be immobilized at the scene and during transport by using one of several available methods. A combination of a rigid cervical collar and supportive blocks on a backboard with straps is effective in limiting motion of the cervical spine and is recommended. The long-standing practice of attempted cervical spine immobilization using sandbags and tape alone is not recommended.

Transportation of patients with acute traumatic cervical spine injuries.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Expeditious and careful transport of patients with acute cervical spine or spinal cord injuries is recommended, from the site of injury by the most appropriate mode of transportation available to the nearest capable definitive care medical facility.

Clinical assessment after acute cervical spinal cord injury.

UNLABELLED: NEUROLOGICAL EXAMINATION: STANDARDS: There is insufficient evidence to support neurological examination standards. GUIDELINES: There is insufficient evidence to support neurological examination guidelines. OPTIONS: The American Spinal Injury Association international standards for neurological and functional classification of spinal cord injury are recommended as the preferred neurological examination tool for clinicians involved in the assessment and care of patients with acute spinal cord injuries. FUNCTIONAL OUTCOME ASSESSMENT: STANDARDS: There is insufficient evidence to support functional outcome assessment standards. GUIDELINES: The Functional Independence Measure is recommended as the functional outcome assessment tool for clinicians involved in the assessment and care of patients with acute spinal cord injuries. OPTIONS: The modified Barthel index is recommended as a functional outcome assessment tool for clinicians involved in the assessment and care of patients with acute spinal cord injuries.

Radiographic assessment of the cervical spine in asymptomatic trauma patients.

STANDARDS: Radiographic assessment of the cervical spine is not recommended in trauma patients who are awake, alert, and not intoxicated, who are without neck pain or tenderness, and who do not have significant associated injuries that detract from their general evaluation.

Radiographic assessment of the cervical spine in symptomatic trauma patients.

STANDARDS: A three-view cervical spine series (anteroposterior, lateral, and odontoid views) is recommended for radiographic evaluation of the cervical spine in patients who are symptomatic after traumatic injury. This should be supplemented with computed tomography (CT) to further define areas that are suspicious or not well visualized on the plain cervical x-rays. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: It is recommended that cervical spine immobilization in awake patients with neck pain or tenderness and normal cervical spine x-rays (including supplemental CT as necessary) be discontinued after either a) normal and adequate dynamic flexion/extension radiographs, or b) a normal magnetic resonance imaging study is obtained within 48 hours of injury. Cervical spine immobilization in obtunded patients with normal cervical spine x-rays (including supplemental CT as necessary) may be discontinued a) after dynamic flexion/extension studies performed under fluoroscopic guidance, or b) after a normal magnetic resonance imaging study is obtained within 48 hours of injury, or c) at the discretion of the treating physician.