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.

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.

Initial closed reduction of cervical spine fracture-dislocation injuries.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. Early closed reduction of cervical spine fracture-dislocation injuries with craniocervical traction is recommended to restore anatomic alignment of the cervical spine in awake patients. Closed reduction in patients with an additional rostral injury is not recommended. Patients with cervical spine fracture-dislocation injuries who cannot be examined during attempted closed reduction, or before open posterior reduction, should undergo magnetic resonance imaging (MRI) before attempted reduction. The presence of a significant disc herniation in this setting is a relative indication for a ventral decompression before reduction. MRI study of patients who fail attempts at closed reduction is recommended. Prereduction MRI performed in patients with cervical fracture dislocation injury will demonstrate disrupted or herniated intervertebral discs in one-third to one-half of patients with facet subluxation. These findings do not seem to significantly influence outcome after closed reduction in awake patients; therefore, the usefulness of prereduction MRI in this circumstance is uncertain.

Pharmacological therapy after acute cervical spinal cord injury.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment with methylprednisolone for either 24 or 48 hours is recommended as an option in the treatment of patients with acute spinal cord injuries that should be undertaken only with the knowledge that the evidence suggesting harmful side effects is more consistent than any suggestion of clinical benefit. GM-1 GANGLIOSIDE: STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment of patients with acute spinal cord injuries with GM-1 ganglioside is recommended as an option without demonstrated clinical benefit.

Blood pressure management after acute spinal cord injury.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Hypotension (systolic blood pressure <90 mmHg) should be avoided if possible or corrected as soon as possible after acute spinal cord injury. Maintenance of mean arterial blood pressure at 85 to 90 mmHg for the first 7 days after acute spinal cord injury to improve spinal cord perfusion is recommended.

Deep venous thrombosis and thromboembolism in patients with cervical spinal cord injuries.

STANDARDS: Prophylactic treatment of thromboembolism in patients with severe motor deficits due to spinal cord injury is recommended. The use of low-molecular-weight heparins, rotating beds, adjusted dose heparin, or a combination of modalities is recommended as a prophylactic treatment strategy. Low-dose heparin in combination with pneumatic compression stockings or electrical stimulation is recommended as a prophylactic treatment strategy. GUIDELINES: Low-dose heparin therapy alone is not recommended as a prophylactic treatment strategy. Oral anticoagulation alone is not recommended as a prophylactic treatment strategy. OPTIONS: Duplex Doppler ultrasound, impedance plethysmography, and venography are recommended for use as diagnostic tests for deep venous thrombosis in the spinal cord-injured patient population. A 3-month duration of prophylactic treatment for deep venous thrombosis and pulmonary embolism is recommended. Vena cava filters are recommended for patients who do not respond to anticoagulation or who are not candidates for anticoagulation therapy and/or mechanical devices.

Nutritional support after spinal cord injury.

STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Nutritional support of patients with spinal cord injuries is recommended. Energy expenditure is best determined by indirect calorimetry in these patients because equation estimates of energy expenditure and subsequent caloric need tend to be inaccurate.

Management of pediatric cervical spine and spinal cord injuries.

STANDARDS: There is insufficient evidence to support diagnostic standards. GUIDELINES: In children who have experienced trauma and are alert, conversant, have no neurological deficit, no midline cervical tenderness, and no painful distracting injury, and are not intoxicated, cervical spine x-rays are not necessary to exclude cervical spine injury and are not recommended. In children who have experienced trauma and who are either not alert, nonconversant, or have neurological deficit, midline cervical tenderness, or painful distracting injury, or are intoxicated, it is recommended that anteroposterior and lateral cervical spine x-rays be obtained. OPTIONS: In children younger than age 9 years who have experienced trauma, and who are nonconversant or have an altered mental status, a neurological deficit, neck pain, or a painful distracting injury, are intoxicated, or have unexplained hypotension, it is recommended that anteroposterior and lateral cervical spine x-rays be obtained. In children age 9 years or older who have experienced trauma, and who are nonconversant or have an altered mental status, a neurological deficit, neck pain, or a painful distracting injury, are intoxicated, or have unexplained hypotension, it is recommended that anteroposterior, lateral, and open-mouth cervical spine x-rays be obtained. Computed tomographic scanning with attention to the suspected level of neurological injury to exclude occult fractures or to evaluate regions not seen adequately on plain x-rays is recommended. Flexion/extension cervical x-rays or fluoroscopy may be considered to exclude gross ligamentous instability when there remains a suspicion of cervical spine instability after static x-rays are obtained. Magnetic resonance imaging of the cervical spine may be considered to exclude cord or nerve root compression, evaluate ligamentous integrity, or provide information regarding neurological prognosis. STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Thoracic elevation or an occipital recess to prevent flexion of the head and neck when restrained supine on an otherwise flat backboard may allow for better neutral alignment and immobilization of the cervical spine in children younger than 8 years because of the relatively large head in these younger children and is recommended. Closed reduction and halo immobilization for injuries of the C2 synchondrosis between the body and odontoid is recommended in children younger than 7 years. Consideration of primary operative therapy is recommended for isolated ligamentous injuries of the cervical spine with associated deformity.

Diagnosis and management of traumatic atlanto-occipital dislocation injuries.

STANDARDS: There is insufficient evidence to support diagnostic standards. GUIDELINES: There is insufficient evidence to support diagnostic guidelines. OPTIONS: A lateral cervical x-ray is recommended for the diagnosis of atlanto-occipital dislocation. If a radiological method for measurement is used, the basion-axial interval-basion-dental interval method is recommended. The presence of upper cervical prevertebral soft tissue swelling on an otherwise nondiagnostic plain x-ray should prompt additional imaging. If there is clinical suspicion of atlanto-occipital dislocation, and plain x-rays are nondiagnostic, computed tomography or magnetic resonance imaging is recommended, particularly for the diagnosis of non-Type II dislocations. STANDARDS: There is insufficient evidence to support treatment standards. GUIDELINES: There is insufficient evidence to support treatment guidelines. OPTIONS: Treatment with internal fixation and arthrodesis using one of a variety of methods is recommended. Traction may be used in the management of patients with atlanto-occipital dislocation, but it is associated with a 10% risk of neurological deterioration.

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.