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Progressive multifocal leukoencephalopathy (PML), a rare devastating demyelinating disease caused by the polyomavirus JC (JCV), occurs in severely immunocompromised patients, most of whom have advanced-stage HIV infection. Despite combination antiretroviral therapy (cART), 50% of patients die within 6 months of PML onset. We conducted a multicenter, open-label pilot trial evaluating the survival benefit of a five-drug cART designed to accelerate HIV replication decay and JCV-specific immune recovery. All the patients received an optimized cART with three or more drugs for 12 months, plus the fusion inhibitor enfuvirtide during the first 6 months. The main endpoint was the one-year survival rate. A total of 28 patients were enrolled. At entry, median CD4+ T-cell count was 53 per microliter and 86% of patients had detectable plasma HIV RNA and CSF JCV DNA levels. Seven patients died, all before month 4. The one-year survival estimate was 0.75 (95% confidence interval, 0.61 to 0.93). At month 6, JCV DNA was undetectable in the CSF of 81% of survivors. At month 12, 81% of patients had undetectable plasma HIV RNA, and the median CD4+ T-cell increment was 105 per microliter. In univariate analysis, higher total and naive CD4+ T-cell counts and lower CSF JCV DNA level at baseline were associated with better survival. JCV-specific functional memory CD4+ T-cell responses, based on a proliferation assay, were detected in 4% of patients at baseline and 43% at M12 (P = 0.008). The early use of five-drug cART after PML diagnosis appears to improve survival. This is associated with recovery of anti-JCV T-cell responses and JCV clearance from CSF. A low CD4+ T-cell count (particularly naive subset) and high JCV DNA copies in CSF at PML diagnosis appear to be risk factors for death. ClinicalTrials.gov NCT00120367.

Classical Hodgkin Lymphoma incidence increases in HIV-1-infected patients (HIV-cHL). HIV infection is associated with higher B-cell activation. Here, in 38 HIV-cHL patients from the French cohort ANRS-CO16 Lymphovir, we examined longitudinally over 24 months the serum levels of the B-cell activating cytokines IL10, IL6, and BAFF, and blood distribution of B-cell subsets. Fourteen HIV-cHL patients were also compared to matched HIV-infected controls without cHL. IL10, IL6, and BAFF levels were higher in HIV-cHL patients than in controls (p < 0.0001, p = 0.002, and p < 0.0001, respectively). Cytokine levels increased in patients with advanced-stage lymphoma compared to those with limited-stage (p = 0.002, p = 0.03, and p = 0.01, respectively). Cytokine levels significantly decreased following HIV-cHL diagnosis and treatment. Blood counts of whole B-cells were similar in HIV-cHL patients and controls, but the distribution of B-cell subsets was different with higher ratios of naive B-cells over memory B-cells in HIV-cHL patients. Blood accumulation of naive B-cells was more marked in patients with advanced cHL stages (p = 0.06). During the follow-up, total B-cell counts increased (p < 0.0001), and the proportion of naive B-cells increased further (p = 0.04). Together the results suggest that in HIV-infected patients, cHL is associated with a particular B-cell-related environment that includes increased production of B-cell-activating cytokines and altered peripheral distribution of B-cell subsets. This B-cell-related environment may fuel the process of tumorigenesis.

We designed a prospective multicentre outcome study to evaluate a diagnostic strategy based on clinical probability, spiral CT, and venous compression ultra-sonography of the legs in patients with suspected pulmonary embolism (PE). The main aim was to assess the safety of withholding anticoagulant treatment in patients with low or intermediate clinical probability of PE and negative findings on spiral CT and ultrasonography. 1041 consecutive inpatients and outpatients with suspected PE were included. Patients with negative spiral CT and ultrasonography and clinically assessed as having a low or intermediate clinical probability were left untreated. Those with high clinical probability underwent lung scanning, pulmonary angiography, or both. All patients were followed up for 3 months. PE was diagnosed in 360 (34–6%) patients; 55 had positive ultrasonography despite negative spiral CT. Of 601 patients with negative spiral CT and ultrasonography, 76 were clinically assessed as having a high probability of PE; lung scanning or angiography showed PE in four (5·3% [95% Cl 1·5–13·1]). The remaining 525 patients were assessed as having low or intermediate clinical probability, and 507 of them were not treated. Of these patients, nine experienced venous thromboembolism during follow-up (1·8% [0·8–3·3]). The diagnostic strategy proved inconclusive in 95 (9·1%) patients, and pulmonary angiography was done in 74 (7·1%). Withholding of anticoagulant therapy is safe when the clinical probability of PE is assessed as low or intermediate and spiral CT and ultrasonography are negative. Published online Nov 26, 2002 http://image.thelancet.com/extras/02art2278web.pdf

This retrospective study included 914 patients who underwent a lymph node dissection at our institute between 1980 and 1985. The primary tumor sites were oral cavity, 287; hypopharynx, 249; larynx, 247; and oropharynx, 131. On the basis of anatomic considerations, the sentinel nodes for well-lateralized oral cavity tumors were defined as homolateral levels I, II, and III; for oropharyngeal, hypopharyngeal, and laryngeal tumors, the sentinel nodes were defined as levels II and III. We took into account the ipsilateral side of the neck for well-lateralized tumors, and both sides for medium or large tumors. For clinically positive nodes of more than 3 cm, a radical neck dissection was performed. Other patients underwent a selective neck dissection on sentinel nodes, with immediate pathologic evaluation. Modified radical neck dissections with contralateral selective dissection were performed when frozen sections were positive. Patients with positive nodes were given postoperative radiotherapy. The prognostic factors studied, using the Cox survival model adjusted on the primary tumor site, surprisingly showed a nonsignificant value for extracapsular spread ( P = 0.09), and a significant value for the number of positive nodes ( P <0.001) and for the positive node in or out of the sentinel node sites ( P <0.001). Although the node location factor can be used instead of positive node in or out of the sentinel node site, it has a less significant prognostic value. The most significant prognostic factors are the site of the positive node in or out of the sentinel node and the number of positive nodes; and a more accurate approach can be obtained by combining both factors. Node location in the upper or lower neck remains a substitute prognostic factor for the site of the positive node in or out of the sentinel node.

Human immunodeficiency virus (HIV) infection is associated with a high risk of classical Hodgkin's lymphoma (cHL) in the combined antiretroviral therapy (cART) era. We analyzed the characteristics and outcome of HIV-associated cHL diagnosed in the modern cART era. The French ANRS-CO16 Lymphovir cohort enrolled 159 HIV-positive patients with lymphoma, including 68 (43%) with cHL. HIV-HL patients were compared with a series of non-HV-infected patients consecutively diagnosed with HL. Most patients (76%) had Ann-Arbor stages III-IV and 96% of patients were treated with ABVD. At diagnosis, median CD4 T-cell count was 387/µL and 94% of patients were treated with cART. All patients received cART after diagnosis. Five patients died from early progression (n = 2), sepsis (1) or after relapse (2). Two additional patients relapsed during follow-up. Two-year overall and progression free survivals (PFS) were 94% [95% CI, 89%, 100%] and 89% [82%, 97%], respectively. The only factor associated with progression or death was age with a relative risk of 8.1 [1.0; 67.0] above 45 years. The PFS of Lymphovir patients appeared similar to PFS of HIV-negative patients, 86% [82%, 90%], but patients with HIV infection displayed higher risk features than HIV-negative patients. Although high-risk features still predominate in HIV-HL, the prognosis of these patients, treated with cART and mainly ABVD, has markedly improved in the modern cART era and is now similar to non-HIV-infected patients.

Background. Human immunodeficiency virus (HIV) infection is associated with a high risk of classical Hodgkin's lymphoma (cHL) in the combined antiretroviral therapy (cART) era. Methods. We analyzed the characteristics and outcome of HIV-associated cHL diagnosed in the modern cART era. The French ANRS-CO16 Lymphovir cohort enrolled 159 HIV-positive patients with lymphoma, including 68 (43%) with cHL. HIV-HL patients were compared with a series of non-HV-infected patients consecutively diagnosed with HL. Results. Most patients (76%) had Ann-Arbor stages III-IV and 96% of patients were treated with ABVD. At diagnosis, median CD4 T-cell count was 387/μL and 94% of patients were treated with cART. All patients received cART after diagnosis. Five patients died from early progression (n = 2), sepsis (1) or after relapse (2). Two additional patients relapsed during follow-up. Two-year overall and progression free survivals (PFS) were 94% [95% CI, 89%, 100%] and 89% [82%, 97%], respectively. The only factor associated with progression or death was age with a relative risk of 8.1 [1.0; 67.0] above 45 years. The PFS of Lymphovir patients appeared similar to PFS of HIV-negative patients, 86% [82%, 90%], but patients with HIV infection displayed higher risk features than HIV-negative patients. Conclusions. Although high-risk features still predominate in HIV-HL, the prognosis of these patients, treated with cART and mainly ABVD, has markedly improved in the modern cART era and is now similar to non-HIV-infected patients.

A novel gene, Xenopus Polycomblike 2 (XPcl2), which encodes a protein similar to Drosophila Polycomblike was cloned and characterized. Polycomblike belongs to the Polycomb group proteins, which maintain stable expression patterns for the clustered homeotic genes in the Drosophila embryo by forming multimeric complexes on chromatin. XPcl2 shows greater amino acid sequence homology to human and mouse M96 (hPcl2, mPcl2) than Xenopus Pcl1 (XPcl1), mouse Tctex3 (mPcl1) and human PHF1 (hPcl1), indicating that at least two types of Polycomblike genes are conserved between amphibians and mammals. XPcl2 mRNA is present both maternally and zygotically, and the temporal expression profile is distinct from XPcl1, another member of the Polycomblike family in Xenopus. XPcl2 is highly expressed in the anterior-dorsal region of Xenopus following the neurula stage in a manner similar to XPcl1. Overexpression of XPcl2 disturbs the development of the anterior central nervous system, eye and cement gland. In the XPcl2-overexpressing embryo, a hindbrain marker, Krox20, and a spinal cord marker, HoxB9, are expressed more posteriorly, suggesting an alteration in the anterior-posterior patterning of the neural tissue. In addition, XPcl2 represses Zic3- and noggin-induced anterior neural markers, but not neural crest markers in animal cap explants. These results indicate that XPcl2 regulates anterior neural tissue development and the anterior-posterior patterning of the neural tissue.