Risk‐tailored CNS prophylaxis in a mono‐institutional series of 200 patients with diffuse large B‐cell lymphoma treated in the rituximab era

The most effective strategy to prevent central nervous system (CNS) dissemination in diffuse large B‐cell lymphoma (DLBCL) remains an important, unmet clinical need. Herein, we report a retrospective analysis of risk‐tailored CNS prophylaxis in 200 human immunodeficiency virus‐negative adults with DLBCL treated with rituximab‐CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or similar. High risk of CNS relapse was defined by involvement of specific extranodal organs, or simultaneous presence of advanced stage and high serum lactate dehydrogenase level; CNS prophylaxis with high‐dose methotrexate ± intrathecal chemotherapy (IT) was routinely used in high‐risk patients diagnosed after 2007. CNS relapse risk was low in 93 patients and high in 107; 40 high‐risk patients received prophylaxis, which consisted of IT alone in 7. At a median follow‐up of 60 months, one low‐risk and nine high‐risk patients (1% vs. 8%; P = 0·01) experienced CNS relapse. In the high‐risk group, CNS relapses occurred in 8/67 (12%) patients who did not receive prophylaxis and in 1/40 (2·5%) patients who did; the latter occurred in a patient managed with IT alone. CNS relapse rate was 12% (9/74) for patients treated with “inadequate” prophylaxis (none or IT only) and 0% (0/33) for patients managed with intravenous prophylaxis (P = 0·03). In conclusion, high‐dose methotrexate‐based prophylaxis significantly reduces CNS failures in high‐risk patients stratified by involvement of specific extranodal sites and International Prognostic Index.     

The cytisine derivatives,CC4 and CC26, reduce nicotine-induced conditioned place preference in zebrafish by acting on heteromeric neuronal nicotinic acetylcholine receptors

Rationale

Cigarette smoking is one of the most serious health problems worldwide and people trying to stop smoking have high rates of relapse. Zebrafish (Danio rerio), by combining pharmacological and behavioral assays, is a promising animal model for rapidly screening new compounds to induce smoking cessation.

Objectives

This study aims to identify possible acetylcholine nicotinic receptors (nAChRs) involved in mediating nicotine (NIC)-induced conditioned place preference (CPP) in zebrafish and investigate the effect of the CC4 and CC26 cytisine derivatives in reducing NIC-induced CPP.

Methods

CPP was evaluated using a two-compartment chamber, and the zebrafish were given CC4 (0.001–5 mg/kg), CC26 (0.001–1 mg/kg), cytisine (0.1–2.5 mg/kg), and varenicline (1–10 mg/kg) alone or with NIC (0.001 mg/kg). Swimming activity was evaluated using a square observational chamber. The affinity of the nicotinic ligands for native zebrafish brain nAChRs was evaluated by binding studies using [³H]-Epibatidine (Epi) and [¹²⁵I]-αBungarotoxin (αBgtx) radioligands, and their subtype specificity was determined by means of electrophysiological assay of oocyte-expressed α4β2 and α7 subtypes.

Results

CC4 and CC26 induced CPP with an inverted U-shaped dose–response curve similar to that of NIC. However, when co-administered with NIC, they blocked its reinforcing or slightly aversive effect. Binding and electrophysiological studies showed that this effect was due to binding to high-affinity heteromeric but not α7-containing receptors.

Conclusions

We have further characterized CC4 and identified a new compound (CC26) that may be active in inducing smoking cessation. Zebrafish is a very useful model for screening new compounds that can affect the rewarding properties of NIC.     

Autoantibodies against a 72-kDa ductal cell membrane glycoprotein in a patient affected by Sjögren's syndrome and gastric MALT lymphoma

Sj?gren's syndrome is a chronic autoimmune disease affecting exocrine glands, resulting in xerostomia and xerophthalmia. Lymphocytic infiltration and fibrosis of exocrine glands as well as the presence of autoantibodies against organ-specific and non-organ-specific antigens are the hallmarks of the disease. We investigated whether some patients affected by Sj?gren's syndrome might have autoantibodies directed against epithelial duct cell membrane proteins. We screened sera from patients affected by Sj?gren's syndrome by indirect immunofluorescence on monkey salivary gland sections and FG-Met-2 cells (a pancreatic carcinoma cell line with ductal features) for the presence of antisalivary duct antibodies. Positive sera were employed in immunoprecipitation experiments on (35)S-methionine in vivo labeled and surface-biotinylated FG-Met-2 cells. The serum of a patient affected by Sj?gren's syndrome and gastric mucosa-associated lymphoid tissue (MALT) lymphoma gave positive and distinct membrane immunostaining on FG-Met-2 cells. Immunoprecipitation with the patient's serum from (35)S-methionine-labeled cell extracts followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis (PAGE) and autoradiography showed the presence of autoantibodies against a 72-kDa protein. After biotin-surface labeling of FG-Met-2 cells, a band with identical electrophoretic mobility was immunoprecipitated by the serum, demonstrating that the 72-kDa band is a membrane glycoprotein. We demonstrated by three complementary approaches, i.e., immunocytochemistry, (35)S-methionine in vivo labeling, and cell surface biotinylation, the presence of autoantibodies directed against a duct cell membrane protein of 72-kDa in a patient affected by Sj?gren's syndrome and gastric MALT lymphoma. Autoantibodies directed against this novel membrane autoantigen may be an additional serological marker in some cases of Sj?gren's syndrome.     

Can the pivot-shift be eliminated by anatomic double-bundle anterior cruciate ligament reconstruction?

Purpose  

To assess the ability of anatomic double-bundle anterior cruciate ligament reconstruction in eliminating the pivot-shift phenomenon when identified by a quantitative measuring system (computer navigation or magnetic resonance imaging).     

Surgical Technique: Articulated External Fixator for Treatment of Complex Knee Dislocation

Background  

Knee dislocation is a severe but relatively uncommon injury caused by violent trauma that can result in long-term complications, such as arthrofibrosis, stiffness, instability, and pain. Perhaps owing in part to its rarity, treatment of this injury is controversial. We therefore describe a treatment approach for these complex cases involving a novel dynamic knee external fixator.