PROGNOSTIC FACTORS, MANAGEMENT AND OUTCOME OF AN INTERNATIONAL SERIES OF 41 PATIENTS WITH PRIMARY MEDIASTINAL LARGE B‐CELL LYMPHOMA (PMLBCL) AND CENTRAL NERVOUS SYSTEM (CNS) INVOLVEMENT
Andrés J.M. FerreriVittoria TarantinoG. CabrasFelicetto FerraraPier Luigi ZinzaniLuca ArcainiAlessia CastellinoAlessandra TucciFederica CocitoAndrew DaviesM. M.B Salvador ChalupKate CwynarskiFernanda NogueiraLuigi PetrucciCristina MuziDaniela OnofrilloAndrea FerrarioPraveen RamakrishnanPotito Rosario ScalzulliMonica TaniMaria Chiara TisiSotirios G. PapageorgiouTeresa CalimeriPiera AngelilloMarco FoppoliMaria DimouMaurilio PonzoniEmilio IannittoT. P. Vassilakopoulos
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Introduction: CNS dissemination is an uncommon event in PMLBCL. International cooperation is an important tool to improve our knowledge on this poorly-investigated condition. Methods: Data from PMLBCL pts with CNS disease at presentation or relapse treated at 24 Centers from 6 countries were analyzed. Results: 41 pts (median age 32, range 14-52; 22 males) were considered. At initial lymphoma diagnosis, 20 (49%) had advanced stage, 21 (51%) B symptoms, 39 (95%) bulky disease, 37 (90%) raised LDH, 18 (44%) had extranodal disease (16 in abdomen), 26 (63%) had an aaIPI ≥2. First-line treatment was CHOP14/21 in 20 pts, daEPOCH in 6, M/VACOP-B in 15, combined with rituximab in 39 (95%), and followed by mediastinal irradiation in 14. CNS prophylaxis was administered in 6 pts. CNS involvement was recorded at initial diagnosis in one (2%) pt, at first relapse in 34 (83%), at 3rd-4th relapse in 6 (15%), with a median time to CNS relapse of 7 (0-24) months. CNS was the only site of recurrence in 24 (59%) pts, all at first relapse. Brain or cerebellum were involved in 38 (93%) pts, associated with meningeal infiltration in 6 of them, spinal cord in 1; meninges were the exclusive site of disease in 2 (5%) pts. Treatment was followed by complete remission in 13 pts (32%; 95%CI = 18-46), all of them were treated at presentation or first relapse, and, with a single exception, received high-dose-methotrexate (HD-MTX)-based therapy plus ASCT ± WBRT (Table). Twenty-four treated pts experienced further tumor failure, invariably in the CNS, with concomitant systemic disease in 8; 10 pts with progressive disease limited to the CNS received WBRT, combined with ASCT and/or other drugs, 8 achieving a CR lasting 16-84 months (Table). Pts with CNS involvement at 3rd-4threlapse also had systemic, uncontrolled disease, and did not benefit from treatment. At a median follow-up of 61 (10-173) months, 9 pts remain relapse-free, with a 5-yr PFS after CNS relapse of 21±6%, and 17 pts are alive, with a 5-yr survival after CNS relapse of 42±8%. Systemic disease and meningeal infiltration were not associated with outcome. The 5-yr survival after CNS relapse of the 26 pts treated with HD-MTX-based combinations was 52±10%. Conclusions: Advanced stage, abdominal extranodal disease and high LDH levels are often recorded in PMLBCL pts with CNS recurrence. Unlike other aggressive lymphomas, CNS involvement at presentation and meningeal infiltration are rare in PMLBCL. Prognosis is poor, but HD-MTX-based therapy and consolidative ASCT are associated with encouraging results. WBRT contributes to the achievement of long-lasting remission even in pts with chemorefractory disease. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Lymphoid Cancers - Other No conflicts of interest pertinent to the abstract.Keywords:
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Rituximab, an anti-CD2O monoclonal antibody, is an emerging and effective option for the treatment of patients with refractory steroid-dependent nephrotic syndrome (SDNS), but few studies have assessed the long-term prognosis in these patients. We therefore evaluated the efficacy of rituximab in 35 patients, aged 4-21 years, who experienced SDNS while being treated with immunosuppressants. Patients were monitored for 24-63 months. After the first infusion of rituximab, the number of relapses and the dose of prednisolone were significantly reduced, and the steroid withdrawal period was significantly increased. However, 22 patients (63%) required retreatment with rituximab owing to relapses. At the last observation, only three patients (9%) could discontinue immunosuppressants completely and only three continued to show remission during the observation period. Although rituximab could not induce a complete cure of refractory SDNS, it resulted in longer remission times when immunosuppressants were continued after rituximab therapy, indicating the effectiveness of rituximab followed by immunosuppressants. We also found that patients who experienced more relapses before rituximab therapy were more likely to relapse earlier after rituximab therapy.
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Background: PP and rituximab are two major therapies commonly used in transplantation. They are often used in combination to prevent or treat AMR. Since PP can remove antibodies while rituximab is a B-cell depleting monoclonal antibody. The right sequence of using rituximab and PP is critical to achieve the best treatment efficacy. This meta-analysis analyzed the commonly used PP/rituximab protocols and pointed out a common error in current clinic practice. Methods: We did a PubMed title search for recent 5 years literature in major transplant journals and investigated treatment protocols with rituximab and PP. We tried to address the question whether rituximab treatment followed by multiple sessions of PP will compromise B-cell depleting effects of rituximab. Results: Among a total of 12 papers in which rituximab was used with concomitant PP, three papers did not describe detailed treatment sequence. Rituximab was given after multiple sessions of PP in three studies. In the rest 6 studies, one or two doses of rituximab were administered followed by multiple sessions of PP. The half-life of rituximab is approximately 2-4 weeks with a wide variability between subjects. The clearance rate of rituximab after one session of PP/PE is 47-54%. Multiple (4-5) sessions of PP/PE can clear it to undetectable level. Apparently, the B cell depletion effect of rituximab will be significantly compromised if PP treatment is performed right after the rituximab is given. Significantly, a single dose of rituximab without PP usually completely removed peripheral B cells within 1-2 days and sustained profound B cell suppression up to 2-3 years of observation period. However, when multiple cycles of PP were performed right after rituximab therapy, peripheral B cells were detectable within 1st week in 60-71% of patients. B cell counts started to increase from month 5-6, and recovered to baseline levels with 1-2 years. Conclusion: A combined treatment with rituximab therapy followed by multiple cycles of PP is a very common error in current clinic practice. These treatment protocols significantly diminished treatment efficacy of rituximab. People may argue that the maximum effect of rituximab in depleting circulating B cells was observed within 2 days with more than 90% depletion rate. However, this argument ignores the long-term effect of rituximab on CD20+ B cells in lymphoid tissues. Similar mistaken treatment sequence is commonly found in other protocols which also need to be paid attention to. Authors suggest that PP should be used either before or after 1-2 half-life of any given immune-suppressants, which will help maintain or maximize their effects. Certainly, it is a different issue if PP is used to remove rituximab or other drugs from peripheral blood in order to minimize their severe side effects.
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Objective To assess the potential of MRI subtraction in demonstration of normal meninges.Methods The appearance of normal meninges after administration of Gd-DTPA was evaluated in subtraction images (SI) and conventional T 1W images (T 1WI) in 45 normal volunteers in different anatomic levels (1～4). We evaluated the enhancement subjectively and measured them objectively.Results In 87% of the subjects, T 1WI showed short segments (3 cm) of meningeal enhancement,while continuous patterns were most frequently observed in SI. The differences of the dimensions and maximum length of enhanced meninges were statistically high significant in all levels(Ρ0.01). The relative signal intensities of enhanced meninges and pia mater vessels were significantly higher in SI than that in T 1WI. Mild to moderate enhancements were detected in both SI and T 1WI.Conclusion The subtraction technique can be used clinically for improving enhancement in MRI examinations of meninges.
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About 20% of TTP are resistant to plasma exchange. As reported in a few case reports and small case series, rituximab has been used in the treatment of TTP with some benefit. However, the optimal dosing, frequency, and timing of rituximab remain to be determined. We treated three cases of refractory TTP with rituximab. Case 1 exhibited brain sequelae probably due to the late administration of rituximab, case 2 died before the expected effect of rituximab could occur, and case 3 recovered completely because of the early administration of rituximab. These results suggest that rituximab should be given as early as possible in TTP, but large clinical studies are required to determine the optimal use of rituximab in TTP.
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Meninges comprise three distinct layers, the dura mater, arachnoid, and pia mater that surround the brain, spinal cord and some parts of the nerves.Traditionally the meninges were believed to serve only as protection for tissues that they encase.However recent work shows they have other important functions related to development and regulation of the nervous system.Given the importance of the meninges, it is surprising that we know very little about their development.The embryological origin of the meninges has been debated for over a hundred years.Some studies imply that the meninges develop from the neural crest, while others suggest that they come from the somites.Here, we investigated the temporal development of meninges in birds and mice and found they form at comparable stages.We investigated the origin of avian spinal meninges using chick/quail cell tracing protocols and found they do not develop from the somites as previously thought.We propose that meningeal epithelial blood vessels may have been mistaken as meninges and led to an erroneous conclusion by previous investigators.We present data that show that avian spinal meninges originated from the neural crest supported by data demonstrating that they express the neural crest marker HNK1.Finally using the Wnt1-Cre mouse we show that trunk meninges of mammals also originate from neural crest.
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Although the meninges are often thought of simplistically as a connective tissue sac that contains the CSF and the contents of the CNS, they are far more complex. Anatomically, they comprise several layers. Pathologically, numerous disease processes may affect the meninges; different processes may even involve different areas of the meninges. These factors all influence the MR imaging characteristics of meningeal lesions. This review briefly discusses the anatomy of the meninges, the MR imaging technique when meningeal disease is suspected, and the appearance of the normal meninges. It then focuses on tumors, infections, cysts, and other lesions that primarily involve the meninges, excluding lesions that secondarily involve the meninges.
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