CSF biomarkers in primary CNS lymphoma.

PCNSL is a non-Hodgkin lymphoma (NHL) affecting brain, spinal cord, eyes and leptomeninges. In the past two decades, its prognosis significantly improved due to therapeutic advances but it remains a highly aggressive tumor and early diagnosis is necessary for optimal management. Diagnosis relies on the identification of lymphoma cells in brain tissue obtained by stereotactic biopsy. Alternatively, lymphoma cells may be found in CSF through lumbar puncture (LP) or by a vitrectomy. For several reasons, the diagnosis of PCNSL may be challenging. Misleading radiological presentations are frequent. Dramatic response to steroids may bias histological analysis and deep brain location or frail health status can contraindicate brain biopsy. In the follow-up of patients who have been previously treated, differential diagnosis between tumor relapse and post-treatment may be also difficult. Therefore, the development of complementary reliable diagnostic tools is needed. This review will summarize several diagnostic or prognostic CSF biomarkers which have been proposed in PCNSL, their interests and limits.

Neurolymphomatosis related to direct epineural invasion of the superficial peroneal nerve from subcutaneous B-cell lymphoma.

Neurolymphomatosis is a rare complication of systemic lymphomas, and is classically related to hematogenous spread or intraneural spread of tumor cells from the leptomeninges. Here we report a case of neurolymphomatosis related to direct epineural invasion of the superficial peroneal nerve from subcutaneous localization of B-cell lymphoma. Nerve biopsy revealed striking histological features suggestive of contiguous infiltration of the superficial peroneal nerve by subcutaneous lymphoma. We think this case report sheds new light on neurolymphomatosis pathophysiology with an unreported mechanism in B-cell lymphoma. It also points out that the clinical spectrum in neurolymphomatosis is really variable, pure sensory mononeuritis being a rare presentation. Finally, our case is also strongly illustrative of the contribution of early nerve ultrasonography in the patient diagnosis and in guidance of the nerve biopsy.

The cerebrospinal fluid CD4/CD8 ratio and interleukin-6 and -10 levels in neurosarcoidosis: a multicenter, pragmatic, comparative study.

BACKGROUND AND PURPOSE: Neurosarcoidosis is a rare inflammatory disorder of unknown cause. The aim of this study was to evaluate the value of T/B lymphocyte population counts and the concentrations of the cytokines interleukin (IL) 6 and IL-10 in the cerebrospinal fluid (CSF) of neurosarcoidosis patients. METHODS: A retrospective study CSF biomarkers was conducted in patients with neurosarcoidosis who underwent CSF analysis between 2012 and 2017 as well as various control populations. RESULTS: Forty-three patients with neurosarcoidosis, 14 with multiple sclerosis (MS) and 48 with other inflammatory disorders were analyzed. The CSF IL-6 levels were higher in sarcoidosis patients than in MS patients (median 8 vs. 3 pg/ml, P = 0.006). The CSF CD4/CD8 ratio was higher in sarcoidosis patients than in MS patients and in patients with other inflammatory disorders (median 3.18 vs. 2.36 and 2.10, respectively, P = 0.008). The CSF IL-6 level was higher in patients with active neurosarcoidosis than in non-active neurosarcoidosis patients (median 13 vs. 3 pg/ml, P = 0.0005). In patients with neurosarcoidosis, a CSF IL-6 concentration >50 pg/ml was associated with a higher risk of relapse or progression-free survival (hazard ratio 3.60; 95% confidence interval 1.78-23.14). A refractory neurosarcoidosis patient was treated with an anti-IL-6 monoclonal antibody that produced a complete neurological response. CONCLUSIONS: The CSF CD4/CD8 ratio and IL-6 concentration are increased in neurosarcoidosis compared to MS and other inflammatory disorders. A CSF IL-6 concentration >50 pg/ml is associated with relapse or progression of neurosarcoidosis. IL-10 levels may be elevated in neurosarcoidosis.

Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: a multicenter prospective 'proof of concept' phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†.

BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are mainly diffuse large B-cell lymphomas (DLBCLs) of the non-germinal center B-cell (non-GCB) subtype. This study aimed to determine the efficacy of rituximab plus lenalidomide (R2) in DLBCL-PCNSL. PATIENTS AND METHODS: Patients with refractory/relapsed (R/R) DLBCL-PCNSL or primary vitreoretinal lymphoma (PVRL) were included in this prospective phase II study. The induction treatment consisted of eight 28-day cycles of R2 (rituximab 375/m2 i.v. D1; lenalidomide 20 mg/day, D1-21 for cycle 1; and 25 mg/day, D1-21 for the subsequent cycles); in responding patients, the induction treatment was followed by a maintenance phase comprising 12 28-day cycles of lenalidomide alone (10 mg/day, D1-21). The primary end point was the overall response rate (ORR) at the end of induction (P0 = 10%; P1 = 30%). RESULTS: Fifty patients were included. Forty-five patients (PCNSL, N = 34; PVRL, N = 11) were assessable for response. The ORR at the end of induction was 35.6% (95% CI 21.9-51.2) in assessable patients and 32.0% (95% CI 21.9-51.2) in the intent-to-treat analysis, including 13 complete responses (CR)/unconfirmed CR (uCR; 29%) and 3 partial responses (PR; 7%). The best responses were 18 CR/uCR (40%) and 12 PR (27%) during the induction phase. The maintenance phase was started and completed by 18 and 5 patients, respectively. With a median follow-up of 19.2 months (range 1.5-31), the median progression-free survival (PFS) and overall survival (OS) were 7.8 months (95% CI 3.9-11.3) and 17.7 months (95% CI 12.9 to not reached), respectively. No unexpected toxicity was observed. The peripheral baseline CD4/CD8 ratio impacted PFS [median PFS = 9.5 months (95% CI, 8.1-14.8] for CD4/CD8 ≥ 1.6; median PFS = 2.8 months, [95% CI, 1.1-7.8) for CD4/CD8 < 1.6, P = 0.03). CONCLUSIONS: The R2 regimen showed significant activity in R/R PCNSL and PVRL patients. These results support assessments of the efficacy of R2 combined with methotrexate-based chemotherapy as a first-line treatment of PCNSL. CLINICAL TRIALS NUMBER: NCT01956695.

Campylobacter coli cultured from the stools of a patient with immunoproliferative small intestinal disease.

Campylobacter has been associated with immunoproliferative small intestinal disease (IPSID), on the basis of 16S rDNA sequencing, in situ hybridization, and immunohistochemistry. Here, for the first time, we have cultured Campylobacter from the stools of a patient with IPSID. Phenotypic analysis and whole genome sequencing identified Campylobacter coli. PCR on a IPSID tissue biopsy sample was positive for Campylobacter coli and negative for Campylobacter jejuni. These findings further support a causative role for Campylobacter in the development of IPSID.

Soluble CD23 measurement by CBA: a convenient and reliable quantification method in chronic lymphocytic leukemia.

The soluble form of the transmembrane glycoprotein CD23 corresponding to the low-affinity receptor for the immunoglobulin E (sCD23) is found in the serum of patients with chronic lymphocytic leukemia (CLL). In this disease, an increase in sCD23 level is predictive of poor prognosis at diagnosis as well as during clinical outcome. Quantification of sCD23 is classically performed by enzyme-linked immunosorbent assay (ELISA), a method not routinely used in hematology laboratories. Our aim was to apply cytometric bead array (CBA) technology to measure sCD23 levels. We tested 420 serum samples, 360 from patients and 60 from healthy volunteers. We selected three pairs of monoclonal antibodies recognizing the CD23 molecule that were tested in various conditions of temperature, centrifugation, washing, or chemical supplementation. Satisfactory performances in terms of repeatability (CV: 5%) and reproducibility (CV: 6%) were obtained with the selected pair of antibodies, with a threshold of positivity at 6 ng/mL. CBA and ELISA techniques were correlated with a Spearman coefficient at 0.99. The reproducibility and reliability of the sCD23 CBA assay were confirmed, with a Spearman coefficient at 0.99 in a series of 23 CLL patients and 13 controls tested in two laboratories equipped with different cytometers and using different lots of CBA reagents. Data obtained with serum and plasma samples were correlated with a Spearman coefficient at 0.99. Our study validates a simple method that allows the clinicians to benefit from an indicator of prognosis at the diagnosis as well as a marker of the evolution of CLL disease.

Soluble CD23 measurement by CBA: A convenient and reliable quantification method in Chronic Lymphocytic Leukemia.

The soluble form of the transmembrane glycoprotein CD23 corresponding to the low-affinity receptor for the immunoglobulin E (sCD23) is found in the serum of patients with chronic lymphocytic leukemia (CLL). In this disease, an increase in sCD23 level is predictive of poor prognosis at diagnosis as well as during clinical outcome. Quantification of sCD23 is classically performed by ELISA assay, a method not routinely used in hematology laboratories. Our aim was to apply cytometric bead array (CBA) technology to measure sCD23 levels. We tested 420 serum samples, 360 from patients and 60 from healthy volunteers. We selected 3 pairs of monoclonal antibodies (moAb) recognizing the CD23 molecule that were tested in various conditions of temperature, centrifugation, washing or chemical supplementation. Satisfactory performances in terms of repeatability (CV: 5%) and reproducibility (CV: 6%) were obtained with the selected pair of antibodies, with a threshold of positivity at 6 ng/mL. CBA and ELISA techniques were correlated with a Spearman coefficient at 0.99. The reproducibility and reliability of the sCD23 CBA assay were confirmed, with a Spearman coefficient at 0.99 in a series of 23 CLL patients and 13 controls tested in 2 laboratories equipped with different cytometers and using different lots of CBA reagents. Data obtained with serum and plasma samples were correlated with a Spearman coefficient at 0.99. Our study validates a simple method that allows the clinicians to benefit from an indicator of prognosis at the diagnosis as well as a marker of the evolution of CLL disease.

Laparoscopic surgery for complex Crohn's disease.

In primary Crohn's disease (CD), laparoscopic ileocolic resection has been shown to be both feasible and safe, and is associated with improved outcomes in terms of postoperative morbidity and length of hospital stay. At this time, it is unclear whether the laparoscopic approach can be routinely proposed as a safe procedure for patients with complex CD involving localized abscess, fistula or recurrent disease. The aim of this systematic literature review was to assess the feasibility and safety of laparoscopic surgery for complex or recurrent CD. In the current literature, there are nine non-randomized cohort studies, two of which were case-matched. The mean rate of conversion to open laparotomy reported in these series ranged from 7% to 42%. Morbidity rate and hospital stay following laparoscopic resection for complex CD were similar to those for initial resection or for non-complex CD. In summary, even though strong evidence is lacking and more contributions with larger size are needed, the limited experiences available from the literature confirm that the laparoscopic approach for complex CD is both feasible and safe in the hands of experienced IBD surgeons with extensive expertise in laparoscopic surgery. Further studies are required to confirm these results and determine precisely patient selection criteria.

Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies.

Although anti-CD20 monoclonal antibodies (mAbs) show promise for the treatment of chronic lymphocytic leukemia (CLL), the success of the anti-CD20 mAb rituximab in CLL treatment has been limited. Novel anti-CD20 mAbs with more potent cytotoxic activity have recently been engineered, but so far most have only been tested in vitro with natural killer (NK) cells from healthy donors. Because it is still unclear whether these optimized cytotoxic mAbs will improve NK-cell killing of tumor cells in CLL patients, we characterized the relevant phenotypic and functional features of NK cells from CLL patients in detail. Expression of inhibitory and activating NK-cell receptors and of Fc gamma receptor IIIA (FcγRIIIA) is well preserved in CD16(+)CD56(dim) cytotoxic NK cells from these patients, independently of disease progression. These cells are fully functional following cytokine stimulation. In addition, the FcγRIIIA-optimized LFB-R603 anti-CD20 mAb mediates 100 times greater antibody-dependent cell-mediated cytotoxicity by NK cells from CLL patients and healthy donors than rituximab. Enhanced degranulation against autologous B-CLL cells is observed at lower concentrations of LFB-R603 than rituximab, regardless of CLL prognostic factors. These findings strongly justify further clinical development of anti-CD20 mAbs optimized for FcγR engagement in CLL patients.

Production of oligoglucuronans using a monolithic enzymatic microreactor.

A glucuronan lyase (EC 4.2.2.14) was immobilized on a monolithic Convective Interaction Media (CIM) disk. The immobilization yield was equal to 29% of the initial activity and 35% of the initial protein amount. Degradations of three glucuronans with various O-acetylation degrees were investigated and compared with degradations using free enzyme. The immobilized glucuronan lyase was inhibited by the O-acetylation degree like the free enzyme. (1)H NMR analyses were used to study the O-acetylation degree of oligoglucuronans and demonstrated that the average degrees of polymerization were inclusive between 4 and 13 after 24h of degradation. This first immobilization of a glucuronan lyase constitutes a new tool to produce oligoglucuronans.

[Plasma cell leukaemia]. / La leucémie à plasmocytes.

We report a case of primary plasma cell leukaemia, with an absolute count of plasma cells of 53 Giga/L, diagnosed in a 83-year-old woman. The patient's condition improved, with no circulating plasma cells after 3 weeks of treatment, in response to the combination of thalidomide and dexamethasone administered for 5 days followed by thalidomide alone. The clinical presentation, the morphological, flow cytometric and pathophysiological characteristics of the plasma cell leukaemia and the treatment are summarised in this paper.

[Paraneoplastic hypercorticism associated with a bronchial adenocarcinoma]. / Hypercorticisme paranéoplasique associé à un adénocarcinome bronchique.

Cushing's syndrome is infrequently associated with adenocarcinomas of the lung. We present the clinical features of this syndrome in one case report. The pathogenesis of the syndrome explains the clinical signs, rather different from classical Cushing's disease and also the highly suggestive biological features. Ketoconazole improves clinical signs and biological abnormalities when etiological treatment is not effective.