Therapy-related classical Hodgkin lymphoma after a primary haematological malignancy: a report on 13 cases

The risk of developing Hodgkin lymphoma (HL) is increased in immunodeficiencies or during the treatment of some autoimmune diseases. The development of new therapeutic agents has highlighted the risk of unusual lymphoid proliferations, particularly classical HL (cHL). We report the clinicopathological findings of 13 cHL arising in patients treated for a primary haematological malignancy. Eight patients had received an immunomodulator, protein tyrosine-kinase inhibitor or monoclonal antibody, which may have contributed to the cHL development. Most patients had disseminated disease with poor prognostic factors at cHL diagnosis. Despite the initial presentation, good outcomes were achieved with standard cHL chemotherapy.     

Unbiased plasma proteomics for novel diagnostic biomarkers in cardiovascular disease: identification of quiescin Q6 as a candidate biomarker of acutely decompensated heart failure

Aims Biochemical marker testing has improved the evaluation and management of patients with cardiovascular diseases over the past decade. Natriuretic peptides (NPs), used in clinical practice to assess cardiac dysfunction, exhibit many limitations, however. We used an unbiased proteomics approach for the discovery of novel diagnostic plasma biomarkers of heart failure (HF). Methods and results A proteomics pipeline adapted for very low-abundant plasma proteins was applied to clinical samples from patients admitted with acute decompensated HF (ADHF). Quiescin Q6 (QSOX1), a protein involved in the formation of disulfide bridges, emerged as the best performing marker for ADHF (with an area under the receiver operator characteristic curve of 0.86, 95% confidence interval: 0.79-0.92), and novel isoforms of NPs were also identified. Diagnostic performance of QSOX1 for ADHF was confirmed in 267 prospectively collected subjects of whom 76 had ADHF. Combining QSOX1 to B-type NP (BNP) significantly improved diagnostic accuracy for ADHF by particularly improving specificity. Using thoracic aortic constriction in rats, QSOX1 was specifically induced within both left atria and ventricles at the time of HF onset. Conclusion The novel biomarker QSOX1 accurately identifies ADHF, particularly when combined with BNP. Through both clinical and experimental studies we provide lines of evidence for a link between ADHF and cardiovascular production of QSOX1.     

Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA

Background In angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20(+) large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy. DESIGN AND METHODS: Twenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome. RESULTS: A complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median follow-up of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P<0.004) and the detection of circulating tumor cells (P=0.0019). Despite peripheral Epstein-Barr virus clearance after treatment, the viral load at diagnosis (>100 copy/μg DNA) was associated with shorter progression-free survival (P=0.06). Conclusions We report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20(+) B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted.     

Anti-CD20 IgA can protect mice against lymphoma development: evaluation of the direct impact of IgA and cytotoxic effector recruitment on CD20 target cells

Background

While most antibody-based therapies use IgG because of their well-known biological properties, some functional limitations of these antibodies call for the development of derivatives with other therapeutic functions. Although less abundant than IgG in serum, IgA is the most abundantly produced Ig class in humans. Besides the specific targeting of its dimeric form to mucosal areas, IgA was shown to recruit polymorphonuclear neutrophils against certain targets more efficiently than does IgG1.

Design and Methods

In this study, we investigated the various pathways by which anti-tumor effects can be mediated by anti-CD20 IgA against lymphoma cells.

Results

We found that polymeric human IgA was significantly more effective than human IgG1 in mediating direct killing or growth inhibition of target cells in the absence of complement. We also demonstrated that this direct killing was able to indirectly induce the classical pathway of the complement cascade although to a lesser extent than direct recruitment of complement by IgG. Recruitment of the alternative complement pathway by specific IgA was also observed. In addition to activating complement for lysis of lymphoma cell lines or primary cells from patients with lymphoma, we showed that monomeric anti-CD20 IgA can effectively protect mice against tumor development in a passive immunization strategy and we demonstrated that this protective effect may be enhanced in mice expressing the human FcαRI receptor on their neutrophils.

Conclusions

We show that anti-CD20 IgA antibodies have original therapeutic properties against lymphoma cells, with strong direct effects, ability to recruit neutrophils for cell cytotoxicity and even recruitment of complement, although largely through an indirect way.Key words: Anti-CD20 IgA, lymphoma, FcαRI     

Combined Liver-Kidney Transplantation: Survey of a Single Center in Spain

BackgroundRenal dysfunction is a common complication of advanced liver failure and liver transplantation. Since the introduction of the MELD criteria the proportion of patients with advanced chronic kidney disease and need for liver transplantation has increased. One alternative is the combined liver-kidney transplant (CLKT). The aim of this study was to evaluate the outcome of this type of transplant in our center.MethodsWe retrospectively analyzed all combined simultaneous or sequential transplants from 1989 to 2012. We studied demographic and clinical variables. Survival analysis was performed by Kaplan-Meier method.ResultsIn the study period, 1,265 kidney and 1,050 liver transplantations were performed; 34 were CLKT (to 29 adults and 5 children); 13 of these were simultaneous and 12 sequential liver-kidney. We also carried out 4 triple liver-pancreas-kidney transplantations, 3 simultaneous and 1 sequential. The mean age was 44.1 ± 15 years, and 27 were male (93.1%); 9 (37.5%) were diabetic. The main causes of liver disease were viral (n = 11 [41.3%; hepatitis virus B, C, or both] and alcoholism (9 [31%]). The renal disease etiology was unknown in 16 (55.1%), IgA nephropathy in 2 (6.8%), membranoproliferative glomerulonephritis in 2 (6.8%), and calcineurin inhibitor toxicity in 4 (13.6%). Transjugular renal biopsy was performed in 6 sequential transplants. Survival of patients who received a CLKT was excellent: 91%, 51%, and 40%, at 1, 5, and 10 years, respectively. No significant difference was found between sequential and simultaneous transplants (log rank 0.5).ConclusionsOur results of CLKT show results similar or superior to those of other series and are an alternative to consider in candidates for liver transplantation with chronic kidney disease. Transjugular biopsy is an alternative to study the etiology of renal disease in patients with hepatic dysfunction before or after liver transplantation.     

Posterior Approach for Laparoscopic Pancreaticoduodenectomy to Prevent Replaced Hepatic Artery Injury

Background

Laparoscopic pancreaticoduodenectomy (PD) has become more popular despite its complexity and tendency for higher morbidity.1 Replaced right hepatic artery (RRHA) and replaced common hepatic artery (RCHA), both originating from the superior mesenteric artery (SMA), are the most significant and relatively common vascular anomalies in patients undergoing PD, occurring in 8.6–21 and 0.4–4.5 % of cases, respectively.2 ^, 3 An inadvertent injury to theses arteries may result in an intra- or postoperative bleeding, hepatic or bile duct ischemia, and consequent leakage or delayed stricture in the bilioenteric anastomosis.2 ^– 4 Therefore, preservation of these aberrant hepatic arteries is essential unless their resection is oncologically indicated.2 We describe a posterior approach that can be advantageous in laparoscopic PD for patients with a RRHA or RCHA.

Methods

The posterior approach was used in 81 laparoscopic PDs at the Institute Mutualiste Montsouris between 1994 and 2012.5 In brief, retropancreatic dissection is performed to complete kocherization and expose the posterolateral aspect of the SMA. The origin of the RRHA or RCHA can then be identified and dissected. After division of the pancreatic neck, the portal vein and RRHA or RCHA are separated off the pancreatic neck. In case of the RCHA, the gastroduodenal artery originating from the RCHA is divided during this dissection.

Results

The video shows a secure procedure to preserve a RCHA in laparoscopic PD by early identification and dissection of the aberrant artery via the posterior approach.

Conclusions

The posterior approach can help to prevent inadvertent RRHA or RCHA injury in laparoscopic PD.     

Quels marqueurs osseux chez les patients hémodialysés : phosphatases alcalines osseuses ou ß-CrossLaps ?

BackgroundBone turnover (BT) abnormalities are frequently observed in patients with chronic kidney disease. Bone biopsy remains the gold standard for diagnosis; however, its invasive nature has led to its decreased utilisation. The serum parathyroid hormone (PTH) level is not a reliable bone marker (BM) for BT assessment. The latest international recommendations suggest the use of total alkaline phosphatase (t-ALP) or bone-specific alkaline phosphatase (b-ALP), but not ß-CrossLaps (CTX). We compared b-ALP, t-ALP, and CTX levels in patients on haemodialysis (HD).MethodsAll HD patients at a single institution following a standard 3 × 4 to 3 × 5 hours schedule were included in the study, provided they were free from liver disease. Serum intact PTH, t-ALP, b-ALP, and CTX values were compared at baseline and after 18 months of treatment. A kinetic study was performed for pre- and postdialysis CTX values over a 2-week period. We described the longitudinal evolution of these BMs in two typical patients.ResultsA total of 98 patients on HD (46% female) were evaluated. The mean age was 69.8 ± 11 years and the mean duration of dialysis was 54.4 ± 61 months. At baseline, CTX (2.1 ± 1 μg/L) correlated well with b-ALP (18 ± 11 μg/L; r = 0.64; P < 0.001) and PTH (221 ± 165 pg/mL; r = 0.62; P < 0.001). The changes in these values at 18 months were also correlated (ΔCTX compared with Δb-ALP: r = 0.51; P < 0.001; Δb-ALP compared with ΔPTH: r = 0.37, P < 0.01). b-ALP and t-ALP (245 ± 132 U/L) were closely correlated (r = 0.78), as was their variation over 18 months (r = 0.67), but t-ALP did not correlate with PTH, and correlated poorly with CTX (r = 0.38). The CTX reduction ratio during standard dialysis was approximately 70 to 75% over each session, although predialysis values remained stable.ConclusionIn HD patients, mean CTX values are five times higher than the normal range. CTX appears to be an alternative to b-ALP for assessing BT. b-ALP remains the standard BM, despite being expensive, infrequently available in many laboratories, and not useful for patients with liver disease.     

Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases

We have recently identified missense mutations in prodynorphin (PDYN), the precursor to dynorphin opioid peptides, as the cause for spinocerebellar ataxia (SCA23) in Dutch ataxia cases. We report a screen of PDYN for mutations in 371 cerebellar ataxia cases, which had a positive family history; most are of French origin. Sequencing revealed three novel putative missense mutations and one heterozygous two-base pair deletion in four independent SCA patients. These variants were absent in 400 matched controls and are located in the highly conserved dynorphin domain. To resolve the pathogenicity of the heterozygous variants, we assessed the peptide production of the mutant PDYN proteins. Two missense mutations raised dynorphin peptide levels, the two-base pair deletion terminated dynorphin synthesis, and one missense mutation did not affect PDYN processing. Given the outcome of our functional analysis, we may have identified at least two novel PDYN mutations in a French and a Moroccan SCA patient. Our data corroborates recent work that also showed that PDYN mutations only account for a small percentage (~0.1 %) of European SCA cases.     

The Mediating Effects of Alexithymia,Intolerance of Uncertainty,and Anxiety on the Relationship Between Sensory Processing Differences and Restricted and Repetitive Behaviours in Autistic Adults

Distress caused by sensory processing differences for autistic individuals may be reduced by repetitive behaviours (RRB), including repetitive motor (RMB) and insistence on sameness (ISB) behaviours. Intolerance of uncertainty (IU) and anxiety mediate the relationship between sensory processing and RRB in autistic children. We replicated this model in autistic adults, extending it to include alexithymia. Serial mediation, using data from 426 autistic adults, identified significant direct effects from sensory processing to RMB and ISB, and indirect effects through alexithymia-IU-anxiety for RMB, and IU alone, and alexithymia-IU for ISB. Different mechanisms may underpin RMB and ISB. Alexithymia alongside, IU and anxiety, should be considered when understanding the relationship between sensory processing and RRB, and when offering interventions to support autistic people.