Donor‐specific HLA antibodies: evaluating the risk for graft loss in renal transplant recipients with isotype switch from complement fixing IgG1/IgG3 to noncomplement fixing IgG2/IgG4 anti‐HLA alloantibodies

Human leukocyte antigen alloantibodies have a multitude of damaging effects on the allograft, both complement (C′) activation and Fc‐independent ones. To date, the clinical significance of non‐C′ fixing (NCF) HLA donor‐specific antibodies (DSA) is still unclear. In this study, we investigated whether renal transplant recipients with NCF‐DSA subclasses (IgG2/IgG4, IgA1/IgA2) are at higher risk of graft loss compared to patients with exclusively C′ fixing (IgG1/IgG3). Blood samples from 274 patients were analyzed for HLA IgG and IgA subclasses using a modified single‐antigen bead assay. We identified 50 (18.2%) patients with circulating NCF antibodies either DSA (n = 17) or against third‐party HLA (n = 33). NCF‐DSAs were preferentially of IgG2/IgG4 isotype (11/17) and were mainly directed against HLA class II (13/17). NCF DSA were present as a mixture with strong C′ fixing IgG1/IgG3. Graft survival was similar between patients with exclusively C′ fixing antibodies and those with a mixture panel (log rang test P = 0.162), and also among patients with different immunoglobulin isotype and subclasses (long‐rank test, P = 0.732). We conclude that expansion of DSA to NCF subclasses postrenal transplantation does not seem to be associated with worse graft survival as compared to the presence of exclusive C′ fixing subclasses.     

Intraarterial chemotherapy as an adjuvant treatment in locally advanced gastric cancer

Background and aims D₂ gastrectomy has improved survival in gastric cancer. Adjuvant intravenous chemotherapy, radiotherapy, or multimodal therapy has failed to demonstrate improved survival. The results of intraarterial chemotherapy (IARC) as an adjuvant have been encouraging in a few studies. A prospective randomized trial was designed to evaluate the toxicity and survival in locally advanced gastric cancer using IARC as an adjuvant after potentially curative gastrectomy. Patients and methods Forty patients with locally advanced gastric cancer were randomly selected to undergo either potentially curative gastrectomy and receive IARC (study group) or gastrectomy only (control group). Clinical and histopathologic data were analyzed and the toxicity related to IARC was recorded. Results The groups were comparable (p>0.05). Three patients in the study group had minor toxicity. Five-year survival rate for the study and the control group was 52 and 54%, respectively (p>0.05). Mean survival for the study and the control group was 50±8 and 62±10 months, respectively (p>0.05). The number of recurrences and the failure sites were comparable (p>0.05). Conclusion Intraarterial chemotherapy can be safely applied to gastric cancer patients. As proposed by the protocol, the method cannot be recommended as an adjuvant treatment for locally advanced tumors because it appears that there is no survival benefit compared to potentially curative gastrectomy alone.     

Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling,activation and proliferation

Recent studies on splenic marginal zone lymphoma identified distinct mutations in genes belonging to the B-cell receptor and Toll-like receptor signaling pathways, thus pointing to their potential implication in the biology of the disease. However, limited data is available regarding the exact role of TLRs. We aimed at characterizing the expression pattern of TLRs in splenic marginal zone lymphoma cells and their functional impact on the activation, proliferation and viability of malignant cells in vitro. Cells expressed significant levels of TLR1, TLR6, TLR7, TLR8, TLR9 and TLR10 mRNA; TLR2 and TLR4 showed a low, variable pattern of expression among patients whereas TLR3 and TLR5 mRNAs were undetectable; mRNA specific for TLR signaling molecules and adapters was also expressed. At the protein level, TLR1, TLR6, TLR7, TLR9 and TLR10 were detected. Stimulation of TLR1/2, TLR2/6 and TLR9 with their respective ligands triggered the activation of IRAK kinases, MAPK and NF-κB signaling pathways, and the induction of CD86 and CD25 activation molecules, although in a heterogeneous manner among different patient samples. TLR-induced activation and cell viability were also inhibited by a specific IRAK1/4 inhibitor, thus strongly supporting the specific role of TLR signaling in these processes. Furthermore, TLR2/6 and TLR9 stimulation also significantly increased cell proliferation. In conclusion, we demonstrate that splenic marginal zone lymphoma cells are equipped with functional TLR and signaling molecules and that the stimulation of TLR1/2, TLR2/6 and TLR9 may play a role in regulating disease pathobiology, likely promoting the expansion of the neoplastic clone.     

The CD44+/CD24− phenotype relates to ‘triple-negative’ state and unfavorable prognosis in breast cancer patients

Breast carcinomas have been reported to contain a subpopulation of CD44+/CD24− tumor cells with stem cell–like properties. This study investigates the significance of these two molecules in connection with tumor aggression and prognosis. The phenotypic profile of 139 breast carcinomas was investigated in paraffin sections using markers previously associated with stem cell–like properties (CD44, CD24), the “triple-state” (ER, PR, c-erb-B2), and angiogenesis (CD31). Tumors with >10% of CD44 and CD24 cancer cells were considered positive. The prevalence of CD44+ and CD24+ breast carcinomas in the series was 51.8% and 41.7%, respectively. Patients with the CD44(+)/CD24(−) phenotype had a 10-year lower median age at presentation and harbored tumors with a triple-negative state. They experienced an unfavorable prognosis. Lack of CD44 expression was associated with lymph node involvement, regardless of CD24 status, whereas the lack of both CD44 and CD24 was connected with high histologic grade and unfavorable prognosis which, notably, was the worse among all phenotypes. In multivariate analysis, the CD44(−)/CD24(−) phenotype, the nodal involvement, the vascular density and the ER-/PR-/c-erbB-2-profile were independent prognostic variables. It is concluded that assessment of the CD44/CD24 status may reveal distinct subgroups of breast cancer patients with different clinical behavior. The unsatisfactory response of the triple-negative tumors to current chemotherapy and their intimate link with the CD44(+)/CD24(−) phenotype, makes CD44 targeting an attractive therapeutic alternative for breast cancer patients. The strong association between the CD44(−)/CD24(−) phenotype and prognosis requires further investigation.     

Complex sleep apnea after full-night and split-night polysomnography: the Greek experience

Purpose

Treatment-emergent central sleep apnea (TE-CSA) is defined as the emergence or persistence of central respiratory events during the initiation of positive airway pressure (PAP) without a back-up rate in obstructive sleep apnea (OSA) patients and after significant resolution of obstructive events. Previous studies have estimated a prevalence from 0.56 to 20.3%. The aim of this study was to establish the prevalence of TE-CSA in a Greek adult population.

Methods

One thousand fifty nine patients with newly diagnosed OSA, who were referred to the Sleep Disorders Center of Evangelismos Hospital of Athens over an 18-month period, were included in this study. A split-night polysomnography (PSG), or two formal overnight PSGs (diagnostic and continuous PAP (CPAP) titration study), were performed.

Results

Patients with OSA were divided in two groups; the first group included 277 patients, who underwent two separate studies (diagnostic and CPAP titration study), and the second group 782 patients, who underwent split-night studies. The prevalence of TE-CSA in the first group was 2.53% (7 patients), and in the second group was 5.63% (44 patients).

Conclusions

The prevalence of TE-CSA in Greece was lower compared to most previous reported studies. The significant variation in the prevalence of TE-CSA between different centers throughout the world is mainly associated with the used diagnostic criteria as well as methodological and technical aspects.

     

Defects in Hemopoietic Stem Cell Activity in Ikaros Mutant Mice

Here we provide evidence that the Ikaros family of DNA binding factors is critical for the activity of hemopoietic stem cells (HSCs) in the mouse. Mice homozygous for an Ikaros null mutation display a >30-fold reduction in long-term repopulation units, whereas mice homozygous for an Ikaros dominant negative mutation have no measurable activity. The defect in HSC activity is also illustrated by the ability of wild-type marrow to repopulate unconditioned Ikaros mutants. A progressive reduction in multipotent CFU-S(14) (colony-forming unit-spleen) progenitors and the earliest erythroid-restricted precursors (BFU-E [burst-forming unit-erythroid]) is also detected in the Ikaros mutant strains consistent with the reduction in HSCs. Nonetheless, the more mature clonogenic erythroid and myeloid precursors are less affected, indicating either the action of a compensatory mechanism to provide more progeny or a negative role of Ikaros at later stages of erythromyeloid differentiation. In Ikaros mutant mice, a decrease in expression of the tyrosine kinase receptors flk-2 and c-kit is observed in the lineage-depleted c-kit(+)Sca-1(+) population that is normally enriched for HSCs and may in part contribute to the early hemopoietic phenotypes manifested in the absence of Ikaros.     

An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit

The genus Acremonium (formerly known as Cephalosporium) is a large polyphyletic fungal genus that comprises approximately 150 phylogenetically distant species, commonly isolated from the environment. Clinical cases concern mostly superficial infections after traumatic inoculation, but there are reports of opportunistic invasive infections in immunocompromised patients. Acremonium kiliense has been described as a cause of mycetoma, keratitis, endophthalmitis, endocarditis, and continuous ambulatory peritoneal dialysis–associated peritonitis. We describe an unusual cluster of possible catheter-related bloodstream infections due to this pathogen in patients who underwent haematopoietic cell transplantation.     

A case report of recurrent vascular access thrombosis in a hemodialysis patient reveals combined acquired and inherited thrombophilia

Vascular access thrombosis represents a serious and unfortunately common problem in hemodialysis patients. Usually, but not always, this complication can be attributed to low access blood flow. However, there are some patients who experience thrombosis despite a well functioning vascular access. We describe the case of a 31-year-old Caucasian male, who was hemodialyzed via an arteriovenous fistula for two years due to Alport's syndrome. During this time period he had two episodes of vascular access thrombosis that destroyed two arteriovenous fistulas. Both fistulas were functioning well and the thrombosis events took place in days between the hemodialysis sessions. Thrombophilia was suspected and the relative investigation revealed high levels of factor VIII procoagulant, which is frequent in hemodialysis patients, and resistance to activated protein C. Polymerase chain reaction detected that the patient was heterozygous for factor V Leiden, which is quite common in general population. Thereafter, a new arteriovenous fistula was formed and the patient started oral anticoagulation therapy with warfarin. Now, three years after the last arteriovenous fistula formation, the patient is hemodialyzed without vascular access problems. In conclusion, evaluation of the coagulation cascade in hemodialysis patients with recurrent vascular access thrombosis is necessary.     

Sustained clinical response and high infliximab survival in psoriatic arthritis patients: a 3-year long-term study

OBJECTIVE: To investigate the efficacy, toxicity, and survival of infliximab in patients with psoriatic arthritis (PsA). METHODS: Thirty-two patients with PsA, refractory to at least 2 disease-modifying antirheumatic drugs, were included in this prospective, open-label, uncontrolled study. All had active disease, defined as having a tender or swollen joint count > or =6, Psoriasis Area and Severity Index (PASI) scores > or =10, and erythrocyte sedimentation rate > or =28 mm Hg/h, or C-reactive protein > or =10 mg/L. The primary endpoints were the percentage of patients who achieved the Psoriatic Arthritis Response criteria (PsARC) and the improvement of PASI. Patients were treated with infliximab (5 mg/kg) at weeks 0, 2, 6, and every 8 weeks thereafter for a period of 3 years. Data concerning infliximab efficacy, tolerability, concomitant therapy, adverse events, and drug discontinuation were recorded. The clinical response according to the American College of Rheumatology (ACR) criteria as well as the disease activity for 28 joint indices score (DAS-28) were also recorded. RESULTS: After the third year of treatment, PsARC was achieved by 23/32 of patients, PASI 70 by 24/32, and PASI 90 by 23/32. A significant improvement of ACR and DAS-28 was noted. Clinical improvement was associated with a reduction of acute phase reactants. Eight patients withdrew from the study primarily for acute allergic reactions. After the first year, infliximab survival was 84%, while after the second year, it was 75%, which was maintained throughout the third year of treatment. CONCLUSION: Infliximab was effective, safe, and well tolerated in patients with PsA. The clinical response was maintained for a period of 3 years with high infliximab survival.