Low transplant-related mortality after second allogeneic peripheral blood stem cell transplant with reduced-intensity conditioning in adult patients who have failed a prior autologous transplant

Standard allogeneic stem cell transplantation (SCT) has been associated with a high transplant-related mortality (TRM) in patients who have failed a prior autologous SCT (ASCT). Reduced-intensity conditioning (RIC) regimens may reduce the toxicities and TRM of traditional myeloablative transplants. We report 46 adults who received a RIC peripheral blood SCT from an HLA-identical sibling in two multicenter prospective studies. The median interval between ASCT and allograft was 16 months, and the patients were allografted due to disease progression (n = 43) and/or secondary myelodysplasia (n = 4). Conditioning regimens consisted of fludarabine plus melphalan (n = 41) or busulphan (n = 5). The 100-day incidence of grade II-IV acute graft-versus-host disease (GVHD) was 42% (24% grade III-IV), and 10/30 evaluable patients developed chronic extensive GVHD. Early complete donor chimerism in bone marrow and peripheral blood was observed in 35/42 (83%) patients, and 16 evaluable patients had complete chimerism 1 year post transplant. With a median follow-up of 358 days (450 in 29 survivors), the 1-year incidence of TRM was 24%, and the 1-year overall (OS) and progression-free survival were 63% and 57%, respectively. Patients who had chemorefractory/ progressive disease, a low performance status or received GVHD prophylaxis with cyclosporine A alone (n = 32) had a 1-year TRM of 35% and an OS of 46%, while patients who had none of these characteristics (n = 32) had a 1-year TRM of 35% and an OS of 46% while patients who had none of these characteristics (n = 14) had a TRM of 0% and an OS of 100%. Our results suggest that adult patients who fail a prior ASCT can be salvaged with a RIC allogeneic PBSCT with a low risk of TRM, although patient selection has a profound influence on early outcome.     

Intervertebral disc regeneration: from the degenerative cascade to molecular therapy and tissue engineering

Low back pain is one of the major health problems in industrialized countries, as a leading source of disability in the working population. Intervertebral disc degeneration has been identified as its main cause, being a progressive process mainly characterized by alteration of extracellular matrix composition and water content. Many factors are involved in the degenerative cascade, such as anabolism/catabolism imbalance, reduction of nutrition supply and progressive cell loss. Currently available treatments are symptomatic, and surgical procedures consisting of disc removal are often necessary. Recent advances in our understanding of intervertebral disc biology led to an increased interest in the development of novel biological treatments aimed at disc regeneration. Growth factors, gene therapy, stem cell transplantation and biomaterials‐based tissue engineering might support intervertebral disc regeneration by overcoming the limitation of the self‐renewal mechanism. The aim of this paper is to overview the literature discussing the current status of our knowledge from the degenerative cascade of the intervertebral disc to the latest molecular, cell‐based therapies and tissue‐engineering strategies for disc regeneration. Copyright © 2013 John Wiley & Sons, Ltd.     

New perspectives on the long-term outcome of segmental colectomy for Crohn’s colitis: an observational study on 200 patients

Background and aims

Surgical management of Crohn’s colitis represents one of the most complex situations in colorectal surgery. Segmental colectomy (SC) and total abdominal colectomy with ileorectal anastomosis (TAC-IRA) are the most common procedures, but there are few available data on their long-term outcome. The aim of the present study was to analyze the long-term outcome of patients who underwent segmental colectomy for Crohn’s colitis, with regard to the risk for total abdominal colectomy.

Methods

In this observational, monocentric, retrospective analysis, we analyzed patients who received a segmental colectomy for Crohn’s colitis at our institution. The database was updated by asking patients to complete a questionnaire by telephone or at the outpatient clinic. Only patients followed up at our Hospital were included. Patients were followed up by a specialized multidisciplinary team (IBD Unit). The primary endpoint was the interval between segmental colectomy and, when performed, total abdominal colectomy.

Results

Between 1973 and 2014, 200 patients underwent segmental colectomy for Crohn’s colitis. The median follow-up was 13.5 years (interquartile range [IQR] 7.8–21.5). Overall, 62 patients (31%) had a surgical recurrence, of these, 42 (21%) received total abdominal colectomy. At multivariate analysis, the presence of ≥?3 sites (HR =?2.47; 95% CI 1.22–5.00; p?=?0.018) and perianal disease (HR =?3.23; 95% CI 1.29–8.07; p?=?0.006) proved to be risk factors for total abdominal colectomy.

Conclusions

The risk for surgical recurrence after SC for Crohn’s colitis is acceptable. We recommend a bowel-sparing policy for the treatment of Crohn’s colitis in any case in which the extent of the disease at the moment of surgery makes the conservative approach achievable.

     

Identification of glycoprotein Ib as a target for autoantibody in idiopathic (autoimmune) thrombocytopenic purpura

An antibody (DIL) from a patient with idiopathic thrombocytopenic purpura (ITP) was shown to have autospecificity on the basis of reactions with autologous platelets that were identical to those obtained with platelets from normal subjects. DIL antibody also reacted strongly in an immunofluorescence test with platelets from a patient with Glanzmann's thrombasthenia, but failed to react with platelets from a patient with the Bernard-Soulier syndrome who was known to be deficient in glycoprotein Ib (GPIb). Purified GPIb and control platelets, but not Bernard-Soulier platelets, inhibited the lytic activity of DIL. Using the GPIb-specific monoclonal antibody AP1 and one-dimensional rocket electrophoresis into gels containing rabbit antihuman platelet membrane antibody, it was shown that staphylococcal protein A-Sepharose beads coated with DIL antibody selectively remove GPIb from solubilized platelet preparations. By crossed immunoelectrophoresis it was found that DIL recognizes a determinant on GPIb on the membrane side of the cleavage site of the platelet calcium- activated protease (calpain). These studies provide direct evidence for binding of a platelet autoantibody to a determinant on GPIb relatively close to the site of insertion of this protein into the platelet membrane.     

Diagnosis and management of amiodarone-induced thyrotoxicosis: similarities and differences between North American and European thyroidologists

Objective To investigate how North American thyroidologists assess and treat amiodarone‐induced thyrotoxicosis (AIT) and to compare the results with those of the same questionnaire‐based survey previously carried out among European thyroidologists. Design Members of the American Thyroid Association (ATA) with clinical interests were sent by e‐mail a questionnaire on the diagnosis and management of AIT, 115 responses were received from the United States and Canada, representing about one‐third of ATA members with clinical interests. Results The majority of respondents (91%vs. 68% in Europe, P < 0·05) see < 10 new cases of AIT per year, and AIT seems less frequent than amiodarone‐induced hypothyroidism (AIH) in North America (34% and 66% of amiodarone‐induced thyroid dysfunction, respectively, vs. 75% and 25%, respectively, in Europe, P < 0·001). When AIT is suspected, in North America hormonal assessment is mostly based on serum free T4 (FT4) and TSH measurements, while serum free T3 (FT3) determination is requested less frequently than in Europe; thyroid autoimmunity is included in the initial assessment less than in Europe. Most commonly used additional diagnostic procedures include, as in Europe, thyroid colour‐flow Doppler sonography, and to a lesser extent, thyroid radioactive iodine uptake and scan, but Europeans tend to request multiple tests more than North Americans. Withdrawal of amiodarone is more often considered unnecessary by North American thyroidologists (21%vs. 10% in Europe in type 1 AIT, P < 0·05, 34%vs. 20% in type 2 AIT, P < 0·05). In type 1 AIT thionamides represent the treatment of choice for North Americans as well as for Europeans, but the former use them as monotherapy in 65%vs. 51% of Europeans (P < 0·05) who more often consider potassium perchlorate as an useful addition (31%vs. 15% of North Americans, P < 0·01). Glucocorticoids are the selected treatment for type 2 AIT, alone (62%vs. 46% in Europe, P < 0·05) or in association with thionamides (16%vs. 25% in Europe, P = NS). After restoration of euthyroidism, thyroid ablation in the absence of recurrent thyrotoxicosis is recommended in type 1 AIT less frequently by North Americans. If amiodarone therapy needs to be reinstituted, prophylactic thyroid ablation is advised by 76% in type 1 AIT, while a ‘wait‐and‐see’ strategy is adopted by 61% in type 2 AIT, similar to behaviour of European thyroidologists. Conclusion Similarities and differences exist between expert North American and European thyroidologists concerning the diagnosis and management of AIT. While differences reflect the frequent uncertainty of the underlying mechanism leading to AIT, similarities may represent the basis to refine the diagnostic criteria and to improve the therapeutic outcomes of this challenging clinical situation.     

Cefotaxime plus amikacin as empiric therapy in the treatment of febrile episodes in neutropenic patients with hematologic malignancies

Summary Between October 1980 and October 1981, cefotaxime plus amikacin were used in the treatment of 131 febrile episodes that occurred in 108 neutropenic patients with hematologic malignancies. The overall clinical response was 86.2%. Fevers of unknown origin and clinically or microbiologically documented infections responded in 88.8 and 84.4% of the cases, respectively. Renal toxicity occurred in 3.8% of the cases.In vitro studies showed that cefotaxime and amikacin were active against 78.7 and 94.7% of the pathogens, respectively, despite the high frequency (31%) of multiply resistant strains ofPseudomonas aeruginosa (defined asin vitro simultaneously resistant to carbenicillin, gentamicin, tobramycin and sisomicin) isolated from blood and infected sites. Synergy studies performed against 35 gram-negative bacilli isolated from blood revealed the presence of synergism between cefotaxime and amikacin in 54% of the cases. The peak levels of bactericidal activity in the serum of patients receiving cefotaxime plus amikacin showed median values of 1:128 and 1:8 againstEscherichia coli andP. aeruginosa septicemias, respectively.

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Cefotaxim plus Amikacin als empirische Therapie bei febrilen Episoden neutropenischer Patienten mit malignen hämatologischen Erkrankungen

Zusammenfassung Zwischen Oktober 1980 und Oktober 1981 wurden 131 fieberhafte Episoden bei 108 neutropenischen Patienten mit hämatologischen Neoplasien mit Cefotaxim plus Amikacin behandelt. Insgesamt wurde bei 86,2% der Fälle ein klinischer Erfolg erzielt. Bei Fieber unbekannter Ursache sprachen 88,8% und bei klinisch oder mikrobiologisch dokumentierten Infektionen 84,4% der Patienten auf die Therapie an. Bei 3,8% der Fälle kam es zur toxischen Nierenschädigung.In vitro-Studien zeigten, daß Cefotaxim und Amikacin gegen 78,7% beziehungsweise 94,7% der pathogenen Erreger aktiv waren, obwohl multiresistentePseudomonas aeruginosa-Stämme (definiert als simultane Resistenzin vitro gegen Carbenicillin, Gentamicin, Tobramycin und Sisomycin) 31% der aus Blut und von Infektionsstellen isolierten Erreger ausmachten. Bei 35 Isolaten von grampositiven Stäbchen aus Blut wurden Synergismus-Studien mit Cefotaxim und Amikacin durchgeführt; gegen 54% der Stämme war eine synergistische Aktivität der Kombination nachzuweisen. Die höchste bakterizide Aktivität im Serum nach Gabe von Cefotaxim plus Amikacin betrug im Mittel gegen von Septikämie-Patienten isolierteEscherichia coli 1:128 und gegenP. aeruginosa 1:8.

     

Topical rather than intradermal application of the TLR7 ligand imiquimod leads to human dermal dendritic cell maturation and CD8+ T‐cell cross‐priming

Toll‐like receptor (TLR) ligands are attractive candidate adjuvants for therapeutic cancer vaccines, since TLR signaling stimulates and tunes both humoral and cellular immune responses induced by dendritic cells (DCs). Given that human skin contains a dense network of DCs, which are easily accessible via (intra‐)dermal delivery of vaccines, skin is actively explored as an antitumor vaccination site. Here we used a human skin explant model to explore the potential of TLR ligands as adjuvants for DC activation in their complex microenvironment. We show that topical application of Aldara skin cream, 5% of which comprises the TLR7 agonist imiquimod, significantly enhanced DC migration as compared with that resulting from intradermal injection of the TLR7/8 ligand R848 or the soluble form of imiquimod. Moreover, Aldara‐treated DCs showed highest levels of the costimulatory molecules CD86, CD83, CD40, and CD70. Topical Aldara induced the highest production of pro‐inflammatory cytokines in skin biopsies. When combined with intradermal peptide vaccination, Aldara‐stimulated DCs showed enhanced cross‐presentation of the melanoma antigen MART‐1, which resulted in increased priming and activation of MART‐1‐specific CD8⁺ T cells. These results point to advantageous effects of combining the topical application of Aldara with antitumor peptide vaccination.     

Molecular events underlying interleukin‐6 independence in a subclone of the CMA‐03 multiple myeloma cell line

We explored the molecular mechanisms involved in the establishement of CMA‐03/06, an IL‐6‐independent variant of the multiple myeloma cell line CMA‐03 previously generated in our Institution. CMA‐03/06 cells grow in the absence of IL‐6 with a doubling time comparable with that of CMA‐03 cells; neither the addition of IL6 (IL‐6) to the culture medium nor co‐culture with multipotent mesenchymal stromal cells increases the proliferation rate, although they maintain the responsiveness to IL‐6 stimulation as demonstrated by STAT1, STAT3, and STAT5 induction. IL‐6 independence of CMA‐03/06 cells is not apparently due to the development of an autocrine IL‐6 loop, nor to the observed moderate constitutive activation of STAT5 and STAT3, since STAT3 silencing does not affect cell viability or proliferation. When compared to the parental cell line, CMA‐03/06 cells showed an activated pattern of the NF‐κB pathway. This finding is supported by gene expression profiling (GEP) analysis identifying an appreciable fraction of modulated genes (28/308) in the CMA‐03/06 subclone reported to be involved in this pathway. Furthermore, although more resistant to apoptotic stimuli compared to the parental cell line, CMA‐03/06 cells display a higher sensibility to NF‐κB inhibition induced by bortezomib. Finally, GEP analysis suggests an involvement of a number of cytokines, which might contribute to IL‐6 independence of CMA‐03/06 by stimulating growth and antiapoptotic processes. In conclusion, the parental cell‐line CMA‐03 and its variant CMA‐03/06 represent a suitable model to further investigate molecular mechanisms involved in the IL‐6‐independent growth of myeloma cells. © 2013 Wiley Periodicals, Inc.