Allogeneic stem cell transplantation for patients with chronic myeloid leukemia: Risk stratified approach with a long-term follow-up

The use of allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) was almost abandoned in recent years for very effective targeted therapy with tyrosine kinase inhibitors (TKIs). However, approximately one third of patients still need another treatment including SCT. 38 consecutive CML patients were treated (most in preimatinib era) with allogeneic SCT, using partial T cell depletion (TCD) and preemptive donor lymphocyte infusion (DLI), without post‐transplant graft‐versus‐host disease (GvHD) prophylaxis. Conditioning included busulfan, cyclophosphamide, antithymocytic globulin, and fludarabine followed by donor stem cell transfusion. With a median follow up of 90.5 months (1–134), 32 patients are alive. 97% engrafted. 5‐year leukemia free survival (LFS) and overall survival (OS) were 78.95% and 84.2%, respectively. All patients are in major molecular remission and 78% in complete molecular remission. Transplant‐related mortality (TRM) was 13%. Twenty‐four patients received DLI for residual disease. Acute GvHD, mostly Grades I‐II, occurred in 18% of patients post‐transplant and in 24% of patients receiving DLI. In conclusion, the risk‐adapted approach using only partial TCD and preemptive escalated dose of DLI precluded the need for immunosuppressive medications and reduced the risk of significant GvHD without compromising engraftment and long‐term disease control. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.     

Women's post-chemotherapy parity is affected by offspring number and marital status

Childbearing rates post-chemotherapy for breast cancer (BC) are affected by age and chemotherapy-type but may also depend on personal characteristics. In this single institution retrospective study we evaluated post-chemotherapy fertility and its association with offspring number and marital-status at the time of BC diagnosis.We identified 65 fertile BC patients under 38y, who received adjuvant-chemotherapy. Menses resumption and pregnancies along with offspring-number and marital-status were recorded. Menses resumed in 95.4% and 33.8% gave birth. Of those who did not give birth 46.5% had at least three children at diagnosis and of those without children 83% were unmarried. Our data associates multiparity with lower childbearing post-chemotherapy, suggesting it as a possible surrogate for women's preferences in retrospective studies. Unlike multiparity, marital status association with lower childbearing may be culture-dependent and not a universal surrogate for women's intentions and would be best investigated prospectively.     

A subset of CD8+ T cells acquiring selective suppressive properties may play a role in GvHD management

Difficulty in segregating graft-versus-tumor effect (GvT) from graft-versus-host disease (GvHD) remains a major limitation of allogeneic stem cell transplantation (Allo SCT). Naturally occurring regulatory T cells have been suggested to suppress alloreactive T cells involved in GvHD; however, their non-selective suppressive effect raises concern regarding probable attenuation of the GvT effect. Recent studies suggested inducible CD8 (iCD8) cells to be useful in suppressing autoimmune reactions, although their function in the Allo SCT setting has not been fully explored. The current study assessed in-vitro the properties of iCD8 T cells, generated in response to allogeneic dendritic cells (DCs), imitating the Allo SCT conditions. CD25^? peripheral blood mononuclear cells (PBMCs) were stimulated with allogeneic DCs in mixed lymphocyte culture (MLC). The resultant iCD8⁺CD25⁺ population was isolated and assessed for phenotypic markers, cytokine expression profile, cell proliferation, inhibitory capacity and anti-viral response. The generated CD8⁺CD25⁺FOXP3⁺ T cells selectively inhibited the primary allogeneic response, without attenuating T cell response against other stimuli, such as mitogens or a cytomegalovirus (CMV) recall antigen. In conclusion, iCD8⁺CD25⁺ cells suppress allogeneic stimulation, while maintaining the capacity to respond to infectious pathogens. These cells could be potentially efficient in the Allo SCT setting, where GvHD prevention is required.     

Schizophrenia-like neurophysiological abnormalities in 22q11.2 deletion syndrome and their association to COMT and PRODH genotypes

22q11.2 deletion syndrome (22q11.2DS) is a common genetic risk factor for the development of schizophrenia. We investigated two neurophysiological endophenotypes of schizophrenia – P50 sensory gating and mismatch negativity in 22q11.2DS subject and evaluated their association with catechol O-methyltransferase (COMT) and proline dehydrogenase (PRODH) genetic variants. We also assessed the association of neurophysiological measures with schizophrenia-like symptomatology in 22q11.2DS. Fifty-nine subjects, 41 with 22q11.2DS and 18 typically developing controls, participated in the study. The participants with 22q11.2DS were genotyped for the COMT Val¹⁵⁸Met (rs4680) and PRODH Gln¹⁹Pro (rs2008720) and Arg¹⁸⁵Trp (rs4819756) polymorphisms. Following psychiatric evaluation, all the participants underwent neurophysiological recordings and executive function assessment. The 22q11.2DS group showed poorer sensory gating of the P50 response than the controls. Within the 22q11.2DS group, the COMT Met allele was associated with poorer sensory gating, while both the COMT Met allele and the PRODH Pro-Arg haplotype were associated with smaller mismatch negativity amplitudes. Smaller mismatch negativity amplitudes predicted greater impairment of executive functions and greater severity of schizophrenia-like negative symptoms in 22q11.2DS. The current study demonstrates that sensory gating impairments that are typical of schizophrenia are found in 22q11.2DS subjects. Our results further suggest that COMT and PRODH genetic variations contribute to sensory gating and mismatch negativity schizophrenia-like impairments in 22q11.2DS, possibly via dopaminergic/glutamatergic networks. The associations of mismatch negativity impairments with increased severity of schizophrenia-like negative symptoms and poorer executive functions performance in our 22q11.2DS sample suggest that mismatch negativity is a potential endophenotype for schizophrenia in 22q11.2DS.     

Iron dysregulation in Alzheimer's disease: multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents

Considering the multi-etiological character of Alzheimer's disease (AD), the current pharmacological approaches using drugs oriented towards a single molecular target possess limited ability to modify the course of the disease and thus, offer a partial benefit to the patient. In line with this concept, novel strategies include the use of a cocktail of several drugs and/or the development of a single molecule, possessing two or more active neuroprotective-neurorescue moieties that simultaneously manipulate multiple targets involved in AD pathology. A consistent observation in AD is a dysregulation of metal ions (Fe²⁺, Cu²⁺ and Zn²⁺) homeostasis and consequential induction of oxidative stress, associated with beta-amyloid aggregation and neurite plaque formation. In particular, iron has been demonstrated to modulate the Alzheimer's amyloid precursor holo-protein expression by a pathway similar to that of ferritin L-and H-mRNA translation through iron-responsive elements in their 5′UTRs. This review will discuss two separate scenarios concerning multiple therapy targets in AD, sharing in common the implementation of iron chelation activity: (i) novel multimodal brain-permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities; (ii) natural plant polyphenols (flavonoids), such as green tea epigallocatechin gallate (EGCG) and curcumin, reported to have access to the brain and to possess multifunctional activities, such as metal chelation-radical scavenging, anti-inflammation and neuroprotection.     

How we started performing endovenous thermal ablation procedures: a personal history

This story is a personal journey of two Dutch dermatologists pioneering in the field of endovenous laser ablation of varicose veins, illustrating how innovations find their way in medicine and, in particular, in surgical specialties. After the introduction of these thermal ablative procedures in 2001, we have fully embraced these minimally invasive techniques, and in the process, we have increased our understanding on its mechanism of action and confirmed the clinical relevance of treating varicose veins with endovenous laser ablation. In 2013, thermal ablation is considered a standard of care by physicians as well as patients with varicose veins.