Over the last decade, there has been a dramatic decline in the frequency of organ failure, infection, and severe acute CVHD as causes of non-relapse mortality after allogeneic hematopoietic cell transplantation. Gastrointestinal CVHD, however, remains a significant obstacle to survival. Patients who present with non-progressive symptoms of the upper gut phenotype of GVHD seldom progress to severe CVHD, but may have a prolonged course, they can be successfully treated with prednisone 1 mg/kg/day for a limited time, along with topical and oral glucocorticoid. Patients who present with the mid-gut phenotype of GVHD can be recognized soon after presentation by secretory protein-losing enteropathy and falling serum albumin; their treatment requires prednisone 2 mg/kg/day and probably an additional drug such as mycophenolic acid. Failure to improve identifies a cohort with a poor prognosis; secondary therapy should be started while gut mucosa is still intact, but no secondary therapies have been proven in randomized trials to improve survival. Patients whose initial presentation (large volume diarrhea, low serum albumin, jaundice, mucosal necrosis and sloughing at initial endoscopy) presages a fatal outcome have not been studied prospectively.

Chronic graft versus host disease (GVHD) is still the main cause of long-term non-neoplastic morbidity and mortality in patients receiving an allogeneic hematopoietic stem cell transplantation. Treatment consists of a combination of corticosteroids and calcineurin inhibitors. There is no standardized therapy for cases in which this treatment fails. Recent experimental studies and clinical trials in humans have yielded promising results for imatinib, an inhibitor of tyrosine kinase enzymes involved in the pathogenesis of fibrosis. This article reviews pathophysiologic aspects of scleroderma in the context of GVHD and systemic sclerosis, the experimental bases for the use of tyrosine kinase inhibitors in these diseases, and the first clinical results.

The NIH classification intends to standardize the diagnostic criteria for chronic CVHD and to establish prognosis groups that will help to identify patient risk and thus decide on the most appropriate treatment. This study assesses the predictive value of this classification and analyzes new prognostic factors in a series of 820 patients receiving allogeneic grafts at three sites: Hospital Universitario de Salamanca, Hospital de la Santa Creu i Sant Pau, in Barcelona, and Karolinska Institutet, in Stockholm. In the univariate analysis, the classification limited/extensive, the NIH class, and the type of onset have a significant influence on overall survival and transplant-related mortality. Additionally, the overlap syndrome is associated with a shorter survival in the multivariate analysis, only the NIH class-with on HR of 2.89 (95% Cl: 1.75-4.76; p < 0.007) for mild and moderate versus severe disease-has a significant influence on survival. Excluding the NIH class, the type of onset is Identified as an independent factor for survival. Therefore, the NIH class and the type of onset are confirmed as the most significant variables. This is important in order to identify patients with a higher risk of death after transplantation, and shorter survival. On the other hand, it is a very laborious classification; for this reason it is necessary to establish the degree of involvement of lungs, skin, digestive tract, and liver, and to identify the number of organs, because these factors significantly affect survival.

Pegylation implies progress in filgrastim therapy. The addition of one molecule of polyethylene glycol (PEG) increases the drug's half-life by reducing renal excretion. A single dose of pegfilgrastim is equivalent to a daily administration of G-CSF for recovering from neutropenia after cancer chemotherapy. Pegfilgrastim is also useful to mobilize hematopoietic stem cells. Several studies have researched its efficacy in this context, in patients with myeloma or lymphoma. Outcomes suggest that it has an efficacy similar to daily G-CSF. In allogeneic donors, a single 12-mg dose of pegfilgrastim produces sufficient increase of CD34+ in peripheral blood, with acceptable toxicity. There is interest on the data about the various functional and biologic properties of hematopoietic stem cells mobilized with pegfilgrastim compared to G-CSF, and on the effect that these differences may have on the graft composition. The administration of a single dose of pegfilgrastim after autologous transplantation has been shown to shorten the time for leukocyte recovery in a manner similar to G-CSF

At this time, allogeneic transplantation should be offered only within the context of clinical trials. The likelihood of achieving prolonged complete remission with standard therapy with new drugs and autografting renders allogeneic transplantation unadvisable as first-line treatment in most patients. In this situation, the procedure must be reserved only for young patients with very poor prognostic factors or with progression of the disease offer receiving first-line treatment. After the first relapse, it should be applied to patients with an adverse cytogenetics and early relapse (< 18 months) after optimized treatment that includes new drugs and autologous transplantation. In any case, the patient should undergo transplantation with minimal disease. For the remaining patients, this procedure should not be considered the last therapeutic resort, since in this context there is a very low probability of success. On the other hand, conducting the procedure does not imply that the patient will not benefit a posteriori from other treatments, should they become necessary. Caution must be used when interpreting the available data from comparative studies. We have an obligation to continue exploring and improving this strategy which, to date, constitutes the most effective therapeutic tool available to us.

Our team conducted an original procedure of hematopoietic transplantation of umbilical cord blood (UCB) from an unrelated donor. The procedure consists of co-infusing hematopoietic stem cells selected from the blood of a third-party donor; it is conceived as a tool to shorten the engraftment period without preventing the engraftment of the UCB, even when using units with relatively low cell content and a low HLA compatibility. Between 1999 and 2008 we performed 64 transplantations in 60 adult patients (35 men and 25 women) with a median age of 34 years (range: 76-60) and a median weight of 70 kg (range: 43-95), all of whom were diagnosed with a high risk hematologic neoplasm (leukemia in most cases). Fludarabine, cyclophosphamide, ATG, and whole body irradiation or busulfan were used as conditioners. UCB was infused at medians of 2.4 x 107 CNT/kg (range: 1.14-4.30 x 107), 0.11 x 106 CD34+/kg (range: 0.035-0.37 x 106). Then, hematopoietic stem cells selected from the third-party donor were infused (2.43 x 106/kg [range: 1.05-3.34 x 106], with 0.3 x 104 CD3+/kg [range: 0.05-1.56 x 104]). Granulocyte engraftment occurred (ANC > 0.5 x 109/L) at a median of 10 days (range: 9-34 days), and the granulocyte engraftment of the UCB occurred in 21 days (range: 13-57 days). Complete UCB chimerism was observed in 37 days (range: 11-186 days) (previously double complete chimerism, presence of third-party donor and of cord) and platelet engraftment > 20 x 109/L in 33 days (range: 13 98 days) and > 50 x 109/L in 58 days (range: 14-106 days). Overall 3-year survival reached 51%, and 5 10 year-survival was 47% (plateau). Disease-free survival was 48% at three years, and 45% at 5 to 10 years; the mean follow-up of survivors was 48 months (range: 13-123 months). (Kaplan-Meier). In conclusion, early granulocyte recovery occurred thanks to a foster engraftment of hematopoietic stem from the third-party donor, which are not HLA-restricted; this is associated with a lower morbidity and mortality from infections secondary to neutropenia. There was also a high rate of engraftment and final full UCB chimerism, even with non-histocompatible UCB units (2/6 HLA mismatches) and with relatively low cell counts. In most cases, a single unit of UCB was sufficient. The incidence of severe GVHD and the percentage of relapses have been low. Opportunistic infections have occurred over a long period of time. This procedures makes allogeneic hematopoietic transplantation accessible to almost all patients.

Primary Immune thrombocytopenia or idiopathic thrombocytopenic purpura (ITP) is an acquired immune disorder presenting with abnormal hemorrhagic symptoms resulting from a decrease in the number of platelets. The disorder used to be attributed to increased destruction of platelets mediated by antibodies. In the past few years, the description of its etiopathology has changed. A deficiency in the marrow production of thrombocytes has been demonstrated; because it is associated with increased peripheral platelet destruction, the deficiency cannot be compensated. These findings have justified the realization of studies assessing the utility of second generation thrombopoietin analogues for the treatment of these patients. These drugs include romiplostim or AMG 537 (Nplate), a peptidic analogue that stimulates the thrombopoietin receptor and induces an increase In the production and differentiation of megakaryocytes. Data obtained from the clinical trials that led to the authorization and subsequent follow-up describe romiplostin as an effective and safe drug for adult patients with chronic ITR The overall response rate is 94%; despite variations in the levels of platelets throughout treatment, 50% of patients maintain the response 95% of the time, and 78% of patients discontinue or significantly reduce the use of rescue treatment. The most common adverse event is headache. Reticulin fibrosis has been described, which is reversible after treatment discontinuation.

Patients with amyotrophic lateral sclerosis (ALS) experience progressive and irreversible paralysis as a result of the continued loss of motor neurons, which leads to death in less than five years. To date, there is no treatment that can change the progression of this disease. Bone marrow stem cells have shown neural regenerative and neural repairing properties. Specifically, our group showed in a murine model of the disease that these cells, when injected in the spinal cord, can rescue motor neurons through the secretion of GDNF. Based on these results, we designed a phase I/II clinical trial for the purpose of demonstrating the viability of the intraspinal injection of autologous bone marrow mononuclear cells in patients with bulbar onset ALS, with an evolution between 6 and 36 months, with a forced vital capacity (FVC) 50% and T90 29%. This article describes the technique for extracting 60 mL of bone marrow used for the intervention, processing it by density gradient, and the neurosurgical technique used for implanting it. After 6 months of follow-up, the few adverse events reported in the first seven patients included seem to show that the procedure is safe and viable. Most of these patients, including two with a rapid deterioration, have stabilized the progression of their FVC and the neurologic scales measured. The data obtained so for seem to justify the design of new trials more oriented toward the efficacy of the procedure.

The search for an unrelated donor must be based on the HLA typing of the donor and the host. PCR techniques have facilitated high-resolution HLA typing, but they have also elicited questions about the real impact of the various disparities on the progress of the graft Thus, whereas a donor used to be accepted based on HLA-A and B Identity determined by serology and HLA-DRB1 through molecular biology techniques, now a donor is required to have a 70/70 Identity for loci HLA-A, B, C, DRB7, and DQB7. Furthermore, the real effect of the disparities in the sixth locus of the major histocompatibility complex-HLA-DPBT-is still in doubt. This study intends to conduct a literature review of the clinical impact of the various HLA disparities In transplants from unrelated donors.

Graft-versus-host disease (GVHD) remains the greatest source of morbidity-mortality in allogenic transplant patients. Although in most cases the more easily obtainable clinical and laboratory test parameters suffice to confirm the diagnosis and establish the stage of the disease biopsies of the affected organ are sometimes needed. At present there is great Interest in the study of factors allowing a prognosis of the course and type of response to treatment in patients with CVHD. In this sense, It would be necessary to objectively Identify and validate biomarkers capable of predicting biological or pathological processes in patients with cVHD. To this effect we have performed serial analyses of skin tissue using peripheral blood and tissue biomarkers in a prospective observational study conducted in three transplant centers. The still preliminary results Indicate that certain histopathological findings classically attributed to CVHD ore also seen in patients not clinically affected by the disease--this probably being related to other physiopathological phenomena occurring during transplantation. The study of these findings, combined with biomarker analysis, will allow improved understanding of the underlying etiopathogenesis, as well as the definition of new diagnostic, prognostic and response-evaluating criteria.

In the last decade there has been increasing awareness of the importance of thymus gland function in the reconstitution of host immunity following hematopoietic transplantation. A functional thymus contributes to foster T compartment reconstitution, with an increased diversity of T receptor rearrangement, and a more physiological distribution of the functional subpopulations. Palifermin, a keratinocyte growth factor (KGF) approved for reducing the incidence and severity of oral mucositis, has been proposed as a possible strategy for improving thymus function and immune reconstitution after hematopoietic transplantation. In vitro and animal models show palifermin to protect the thymus from chemo-/radiotherapy induced damage, increasing thymic production, accelerating immune reconstitution, improving response to vaccines, and reducing the incidence of graft-versus-host disease in animal models. To date, no studies have analyzed this possible application in humans. This study reports preliminary data on immune reconstitution in 50 autologous transplant recipients (30 treated with palifermin and 20 controls). The results suggest that palifermin at the doses and involving the regimens indicated for the prevention of oral mucositis has no effect upon thymus gland function in adult patients, and induces no changes in T immune recovery (either CD4 or CD8) or in the percentage of functional T subpopulations or T helper lymphocytes.

Fungi of the genus Aspergillus are found everywhere in the natural environment; they cause invasive pulmonary aspergillosis (IPA), an infectious complication common in immunocompromised individuals, which has a mortality rate of up to 90% in patients with hematological malignancy. The first line of defense of innate immunity is the recognition of Aspergillus conidia by dendritic cells or alveolar macrophages. DC-SIGN is an integrin directly involved in this recognition; its degree of expression in immune cells and its functionality may be partly determined by genetic variations. The objective of this study was to determine whether the presence of polymorphisms of a single nucleotide in the DC-SIGN gene increases the risk of invasive pulmonary aspergillosis. For this purpose, the variants DC-SIGN-139A/G (rs2287886) and DC-SIGN+11C/G (rs7252229) were analyzed In 314 subjects (152 patients with hematologic malignancy and 162 healthy controls). Of the 152 hematologic cancer patients, 81 were diagnosed with demonstrated invasive pulmonary aspergillosis per EORTC/IFICG criteria, and the remaining 71 patients had no symptoms of the infection. An association was found between the variant DC-SIGN-139(A/G) and resistance to IPA. Carriers of the allele A (A/A + A/G) were significantly more resistant to the infection than patients with the G/G genotype (p = 0.0574). Analysis of the serum concentration of the galactomannan antigen supported the hypothesis that this polymorphism may be implicated in the susceptibility to suffer invasive pulmonary aspergillosis. Although the difference was not statistically significant, carriers of the allele G had a higher frequency of positive galactomannans than subjects with the genotype A/A (p = 0.1921). These results suggest that the variant DC-SIGN-139(A/G) in the DC-SIGN gene promoter influences the risk of invasive pulmonary aspergillosis and may therefore be used as a genetic biomarker to stratify patients according to risk.

Oncolytic viruses represent a new treatment modality that may help overcome some of the most important limitations of classical radio- and chemotherapy. This new technique is based on conditioned replication of the viral genome only in cells with the genetic alterations characteristic of tumor lesions. This facilitates the selective lysis of tumor masses concomitant to viral autoamplification. As a result, the pharmacodynamic parameters involved are completely different from those of antitumor drug substances. ICOVIR-5 is an oncolytic adenovirus with a good toxicity and antitumor efficacy profile following intravenous administration. However, prior clinical experience has also revealed its most important limitations for ensuring clinical efficacy. The identification of these limitations, together with the possibilities for manipulating viral genomes, now open to door to the molecular designing of candidates offering more efficient antitumor activity and constituting genuine management alternatives in application to treatment-refractory tumors.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Thomson Reuters Integrity(SM), the drug discovery and development portal, http://www.thomsonreutersintegrity.com. This issue focuses on the following selection of drugs: Abatacept, Adalimumab, AdCD40L, Adefovir, Aleglitazar, Aliskiren fumarate, AM-103, Aminolevulinic acid methyl ester, Amlodipine, Anakinra, Aprepitant, Aripiprazole, Atazanavir sulfate, Axitinib; Belimumab, Bevacizumab, Bimatoprost, Bortezomib, Bupropion/naltrexone; Calcipotriol/betamethasone dipropionate, Certolizumab pegol, Ciclesonide, CYT-997; Darbepoetin alfa, Darunavir, Dasatinib, Desvenlafaxine succinate, Dexmethylphenidate hydrochloride cogramostim; Eltrombopag olamine, Emtricitabine, Escitalopram oxalate, Eslicarbazepine acetate, Eszopiclone, Etravirine, Everolimus-eluting coronary stent, Exenatide, Ezetimibe; Fenretinide, Filibuvir, Fludarabine; Golimumab; Hepatitis B hyperimmunoglobulin, HEV-239, HP-802-247, HPV-16/18 AS04, HPV-6/11/16/18, Human albumin, Human gammaglobulin; Imatinib mesylate, Inotuzumab ozogamicin, Invaplex 50 vaccine; Lapatinib ditosylate, Lenalidomide, Liposomal doxorubicin, Lopinavir, Lumiliximab, LY-686017; Maraviroc, Mecasermin rinfabate; Narlaprevir; Ocrelizumab, Oral insulin, Oritavancin, Oxycodone hydrochloride/naloxone; Paclitaxel-eluting stent, Palonosetron hydrochloride, PAN-811, Paroxetine, Pazopanib hydrochloride, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Pitavastatin calcium, Posaconazole, Pregabalin, Prucalopride succinate; Raltegravir potassium, Ranibizumab, RHAMM R3 peptide, Rosuvastatin calcium; Salclobuzic acid sodium salt, SCY-635, Selenate sodium, Semapimod hydrochloride, Silodosin, Siltuximab, Silybin, Sirolimus-eluting stent, SIR-Spheres, Sunitinib malate; Tapentadol hydrochloride, Tenofovir disoproxil fumarate, Tocilizumab, Tositumomab/iodine (I131) tositumomab, Trabectedin, TransVax™ hepatitis C vaccine; Ustekinumab; V-260, Valspodar, Varenicline tartrate, VCL-IPT1, Vildagliptin, VRC-HIVADV014-00-VP, VRC-HIVDNA009-00-VP, VRC-HIVDNA016-00-VP; Yttrium 90 (90Y) ibritumomab tiuxetan, Yttrium Y90 Epratuzumab; Zibotentan, Zotarolimus-eluting stent.