Brentuximab vedotin and ESHAP is highly effective as second-line therapy for Hodgkin lymphoma patients (long-term results of a trial by the Spanish GELTAMO Group).

BACKGROUND: In this work, we assessed the efficacy and safety of brentuximab vedotin (BV) plus ESHAP (BRESHAP) as second-line therapy for Relapsed/Refractory Hodgkin lymphoma (RRHL) to improve the results before autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: This was a multicenter, open-label, phase I-II trial of patients with RRHL after first-line chemotherapy. Treatment had three 21-day cycles of etoposide, solumedrol, high-dose AraC, and cisplatin. BV was administered at three dose levels (0.9, 1.2, and 1.8 mg/kg) intravenous on day ‒1 to 3 + 3 cohorts of patients. Final BV dose was 1.8 mg/kg. Responding patients proceeded to ASCT, followed by three BV courses (1.8 mg/kg, every 21 days). Main end points for evaluation were maximum tolerable dose and overall and complete response (CR) before ASCT. RESULTS: A total of 66 patients were recruited (median age 36 years; range 18-66): 40 were primary refractory, 16 early relapse and 10 late relapse. There were 39 severe adverse events were reported in 22 patients, most frequently fever (n = 25, 35% neutropenic), including 3 deaths. Grade 3-4 hematological toxicity presented in 28 cases: neutropenia (n = 21), thrombocytopenia (n = 14), and anemia (n = 7). Grade ≥3-4 extrahematological adverse events (≥5%) were non-neutropenic fever (n = 13) and hypomagnesaemia (n = 3). Sixty-four patients underwent stem-cell mobilization; all collected >2×10e6/kg CD34+ cells (median 5.75; range 2.12-33.4). Overall response before transplant was 91% (CI 84% to 98%), including 70% (CRs 95% CI 59% to 81%). 60 patients were transplanted with no failure engraftments. Post-transplant response was CR in 49 patients (82% CI 73% to 91%) and partial responses in six (10% CI 5% to 15%). After a mean follow-up of 27 months, the 30-month time to treatment to failure was 74% (95% CI 68% to 80%), progression-free survival 71% (95% CI 65% to 77%), and overall survival 91% (CI 84% to 98%). CONCLUSION: BRESHAP looks a safe and effective pre-transplant induction regimen, does not jeopardize transplant and allows long-term remissions and survival.

Comorbidities, not age, are predictive of survival after autologous hematopoietic cell transplantation for relapsed/refractory Hodgkin's lymphoma in patients older than 50 years.

Autologous hematopoietic cell transplantation (AHCT) is the standard of care for young patients with relapsed/refractory (R/R) Hodgkin's lymphoma (HL). However, there is limited experience of its efficacy and feasibility in older patients. The characteristics and outcomes of 121 patients aged ≥50 years (42 of them are ≥60 years old) with R/R HL who underwent AHCT were reviewed. After a median follow-up of 3.1 years, overall survival (OS) and progression-free survival (PFS) at 5 years were 64 and 55 %, respectively, with no differences between 50-59-year-old and ≥60-year-old patients. Hematological and extra-hematological toxicities after AHCT were comparable between the two groups of age. In univariate analysis, poorer OS and PFS were associated with disease status other than complete remission, hematopoietic cell transplantation comorbidity index (HCT-CI) scores >1, and Charlson Comorbidity Index (CCI) scores >1. HCT-CI scores >1 were also associated with a higher risk of grade 3-4 extrahematologic toxicity. In multivariate analysis, HCT-CI and CCI remained significantly associated with OS and PFS after adjustment for disease status. Our data show that AHCT can be performed in selected patients with R/R HL ≥50 years with acceptable outcome and toxicity. Comorbidities appear to impact AHCT outcome more than age.

Psoriasis en el embarazo: qué sabemos hoy de las terapias delpasado y del futuro? / Psoriasis in pregnancy: what do we know today about the therapies of the past and the future?

La psoriasis es una enfermedad sistémica que puede ocurrir de múltiples formas durante el embarazo, con severidad variable, incluso con formas que amenazan la vida. Las variantes severas se han asociado a mayores riesgos maternos y fetales, y la mayor parte de los tratamientos tópicos y sistémicos disponibles están contraindicados durante el embarazo por el riesgo de toxicidad fetal. Los tratamientos de primera línea son los emolientes y los corticoides tópicos de baja-moderada potencia y en casos severos la fototerapia nbUVB es el tratamiento de elección. En pacientes con formas muy severas y refractarias otras alternativas de tratamiento son la ciclosporina, los corticoides sistémicos y los agentes biológicos, especialmente los anti-TNF-α, sin embargo, la información disponible sobre el uso de estas moléculas en embarazadas es muy limitada, y sólo deberían considerarse en casos muy seleccionados. El impétigo herpetiforme es una forma propia de psoriasis pustular severa durante el embarazo y las principales alternativas terapéuticas son la inducción del parto o el uso de corticoides sistémicos.

Psoriasis is a systemic disease that can be present during pregnancy in different clinical forms and variable severity; some forms can be life threatening. Severe clinical forms are associated with greater maternal and fetal risks, and topical and systemic treatments available are mainly contraindicated during pregnancy because of fetal toxicity risks. First line treatments are emollients and low-medium potency topical steroids; in severe cases nUVB phototherapy is the preferred treatment. In patients with more severe and recalcitrant clinical forms cyclosporine, systemic steroids and biologics agents specially anti-TNF-α are the options. Nevertheless the available information of the use of these treatments in pregnant women is limited and these drugs should be considered only in very special cases. Herpetiformis impetigo is a proper form of severe pustular psoriasis in pregnancy and the treatments for this entity should be delivery induction or systemic steroids.

Penfigoide gestacional "Herpes gestationis": revisión a partir de un caso clínico / Gestational pemphigoid "Herpes gestationis": review from a clinical case

La embarazada es susceptible a cambios en la piel y fanéreos que pueden ser fisiológicos como patológicos. El reconocimiento de estas entidades es fundamental para un correcto manejo. La clasificación y nomenclatura de las dermatosis del embarazo ha sido controversial y confusa, principalmente dado el pobre conocimiento que se tiene sobre el origen de estas entidades. El objetivo de esta revisión es informar sobre el conocimiento actual del penfigoide gestacional a partir de un caso clínico, centrándose en su diagnóstico y tratamiento como patología multidiscilpinaria.

The pregnant woman is susceptible to both physiologic and pathologic changes of the skin and appendages. Recognition of these entities is important for appropriate management. The classification and nomenclature have been controversial and confusing, mainly because of the poor knowledge that we have regarding the origin of this entities. The purpose of this review is to contribute to the current knowledge of pemphigoid gestationis, based on a case-report its diagnosis and treatment as a multidisciplinary pathology.

Comorbilidades metabólicas y cardiovasculares en psoriasis / Cardiovascular and metabolic comorbidity in psoriasis

La psoriasis es una enfermedad crónica y aumenta el riesgo de mortalidad general, mortalidad cardiovascular y diversas enfermedades metabólicas y cardiovasculares. La inflamación crónica observada en psoriasis y aterosclorosis parece ser la razón de esta asociación. Diabetes, hipertensión, dislipidemia, obesidad, síndrome metabólico y otros factores de riesgo cardiovascular clásicos son más frecuentes en psoriasis; sin embargo, la psoriasis ha demostrado ser un factor de riesgo independiente de mortalidad y de enfermedades cardiovasculares. Infarto al miocardio, enfermedades cerebrovasculares, hígado graso y enfermedad pulmonar obstructiva crónica son alguna de las enfermedades específicas relacionadas con la psoriasis. Todas estas observaciones apoyan la idea de psoriasis como una enfermedad sistémica, más que sólo una condición cutánea.

Psoriasis is a chronic disease and increases the risk of general mortality, cardiovascular mortality and several metabolic and cardiovascular diseases. The chronic inflammation observed in psoriasis and atherosclerosis seems to be the reason for this association. Diabetes, hypertension, dyslipidemia, obesity, metabolic syndrome and other classical cardiovascular risk factors are more common in psoriasis; however, psoriasis has been shown as an independent risk factor for mortality and cardiovascular diseases. Myocardial infarction, cerebrovascular disorders, non-alcoholic fatty liver disease and chronic obstructive pulmonary disease are some specific disease related to psoriasis. All these observations support the idea that psoriasis behaves like a systemic disease, more than just as a cutaneous condition.

[Acute transverse myelitis in seven patients with systemic lupus erythematosus]. / Mielitis transversa aguda en siete pacientes con lupus eritematoso sistémico.

INTRODUCTION: Although the association between transverse myelitis and systemic lupus erythematosus is rather infrequent, it is important to take this form of clinical presentation into account because it is a serious complication, which can potentially be treated but even when dealt with in the early stages does not always have a good prognosis. PATIENTS AND METHODS: We conducted a retrospective review over the past 13 years of the cases that have been admitted to our specific centre for the treatment of spinal cord injuries that were diagnosed as suffering from myelitis associated with disseminated lupus erythematosus. Demographic and clinical data, together with data about acute phase and maintenance treatments, as well as the patients' progress and sequelae are described. RESULTS: The case reports of seven patients, all of whom were young females, are studied. In two cases, myelitis was the initial presentation of lupus. The main disorder was at the dorsal, followed by the cervical, levels. Only two patients had a favourable long-term progression from the neurological point of view (both managed to walk) despite acute treatment with high doses of intravenous corticoids, and regardless of the fact that cyclophosphamide was later used. CONCLUSIONS: Myelitis associated to lupus is a rare manifestation but, owing to its important functional repercussions, it must be taken into account when faced with an acute clinical picture involving the spinal cord; this is particularly the case when it occurs in young females, with or without a previous diagnosis of autoimmune disease.

Dermatosis en los deportistas: [revisión] / Sport dermatoses: [review]

Sports practice has become a part of modern life. As a result, the association of dermatoses with sports increases continuously. Proper diagnosis and treatment of these skin lesions requires familiarity with their characteristics clinical presentations. This article reviews the cutaneous manifestations of traumatic and environmental injuries, infections, and exacerbation of preexisting dermatoses.

Psoriasis y enfermedades afines: experiencia con Re-PUVA en el manejo de psoriasis moderada-severa / Psoriasis and related diseases: experience with Re-PUVA in the treatment of moderate-to-severe psoriasis

Introducción: El manejo de la psoriasis moderada-severa es complejo, y un importante número de pacientes considera que el tratamiento indicado por su médico tratante no es suficientemente agresivo. El uso de tratamientos combinados ha demostrado mayor efectividad que las monoterapias, logrando aclaración de las lesiones en menor tiempo, con dosis más bajas de agentes terapéuticos y menos efectos adversos. Objetivos: Presentar nuestra experiencia con terapia combinada de retinoides más PUVA (Re-PUVA) en pacientes con psoriasis moderada-severa. Pacientes y Métodos: Se trató a nueve pacientes con psoriasis moderada-severa, mayores de 18 años, con terapia combinada de acitretín+PUVA, evaluando respuesta clínica bajo protocolo y seguimiento fotográfico al inicio 8ª y 16ª semana de tratamiento. Se estimaron dosis requeridas, costos, y efectos adversos del tratamiento. Resultados: El tiempo de tratamiento requerido para conseguir aclaración en el 90 por ciento de los pacientes fue de siete semanas. La dosis promedio de acitretín fue de 033 mg/kg/ día y la dosis acumulada de UVA fue de 139 J/cm². El costo estimado para conseguir aclaramiento en el 90 por ciento de los pacientes fue de US$ 634. No se observaron efectos adversos severos. Conclusión: La terapia combinada Re-PUVA demostró ser una excelente opción terapéutica para psoriasis moderada-severa, lográndose óptimos resultados en un corto plazo, a un costo razonable, y sin efectos adversos severos.

TrwB, the coupling protein involved in DNA transport during bacterial conjugation, is a DNA-dependent ATPase.

Bacterial conjugation is an example of macromolecular trafficking between cells, based on the translocation of single-stranded DNA across membranes through a type IV secretion system. TrwBDeltaN70 is the soluble domain of TrwB, an essential integral membrane protein that couples the relaxosome (a nucleoprotein complex) to the DNA transport apparatus in plasmid R388 conjugation. TrwBDeltaN70 crystallographic structure revealed a hexamer with six equivalent subunits and a central channel. In this work, we characterize a DNA-dependent ATPase activity for TrwBDeltaN70. The protein displays positive cooperativity for ATP hydrolysis, with at least three catalytic sites involved. The activity is sensitive to pH and salt concentration, being more active at low pH values. The effective oligonucleotide size required for activation of the ATPase function is between 40 and 45 nucleotides, and the same length is required for the formation of high-molecular-weight TrwBDeltaN70-DNA complexes, as observed by gel filtration chromatography. A mutation in a tryptophan residue (W216A), placed in the central pore formed by the hexameric structure, resulted in a protein that did not hydrolyze ATP. In addition, it exerted a dominant negative effect, both on R388 conjugation frequency and ATP hydrolysis, underscoring the multimeric state of the protein. ATP hydrolysis was not coupled to a DNA unwinding activity under the tested conditions, which included forked DNA substrates. These results, together with TrwB structural similarity to F1-ATPase, lead us to propose a mechanism for TrwB as a DNA-translocating motor.

Coupling factors in macromolecular type-IV secretion machineries.

Type IV secretion systems (T4SSs) are bacterial multiprotein organelles specialised in the transfer of (nucleo)protein complexes across cell membranes. They are essential for conjugation, bacterial-induced tumour formation in plant cells, as observed in Agrobacterium, toxin secretion, like in Bordetella and Helicobacter, cell-to-cell translocation of virulence factors, and intracellular activity of mammalian pathogens like Legionella. By enabling conjugative DNA delivery, these systems contribute to the spread of antibiotic resistance genes among bacteria. These translocons are made up by 10-15 proteins that are analogous to Vir proteins of Agrobacterium and traverse both membranes and the periplasmic space in between in Gram-negative bacteria. Their secretion substrates range from single-stranded DNA/protein complexes to multicomponent toxins and they are assisted by integral inner-membrane coupling factors, the multimeric type-IV coupling proteins (T4CPs), to connect the macromolecular complexes to be transferred with the secretory conduit. To do so, these T4CPs may be required to localise close to the secretion machinery within the donor cell. The T4CP structural prototype is the hexameric protein TrwB of Escherichia coli conjugative plasmid R388, closely related to Agrobacterium VirD4 protein. It is responsible for coupling the relaxosome with the DNA transport apparatus during cell mating. T4CP family members are related to SpoIIIE/FtsK proteins, essential for DNA pumping during sporulation and cell division. These features suggest possible mechanisms for conjugal T4CP function: as a simple coupler between two molecular machines, as a rotating device to pump DNA through the type-IV transport pore, or as a DNA injector, whereby its central channel would function as part of the transport pore.

[Sensory neuropathy and primary biliary cirrhosis]. / Neuropatía sensitiva en la cirrosis biliar primaria.

Primary biliary cirrhosis (PBC) may associate an axonal neuropathy, a somatic and autonomic neuropathy and a very infrequently sensory neuropathy (with or without xanthomata). The aim of this paper is to describe the case of a 46 year old man diagnosed with PBC in stage I-II and a progressive sensory neuropathy (axonopathy) confined to his upper limbs with distal predominance. It had progressed slowly an began asymmetrically. A complete clinical study excluded other causes of neuropathy. We followed him clinically and electromyographically and he remains stable after two years evolution. The sensory neuropathy in this case, a primary biliary cirrhosis, is compatible with an assymetric sensory neuropathy limited to the upper limbs with assymmetric beginning.

Fetal gender and aneuploidy detection using fetal cells in maternal blood: analysis of NIFTY I data. National Institute of Child Health and Development Fetal Cell Isolation Study.

OBJECTIVES: The National Institute of Child Health and Human Development Fetal Cell Isolation Study (NIFTY) is a prospective, multicenter clinical project to develop non-invasive methods of prenatal diagnosis. The initial objective was to assess the utility of fetal cells in the peripheral blood of pregnant women to diagnose or screen for fetal chromosome abnormalities. METHODS: Results of fluorescence in situ hybridization (FISH) analysis on interphase nuclei of fetal cells recovered from maternal blood were compared to metaphase karyotypes of fetal cells obtained by amniocentesis or chorionic villus sampling (CVS). After the first 5 years of the study we performed a planned analysis of the data. We report here the data from 2744 fully processed pre-procedural blood samples; 1292 samples were from women carrying singleton male fetuses. RESULTS: Target cell recovery and fetal cell detection were better using magnetic-based separation systems (MACS) than with flow-sorting (FACS). Blinded FISH assessment of samples from women carrying singleton male fetuses found at least one cell with an X and Y signal in 41.4% of cases (95% CI: 37.4%, 45.5%). The false-positive rate of gender detection was 11.1% (95% CI: 6.1,16.1%). This was higher than expected due to the use of indirectly labeled FISH probes in one center. The detection rate of finding at least one aneuploid cell in cases of fetal aneuploidy was 74.4% (95% CI: 76.0%, 99.0%), with a false-positive rate estimated to be between 0.6% and 4.1%. CONCLUSIONS: The sensitivity of aneuploidy detection using fetal cell analysis from maternal blood is comparable to single marker prenatal serum screening, but technological advances are needed before fetal cell analysis has clinical application as part of a multiple marker method for non-invasive prenatal screening. The limitations of the present study, i.e. multiple processing protocols, are being addressed in the ongoing study.

The bacterial conjugation protein TrwB resembles ring helicases and F1-ATPase.

The transfer of DNA across membranes and between cells is a central biological process; however, its molecular mechanism remains unknown. In prokaryotes, trans-membrane passage by bacterial conjugation, is the main route for horizontal gene transfer. It is the means for rapid acquisition of new genetic information, including antibiotic resistance by pathogens. Trans-kingdom gene transfer from bacteria to plants or fungi and even bacterial sporulation are special cases of conjugation. An integral membrane DNA-binding protein, called TrwB in the Escherichia coli R388 conjugative system, is essential for the conjugation process. This large multimeric protein is responsible for recruiting the relaxosome DNA-protein complex, and participates in the transfer of a single DNA strand during cell mating. Here we report the three-dimensional structure of a soluble variant of TrwB. The molecule consists of two domains: a nucleotide-binding domain of alpha/beta topology, reminiscent of RecA and DNA ring helicases, and an all-alpha domain. Six equivalent protein monomers associate to form an almost spherical quaternary structure that is strikingly similar to F1-ATPase. A central channel, 20 A in width, traverses the hexamer.

Enzymology of type IV macromolecule secretion systems: the conjugative transfer regions of plasmids RP4 and R388 and the cag pathogenicity island of Helicobacter pylori encode structurally and functionally related nucleoside triphosphate hydrolases.

Type IV secretion systems direct transport of protein or nucleoprotein complexes across the cell envelopes of prokaryotic donor and eukaryotic or prokaryotic recipient cells. The process is mediated by a membrane-spanning multiprotein assembly. Potential NTPases belonging to the VirB11 family are an essential part of the membrane-spanning complex. Three representatives of these NTPases originating from the conjugative transfer regions of plasmids RP4 (TrbB) and R388 (TrwD) and from the cag pathogenicity island of Helicobacter pylori (HP0525) were overproduced and purified in native form. The proteins display NTPase activity with distinct substrate specificities in vitro. TrbB shows its highest specific hydrolase activity with dATP, and the preferred substrate for HP0525 is ATP. Analysis of defined TrbB mutations altered in motifs conserved within the VirB11 protein family shows that there is a correlation between the loss or reduction of NTPase activity and transfer frequency. Tryptophan fluorescence spectroscopy of TrbB and HP0525 suggests that both interact with phospholipid membranes, changing their conformation. NTPase activity of both proteins was stimulated by the addition of certain phospholipids. According to our results, Virb11-like proteins seem to most likely be involved in the assembly of the membrane-spanning multiprotein complex.

Export of a cysteine-free misfolded secretory protein from the endoplasmic reticulum for degradation requires interaction with protein disulfide isomerase.

Protein disulfide isomerase (PDI) interacts with secretory proteins, irrespective of their thiol content, late during translocation into the ER; thus, PDI may be part of the quality control machinery in the ER. We used yeast pdi1 mutants with deletions in the putative peptide binding region of the molecule to investigate its role in the recognition of misfolded secretory proteins in the ER and their export to the cytosol for degradation. Our pdi1 deletion mutants are deficient in the export of a misfolded cysteine-free secretory protein across the ER membrane to the cytosol for degradation, but ER-to-Golgi complex transport of properly folded secretory proteins is only marginally affected. We demonstrate by chemical cross-linking that PDI specifically interacts with the misfolded secretory protein and that mutant forms of PDI have a lower affinity for this protein. In the ER of the pdi1 mutants, a higher proportion of the misfolded secretory protein remains associated with BiP, and in export-deficient sec61 mutants, the misfolded secretory protein remain bounds to PDI. We conclude that the chaperone PDI is part of the quality control machinery in the ER that recognizes terminally misfolded secretory proteins and targets them to the export channel in the ER membrane.

Characterization of ATP and DNA binding activities of TrwB, the coupling protein essential in plasmid R388 conjugation.

TrwB is the conjugative coupling protein of plasmid R388. TrwBDeltaN70 contains the soluble domain of TrwB. It was constructed by deletion of trwB sequences containing TrwB N-proximal transmembrane segments. Purified TrwBDeltaN70 protein bound tightly the fluorescent ATP analogue TNP-ATP (K(s) = 8.7 microM) but did not show measurable ATPase or GTPase activity. A single ATP binding site was found per TrwB monomer. An intact ATP-binding site was essential for R388 conjugation, since a TrwB mutant with a single amino acid alteration in the ATP-binding signature (K136T) was transfer-deficient. TrwBDeltaN70 also bound DNA nonspecifically. DNA binding enhanced TrwC nic cleavage, providing the first evidence that directly links TrwB with conjugative DNA processing. Since DNA bound by TrwBDeltaN70 also showed increased negative superhelicity (as shown by increased sensitivity to topoisomerase I), nic cleavage enhancement was assumed to be a consequence of the increased single-stranded nature of DNA around nic. The mutant protein TrwB(K136T)DeltaN70 was indistinguishable from TrwBDeltaN70 with respect to the above properties, indicating that TrwB ATP binding activity is not required for them. The reported properties of TrwB suggest potential functions for conjugative coupling proteins, both as triggers of conjugative DNA processing and as motors in the transport process.

[Acute transverse myelitis in systemic lupus erythematosus]. / Mielitis transversa aguda en el lupus eritematoso sistémico.

Acute transverse myelitis as complication of systemic lupus erythematosus is a known and well-characterized although uncommon clinical entity. We report here four cases of lupic myelitis collected at our hospital in the last few years and review the available literature of the last ten years, approximately the time when NMR became generally available. The clinical picture can be very variable and therefore, when facing a picture of acute myelitis, lupus should be included in the differential diagnosis; biochemistry evaluating the lupus "activity" is of poor diagnostic value, nuclear magnetic resonance is not conclusive for the etiologic diagnosis of myelitis and its prognosis has improved with therapy including pulses of steroid and immunosuppressant agents.

[Devic's optic neuromyelitis: analysis of 7 cases]. / Neuromielitis óptica de Devic: análisis de siete casos.

INTRODUCTION: Devic's optic neuromyelitis is an unusual condition characterized by the association of unilateral or bilateral optic neuritis and myelitis, both of which are relapsing. Prognosis is usually poor, both for the optic nerve and for the spinal medulla which becomes cavitated. This leads to severe handicap and deterioration in quality of life, except in cases presenting as children. PATIENTS AND METHODS: We studied seven cases of this condition and describe their clinical and neuroimaging features, cerebrospinal fluid (CSF), evaluation, complications, prognosis and treatment. This data was compared with that in the literature. RESULTS AND CONCLUSIONS: 1. It is an unusual condition--only 7 cases have been seen at our centre--making up approximately 0.1% of the inflammatory pathology of the spinal cord seen. 2. During the first few hours or days the clinical and radiological findings may not correspond. There may be marked deterioration of CNS function but with normal neuroimaging findings. This may lead to serious problems in diagnosis, which can usually be resolved by repeating the investigation. 3. Differential diagnosis should be made with intramedullary tumors when on neuroimaging there is increased spinal cord diameter with uptake of contrast, and psychiatric disorders when this is normal. 4. The condition usually deteriorates leading to severe disability, since loss of visual acuity is added to the severe spinal cord lesion. 5. Diagnosis should be made by application of the criteria of clinical evolution, imaging and biochemistry defined in the literature, although firm diagnosis can only be made on anatomopathological studies, usually at autopsy.