Haploidentical hematopoietic stem cell transplantation in children with high-risk hematologic malignancies: outcomes with two different strategies for GvHD prevention. Ex vivo T-cell depletion and post-transplant cyclophosphamide: 10 years of experience at a single center.

Forty patients with high-risk hematologic malignancies, median age 9 years, underwent haploidentical-HSCT from April 2005 to April 2015. Seventeen patients were transplanted with CD3-depleted PBSCs by negative selection (TCD group) following a reduced-intensity conditioning regimen (RIC), and 23 patients received T-cell-replete PBSCs followed by post-transplantation cyclophosphamide (PT-Cy group) after myeloablative conditioning (n=16) or RIC (n=7). Outcomes are reported for the TCD and PT-Cy recipients, respectively. Engraftment was achieved in 88% versus 100%. Median time to neutrophils>500/µL was 10 days versus 15 days. Platelets>20 000/µL occurred at a median of 16 days versus 20 days, respectively. Transplant-related mortality (TRM) was 24% versus 26% at 1 year. The cumulative incidence (CI) of grade III-IV acute GvHD was 7% versus 5%, and chronic GvHD 9% versus 53% (P=0.029). Relapse at 2 years was 31% versus 24%. Actuarial overall survival rates at 2 years were 47% versus 48%. Causes of death were infections (n=3), sinusoidal obstructive syndrome (n=4), acute GvHD (n=2) and relapse (n=9). These results indicate that haploidentical-HSCT is feasible in Uruguay. The TRM rate is of concern and should be the focus of continuing attention. Chronic GvHD risk was higher in the PT-Cy approach, so modifications are justified.

Feasibility and outcome of haploidentical SCT in pediatric high-risk hematologic malignancies and Fanconi anemia in Uruguay.

In total, 17 pediatric patients with hematologic malignancies (n=14) and Fanconi anemia (FA) (n=3) underwent haploidentical SCT with T-cell depletion. The patients were conditioned with reduced-intensity regimens, and CYA was used for GVHD prophylaxis. Successful engraftment occurred in 16 patients (94%). One patient failed to achieve a primary engraftment. Another patient rejected the first SCT after 10 weeks and had a successful second transplant. Of all engrafted patients, only one developed severe acute GVHD. Ten patients were alive at a median follow-up of 18 months (range, 5-62 months). The 5-years' OS was 53.8%. The three patients with FA are currently well with full-donor chimerism at 16, 6 and 5 months post transplant, respectively. The OS of 14 patients with high-risk hematologic malignancies was 47.6%. Three patients died as a result of post transplant leukemia relapse. CMV infection, GVHD and organ injury were other causes of mortality. Haploidentical SCT was found to be an alternative feasible treatment in Uruguay for patients who need allogenic transplantation but lack an HLA-identical family donor. It should be considered as an early option in FA patients before transformation or significant exposure to blood products.

Resonancia magnética mamaria preoperatoria: la gran polémica / Preoperative breast MRI: the great controversy

Preoperative examination intended to detect multifocality, multicentricity and bilaterality-once considered the strongest indication of breast magnetic resonance imaging (MRI)-is currently being strongly questioned in medical literature. This paper aims at evaluating, based on our experience at Clínica Alemana, Santiago, Chile, breast MRI ability to improve preoperative radiological tumour staging by conventional methods, as well as to determine the proportion of patients in which this diagnostic procedure generated changes in the surgical management. We retrospectively reviewed preoperative MRI studies carried out between January 2009 and June 2010. Classification: Group 1: MRI provided no new information. Group 2: by detecting additional lesions, MRI improved radiological staging without changing the type of surgery planned. Group 3: MRI showed new benign lesions and caused unnecessary surgery. Group 4: MRI successfully changed the type of surgery planned based on conventional studies. A total of 419 breast MRI scans were performed during a 18-month period; 39 percent of them were carried out preoperatively. For the analysis, 128 patients were enrolled and distributed in the following categories: Group 1 (66 percent), Group 2 (20 percent), Group 3 (2 percent) and Group 4 (12 percent). In 95.3 percent of the patients, a single surgery with clear margins was performed. This work demonstrated the usefulness of preoperative MRI in our practice, i.e., it allowed for a better radiological staging in one third of the patients and even successfully changed the surgical approach in 12 percent of cases.

El estudio preoperatorio en búsqueda de multifocalidad, multicentricidad y bilateralidad -antes considerada la indicación más sólida de la resonancia magnética (RM) mamaria- hoy se encuentra fuertemente cuestionada en la literatura. En este trabajo nos propusimos evaluar la capacidad de la RM mamaria en nuestro centro para mejorar la etapificación radiológica preoperatoria realizada por métodos convencionales y determinar la proporción de las pacientes en que genera cambio en el enfoque quirúrgico. Hemos revisado retrospectivamente las RM preoperatorias entre enero de 2009 y junio de 2010. Clasificación: Grupo1: la RM no aportó información nueva. Grupo 2: al detectar lesiones adicionales, mejoró la etapificación radiológica, sin cambiar el tipo de la cirugía planificada. Grupo3: demostró nuevas lesiones no malignas y causó cirugía inútil. Grupo 4: cambió correctamente el tipo de cirugía planeada en base a los estudios convencionales. En los 18 meses se realizaron 419 RM mamarias, el 39 por ciento de ellas en preoperatorio. Para el análisis se han reclutado 128 pacientes con la siguiente distribución en los grupos predeterminados: Grupo 1(66 por ciento), Grupo 2(20 por ciento), Grupo 3(2 por ciento) y Grupo 4(12 por ciento). En el 95,3 por ciento de las pacientes se logró realizar una sola cirugía con márgenes libres. Este trabajo demostró la utilidad de la RM preoperatoria en nuestra práctica: permite una mejor etapificación radiológica en el tercio de las pacientes e incluso cambia correctamente el enfoque quirúrgico en el 12 por ciento de los casos.

Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions.

Functional inducible NOS (iNOS) may be involved in the prolonged lifespan of chronic lymphocytic leukemia cells (B-CLL), although the exact mechanisms implicated remain elusive as yet. In this work, we have examined iNOS expression in normal B lymphocytes and B-CLL cells in pro- and antiapoptotic conditions. Our results demonstrate: (1) The existence of a new splice variant characterized by a complete deletion of exon 14 (iNOS 13-16(14del)), which was preferentially detected in normal B lymphocytes and may represent an isoform that could play a role in the regulation of enzyme activity. (2) The existence of another alternatively spliced iNOS mRNA transcript involving a partial deletion of the flavodoxin region (iNOS 13-16(neg)) was correlated to a decreased B-CLL cell viability. The 9-beta-D-arabinofuranosyl-2-fluoradenine or fludarabine (F-ara) treatment induced iNOS 13-16(neg) transcript variants, whereas IL-4 enhanced both the transcription of variants, including these exons (iNOS 13-16(pos)), and the expression of a 122 kDa iNOS protein. These results suggest that in B-CLL, a regulation process involving nitric oxide (.- NO) levels could occur by a post-transcriptional mechanism mediated by soluble factors. Our results also provide an insight into a new complementary proapoptotic action of F-ara in B-CLL by the induction of particular iNOS splice variants, leading to the activation of a caspase-3-dependent apoptotic pathway.

Do CLL B cells correspond to naive or memory B-lymphocytes? Evidence for an active Ig switch unrelated to phenotype expression and Ig mutational pattern in B-CLL cells.

Recent work suggests that chronic lymphocytic leukemia (B-CLL) expressing unmutated immunoglobulin V genes could correspond to the proliferation of naive B cells whereas those expressing mutated genes, may correspond to the proliferation of post-germinal center B cells. Current data from gene profiling expression have failed to demonstrate a clear-cut distinction between these two forms of B-CLL disease. In the present study, we have investigated the complete V(H) nucleotide sequence and the presence of RNA transcripts from different C(H) domains in 25 B-CLL patients. Our results demonstrate that: (1) expression of IgD is not related to the mutational frequency and activation of the isotype switch pathway; (2) isotype switch, leading to simultaneous expression at the transcriptional and protein level of IgM, IgD, IgG and IgA, occurs in a small percentage of patients, and (3) different mechanisms such as VDJ duplication and trans-splicing or RNA splicing of long nuclear transcript, could be involved in isotype switch. Our results highlight the difficulty in assigning a normal counterpart to B-CLL cells and raise the possibility that a different B cell development pathway, independent from classical germinal centers, might exist in B-CLL.

Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death.

Peroxynitrite (ONOO-) is a potent oxidizing and nitrating agent produced by the reaction of nitric oxide with superoxide. It readily nitrates phenolic compounds such as tyrosine residues in proteins, and it has been demonstrated that nitration of tyrosine residues in proteins inhibits their phosphorylation. During immune responses, tyrosine phosphorylation of key substrates by protein tyrosine kinases is the earliest of the intracellular signaling pathways following activation through the TCR complex. This work was aimed to evaluate the effects of ONOO- on lymphocyte tyrosine phosphorylation, proliferation, and survival. Additionally, we studied the generation of nitrating species in vivo and in vitro during immune activation. Our results demonstrate that ONOO-, through nitration of tyrosine residues, is able to inhibit activation-induced protein tyrosine phosphorylation in purified lymphocytes and prime them to undergo apoptotic cell death after PHA- or CD3-mediated activation but not upon phorbol ester-mediated stimulation. We also provide evidence indicating that peroxynitrite is produced during in vitro immune activation, mainly by cells of the monocyte/macrophage lineage. Furthermore, immunohistochemical studies demonstrate the in vivo generation of nitrating species in human lymph nodes undergoing mild to strong immune activation. Our results point to a physiological role for ONOO- as a down-modulator of immune responses and also as key mediator in cellular and tissue injury associated with chronic activation of the immune system.

Linfoma de celulas B tipo Malt de origen pielocalicial / B cell lymphoma, Malt type, of renal pelvis

Los procesos malignos de tipo linfomatosos que afectan el riñon son infrecuentes, y por lo general lo comprometen como una expresión más de una enfermedad sistémica. Clínicamente pueden ser asintomáticos y presentar hematuria e insuficiencia renal progresiva. El tratamiento es el de su enfermedad de base; en algunas situaciones está indicada la nefrectomía. Se presenta el caso de un paciente de 83 años de edad, en el estudio de rutina por prostatismo se detecta masa ocupante renal derecha. Con diagnóstico de tumor de vía excretora se realiza nefroureterectomía. El estudio anatomopatógico diferedo informa linfoma de células B tipo Malt (tumor linfoide asociado a mucosa), de origen pielocalicial con infiltración renal. Se realizan consideraciones anatomipatológicas, clínicas, diagnósticas y tertapéuticas de este tipo de linfoma, así como revisión de la bibliografía

Linfoma de celulas B tipo Malt de origen pielocalicial / B cell lymphoma, Malt type, of renal pelvis

Los procesos malignos de tipo linfomatosos que afectan el riñon son infrecuentes, y por lo general lo comprometen como una expresión más de una enfermedad sistémica. Clínicamente pueden ser asintomáticos y presentar hematuria e insuficiencia renal progresiva. El tratamiento es el de su enfermedad de base; en algunas situaciones está indicada la nefrectomía. Se presenta el caso de un paciente de 83 años de edad, en el estudio de rutina por prostatismo se detecta masa ocupante renal derecha. Con diagnóstico de tumor de vía excretora se realiza nefroureterectomía. El estudio anatomopatógico diferedo informa linfoma de células B tipo Malt (tumor linfoide asociado a mucosa), de origen pielocalicial con infiltración renal. Se realizan consideraciones anatomipatológicas, clínicas, diagnósticas y tertapéuticas de este tipo de linfoma, así como revisión de la bibliografía(AU)

Detection of a soluble antigen defined by monoclonal antibody 83D4 in serous effusions associated with breast carcinoma.

Monoclonal antibody (MoAb) 83D4 was generated by immunization with cell suspensions obtained from sections of formol-fixed paraffin embedded human breast cancer. It recognized an antigen expressed in breast carcinomas but not in normal breast tissue. Pleural and ascitic fluids from 66 patients were studied by an 83D4 heterologous sandwich radioimmunoassay (SRIA) using solid-phase immobilized wheat germ agglutinin to detect the 83D4 soluble antigen. Using a cutoff level of 5 units/ml of 83D4 antigen, higher values were found in 22 of 27 breast cancer-associated effusions (mean = 10.72 +/- 6.80 units/ml). The 20 nonmalignant effusion fluids tested showed lower values (mean = 1.16 +/- 1.49 units/ml, P less than 0.001). The antigen was undetectable or present in low levels in effusions from patients with hematologic malignancies. When SRIA results were compared with conventional cytologic diagnosis in breast-cancer effusions, elevated levels of 83D4 soluble antigen were found in all patients (8 of 8) in whom malignant cells had been detected, in 4 of 8 patients with the diagnosis of "suspected malignancy," and in 10 of 11 patients with negative cytologic findings. Using an immunoglucosidase method on cell smears of various origins, MoAb 83D4 stained metastatic cells of breast and ovary carcinomas but did not reactive with mesothelial cells and other normal or malignant cell types. These results suggest that quantitation of the 83D4 soluble antigen may be used to improve the diagnosis of cancer in serous effusions.

[Dysplasic nevus syndrome]. / Síndrome nevos displásicos.

We present a case of malignant melanoma arising in a pacient we postulate as a "nevus dysplasia" syndrome carrier. A revision is realized about the subject emphasithing the importance in the recognition and correct valuation of the entity, that is essential for the malignant melanoma prophylaxis.

[Multiple neurofibromas with zoniform distribution]. / Neurofibromas múltiples con distribución zoniforme.

A patient with a zoniform neurofibromas of the left arm and forearm is studied. The disease is associated to an epithelial pathology of trichylemi cysts of the scalp. The differential diagnosis can be that of Von Recklinhausen's disease. By the lack of positive elements for these disease, the authors consider it is a nevi malformation with nervous cells, that it presents clinically by multiples neurofibromas with a characteristic distribution.

[Cutaneo-visceral disseminated flat angioma, glaucoma, hypospadias and testicular ectopy]. / Angioma plano diseminado cutáneo visceral, glaucoma, hipospadias y ectopia testicular.

A case of associated disease in a child is described. It consisted of a disseminated capillary naevus with a vascular malformation in the gastrointestinal tract, bilateral congenital glaucoma, hypospadias, and bilateral ectopic testicles.

[Allergic contact dermatitis to ethylenediamine in skin grafts for burns]. / Dermatitis por contacto alérgica a etilendiamina en injertos de piel por quemaduras.

A 49 years old patient who had been sensibilized with ethylendiamine in a previous work (furniture polishing) developed at his present work (casein production) an allergic contact dermatitis in large grafting areas of his lower limbs due to burning. The disease had exacerbations during the following months and cured with the suppression of the allergene.

Erisipela recidivante. / Recurrent erysipelas

La erisipela recidivante constituye un problema terapeutico. La penicilina administrada durante lapsos prolongados, no evita las recidivas. Se discriben 8 casos de erisipela recidivante, en los que se pone en evidencia una hipersensibilidad al estreptococo beta hemolitico; y en los que se instituye un tratamiento de desensibilizacion especifica con estreptococo beta hemolitico; con resultados hasta el momento auspiciosos, permitindo vislumbrar una terapia eficaz para la erisipela recidivante

Erisipela recidivante. / Recurrent erysipelas

La erisipela recidivante constituye un problema terapeutico. La penicilina administrada durante lapsos prolongados, no evita las recidivas. Se discriben 8 casos de erisipela recidivante, en los que se pone en evidencia una hipersensibilidad al estreptococo beta hemolitico; y en los que se instituye un tratamiento de desensibilizacion especifica con estreptococo beta hemolitico; con resultados hasta el momento auspiciosos, permitindo vislumbrar una terapia eficaz para la erisipela recidivante