Brentuximab vedotin followed by bendamustine supercharge for refractory or relapsed Hodgkin lymphoma.

We evaluated the impact on progression-free survival (PFS) of achieving a deep metabolic response at 2-deoxy-2[18F] fluoro-d-glucose positron emission tomography (FDG-PET) in patients with refractory or relapsed (R/R) classic Hodgkin lymphoma (cHL) following a new salvage regimen named Bv+Bs (brentuximab vedotin + bendamustine supercharge), from 2013 to 2017. In this real-life study, 20 consecutive patients (aged <60 years) with R/R cHL after failure of ≥1 salvage treatments received Bv+Bs regimen consisting of 3-days outpatient IV infusions of 1.8 mg/kg of Bv on day 1 of each 3-week cycle combined in sequence to bendamustine on days 2 and 3 of the treatment cycle at a fixed dose of 120 mg/m2 per day, for a total of 4 courses. A robust primary prophylaxis approach, including premedication, antimicrobials, stimulating factors, and cytomegalovirus monitoring, was systematically performed. The 20 patients (all evaluable) underwent 4 courses of Bv+Bs with a median dose intensity of 100% for both Bv and Bs. Ten patients (50%) experienced grade ≥3 treatment-related adverse events, without requiring hospitalization. At post-Bv+Bs reevaluation, 80% of patients had deep metabolic responses with Deauville 5-point scale scores ≤2. Thereafter, 14 patients (70%) received autologous hematopoietic stem cell transplantation (HSCT; peripheral blood stem cells previously harvested in 12 cases), and 4 patients (10%) received allogeneic HSCT. At a median follow-up of 27 months from Bv+Bs regimen initiation, the 2-year PFS of the entire population was 93.7% (95% confidence interval, 62.7% to 99.6%). Our data suggest that Bv+Bs regimen-driven strategy may be a promising salvage option to improve long-term control of high-risk Hodgkin lymphoma.

Edad al momento del trasplante: ¿Quiénes tienen riesgo de mala evolución ? / Age at transplantation: who are at risk of a poor outcome ?

Introducción: Si bien la sobrevida de paciente e injerto en niños con trasplante renal (TxR) ha mejorado, algunos sugieren que la edad al TxR es predictora de malos resultados, y los mayores tendrían peor evolución. Objetivo: Definir sobrevida de paciente e injerto según edad al TxR, y factores pronósticos de fracaso en aquellos con peor evolución. Material y métodos: Cohorte retrospectivo de todos los pacientes con TxR en el Hospital Garrahan desde el 01-01-2002 hasta el 01-03-2016. Resultados: de 431 pacientes, 44, (10%) tenían < 6a, 179 (42%)> 6 y <12 y 208 (48%) ≥12 años. La sobrevida del paciente a 8 años fue 97%, 99% y 95% (p=0,2), y la del injerto de: 86%, 69% y 30% respectivamente (p=<0,001). En los ≥ de 12 años, con peor evolución, se incluyeron al análisis univariado como factores de riesgo de pérdida de injerto: GSFS como causa de IRC : HR: 9,4; (p<0,001), Rechazo Agudo (RA) temprano: HR: 8,1; (p<0,001), RA tardío: HR: 4,3; (p<0.001), DGF: HR: 4,1; (p<0,001), No adherencia: HR: 2,3; (p=0,02), Edad de DC > 35a: HR: 1,95 (p=0,1), Tiempo en diálisis: HR: 1,1 (p=0,1), Número de incompatibilidades HLAB y HLADR: HR: 0,8 (p=0,3), Tiempo de Isquemia : 0,9 (p=0,5), Sexo del receptor: HR:0,8 (p=0,6), Donante Cadavérico: HR: 1,2; (p=0,6), 2do TxR : HR: 1,2; (p=0,7). En análisis multivariado: RA tardío: HR: 12,9 (p<0,001), GSFS como causa de IRC: HR: 12,5 (p<0,001), RA temprano: HR: 9 (p<0,001), y DGF: HR: 4,9 (p<0,001). Conclusión: la sobrevida del injerto en adolescentes es inferior. Merecen atención, la prevención de la no adherencia asociada a rechazo, el paciente con GSFS y el retardo de la función pos TxR (AU)

Introduction: Although patient and graft survival of children with a kidney transplantation (KTx) has improved, it has been suggested that older age at KTx is a predictive factor of poor outcome. Aim: To evaluate patient and graft survival according to age at KTx and define predictive factors in those with a poor outcome. Material and methods: A retrospective cohort study was conducted in all patients who underwent KTx at Garrahan Hopital between 01-01-2002 and 01-03-2016. Results: Of 431 patients, 44 (10%) were <6yr, 179 (42%) >6yr, and <12yr, and 208 (48%) ≥12yr. Eight-year patient survival was 97%, 99%, and 95% (p=0.2) and graft survival was 86%, 69%, and 30% (p=<0.001), respectively. In children ≥12 yr, with a worse outcome, the following risk factors of graft loss were included in univariate analysis: FSGS-related CFR: HR: 9.4; (p<0.001), early acute rejection (AR): HR: 8.1; (p<0.001), late AR: HR: 4.3; (p<0.001), DGF: HR: 4.1; (p<0.001), non-adherence: HR: 2.3; (p=0.02), age of deceased donor >35yr: HR: 1.95 (p=0.1), time on dialysis: HR: 1.1 (p=0.1), number of HLA-B and HLA-DR mismatches: HR: 0.8 (p=0.3), cold ischemia time: 0.9 (p=0.5), recipient sex: HR:0.8 (p=0.6), deceased donor: HR: 1.2; (p=0.6), second KTx: HR: 1.2; (p=0.7; and in multivariate analysis: late AR: HR: 12.9 (p<0.001), FSGS-related CFR: HR: 12.5 (p<0.001), early AR: HR: 9 (p<0.001), and DGF: HR: 4.9 (p<0.001). Conclusion: Graft survival is lower in adolescents. Prevention of rejection associated with non-adherence, FSGS, and post-KTx DGF should be taken into account (AU)

Sobrevida de pacientes e injerto en niños con trasplante renal: experiencia del Hospital Garrahan en dos períodos / Patient and graft survival in children with a kidney transplant: The experience at Garrahan Hospital over two periods

En adultos y niños con trasplante renal (TxR) la sobrevida de paciente e injerto ha mejorado. En Argentina no existen datos de sobrevida en niños con TxR en diferentes décadas. El objeto de este trabajo fue valorar en niños con TxR sobrevida de paciente e injerto y analizar causas de muerte, perdida de injerto y factores de riesgo de pérdida. Dado que desde el año 2001 se unificaron prácticas de diagnóstico y tratamiento, se compararon dos periodos: 1988-2000 y 2001-2015. Se incluyeron 773 niños. A 1, 3, 5, 7 y 10 años, En TxR de DV (n=327), la sobrevida del paciente fue de 99%, 99%, 98%, 95%, 95% vs 100% y 96%, 96%, 96% y 96% (p=0.74); la del injerto de 97%, 91%, 85%, 78% y 67% vs 95%, 88%, 85%, 81% y 76% (p=0.81). En TxR de DC (n=446) la sobrevida de paciente fue de 97%, 93%, 90%, 89% y 87% en el 1er. periodo vs. 100%, 99% y 98% 98% y 98% en el 2do (p<0.001); la del injerto de 83%, 75%, 68%, 64% y 52% vs. 95%, 87%, 83%, 76% y 61% respectivamente (p<0. 001). El Rechazo Crónico fue la 1er causa de perdida (61% vs 62%); la 2da la muerte del paciente con injerto funcionante. La sepsis bacteriana fue la 1era causa de muerte (56% vs 67%). Ningún niño falleció por neoplasia entre el 2001 y 2015. En DV, fueron predictores de perdida de injerto: DGF (HR: 4.8; p<0.001), edad al TxR > 12 años (HR: 2.7; p=0.002) y RA tardío (HR: 2.1; p=0.009). En DC la necesidad de diálisis en la 1er semana post TxR (DGF): (HR: 4.4; p<0.001), el rechazo agudo (RA) tardío (HR: 3.7; p<0.001), GSFS como causa de IRC (HR: 2.5; p=0.01), y RA temprano (HR: 2.2; p=0.02). Conclusión: En el 2do periodo la sobrevida de paciente e injerto los TxR con DC mejoro, y en los TxR con DV no tuvo cambios. El rechazo crónico continúa siendo la 1era causa de perdida. Ningún paciente tuvo neoplasia (AU)

Patient and graft survival in kidney transplantation (KTx) has improved. In Argentina there are no data comparing transplant outcomes in children over different eras. The aim of this study was to evaluate patient and graft survival in children with KTx and to analyze cause of death, graft loss, and risk factors of graft loss. As diagnostic and treatment practices were unified in 2001, two periods were compared: 1988-2000 and 2001-2015. Overall, 773 children were included. Survival at 1, 3, 5, 7, and 10 years after a living-related donor (LRD) KTx was 99%, 99%, 98%, 95%, 95% vs 100% y 96%, 96%, 96% and 96% (p=0.74); graft survival was 97%, 91%, 85%, 78% y 67% vs 95%, 88%, 85%, 81%, and 76% (p=0.81). Patient survival after deceased donor (DD) KTx (n=446) was 97%, 93%, 90%, 89%, and 87% in the 1st period vs. 100%, 99% y 98% 98%, and 98% in the 2nd (p<0.001); graft survival was 83%, 75%, 68%, 64%, and 52% vs. 95%, 87%, 83%, 76%, and 61%, respectively (p<0. 001). Chronic rejection was the first cause of graft loss (61% vs 62%); the second was death of the patient with a functioning graft. Bacterial sepsis was the first cause of death (56% vs 67%). None of the patients died because of malignancies between 2001 and 2015. Among LRD transplants predicting factors of graft loss were: DGF (HR: 4.8; p<0.001), age at KTx >12 years (HR: 2.7; p=0.002), and late acute rejection (AR) (HR: 2.1; p=0.009). Among DD need for dialysis in the first week post-KTx (DGF): (HR: 4.4; p<0.001), late AR (HR: 3.7; p<0.001), FSGS-related CFR (HR: 2.5; p=0.01), and early AR (HR: 2.2; p=0.02). Conclusion: In the second period patient and graft survival after DD improved, while that of KTx with LRD remained unchanged. Chronic rejection continues being the first cause of graft loss. None of the patients developed malignancies.

It could suddenly happen: delayed rupture of the trachea after total thyroidectomy. A case report.

INTRODUCTION: We report the case of a patient who presented with subcutaneous emphysema, dyspnea and cough 7 days after total thyroidectomy for cancer. In addition we review the Literature and discuss the therapeutic challenges as well as management options. CASE REPORT: A 17-year old female patient underwent a total thyroidectomy with right cervical lymph adenectomy for papillar cancer. Lung metastases are present. On postoperative day 7 she presented with face and neck swelling due to subcutaneous emphysema, dyspnea and persistent cough. The radiological evaluation revealed a tear on the right antero-lateral wall of the trachea. The patient underwent surgical exploration of the neck which confirmed the tracheal rupture and showed an important tracheal necrosis all around the tear. Due to the impossibility to make primary closure of the trachea or a tracheal resection, the tear was repaired with muscular flap interposition, (around the trachea as a scarf ), using the contralateral clavicular part of sternocleidomastoid muscle and prethyroid muscles bilaterally. The postoperative course was uneventful and the patient is alive 20 months after surgery and iodine induced adjuvant therapy. CONCLUSION: Delayed tracheal rupture should be suspected in all patients who present subcutaneous emphysema after thyroid surgery. The lesion should be promptly treated with primary closure or tracheal resection when possible. Muscular flap interposition could be a safe alternative option when the other procedures are contraindicated.

Tuning a Schottky barrier in a photoexcited topological insulator with transient Dirac cone electron-hole asymmetry.

The advent of Dirac materials has made it possible to realize two-dimensional gases of relativistic fermions with unprecedented transport properties in condensed matter. Their photoconductive control with ultrafast light pulses is opening new perspectives for the transmission of current and information. Here we show that the interplay of surface and bulk transient carrier dynamics in a photoexcited topological insulator can control an essential parameter for photoconductivity-the balance between excess electrons and holes in the Dirac cone. This can result in a strongly out of equilibrium gas of hot relativistic fermions, characterized by a surprisingly long lifetime of more than 50 ps, and a simultaneous transient shift of chemical potential by as much as 100 meV. The unique properties of this transient Dirac cone make it possible to tune with ultrafast light pulses a relativistic nanoscale Schottky barrier, in a way that is impossible with conventional optoelectronic materials.

Farmacovigilancia de inhibidores de calcineurina en trasplante renal y hepático pediátrico / Pharmacovigilance of calcineurin inhibitors in pediatric kidney and liver transplantation

Objetivo: Desarrollar un programa de farmacovigilancia de pacientes pediátricos trasplantados hepáticos y renales centrado en inmunosupresores calcineurínicos del Hospital de Pediatría JP Garrahan de Argentina. Métodos: Se evaluaron las reacciones adversas a medicamentos (RAM) de los pacientes pediátricos trasplantados renales y hepáticos de nuestro hospital tratados con inhibidores de calcineurina (ciclosporina y tacrolimus) por revisión retrospectiva de historias clínicas de pacientes trasplantados en 2010-2011, y análisis prospectivo por farmacovigilancia activa de trasplantados fuera de dicho período, cuyas complicaciones se hayan presentado en los ateneos semanales del Servicio de Trasplante desde marzo de 2011. Las RAM se notificaron a la autoridad sanitaria nacional. Resultados: Se analizaron un total de 59 pacientes, 28 trasplantados renales y 31 hepáticos. Se notificaron, en ambos trasplantes, 60 RAM a ciclosporina destacándose (número de casos) hipertensión arterial (19) y nefrotoxicidad (6). Asimismo, se registraron 46 RAM a tacrolimus, incluyendo hipomagnesemia (25), hipertensión (7) y nefrotoxicidad (5). El 95% y 96% de los eventos adversos a ciclosporina y a tacrolimus, respectivamente, han sido agrupados como probables o definitivos. El 70% y 98% de los eventos adversos a ciclosporina y a tacrolimus respectivamente, han sido de severidad moderada o grave. Conclusiones: Este es el primer proyecto en América Latina que propone y desarrolla el estudio cuali-cuantitativo intensivo de RAM a inhibidores de calcineurina en trasplante pediátrico renal y hepático. Es necesario estimular la notificación espontánea así como continuar el seguimiento de RAM a mediano y largo plazo para mejorar la calidad de vida del paciente trasplantado (AU)

Aim: To develop a pharmacovigilance program of calcineurin inhibitors used in pediatric renal and liver transplant patients at Hospital de Pediatría JP Garrahan, Argentina. Methods: Adverse drug reactions (ADRs) of pediatric patients with kidney and liver transplantation treated with calcineurin inhibitors (cyclosporine and tacrolimus) were evaluated by retrospective review of medical records of patients transplanted between 2010 and 2011. In addition, we carried out active pharmacovigilance since March, 2011. ADRs were reported to the National Health Authority. Results: A total of 59 patients, 28 kidney transplant and 31 liver tarnsplant patients were analyzed. In both transplants, 60 ADRs to cyclosporine were reported including (number of cases), hypertension (19) and nephrotoxicity (6). In addition, 46 ADRs to tacrolimus were registered as hypomagnesemia (25), hypertension (7) and nephrotoxicity (5). A total of 95% and 96% of the adverse events to cyclosporine and tacrolimus, respectively, were defined as probable or definitive. Lastly, 70% and 98% of the events to cyclosporine and tacrolimus respectively, have been moderately severe or severe. Conclusions: This is the first study in Latin America that developed an intensive qualitative and quantitative analysis of the ADRs to calcineruin inhibitors in pediatric kidney and liver transplant patients. Spontaneous reporting should be motivated as well as monitoring ADRs should continue in the medium and long term for improving patient's quality of life (AU)

[Pharmacovigilance of calcineurin inhibitor in peidatric kidney and liver transplantation]. / Farmacovigilancia de inhibidores de calcineurina en trasplante renal y hepático pediátrico.

AIM: To develop a pharmacovigilance program of calcineurin inhibitors used in pediatric renal and liver transplant patients at Hospital de Pediatría JP Garrahan, Argentina. METHODS: Adverse drug reactions (ADRs) of pediatric patients with kidney and liver transplantation treated with calcineurin inhibitors (cyclosporine and tacrolimus) were evaluated by retrospective review of medical records of patients transplanted between 2010 and 2011. In addition, we carried out active pharmacovigilance since March, 2011. ADRs were reported to the National Health Authority. RESULTS: A total of 59 patients, 28 kidney transplant and 31 liver tarnsplant patients were analyzed. In both transplants, 60 ADRs to cyclosporine were reported including (number of cases), hypertension (19) and nephrotoxicity (6). In addition, 46 ADRs to tacrolimus were registered as hypomagnesemia (25), hypertension (7) and nephrotoxicity (5). A total of 95% and 96% of the adverse events to cyclosporine and tacrolimus, respectively, were defined as probable or definitive. Lastly, 70% and 98% of the events to cyclosporine and tacrolimus respectively, have been moderately severe or severe. CONCLUSIONS: This is the first study in Latin America that developed an intensive qualitative and quantitative analysis of the ADRs to calcineruin inhibitors in pediatric kidney and liver transplant patients. Spontaneous reporting should be motivated as well as monitoring ADRs should continue in the medium and long term for improving patient's quality of life.

Objetivo: Desarrollar un programa de farmacovigilancia de pacientes pediátricos trasplantados hepáticos y renales centrado en inmunosupresores calcineurínicos del Hospital de Pediatría JP Garrahan de Argentina. Métodos: Se evaluaron las reacciones adversas a medicamentos (RAM) de los pacientes pediátricos trasplantados renales y hepáticos de nuestro hospital tratados con inhibidores de calcineurina (ciclosporina y tacrolimus) por revisión retrospectiva de historias clínicas de pacientes trasplantados en 2010-2011, y análisis prospectivo por farmacovigilancia activa de trasplantados fuera de dicho período, cuyas complicaciones se hayan presentado en los ateneos semanales del Servicio de Trasplante desde marzo de 2011. Las RAM se notificaron a la autoridad sanitaria nacional. Resultados: Se analizaron un total de 59 pacientes, 28 trasplantados renales y 31 hepáticos. Se notificaron, en ambos trasplantes, 60 RAM a ciclosporina destacándose (número de casos) hipertensión arterial (19) y nefrotoxicidad (6). Asimismo, se registraron 46 RAM a tacrolimus, incluyendo hipomagnesemia (25), hipertensión (7) y nefrotoxicidad (5). El 95% y 96% de los eventos adversos a ciclosporina y a tacrolimus, respectivamente, han sido agrupados como probables o definitivos. El 70% y 98% de los eventos adversos a ciclosporina y a tacrolimus respectivamente, han sido de severidad moderada o grave. Conclusiones: Este es el primer proyecto en América Latina que propone y desarrolla el estudio cuali-cuantitativo intensivo de RAM a inhibidores de calcineurina en trasplante pediátrico renal y hepático. Es necesario estimular la notificación espontánea así como continuar el seguimiento de RAM a mediano y largo plazo para mejorar la calidad de vida del paciente trasplantado.

Surgical results and survival of older patients with unsuspected N2 (stage IIIA) non-small cell lung cancer.

PURPOSES: The optimal treatment of N2 non-small cell lung cancer (NSCLC) in older patients is still debate and represent an important treatment and ethical problem. PATIENTS AND METHODS: Between January 2000 to December 2010, 273 older patients underwent lung resection for (NSCLC). RESULTS: The overall-operative mortality was 9.5%. Risk factors for in-hospital mortality were pneumonectomy and poli-vasculopathy. One, 3 and 5-year survival were 73%, 23% and 16% respectively. CONCLUSIONS: In potentially operable older patients with NSCLC we need to make every effort to exclude N2 involvement because very poor long-term survival. Pneumonectomy in older patients gains prohibitive in-hospital mortality.

The collagen prolyl hydroxylases are novel transcriptionally silenced genes in lymphoma.

BACKGROUND: Prolyl hydroxylation is a post-translational modification that affects the structure, stability and function of proteins including collagen by catalysing hydroxylation of proline to hydroxyproline through action of collagen prolyl hydroxylases3 (C-P3H) and 4 (C-P4H). Three C-P3Hs (nomenclature was amended according to approval by the HGNC symbols and names at http://www.genenames.org/ and Entrez database at http://www.ncbi.nlm.nih.gov/gene) leucineproline-enriched proteoglycan (leprecan) 1 (Lepre1), leprecan-like 1 (Leprel1), leprecan-like 2 (Leprel2) and two paralogs Cartilage-Related Protein (CRTAP) and leprecan-like 4 (Leprel4) are found in humans. The C-P4Hs are tetrameric proteins comprising a variable α subunit, encoded by the P4HA1, P4HA2 and P4HA3 genes and a constant ß subunit encoded by P4HB. METHODS: We used RT-PCR, qPCR, pyrosequencing, methylation-specific PCR, western blotting and immunohistochemistry to investigate expression and regulation of the C-P3H and C-P4H genes in B lymphomas and normal bone marrow. RESULTS: C-P3H and C-P4H are downregulated in lymphoma. Down-regulation is associated with methylation in the CpG islands and is detected in almost all common types of B-cell lymphoma, but the CpG islands are unmethylated or methylated at lower levels in DNA isolated from normal bone marrow and lymphoblastoid cell lines. Methylation of multiple C-P3H and C-P4H genes is present in some lymphomas, particularly Burkitt's lymphoma. CONCLUSIONS: Methylation of C-P3H and C-P4H is common in B lymphomas and may have utility in differentiating disease subtypes.

Site-specific CpG methylation in the CCAAT/enhancer binding protein delta (CEBPδ) CpG island in breast cancer is associated with metastatic relapse.

BACKGROUND: The CCAAT/enhancer binding protein delta (CEBPδ) is a member of a highly conserved family of basic region leucine zipper transcription factors. It has properties consistent with a tumour suppressor; however, other data suggest that CEBPδ may be involved in the metastatic process. METHODS: We analysed the expression of CEBPδ and the methylation status of the CpG island in human breast cancer cell lines, in 107 archival cases of primary breast cancer and in two series of metastatic breast cancers using qPCR and pyrosequencing. RESULTS: Expression of CEBPδ is downregulated in primary breast cancer by site-specific methylation in the CEBPδ CpG island. Expression is also downregulated in 50% of cases during progression from primary carcinoma to metastatic lesions. The CEBPδ CpG island is methylated in 81% metastatic breast cancer lesions, while methylation in the CEBPδ CpG island in primary cancers is associated with increased risk of relapse and metastasis. CONCLUSION: CCAAT/enhancer binding protein delta CpG island methylation is associated with metastasis in breast cancer. Detection of methylated CEBPδ genomic DNA may have utility as an epigenetic biomarker of primary breast carcinomas at increased risk of relapse and metastasis.

NT5E CpG island methylation is a favourable breast cancer biomarker.

BACKGROUND: Relapse risk assessment and individual treatment recommendations remain suboptimal for breast cancer patients. In the light of existing preclinical and clinical data, we studied NT5E (5'-nucleotidase, ecto) expression and NT5E CpG island methylation in breast cancer. METHODS: We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse NT5E in breast carcinoma cell lines and primary and breast carcinomas. RESULTS: NT5E CpG island methylation was inversely associated with NT5E expression in breast carcinoma cell lines. In clinical series, patients whose primary tumours had NT5E CpG island methylation were less likely to develop metastasis (P=0.003, OR=0.34, 95% CI: 0.17-0.69). In 3/4 paired samples, NT5E was methylated in primary tumours and demethylated in CNS metastases. Patients progressing to non-visceral as compared with visceral metastases were more likely to have NT5E CpG island methylation in primary tumours (P=0.01, OR=11.8). Patients with tumours lacking detectable methylation had shorter disease-free survival (DFS) (P=0.001, HR=2.7) and overall survival (OS) (P=0.001, HR=3). The favourable prognostic value of NT5E methylation was confirmed in oestrogen receptor negative (P=0.011, HR=3.27, 95% CI: 1.31-8.12) and in triple negative cases (P=0.004; HR=6.2, 95% CI: 1.9-20). Moreover, we observed a more favourable outcome to adjuvant chemotherapy in patients whose tumours were positive for NT5E CpG island methylation: DFS (P=0.0016, HR=5.1, 95% CI: 1.8-14.37) and OS (P=0.0005, HR=7.4, 95% CI: 2.416-23.08). CONCLUSION: NT5E CpG island methylation is a promising breast cancer biomarker.

Methylation of the calcium channel regulatory subunit α2δ-3 (CACNA2D3) predicts site-specific relapse in oestrogen receptor-positive primary breast carcinomas.

BACKGROUND: Calcium is an important intracellular messenger that mediates many biological processes that are relevant to the malignant process. Calcium ion channels are key in controlling the intracellular calcium, and little is known about their role in human cancer. METHODS: We used qPCR and pyrosequencing to investigate expression and epigenetic regulation of the calcium channel regulatory subunit α(2)δ-3 (CACNA2D3) in breast cancer cell lines, primary cancers and metastatic lesions. RESULTS: Expression of CACNA2D3 mRNA is regulated in breast cancer cell lines by methylation in the CpG island located in the 5' regulatory region of the gene. Expression is upregulated by azacytidine (AZA) in cells with CpG island methylation but unaffected in cells lacking methylation. In primary breast carcinomas, methylation is more common in cancers, which subsequently relapse with loco-regional and, particularly, visceral metastatic disease in both oestrogen receptor-α (ER)-positive and -negative cases. Furthermore, CACNA2D3 CpG island is frequently methylated in breast cancer that has metastasised to the central nervous system. CONCLUSION: Methylation-dependent transcriptional silencing of CACNA2D3 may contribute to the metastatic phenotype of breast cancer. Analysis of methylation in the CACNA2D3 CpG island may have potential as a biomarker for risk of development of metastatic disease.

NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity.

BACKGROUND: Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known. METHODS: We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse expression and regulation of NT5E in malignant melanoma cell lines and primary and metastatic melanomas. RESULTS: NT5E is subject to epigenetic regulation in melanoma. NT5E mRNA is downregulated by methylation-dependent transcriptional silencing in the melanoma cell lines SKMel2, SKMel23, WM35, Mel501, Mel505 and C81-61 and expression is reactivated by azacytidine. In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases of melanoma, methylation in the NT5E CpG island occurs in both primary and metastatic melanomas and correlates with transcriptional downregulation of NT5E mRNA. Relapse with metastatic disease, particularly to the visceral sites and brain, is more common in primary melanomas lacking NT5E methylation. Primary melanomas with methylation in NT5E show limited metastatic potential or more commonly metastasise predominantly to nodal sites rather than viscera and brain (P=0.01). CONCLUSION: Deregulation of NT5E expression in melanoma occurs via epigenetic changes in the NT5E CpG island. Confirmation of our results in larger clinical series would support the candidacy of NT5E as a clinical biomarker in melanoma, which could be applied in both primary and relapsed disease. Inhibition of NT5E may have therapeutic potential in melanoma, particularly in patients with more aggressive disease metastatic to viscera or the brain.

High frequency of complex TP53 mutations in CNS metastases from breast cancer.

BACKGROUND: Brain metastasis from breast cancer is usually associated with a poor prognosis and early death. Alteration of p53 may contribute to malignant progression by abrogation of apoptosis induced by oncogene activation and by acquisition of gain-of-function properties, which promote tumour aggression. Mutation in TP53 occurs at high frequency in carcinomas of the lung and gastro-intestinal tract, but is much less frequent, at 25%, in primary breast cancer. The frequency of TP53 alteration in the central nervous system (CNS) metastatic breast cancer is not known. METHODS: In all, 23 cases of histologically confirmed CNS metastatic breast cancer were identified and the coding sequence of TP53 determined. TP53 was also sequenced in two control series of primary breast carcinomas from independent clinical centres. RESULTS: We demonstrate a strikingly high frequency of TP53 mutation in the CNS metastatic lesions with an over-representation of complex mutations (non-sense/deletions/insertions). Complex mutations occur in metastatic lesions in both triple-negative breast cancer and hormone receptor/HER2-positive cases. Analysis of paired primary carcinomas and brain metastatic lesions revealed evidence for both clonal selection and generation of new mutations (missense and complex) in progression from a primary breast carcinoma to brain metastasis. CONCLUSION: Mutation in TP53 is the most common genetic alteration reported during metastasis to the brain in breast cancer.

Catamenially recurring pneumothorax with partial liver herniation: a particular view.

Few cases of catamenial pneumothorax with complete or partial diaphragmatic hernias are reported in the literature. We present herein the case of a 38-year-old woman affected by recurrent right-sided spontaneous pneumothorax during menstrual periods. CT scan revealed normal lung parenchyma and multiple diaphragmatic nodes suspected for endometrial implants. The patient underwent right thoracoscopy and the presence of multiple diaphragmatic perforations of the tendinous part was observed as well as partial hepatic hernia. Through a video-assisted procedure, pleural biopsies and diaphragmatic plication containing the tendinous part with total pleural abrasion and talc pleurodesis were performed. No endometrial implants were found on histologic examination of pleural biopsies. The surgical procedure was uneventful and totally successful. On the basis of the clinical data and endoscopic view, we consider our case as catamenially recurring pneumothorax.

Disfunción crónica del injerto renal antes y después de la conversión de ciclosporina a sirolimus / Chronic allograft failure before and after a switch from cyclosporine to sirolimus

El propósito de este estudio fue evaluar la progresión de la disfunción crónica del injerto en receptores pediátricos de un TxR que recibían CsA como parte de su inmunosupresión y ésta fue reemplazada por SRL, a causa de un lento y progresivo aumento de la creatinina sérica, signos histológicos de nefropatía crónica del trasplante y ausencia de rechazo agudo en la biopsia renal. Se empleó la inversa la de creatinina sérica (1/CrS) para estimar la velocidad de progresión de la disfunción crónica del injerto, durante el año previo al cambio de la medicación y dos años después del mismo. Analizamos 26 pacientes trasplantados a los 9.76 ± 3.9 años que recibían CsA y en quienes se reemplazó ésta por SRL a los 57.07 ± 39.1 meses post trasplante. La pendiente de la 1/CrS disminuyó de -0.016 mg/dl/mes antes del cambio a -0.002 mg/dl/mes durante el primer año después del mismo y a -0.001 mg/dl/mes durante el segundo año (p= 0.007). Cuando separamos los pacientes según el grado de NCT que mostraban las biopsias renales, aquellos pacientes que tenían NCT grado I (n= 11), la pendiente de la 1/CrS mejoró de -0.012 mg/dl/mes basal a -0.006 mg/dl/mes durante el primer año y a +0.001 mg/dl/mes durante el segundo año (p= 0.01). En cambio, los pacientes que tenían NCT grado II en sus biopsias, mostraron mejoría de la pendiente de la 1/CrS durante el primer año luego del cambio, pero la misma no fue sostenida ni significativa durante el segundo año de observación. Entre ambos grupos, las únicas variables que mostraron diferencias significativas fueron el filtrado glomerular y el tiempo post trasplante al momento del cambio de la inmunosupresión. Conclusión: nuestros resultados muestran una significativa disminución de la velocidad de progresión de la disfunción crónica del injerto cuando se reemplaza la CsA por SRL en pacientes con mínimos cambios morfológicos en la biopsia renal y con un filtrado glomerular cercano a 60 ml/min/1.73.

Conductance fluctuations and field asymmetry of rectification in graphene.

We investigate conductance fluctuations as a function of carrier density n and magnetic field in diffusive mesoscopic samples made from monolayer and bilayer graphene. We show that the fluctuations' correlation energy and field, which are functions of the diffusion coefficient, have fundamentally different variations with n, illustrating the contrast between massive and massless carriers. The field dependent fluctuations are nearly independent of n, but the n-dependent fluctuations are not universal and are largest at the charge neutrality point. We also measure the second-order conductance fluctuations (mesoscopic rectification). Its field asymmetry, due to electron-electron interaction, decays with conductance, as predicted for diffusive systems.

Transport and elastic scattering times as probes of the nature of impurity scattering in single-layer and bilayer graphene.

Transport and elastic scattering times, tau{tr} and tau{e}, are experimentally determined from the carrier density dependence of the magnetoconductance of monolayer and bilayer graphene. Both times and their dependences on carrier density are found to be very different in the monolayer and the bilayer. However, their ratio tau{tr}/tau{e} is found to be close to 1.8 in the two systems and nearly independent of the carrier density. These measurements give insight on the nature (neutral or charged) and range of the scatterers. Comparison with theoretical predictions suggests that the main scattering mechanism in our samples is due to strong (resonant) scatterers of a range shorter than the Fermi wavelength, likely candidates being vacancies, voids, adatoms or short-range ripples.

Enfermedad linfroproliferativa en trasplante renal y hepático / Lymproproliferative disease in kidney and liver transplantation

La enfermedad linfoproliferativa post trasplante (PTLD) es la neoplasia más frecuente observada en receptores pediátricos de órganos sólidos. Analizamos 883 pacientes trasplantados: 547 trasplantes renales (TxR) y 336 trasplantes hepáticos (TxH). 44 de ellos desarrollaron un PTLD luego de estos procedimientos. La incidencia en TxR fue del 4.02 por ciento (22 de 547) y en TxH de 5.75 por ciento (22 de 336). El tiempo medio de la aparición del PTLD fue de 37.47 más menos 35 meses. Localización: cavun 50 por ciento, adenopatías cervicales 14.4 por ciento, masa abdominal 11.4 por ciento, adenopatías axilares e inguinales 9 por ciento, compromiso del SNC 4.5 por ciento, piso de la boca 4.5 por ciento , higado ortótopico 2.3 por ciento, páncreas 2.3 por ciento, injerto renal 2.3 por ciento. Los diagnósticos histopatológicos obtenidos fueron: hiperplasia plasmocitica 52.3 por ciento, lesiones polimorfas 20.5 por ciento, y lesiones monomorgas (linforma B o Linfoma de células grandes) 27.2 por ciento de los pacientes. El tratamiento indicado incluyó reducción de la inmunosupresión de mantenimiento en todos los pacientes, excéresis en 22 pacientes, anticuerpos antCD20 en 17 de ellos y quimioterapia (régimen de CHOP) en 6 pacientes. La sobrevida fue del 79 por ciento (IC 64 por ciento-88 por ciento) a 5 años de seguimiento. Conclusión: En nuestra serie la incidencia de PTLAD es similar a la de otros autores. La respuesta al tratamiento con disminución de la inmunosupresón, empleo de monoclonales, ha sido satisfactoria. El seguimiento cercano, el alto índice de sospecha para el diagnóstico precóz y la individualización de la inmunosupresión para cada paciente, fueron conductas eficaces.