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.

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.

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.

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.

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 (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.

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.

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.

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.

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.

Pressure dependence of the superconducting transition temperature of magnesium diboride.

We studied the pressure and temperature dependence of the electrical resistivity of the superconducting compound magnesium diboride (MgB(2)). The superconducting transition temperature decreases monotonically with pressure, being parabolic or linear, depending on samples. The rate of decrease under pressure is higher than in conventional superconductors. We discuss our results in terms of the semimetallic character of the electronic band structure of MgB(2).

Adolescencia, adherencia y transición: Experiencia de un centro de trasplante renal pediátrico / Adolescence, adherence, and transition: Experience from a pediatric renal transplant center

Con el advenimiento de nuevas técnicas quirúrgicas y medicaciones inmunosupresoras la sobrevida de los niños trasplantados mejoró, llegando a la adultez. La continuidad de su tratamiento requiere un proceso planificado que permita su tránsito a un sistema de salud orientado al adulto. El objeto de este trabajo es mostrar la transición a centros de adultos en una cohorte de pacientes trasplantados renales en el Hospital Garrahan, describir sus características clínicas y demográficas, su evolución, y oportunidades de mejora implementadas. Debido a cambios médicos y su abordaje desde la interdisciplina, se dividió a la población en tres periodos: era 1 (1988-1999), era 2 (2000-2009), y era 3 (2010- 2023). En la era 1, 179 adolescentes continuaron su atención médica en un centro de adultos, 212 en la era 2 y 201 en la era 3. En la era 1 el seguimiento estaba coordinado por el nefrólogo de cabecera y eran consultados los servicios de Urología, Servicio Social y Salud Mental. En la era 2, se fortaleció el trabajo en interdisciplina y aún más a partir del 2011. Surgieron centros de trasplante de adultos que recibían adolescentes y médicos dedicados a ellos en forma preferencial. En la actualidad la transición comienza a los 12 años y progresa hasta los 18. El modelo implementado es la transición directa, entre el nefrólogo pediatra y el de adultos, con varias consultas secuenciales en ambos centros. Si bien la sobrevida del paciente e injerto mejoraron, el rechazo, asociado a no adherencia, es una asignatura por mejorar (AU)

With the advent of new surgical techniques and immunosuppressive medications, the survival of transplanted children has improved, allowing them to reach adulthood. The continuity of their treatment requires a planned process that facilitates their transition to an adult-oriented healthcare system. The aim of this study was to examine the transition to adult centers in a cohort of renal transplant patients at Garrahan Hospital, describing their clinical and demographic characteristics, their evolution, and the improvement opportunities implemented. Based on medical changes and the interdisciplinary approach, the population was divided into three periods: era 1 (1988- 1999), era 2 (2000-2009), and era 3 (2010-2023). In era 1, 179 adolescents continued their medical care in an adult center, 212 in era 2, and 201 in era 3. In era 1, follow-up was coordinated by the attending nephrologist with consultations from Urology, Social Services, and Mental Health Services. In era 2, interdisciplinary work was strengthened, and even more so since 2011. Adult transplant centers were created to receive adolescents with physicians dedicated to their care on a preferential basis. Currently, the transition begins at 12 years of age and progresses up to 18. The implemented model involves direct transition between the pediatric nephrologist and the adult nephrologist, with several sequential consultations in both centers. Although patient and graft survival have improved, rejection associated with non-adherence remains an area for improvement

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.

Genotoxicity biomarkers and acetylcholinesterase activity in natural populations of Mytilus galloprovincialis along a pollution gradient in the Gulf of Oristano (Sardinia, western Mediterranean).

A year-round biomonitoring study on blue mussels (Mytilus galloprovincialis) was carried out in 4 selected sites along the Gulf of Oristano (Sardinia, Italy): a commercial port (Port), the outlet of the S'Ena Arrubia and Marceddì lagoons (in the catchment area of intensive agricultural and diary activities, and abandoned mining), and a reference site (North). Heavy metal concentrations in sediments from Marceddì were 2-3 to 10-20 times higher in Pb, Cd and Zn, respectively, than those found at North and S'Ena Arrubia. Higher values (P<0.05) of micronuclei frequency were detected in mussels from Marceddì and Port compared to those detected in mussels from North and S'Ena Arrubia. DNA damage in animals from North was significantly lower than that at the other sites. Results of acetylcholinesterase inhibition consistently showed the strongest effects in mussels from Port and Marceddì. Our results suggest that these biomarkers can be used in coastal marine biomonitoring as early signals of exposure and adverse effects along a pollution gradient.

In vivo and in vitro exposures of carp and carp tissues to graded concentrations of endocrine disrupting chemicals.

The objective of this study was to correlate morphological and biochemical parameters of reproductive activity in fish exposed to graded concentrations of endocrine disrupting chemicals. Two-year-old carps were exposed for two weeks to graded concentrations of ethynyl-estradiol, tamoxifen, and flutamide. For each chemical, morphological alterations of the gonads and liver were described according to biomarker and sex steroid levels. In parallel, isolated follicular cells (FCs) and testis fragments were incubated in the presence or absence of carp pituitary homogenate and 25-hydroxycholesterol. Media were analyzed for sex steroid level evaluations.

Fish community characterization in two stretches upstream and downstream of the Lambro River confluence with the Po River.

This study aimed to characterize the fish community in two stretches of the Po River, upstream and downstream of the Lambro River confluence, to verify the environmental effects of the presence of endocrine disrupters (EDs). More than 5000 specimens were captured, identified at the species level, and recorded for biometric parameters. Plasma, liver, and gonad fragments were sampled for histological and biochemical analyses. Few specimens belonging to carp and barbel showed gonads with the concomitant presence of male and female tissues and altered plasma levels of vitellogenin and sex steroids; thus, these species will be considered for successive environmental studies.

Sirolimus in pediatric renal transplantation.

Side effects of calcineurin inhibitors (CNIs) include nephrotoxicity and hypertension. Moreover, children have a higher risk of infections and posttransplantation lymphoproliferative disorders. We retrospectively evaluated the efficacy and safety of Sirolimus (SRL) in 18 patients, who were 10.52 +/- 5.03 years at time of transplantation and received a CNI as the core immunosuppression. The most common indications for starting SRL therapy were chronic allograft nephropathy, Epstein-Barr virus-associated neoplasia, and thrombotic microangiopathy. The patients were converted to SRL at 49.14 +/- 45.9 months posttransplantation. Mean follow-up after the switch to SRL was 13.83 +/- 7.24 months. All patients who began SRL therapy remained on that medication. We observed a significant improvement (P < .05) in glomerular filtration rate assessed using the Schwartz formula at 3 months, which was sustained thereafter. There were no changes in proteinuria, plasma lipids, and platelet number. Although the prevalence of hypertensive patients decreased during follow-up, it was not significant. There was one steroid-sensitive, acute rejection episode. Serious adverse events included 1 death due to a relapse of B lymphoma, 1 sepsis, and 1 pancreatic pseudo-cyst. Adverse events were present in 17% of patients: 3 Herpes Simplex infections, and 1 dose-related lymphedema. Further studies are necessary to assess the impact of adverse events in the pediatric transplant population receiving SRL as immunosuppression.

Stair-climbing test to evaluate maximum aerobic capacity early after lung resection.

BACKGROUND: The aim of this study was to investigate the extent of reduction in maximum oxygen consumption in the early postoperative period after lung resection for lung carcinoma. METHODS: A total of 115 patients who underwent lung resection (95 lobectomies, 20 pneumonectomies) performed a maximal stair-climbing test the day before operation and the day of discharge from the hospital (8 +/- 3.3 days after the operation). RESULTS: The postoperative test showed a 15% reduction in maximum oxygen consumption (VO2max) with respect to the preoperative test (Student's t test, p < 0.0001). This reduction was greater after pneumonectomy (21.4%) than after lobectomy (14%) (Student's t test, p < 0.05). A multiple regression analysis showed that the only significant independent predictors of both preoperative and postoperative VO2max were the age of the patient and the level of arterial oxygen content. CONCLUSIONS: The early postoperative reduction in VO2max was greater after pneumonectomy than after lobectomy and the exercise performance was significantly influenced by the level of arterial oxygen content both before and early after the operation.

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.