Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters.

Inactivating mutations of the Ten-Eleven Translocation 2 (TET2) gene were first identified in myeloid malignancies and more recently in peripheral T-cell lymphomas (PTCLs). In the present study, we investigated the presence of TET2 coding sequence mutations and their clinical relevance in a large cohort of 190 PTCL patients. TET2 mutations were identified in 40 of 86 (47%) cases of angioimmunoblastic T-cell lymphoma (AITL) and in 22 of 58 (38%) cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), but were absent in all other PTCL entities, with the exception of 2 of 10 cases of enteropathy-associated T-cell lymphoma. Among PTCL-NOS, a heterogeneous group of lymphoma-comprising cases likely to derive from Th follicular (T(FH)) cells similarly to AITL, TET2 mutations were more frequent when PTCL-NOS expressed T(FH) markers and/or had features reminiscent of AITL (58% vs 24%, P = .01). In the AITL and PTCL-NOS subgroups, TET2 mutations were associated with advanced-stage disease, thrombocytopenia, high International Prognostic Index scores, and a shorter progression-free survival.

Consolidation whole abdomen irradiation following adjuvant carboplatin-paclitaxel based chemotherapy for advanced uterine epithelial cancer: feasibility, toxicity and outcomes.

BACKGROUND: To evaluate feasibility and preliminary outcomes associated with sequential whole abdomen irradiation (WAI) as consolidative treatment following comprehensive surgery and systemic chemotherapy for advanced endometrial cancer. METHODS: We conducted a retrospective analysis of patients treated at our institution from 2000 to 2011. Inclusion criteria were stage III-IV endometrial cancer patients with histological proof of one or more sites of extra-uterine abdomen-confined disease, treated with WAI as part of multimodal therapy. Endpoints were feasibility, acute toxicity, late effects, recurrence-free survival (RFS) and overall survival (OS). Twenty patients were identified. Chemotherapy consisted of 3 to 6 cycles of a platinum-paclitaxel regimen in 18 patients. WAI was delivered using conventional technique to a median total dose of 27.5 Gy. RESULTS: No grade 4 toxicities occurred during chemotherapy or radiotherapy. No radiation dose reduction was necessary. Three patients developed small bowel obstruction, all in the context of recurrent intraperitoneal disease. Kaplan-Meier estimates and 95% confidence intervals for RFS and OS at one year were 63% (38-80%) and 83% (56-94%) and at 3 years 57% (33-76%) and 62% (34-81%), respectively. On univariate Cox analysis, stage IVB and serous papillary (SP) histology were found to be statistically significantly (at the p = 0.05 level) associated with worse RFS and OS. The peritoneal cavity was the most frequent site of initial failure. CONCLUSIONS: Consolidative WAI following chemotherapy is feasible and can be performed without interruption with manageable acute and late toxicity. Patients with endometrioid adenocarcinoma, especially stage FIGO III, had favorable outcomes possibly meriting prospective evaluation of the addition of WAI following chemotherapy in selected patients. Patients with SP do poorly and do not routinely benefit from this approach.

Intragastric and Intranasal Administration of Lactobacillus paracasei NCC2461 Modulates Allergic Airway Inflammation in Mice.

Introduction. Preclinical and clinical evidences for a role of oral probiotics in the management of allergic diseases are emerging. Aim. We aimed at testing the immunomodulatory effects of intranasal versus intragastric administration of Lactobacillus paracasei NCC2461 in a mouse model of allergic airway inflammation and the specificity of different probiotics by comparing L. paracasei NCC2461 to Lactobacillus plantarum NCC1107. Methods. L. paracasei NCC2461 or L. plantarum NCC1107 strains were administered either intragastrically (NCC2461) or intranasally (NCC2461 or NCC1107) to OVA-sensitized mice challenged with OVA aerosols. Inflammatory cell recruitment into BALF, eotaxin and IL-5 production in the lungs were measured. Results. Intranasal L. paracasei NCC2461 efficiently protected sensitized mice upon exposure to OVA aerosols in a dose-dependent manner as compared to control mice. Inflammatory cell number, eotaxin and IL-5 were significantly reduced in BALF. Intranasal supplementation of L. paracasei NCC2461 was more potent than intragastric application in limiting the allergic response and possibly linked to an increase in T regulatory cells in the lungs. Finally, intranasal L. plantarum NCC1107 reduced total and eosinophilic lung inflammation, but increased neutrophilia and macrophages infiltration. Conclusion. A concerted selection of intervention schedule, doses, and administration routes (intranasal versus intragastric) may markedly contribute to modulate airway inflammation in a probiotic strain-specific manner.

Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias resulting in short-limbed dwarfism, joint pain, and stiffness. PSACH and the largest proportion of autosomal dominant MED (AD-MED) results from mutations in cartilage oligomeric matrix protein (COMP); however, AD-MED is genetically heterogenous and can also result from mutations in matrilin-3 (MATN3) and type IX collagen (COL9A1, COL9A2, and COL9A3). In contrast, autosomal recessive MED (rMED) appears to result exclusively from mutations in sulphate transporter solute carrier family 26 (SLC26A2). The diagnosis of PSACH and MED can be difficult for the nonexpert due to various complications and similarities with other related diseases and often mutation analysis is requested to either confirm or exclude the diagnosis. Since 2003, the European Skeletal Dysplasia Network (ESDN) has used an on-line review system to efficiently diagnose cases referred to the network prior to mutation analysis. In this study, we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED.

Continuous positive airway pressure causes lung injury in a model of sepsis.

Continuous positive airway pressure, aimed at preventing pulmonary atelectasis, has been used for decades to reduce lung injury in critically ill patients. In neonatal practice, it is increasingly used worldwide as a primary form of respiratory support due to its low cost and because it reduces the need for endotracheal intubation and conventional mechanical ventilation. We studied the anesthetized in vivo rat and determined the optimal circuit design for delivery of continuous positive airway pressure. We investigated the effects of continuous positive airway pressure following lipopolysaccharide administration in the anesthetized rat. Whereas neither continuous positive airway pressure nor lipopolysaccharide alone caused lung injury, continuous positive airway pressure applied following intravenous lipopolysaccharide resulted in increased microvascular permeability, elevated cytokine protein and mRNA production, and impaired static compliance. A dose-response relationship was demonstrated whereby higher levels of continuous positive airway pressure (up to 6 cmH(2)O) caused greater lung injury. Lung injury was attenuated by pretreatment with dexamethasone. These data demonstrate that despite optimal circuit design, continuous positive airway pressure causes significant lung injury (proportional to the airway pressure) in the setting of circulating lipopolysaccharide. Although we would currently avoid direct extrapolation of these findings to clinical practice, we believe that in the context of increasing clinical use, these data are grounds for concern and warrant further investigation.

Effects of nasal continuous airway pressure on pulmonary and systemic output in preterm infants

Objective: Respiratory assistance with nasal continuous positive airway pressure (n-CPAP) is an effective treatment in premature newborns presenting respiratory distress. The aim of the study was to depict cardiac function, systemic (Qs) and pulmonary output (Qp) by echocardiography in stable premature infants requiring prolonged n-CPAP. Our hypothesis was that n-CPAP could reduce pulmonary blood flow. Patients and methods: All premature infants < 32 weeks gestation, > 7 days-old, requiring n-CPAP without severe respiratory compromise nor need for additional oxygen were prospectively included. Every patient had a first echocardiography while on n-CPAP. N-CPAP was then discontinued for two hours and a second echocardiography was performed. Results: 17 premature infants were included. Mean gestational age was 28 ± 2 weeks and mean weight 1.1 ± 0.3 kg. Following retrieval of n-CPAP we observed an increase in Qp of 53 ml/kg/min (95% CI 19-87 ml/kg/min), but no significant change in Qs. Consecutively a significant increase in Qp/Qs ratio of 16% was found (95% CI 7-29%). Conclusions: Nasal continuous positive airway pressure has hemodynamic effects in preterm infants in stable pulmonary and cardiac conditions. It reduces pulmonary output without interference with systemic output.

Recurrent Macular Edema in Central Retinal Vein Occlusion Treated with Intravitreal Ranibizumab using a Modified Treat and Extend Regimen.

Background: The aim of this study was to evaluate the stability over time of the individually defined interval of intravitreal ranibizumab injection (IVR) for the treatment of recurrent macular edema (ME) in central retinal vein occlusion (CRVO). Patients and Methods: A case series of treatment naïve patients followed in the Jules Gonin Eye Hospital for macular edema due to central retinal vein occlusion is presented. Patients were treated monthly with IVR until complete absence of fluid on qualitative SD-OCT with a minimum of 5 monthly IVR. Thereafter, they were followed according to a modified treat and extend regimen (mTER). Results: Twelve eyes (12 patients) with ME due to CRVO were included. The mean follow-up period was 31.3 months. Analysis showed that best corrected visual acuity (BCVA), central macular thickness and qualitative spectral domain optical coherence tomography (SD-OCT) showed comparable results under monthly interval, after titration of an individualized interval and when performed in a series. 78 % of treating intervals were within ± 2 weeks of the first individually adjusted interval. The mean first defined interval was 4.3 weeks and the mean interval over time was 5.5 weeks (p = 0.003). There was a trend towards longer interval over time. Conclusion: The adjusted interval of retreatment of patients with ME due to CRVO showed a high stability with a trend toward longer duration over time. An mTER regimen seems to be valuable to follow patients with ME with good stabilization of VA.

Sofosbuvir and ribavirin before liver re-transplantation for graft failure due to recurrent hepatitis C: a case report.

BACKGROUND: Recurrent hepatitis C virus infection after liver transplantation is associated with reduced graft and patient survival. Re-transplantation for graft failure due to recurrent hepatitis C is controversial and not performed in all centers. CASE PRESENTATION: We describe a 54-year-old patient with hepatitis C virus genotype 1b infection and a null response to pegylated interferon-α and ribavirin who developed decompensated graft cirrhosis 6 years after a first liver transplantation. Treatment with sofosbuvir and ribavirin allowed for rapid negativation of serum HCV RNA and was well tolerated despite advanced liver and moderate renal dysfunction. Therapeutic drug monitoring did not reveal any clinically significant drug-drug interactions. Despite virological response, the patient remained severely decompensated and re-transplantation was performed after 46 days of undetectable serum HCV RNA. The patient is doing well 12 months after his second liver transplantation and remains free of hepatitis C virus. CONCLUSIONS: The use of directly acting antivirals may allow for successful liver re-transplantation for recipients who remain decompensated despite virological response and is likely to improve the outcome of liver re-transplantation for end-stage recurrent hepatitis C.

How to prevent venous cannula orifice obstruction during extracorporeal circulation.

Venous cannula orifice obstruction is an underestimated problem during augmented cardiopulmonary bypass (CPB), which can potentially be reduced with redesigned, virtually wall-less cannula designs versus traditional percutaneous control venous cannulas. A bench model, allowing for simulation of the vena cava with various affluent orifices, venous collapse and a worst case scenario with regard to cannula position, was developed. Flow (Q) was measured sequentially for right atrial + hepatic + renal + iliac drainage scenarios, using a centrifugal pump and an experimental bench set-up (afterload 60 mmHg). At 1500, 2000 and 2500 RPM and atrial position, the Q values were 3.4, 6.03 and 8.01 versus 0.77*, 0.43* and 0.58* l/min: p<0.05* for wall-less and the Biomedicus(®) cannula, respectively. The corresponding pressure values were -15.18, -31.62 and -74.53 versus -46.0*, -119.94* and -228.13* mmHg. At the hepatic position, the Q values were 3.34, 6.67 and 9.26 versus 2.3*, 0.42* and 0.18* l/min; and the pressure values were -10.32, -20.25 and -42.83 versus -23.35*, -119.09* and -239.38* mmHg. At the renal position, the Q values were 3.43, 6.56 and 8.64 versus 2.48*, 0.41* and 0.22* l/min and the pressure values were -9.64, -20.98 and -63.41 versus -20.87 -127.68* and -239* mmHg, respectively. At the iliac position, the Q values were 3.43, 6.01 and 9.25 versus 1.62*, 0.55* and 0.58* l/min; the pressure values were -9.36, -33.57 and -44.18 versus -30.6*, -120.27* and -228* mmHg, respectivly. Our experimental evaluation demonstrates that the redesigned, virtually wall-less cannulas, allowing for direct venous drainage at practically all intra-venous orifices, outperform the commercially available control cannula, with superior flow at reduced suction levels for all scenarios tested.

Traitement par thoracoscopie du pneumothorax récidivant [Thoracoscopic treatment of recurrent pneumothorax].

Spontaneous pneumothorax (PNO) is usually due to rupture of a small subpleural bleb into the pleural cavity and affects mainly young men. After simple drainage, recurrence occurs in about 50% of cases. The risk of recurrence increases after each new PNO. Secondary PNO complicates an underlying pulmonary disease, especially chronic obstructive pulmonary disease with emphysema. A new form of secondary PNO has emerged in the recent years in AIDS patients with pneumocystis carinii pneumonia. We have shifted to a thoracoscopic therapy of PNO since May 1991. 25 PNO in 24 patients (1 bilateral) have been treated since that time up to April 1993. 19 PNO were primary, whereas 6 were secondary, included 3 iatrogenic PNO. Resection of the leaking parenchymal area was performed in 20 patients, and parietal partial pleurectomy was done in 20 cases. In the remaining cases, fibrin glue was applied on the lesion and in 3 cases, chemical pleurodesis was attempted using silver nitrate or talc. 1 AIDS patient died of ARDS. 3 patients had recurrent PNO and had thoracotomy without complication. 21 patients did well. Partial PNO recurred in one of them 4 months later, and was treated by simple needle aspiration. Thoracoscopy is a useful method to treat recurrent or persistent spontaneous PNO. After only 25 cases, our success rate in primary PNO is 90%. There should be a learning curve. On the basis of our experience, we believe that recognition of the lesion and its resection as well as apical parietal pleurectomy are necessary to obtain good results and a low recurrence rate.