Pathology of peripheral T-cell lymphomas: where do we stand?

Peripheral T-cell lymphomas (PTCLs) are heterogeneous and uncommon malignancies characterized by a usually aggressive clinical course. The current World Health Organization (WHO) classification delineates many entities grouped according to the clinical presentation as predominantly leukemic, cutaneous, extranodal, or nodal diseases. Yet, few genetic lesions serve as entity-defining markers. Using high-throughput methods, new recurrent genetic and molecular alterations are being discovered that are expected to refine the current classification and serve as diagnostic genetic markers and targets for novel therapies. There is increasing evidence that certain cellular subsets, in particular follicular helper T cells and gamma delta T cells, represent important defining markers and/or determinants of the biology of certain entities; nevertheless, the cellular derivation of many PTCL entities remains poorly characterized and there is evidence of plasticity in terms of cellular derivation (alpha-beta, gamma-delta, natural killer [NK]) especially in several extranodal entities with a cytotoxic profile. While most clonal NK/T-cell proliferations are in general highly malignant, some more indolent forms of NK or T-cell lympho-proliferations are being identified.

Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory.

Immune protection from intracellular pathogens depends on the generation of terminally differentiated effector and of multipotent memory precursor CD8 T cells, which rapidly regenerate effector and memory cells during recurrent infection. The identification of factors and pathways involved in CD8 T cell differentiation is of obvious importance to improve vaccination strategies. Here, we show that mice lacking T cell factor 1 (Tcf-1), a nuclear effector of the canonical Wingless/Integration 1 (Wnt) signaling pathway, mount normal effector and effector memory CD8 T cell responses to infection with lymphocytic choriomeningitis virus (LCMV). However, Tcf-1-deficient CD8 T cells are selectively impaired in their ability to expand upon secondary challenge and to protect from recurrent virus infection. Tcf-1-deficient mice essentially lack CD8 memory precursor T cells, which is evident already at the peak of the primary response, suggesting that Tcf-1 programs CD8 memory cell fate. The function of Tcf-1 to establish CD8 T cell memory is dependent on the catenin-binding domain in Tcf-1 and requires the Tcf-1 coactivators and Wnt signaling intermediates beta-catenin and gamma-catenin. These findings demonstrate that the canonical Wnt signaling pathway plays an essential role for CD8 central memory T cell differentiation under physiological conditions in vivo. They raise the possibility that modulation of Wnt signaling may be exploited to improve the generation of CD8 memory T cells during vaccination or for therapies designed to promote sustained cytotoxic CD8 T cell responses against tumors.

AIDS defining opportunistic infections in patients with high CD4 counts in the combination antiretroviral therapy (cART) era: things ain't what they used to be.

INTRODUCTION: According to reports from observational databases, classic AIDS-defining opportunistic infections (ADOIs) occur in patients with CD4 counts above 500/µL on and off cART. Adjudication of these events is usually not performed. However, ADOIs are often used as endpoints, for example, in analyses on when to start cART. MATERIALS AND METHODS: In the database, Swiss HIV Cohort Study (SHCS) database, we identified 91 cases of ADOIs that occurred from 1996 onwards in patients with the nearest CD4 count >500/µL. Cases of tuberculosis and recurrent bacterial pneumonia were excluded as they also occur in non-immunocompromised patients. Chart review was performed in 82 cases, and in 50 cases we identified CD4 counts within six months before until one month after ADOI and had chart review material to allow an in-depth review. In these 50 cases, we assessed whether (1) the ADOI fulfilled the SHCS diagnostic criteria (www.shcs.ch), and (2) HIV infection with CD4 >500/µL was the main immune-compromising condition to cause the ADOI. Adjudication of cases was done by two experienced clinicians who had to agree on the interpretation. RESULTS: More than 13,000 participants were followed in SHCS in the period of interest. Twenty-four (48%) of the chart-reviewed 50 patients with ADOI and CD4 >500/µL had an HIV RNA <400 copies/mL at the time of ADOI. In the 50 cases, candida oesophagitis was the most frequent ADOI in 30 patients (60%) followed by pneumocystis pneumonia and chronic ulcerative HSV disease (Table 1). Overall chronic HIV infection with a CD4 count >500/µL was the likely explanation for the ADOI in only seven cases (14%). Other reasons (Table 1) were ADOIs occurring during primary HIV infection in 5 (10%) cases, unmasking IRIS in 1 (2%) case, chronic HIV infection with CD4 counts <500/µL near the ADOI in 13 (26%) cases, diagnosis not according to SHCS diagnostic criteria in 7 (14%) cases and most importantly other additional immune-compromising conditions such as immunosuppressive drugs in 14 (34%). CONCLUSIONS: In patients with CD4 counts >500/ µL, chronic HIV infection is the cause of ADOIs in only a minority of cases. Other immuno-compromising conditions are more likely explanations in one-third of the patients, especially in cases of candida oesophagitis. ADOIs in HIV patients with high CD4 counts should be used as endpoints only with much caution in studies based on observational databases.

Molecular characterisation of the NSP4 gene of group A human rotavirus G2P[4] strains circulating in São Paulo, Brazil, from 1994 and 2006 to 2010

Group A human rotaviruses (HuRVA) are causative agents of acute gastroenteritis. Six viral structural proteins (VPs) and six nonstructural proteins (NSPs) are produced in RV-infected cells. NSP4 is a diarrhoea-inducing viral enterotoxin and NSP4 gene analysis revealed at least 15 (E1-E15) genotypes. This study analysed the NSP4 genetic diversity of HuRVA G2P[4] strains collected in the state of São Paulo (SP) from 1994 and 2006-2010 using reverse transcription-polymerase chain reaction, sequencing and phylogenetic analysis. Forty (97.6%) G2P[4] strains displayed genotype E2; one strain (2.4%) displayed genotype E1. These results are consistent with the proposed linkage between VP4/VP7 (G2P[4]) and the NSP4 (E2) genotype of HuRVA. NSP4 phylogenetic analysis showed distinct clusters, with grouping of most strains by their genotype and collection year, and most strains from SP were clustered together with strains from other Brazilian states. A deduced amino acid sequence alignment for E2 showed many variations in the C-terminal region, including the VP4-binding domain. Considering the ability of NSP4 to generate host immunity, monitoring NSP4 variations, along with those in the VP4 or VP7 protein, is important for evaluating the circulation and pathogenesis of RV. Finally, the presence of one G2P[4]E1 strain reinforces the idea that new genotype combinations emerge through reassortment and independent segregation.

Immunotherapy for ovarian cancer: recent advances and perspectives.

PURPOSE OF REVIEW: Epithelial ovarian cancer is the most frequent cause of gynecologic cancer-related mortality in women, and prognosis for patients with recurrent or metastatic disease is extremely poor. Therefore, there is an enormous unmet need for the development of novel therapies in this indication. Although surgery and chemotherapy can improve survival rates, it is necessary to integrate alternative strategies, such as immunotherapy to improve the outcomes for patients with advanced ovarian cancer. RECENT FINDINGS: We will discuss the rationale of immunotherapy and some of the mechanisms of immunogenicity in ovarian cancer. We will highlight current results with cancer vaccines, adoptive T-cell therapy and immunomodulatory agents and will summarize the immune effects of selected chemotherapeutic agents, radiotherapy and recent results with combinatorial approaches in this disease setting. We will also discuss recent and potential future therapeutic interventions that might circumvent tumor-mediated immunosuppression. SUMMARY: Dramatic increase in the number of immunotherapy clinical trials was seen in the past decade with promising results in enhancing antitumor immune response and cancer vaccine efficacy. The future challenge for immunotherapy against ovarian cancer is to use a combinatorial approach to test rational, potentially synergistic immunotherapy combinations that can induce efficient antitumor immunity and prolong patients' survival.

Extrapleural Pneumonectomy With Venous Confluence Resection for Stage IVA Thymic Tumors.

We report 4 patients with stage IVA thymic tumors who underwent extrapleural pneumonectomy and thymectomy with venous confluence resection using a temporary percutaneous venous jugular-femoral bypass technique. The superior vena cava was replaced in 2 patients, and the innominate vein was resected in 2 patients. Complete tumor resection was obtained in all patients. There was no 90-day postoperative mortality. One patient died at 6 months postoperatively of an unrelated cause, without recurrent disease, and 3 are alive and disease-free with a follow-up ranging from 19 to 80 months. Extrapleural pneumonectomy can be combined with thymectomy and venous confluence resection for stage IVA thymic tumors.

New clinical practice guideline on enteral feeding in very low birth weight infants; first part.

The nutrition of very low birth weight (VLBW) infants is aimed at promoting a similar growth to that occurring in the uterus. However, in practice this is difficult to achieve and extrauterine growth restriction is frequent. The current tendency is to avoid this restriction by means of early parenteral and enteral nutrition. Nonetheless, uncertainty about many of the practices related with nutrition has resulted in a great variation in the way it is undertaken. In 2009 and 2011 in our hospital there was an unexpected increase in necrotizing enterocolitis. To check to see whether our nutrition policy was involved, we undertook a systematic review and drew up clinical practice guidelines (CPG) about enteral feeding in VLBW infants. New considerations about the duration of the fortification and the use of probiotics have led to an update of these CPG. METHODS: A total of 21 clinical questions were designed dealing with the type of milk, starting age, mode of administration, rate and volume of the increments, fortification, use of probiotics and protocol. After conducting a systematic search of the available evidence, the information was contrasted and summarized in order to draw up the recommendations. The quality of the evidence and the strength of the recommendations were determined from the SIGN scale. COMMENT: These CPG aim to help physicians in their decision making. The protocolized application of well-proven measurements reduces the variation in clinical practice and improves results.

Angiogenesehemmung in der Neuroonkologie. Eine vielversprechende Therapiestrategie gegen maligne Gliome [Angiogenesis inhibition in neurooncology. A very promising therapy strategy for malignant glioma]

The application of angiogenesis inhibitors in neurooncology is increasing. Initially, these drugs seemed to be very promising because of the surprisingly high neuroradiological response rates that were observed in first clinical trials. Meanwhile, this enthusiasm is waning, as the high response rates did not translate into substantial improvements in progression-free and overall survival. Tumor progression during or after antiangiogenic therapy is often associated with rapid clinical neurological deterioration and sometimes even with diffuse infiltrative gliomatosis-like neuroradiological phenotypes. Thus, the characterization and understanding of escape mechanisms are needed. The identification of criteria for defining the personalized use of angiogenesis inhibitors remains a challenge.

Long-term outcome of congenital aortic valve stenosis: predictors of reintervention.

OBJECTIVES: To evaluate long-term outcome of initial aortic valve intervention in a paediatric population with congenital aortic stenosis, and to determine risk factors associated with reintervention. PATIENTS AND METHODS: From 1985 to 2009, 77 patients with congenital aortic stenosis and a mean age of 5.8±5.6 years at diagnosis were followed up in our institution for 14.8±9.1 years. RESULTS: First intervention was successful with 86% of patients having a residual peak aortic gradient 1 regurgitation increased by 7%. Long-term survival after the first procedure was excellent, with 91% survival at 25 years. At a mean interval of 7.6±5.3 years, 30 patients required a reintervention (39%), mainly because of a recurrent aortic stenosis. Freedom from reintervention was 97, 89, 75, 53, and 42% at 1, 10, 15, 20, and 25 years, respectively. Predictors of reintervention were residual peak aortic gradient (p=0.0001), aortic regurgitation post-intervention >1 (p=0.02), prior balloon aortic valvuloplasty (p=0.04), and increased left ventricular posterior wall thickness (p=0.1). CONCLUSIONS: Aortic valve intervention is a safe and effective procedure for congenital aortic stenosis with excellent survival results. However, rate of reintervention is high and influenced by increased left ventricular posterior wall thickness pre-intervention, prior balloon valvuloplasty, higher residual peak systolic valve gradient, and more than mild regurgitation post-intervention. The study highlights that long-term follow-up is recommended for these patients.

Bosentan and/or Sildenafil for non-operable chronic thromboembolic pulmonary hypertension

Objectives: To evaluate outcome of patients treated "off-label" by bosentan and/or sildenafil for chronic thromboembolic pulmonary hypertension (CTEPH). Patients and methods: Since 2003, 18 patients (mean age 69 ± 11 years) have been treated with bosentan and/or sildenafil for CTEPH (mean pulmonary arterial resistance 8.1 ± 3.7 U Wood) in Lausanne University Hospital, with a follow-up of at least 12 months. Sixteen of them were inoperable because of distal disease and/or age or significant co-morbidities and 2 had persistent or recurrent pulmonary hypertension despite surgery. Efficacy of treatment was evaluated by comparison of New York Heart Association functional class (NYHA), six-minute walk test (6-MWT) and serum levels of N-terminal-pro brain natriuretic peptide (NT pro-BNP) at baseline (T0) and at 12 months (T12). Wilcoxon rank test was used for statistics. Results: At T0, median NYHA class was III (range II-IV), 6-MWT was 348 meters (5 and 95 centiles:0, 539) and NT pro-BNP was 387 mmol/l (58, 3508). At T12, 11 patients were treated with bosentan, 5 with sildenafil, 1 with inhaled Iloprost (because of failure of the two other treatments) and 1 with a combination of sildenafil and Iloprost. NYHA had improved in 10 patients, remained stable in 7 and worsened in 1 (median decrease 0.5 (-2; 0.2) p = 0.013). Six-MWT improved by a median of 15 meters (-142, +270) (p = 0.047) and NT pro-BNP decreased by a median of 65 mmol/l (-2988, +187) (p = n.s.). Among the 10 patients with a follow-up of 2 years or longer, two thirds remained stable and one third had worsened at 24 month. Treatments were well tolerated and only one patient had significant side effects (cutaneous reaction to bosentan) necessitating a switch to another treatment. Conclusion: In agreement with published data, bosentan and sildenafil improved functional status (NYHA, 6-MWT) and haemodynamics (NT pro BNP) in our patients with inoperable CTEPH. However these medications should not be used as substitute for surgery when the latter is applicable.

Postoperative epidural hematoma contributes to delayed upper cord tethering after decompression of Chiari malformation type I.

Symptomatic arachnoiditis after posterior fossa surgical procedures such as decompression of Chiari malformation is a possible complication. Clinical presentation is generally insidious and delayed by months or years. It causes disturbances in the normal flow of cerebrospinal fluid and enlargement of a syrinx cavity in the upper spinal cord. Surgical de-tethering has favorable results with progressive collapse of the syrinx and relief of the associated symptoms. Case Description: A 30-year-old male with Chiari malformation type I was treated by performing posterior fossa bone decompression, dura opening and closure with a suturable bovine pericardium dural graft. Postoperative period was uneventful until the fifth day in which the patient suffered intense headache and progressive loose of consciousness caused by an acute posterior fossa epidural hematoma. It was quickly removed with complete clinical recovering. One year later, the patient experienced progressive worsened of his symptoms. Upper spinal cord tethering was diagnosed and a new surgery for debridement was required. Conclusions: The epidural hematoma compressing the dural graft against the neural structures contributes to the upper spinal cord tethering and represents a nondescribed cause of postoperative fibrosis, adhesion formation, and subsequent recurrent hindbrain compression.

Metastatic Crohn’s disease.

A 51 year old man presented to the department of Dermatology, Regional University Hospital of Málaga, Málaga, Spain, in May 2013, with remarkable lesions on the perineal, perianal and gluteal regions reaching the top of the lower limbs, which he had first noted two years earlier. The physical examination revealed large erythematous-brownish plaques with a granulomatous appearance, polypoid lesions and areas of ulceration. In addition, Mycobacterium tuberculosis culture and serum QuantiFERON® TB Gold were negative. The patient was diagnosed to have metastatic Crohn’s disease which is an uncommon complication of Crohn’s disease.

Multifocal epithelial tumors and field cancerization: stroma as a primary determinant.

It is increasingly evident that cancer results from altered organ homeostasis rather than from deregulated control of single cells or groups of cells. This applies especially to epithelial cancer, the most common form of human solid tumors and a major cause of cancer lethality. In the vast majority of cases, in situ epithelial cancer lesions do not progress into malignancy, even if they harbor many of the genetic changes found in invasive and metastatic tumors. While changes in tumor stroma are frequently viewed as secondary to changes in the epithelium, recent evidence indicates that they can play a primary role in both cancer progression and initiation. These processes may explain the phenomenon of field cancerization, i.e., the occurrence of multifocal and recurrent epithelial tumors that are preceded by and associated with widespread changes of surrounding tissue or organ "fields."

Drivers of human resource management competences development in Brazilian multinational subsidiaries: a multilevel research

This article aims to verify the factors associated with the development of human resource management (HRM) competences in foreign subsidiaries of Brazilian multinationals. These competences are essential in that they allow foreign units to adopt HRM practices that are consistent with the countries or markets in which they operate. A multilevel research was conducted, involving headquarters and subsidiaries of major Brazilian companies; the empirical analysis employed hierarchical linear modelling. Despite the recurrent debate on global standardisation versus local adaptation, it was identified that the integration of international HRM policies (addressing simultaneously global guidelines and local response) may stimulate competences development. In addition, interaction in external networks in the host country may enhance the development of HRM competences in the subsidiaries. However, specific cultural factors of the company may inhibit development activity in units abroad.

War Signals: A Theory of Trade, Trust and Conflict

We construct a dynamic theory of civil conflict hinging on inter-ethnic trust and trade. The model economy is inhabitated by two ethnic groups. Inter-ethnic trade requires imperfectly observed bilateral investments and one group has to form beliefs on the average propensity to trade of the other group. Since conflict disrupts trade, the onset of a conflict signals that the aggressor has a low propensity to trade. Agents observe the history of conflicts and update their beliefs over time, transmitting them to the next generation. The theory bears a set of testable predictions. First, war is a stochastic process whose frequency depends on the state of endogenous beliefs. Second, the probability of future conflicts increases after each conflict episode. Third, "accidental" conflicts that do not reflect economic fundamentals can lead to a permanent breakdown of trust, plunging a society into a vicious cycle of recurrent conflicts (a war trap). The incidence of conflict can be reduced by policies abating cultural barriers, fostering inter-ethnic trade and human capital, and shifting beliefs. Coercive peace policies such as peacekeeping forces or externally imposed regime changes have instead no persistent effects.