Tumorigenesis and peritoneal colonization from fallopian tube epithelium

Ovarian cancer is the most lethal gynecological malignancy, primarily because its origin and initiation factors are unknown. A secretory murine oviductal epithelial (MOE) model was generated to address the hypothesis that the fallopian tube is an origin for high-grade serous cancer. MOE cells were stably altered to express mutation in p53, silence PTEN, activate AKT, and amplify KRAS alone and in combination, to define if this cell type gives rise to tumors and what genetic alterations are required to drive malignancy. Cell lines were characterized in vitro and allografted into mice. Silencing PTEN formed high-grade carcinoma with wide spread tumor explants including metastasis into the ovary. Addition of p53 mutation to PTEN silencing did not enhance this phenotype, whereas addition of KRAS mutation reduced survival. Interestingly, PTEN silencing and KRAS mutation originating from ovarian surface epithelium generated endometrioid carcinoma, suggesting that different cellular origins with identical genetic manipulations can give rise to distinct cancer histotypes. Defining the roles of specific signaling modifications in tumorigenesis from the fallopian tube/oviduct is essential for early detection and development of targeted therapeutics. Further, syngeneic MOE allografts provide an ideal model for pre-clinical testing in an in vivo environment with an intact immune system.

The prevalence of CALR mutations in a cohort of patients with myeloproliferative neoplasms

INTRODUCTION: To investigate the prevalence of calreticulin (CALR) mutations in JAK2- and MPL-non-mutated patients with suspected myeloproliferative neoplasm (MPN) from a large MPN clinic and confirm a diagnosis of MPN.

METHODS: JAK2/MPL-non-mutated patients from the Belfast City Hospital (BCH) with either of the MPNs - ET or MF - and diagnosed between 1988 and 2014 were selected for CALR screen. All cases were validated according to the WHO 2008 classification for MPNs. Statistical analysis was performed with Minitab 16 Statistical Software package. Exon 9 of CALR was amplified by PCR using genomic DNA, and mutations were detected by fragment analysis.

RESULTS: Of the 62 JAK2/MPL-non-mutated MPN patients screened, 57 had ET and 5 had MF; 34 patients (53.1%) carried CALR mutations. Three of 5 MF patients were CALR positive. Thirty-one ET patients (54.3%) harboured CALR mutation, whereas 26 (45.7%) were classified as 'triple negatives'.

CONCLUSION: Detection of CALR mutations in a cohort of JAK2/MPL-non-mutated patients with suspected MPN confirmed the diagnosis of MPN in around 53% of cases. This is lower than initially reported, but similar to subsequent studies. However, a sizable cohort of patients remains lacking a specific molecular marker.

Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

Diagnosis and workup of 522 consecutive patients with neuroendocrine neoplasms in Switzerland.

BACKGROUND: Neuroendocrine neoplasms (NENs) are difficult to diagnose. We used SwissNET data to characterise NEN patients followed in the two academic centres of western Switzerland (WS), and to compare them with patients followed in eastern Switzerland (ES) as well as with international guidelines. METHOD: SwissNET is a prospective database covering data from 522 consecutive patients (285 men, 237 women) from WS (n = 99) and ES (n = 423). RESULTS: Mean ± SD age at diagnosis was 59.0 ± 15.7 years. Overall, 76/522 experienced a functional syndrome, with a median interval of 1.0 (IQR: 1.0-3.0) year between symptoms onset and diagnosis. A total of 51/522 of these tumours were incidental. The primary tumour site was the small intestine (29%), pancreas (21%), appendix (18%) and lung (11%) in both regions combined. In all, 513 functional imaging studies were obtained (139 in WS, 374 in ES). Of these, 381 were 111In-pentetreotide scintigraphies and 20 were 68Ga-DOTATOC PET. First line therapy was surgery in 87% of patients, medical therapy (biotherapy or chemotherapy) in 9% and irradiation in 3% for both regions together. CONCLUSION: Swiss NEN patients appear similar to what has been described in the literature. Imaging by somatostatin receptor scintigraphy (SRS) is widely used in both regions of Switzerland. In good accordance with published guidelines, data on first line therapy demonstrate the crucial role of surgery. The low incidence of biotherapy suggests that long-acting somatostatin analogues are not yet widely used for their anti-proliferative effects. The SwissNET initiative should help improve compliance with ENETS guidelines in the workup and care of NEN patients.

Cytological diagnosis of pancreatic neuroendocrine neoplasms

The main cytological features of neuroendocrine pancreatic neoplasm are described along with a discussion about the difficulties in classification/grading and the new reporting system for reporting pancreatic cytopathology. An overview about the ancillary techniques and the differential diagnosis is also given.

Efecto antibacteriano de algunas tetraciclinas sobre bacterias fagocitadas por leucocitos polimorfonucleares obtenidos de exudado peritoneal de conejo

Tesis (Maestría en Ciencias con Especialidad en Microbiología Médica) UANL

Caracterización de las variables nutricionales en pacientes incidentes de diálisis peritoneal rts 2011-2012

Los pacientes con enfermedad renal crónica (ERC) terminal se caracterizan por presentar alteraciones nutricionales que se perpetúan independiente de la modalidad de la Terapia de Reemplazo Renal (TRR). En la diálisis peritoneal, tanto APD (automated peritoneal dialysis) como la CAPD (continuous ambulatory peritoneal dialysis) existe un alto riesgo de pérdida de albúmina por el filtrado peritoneal, sin diferencias claras en el estatus nutricional. El presente estudio caracteriza el estado nutricional de los pacientes incidentes en diálisis peritoneal de RTS Bogotá Regional 1, con un seguimiento de un año, para conocer los cambios en las variables nutricionales. Se realizó un estudio de cohortes retrospectivo, analizando 2 grupos según el tipo de diálisis peritoneal escogida (APD o CAPD), con un análisis análisis descriptivo trimestral de las características nutricionales y posteriormente una comparación entre las 2 modalidades de TRR. Encontrando un promedio de edad de 60,8 años, la mayoría hombres y etiología principal nefropatía diabética. La mayoría de las variables nutricionales permanecieron sin cambios durante seguimiento. El Test de equilibrio peritoneal para glucosa y creatinina mostró valores promedio bajo y promedio alto y la mayoría de pacientes un rango nutricional normal. Al comparar APD y CAPD, solo se encontraron de forma aislada, diferencias significativas en algunas variables aisladas. Este es el primer estudio en Colombia que evalúa diferentes aspectos nutricionales en diálisis peritoneal. Aunque con limitaciones metodológicas, es un punto de partida para la realización de estudios más robustos que del estado nutricional de los pacientes en diálisis peritoneal

Survival of European patients diagnosed with lymphoid neoplasms in 2000-2002: results of the HAEMACARE project

The European Cancer Registry-based project on hematologic malignancies (HAEMACARE), set up to improve the availability and standardization of data on hematologic malignancies in Europe, used the European Cancer Registry-based project on survival and care of cancer patients (EUROCARE-4) database to produce a new grouping of hematologic neoplasma(defined by the International Classification of Diseases for Oncology, Third Edition and the 2001/2008 World Health Organization classifications) for epidemiological and public health purposes. We analyzed survival for lymphoid neoplasms in Europe by disease group, comparing survival between different European regions by age and sex. Design and Methods Incident neoplasms recorded between 1995 to 2002 in 48 population-based cancer registries in 20 countries participating in EUROCARE-4 were analyzed. The period approach was used to estimate 5-year relative survival rates for patients diagnosed in 2000-2002, who did not have 5 years of follow up. Results: The 5-year relative survival rate was 57% overall but varied markedly between the defined groups. Variation in survival within the groups was relatively limited across European regions and less than in previous years. Survival differences between men and women were small. The relative survival for patients with all lymphoid neoplasms decreased substantially after the age of 50. The proportion of ‘not otherwise specified’ diagnoses increased with advancing age.Conclusions: This is the first study to analyze survival of patients with lymphoid neoplasms, divided into groups characterized by similar epidemiological and clinical characteristics, providing a benchmark for more detailed analyses. This Europe-wide study suggests that previously noted differences in survival between regions have tended to decrease. The survival of patients with all neoplasms decreased markedly with age, while the proportion of ‘not otherwise specified’ diagnoses increased with advancing age. Thus the quality of diagnostic work-up and care decreased with age, suggesting that older patients may not be receiving optimal treatment

Reduced cytokine production by glycogen-elicited peritoneal cells from diabetic rats

IL-1 beta, TNF-alpha, cytokine-induced neutrophil chemoattractant-2 alpha/beta, and IL-10 measurements were performed in elicited peritoneal cells from control, diabetic, and insulin-treated diabetic rats. Production/liberation of these cytokines was decreased in elicited peritoneal cells from diabetic rats. These changes were abolished by insulin treatment of diabetic rats. The alterations observed might be involved in the impaired inflammatory response and high occurrence of apoptosis observed in neutrophils under diabetic states.

Involvement of proteinase-activated receptors 1 and 2 in spreading and phagocytosis by murine adherent peritoneal cells: Modulation by the C-terminal of S100A9 protein

Proteinase-activated receptors (PAR) are widely recognized for their modulatory properties in inflammatory and immune responses; however, their direct role on phagocyte effector functions remains unknown. S100A9, a protein secreted during inflammatory responses, deactivates activated peritoneal macrophages, and its C-terminal portion inhibits spreading and phagocytosis of adherent peritoneal cells. Herein, the effect of PAR1 and PAR2 agonists was investigated on spreading and phagocytosis by adherent peritoneal cells, as well as the ability of murine C-terminal of S100A9 peptide (mS100A9p) to modulate this effect. Adherent peritoneal cells obtained from mouse abdominal cavity were incubated with PAR1 and PAR2 agonists and spreading and phagocytosis of Candida albicans particles were evaluated. PAR1 agonists increased both the spreading and the phagocytic activity, but PAR2 agonists only increased the spreading index. mS100A9p reverted both the increased spreading and phagocytosis induced by PAR1 agonists, but no interference in the increased spreading induced by PAR2 agonists was noticed. The shorter homologue peptide to the C-terminal of mS100A9p, corresponding to the H(92)-E(97) region, also reverted the increased spreading and phagocytosis induced by PAR1 agonists. These findings show that proteinase-activated receptors have an important role for spreading and phagocytosis of adherent peritoneal cells, and that the pepticle corresponding to the C-terminal of S100A9 protein is a remarkable candidate for use as a novel compound to modulate PAR1 function. (C) 2009 Elsevier B.V. All rights reserved.

A politics of what: the enactment of peritoneal dialysis in indigenous Australians

This paper explores, on the one hand, the requirements of the technologies and practices that have been developed for a particular type of renal patient and health network in Australia. On the other, we examine the cultural and practical specificities entailed in the performance of these technologies and practices in the Indigenous Australian context. The praxiographic orientation of the actor-network approach – which has been called 'the politics of what' (Mol 2002) – enabled us to understand the difficulties involved in translating renal healthcare networks across cultural contexts in Australia; to understand the dynamic and contested nature of these networks; and to suggest possible strategies that make use of the tensions between these two disparate networks in ways that might ensure better healthcare for Indigenous renal patients.

Effect of timing of dialysis commencement on clincial outcomes of patients with planned initiation of peritoneal dialysis in the ideal trial

Background: Since the mid-1990s, early dialysis initiation has dramatically increased in many countries. The Initiating Dialysis Early and Late (IDEAL) study demonstrated that, compared with late initiation, planned early initiation of dialysis was associated with comparable clinical outcomes and increased health care costs. Because residual renal function is a key determinant of outcome and is better preserved with peritoneal dialysis (PD), the present pre-specified subgroup analysis of the IDEAL trial examined the effects of early-compared with late-start dialysis on clinical outcomes in patients whose planned therapy at the time of randomization was PD.

Methods: Adults with an estimated glomerular filtration rate (eGFR) of 10 - 15 mL/min/1.73 m2 who planned to be treated with PD were randomly allocated to commence dialysis at an eGFR of 10 - 14 mL/min/1.73 m2 (early start) or 5 - 7 mL/min/1.73 m2 (late start). The primary outcome was all-cause mortality.

Results: Of the 828 IDEAL trial participants, 466 (56%) planned to commence PD and were randomized to early start (n = 233) or late start (n = 233). The median times from randomization to dialysis initiation were, respectively, 2.03 months [interquartile range (IQR):1.67 - 2.30 months] and 7.83 months (IQR: 5.83 - 8.83 months). Death occurred in 102 early-start patients and 96 late-start patients [hazard ratio: 1.04; 95% confidence interval (CI): 0.79 - 1.37]. No differences in composite cardiovascular events, composite infectious deaths, or dialysis-associated complications were observed between the groups. Peritonitis rates were 0.73 episodes (95% CI: 0.65 - 0.82 episodes) per patient-year in the early-start group and 0.69 episodes (95% CI: 0.61 - 0.78 episodes) per patient-year in the late-start group (incidence rate ratio: 1.19; 95% CI: 0.86 - 1.65; p = 0.29). The proportion of patients planning to commence PD who actually initiated dialysis with PD was higher in the early-start group (80% vs 70%, p = 0.01).

Conclusion: Early initiation of dialysis in patients with stage 5 chronic kidney disease who planned to be treated with PD was associated with clinical outcomes comparable to those seen with late dialysis initiation. Compared with early-start patients, late-start patients who had chosen PD as their planned dialysis modality were less likely to commence on PD.

Neuroendocrine neoplasms of the GI tract : the role of cytotoxic chemotherapy

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of neoplasms derived from peptide- and amine-secreting cells of the neuroendocrine system. NENs commonly arise in the GI tract but can arise in most organs of the body. NENs in different organs share many common pathologic features. Although the incidence of NENs is not high, the prevalence is not low because many patients may live relatively long periods without major symptoms from the disease. While many of these tumors lead an indolent clinical course, they constitute a therapeutic challenge when they progress, metastasize and become symptomatic. Treatment requires a multidisciplinary approach including cytotoxic chemotherapy. Almost all clinical trials investigating cytotoxic chemotherapy in NENs are small single-arm studies and guidelines are derived from expert opinion and from extrapolating results from small cell lung cancer studies. This article briefly reviews NENs before focusing on reviewing data on the role of cytotoxic chemotherapy studies in NENs.