Разработка и валидация номограммы, позволяющей прогнозировать выживаемость без прогрессирования при терапии пазопанибом по поводу распространенного рака почки

Цель исследования – разработка и валидация номограммы, позволяющей прогнозировать 12-месячную выживаемость без прогрессирования (ВБП) у пациентов, получающих пазопаниб в качестве первой линии терапии распространенного рака почки.Материалы и методы. Проведено статистическое моделирование данных 557 пациентов, получавших пазопаниб, в исследовании III фазы COMPARZ. Известные прогностические факторы были внесены в мультивариантную модель по Cox. Рассмотренные параметры включали уровень нейтрофилов, содержание альбумина и щелочной фосфатазы в сыворотке, время между постановкой диагноза и началом лечения, а также наличие костных метастазов. Для валидации были использованы данные по группе участников плацебоконтролируемого исследования III фазы, получавших пазопаниб.Результаты. Данная модель включала 10 прогностических факторов, представленных в виде номограммы, позволяющей прогнозировать 12-месячную ВБП. Сопоставления, проведенные с целью калибровки разработанной модели, позволяют предполагать достаточное соответствие расчетных вероятностей ВБП ее фактическим показателям. Индекс конкордантности для 12-месячной ВБП составил 0,625. Отмечена достоверная взаимосвязь (p < 0,05) между ВБП и наличием костных метастазов, интервалом времени между постановкой диагноза и началом лечения, а также уровнями альбумина и щелочной фосфатазы. Прогностическая роль последних 2 параметров оказалась весьма существенной.Выводы. Номограмма позволяет с достаточной точностью прогнозировать ВБП у пациентов с распространенным раком почки, получающих пазопаниб, в зависимости от исходных клинических характеристик.Цель исследования – разработка и валидация номограммы, позволяющей прогнозировать 12-месячную выживаемость без прогрессирования (ВБП) у пациентов, получающих пазопаниб в качестве первой линии терапии распространенного рака почки.Материалы и методы. Проведено статистическое моделирование данных 557 пациентов, получавших пазопаниб, в исследовании III фазы COMPARZ. Известные прогностические факторы были внесены в мультивариантную модель по Cox. Рассмотренные параметры включали уровень нейтрофилов, содержание альбумина и щелочной фосфатазы в сыворотке, время между постановкой диагноза и началом лечения, а также наличие костных метастазов. Для валидации были использованы данные по группе участников плацебоконтролируемого исследования III фазы, получавших пазопаниб.Результаты. Данная модель включала 10 прогностических факторов, представленных в виде номограммы, позволяющей прогнозировать 12-месячную ВБП. Сопоставления, проведенные с целью калибровки разработанной модели, позволяют предполагать достаточное соответствие расчетных вероятностей ВБП ее фактическим показателям. Индекс конкордантности для 12-месячной ВБП составил 0,625. Отмечена достоверная взаимосвязь (p < 0,05) между ВБП и наличием костных метастазов, интервалом времени между постановкой диагноза и началом лечения, а также уровнями альбумина и щелочной фосфатазы. Прогностическая роль последних 2 параметров оказалась весьма существенной.Выводы. Номограмма позволяет с достаточной точностью прогнозировать ВБП у пациентов с распространенным раком почки, получающих пазопаниб, в зависимости от исходных клинических характеристик

Long-term outcome among men with conservatively treated localised prostate cancer

Optimal management of clinically localised prostate cancer presents unique challenges, because of its highly variable and often indolent natural history. There is an urgent need to predict more accurately its natural history, in order to avoid unnecessary treatment. Medical records of men diagnosed with clinically localised prostate cancer, in the UK, between 1990 and 1996 were reviewed to identify those who were conservatively treated, under age 76 years at the time of pathological diagnosis and had a baseline prostate-specific antigen (PSA) measurement. Diagnostic biopsy specimens were centrally reviewed to assign primary and secondary Gleason grades. The primary end point was death from prostate cancer and multivariate models were constructed to determine its best predictors. A total of 2333 eligible patients were identified. The most important prognostic factors were Gleason score and baseline PSA level. These factors were largely independent and together, contributed substantially more predictive power than either one alone. Clinical stage and extent of disease determined, either from needle biopsy or transurethral resection of the prostate (TURP) chips, provided some additional prognostic information. In conclusion, a model using Gleason score and PSA level identified three subgroups comprising 17, 50, and 33% of the cohort with a 10-year prostate cancer specific mortality of <10, 10–30, and >30%, respectively. This classification is a substantial improvement on previous ones using only Gleason score, but better markers are needed to predict survival more accurately in the intermediate group of patients

Impairment of exogenous lactate clearance in experimental hyperdynamic septic shock is not related to total liver hypoperfusion

Introduction: Although the prognostic value of persistent hyperlactatemia in septic shock is unequivocal, its physiological determinants are controversial. Particularly, the role of impaired hepatic clearance has been underestimated and is only considered relevant in patients with liver ischemia or cirrhosis. Our objectives were to establish whether endotoxemia impairs whole body net lactate clearance, and to explore a potential role for total liver hypoperfusion during the early phase of septic shock. Methods: After anesthesia, 12 sheep were subjected to hemodynamic/perfusion monitoring including hepatic and portal catheterization, and a hepatic ultrasound flow probe. After stabilization (point A), sheep were alternatively assigned to lipopolysaccharide (LPS) (5 mcg/kg bolus followed by 4 mcg/kg/h) or sham for a three-hour study period. After 60 minutes of shock, animals were fluid resuscitated to normalize mean arterial pressure. Repeated series of measurements were performed immediately after fluid resuscitation (point B), and one (point C) and two hours later (point D). Monitoring included systemic and regional hemodynamics, blood gases and lactate measurements, and ex-vivo hepatic mitochondrial respiration at point D. Parallel exogenous lactate and sorbitol clearances were performed at points B and D. Both groups included an intravenous bolus followed by serial blood sampling to draw a curve using the least squares method. Results: Significant hyperlactatemia was already present in LPS as compared to sham animals at point B (4.7 (3.1 to 6.7) versus 1.8 (1.5 to 3.7) mmol/L), increasing to 10.2 (7.8 to 12.3) mmol/L at point D. A significant increase in portal and hepatic lactate levels in LPS animals was also observed. No within-group difference in hepatic DO2, VO2 or O2 extraction, total hepatic blood flow (point D: 915 (773 to 1,046) versus 655 (593 to 1,175) ml/min), mitochondrial respiration, liver enzymes or sorbitol clearance was found. However, there was a highly significant decrease in lactate clearance in LPS animals (point B: 46 (30 to 180) versus 1,212 (743 to 2,116) ml/min, P <0.01; point D: 113 (65 to 322) versus 944 (363 to 1,235) ml/min, P <0.01). Conclusions: Endotoxemia induces an early and severe impairment in lactate clearance that is not related to total liver hypoperfusion

Spatial Connectivity and Drivers of Shark Habitat Use Within a Large Marine Protected Area in the Caribbean, The Bahamas Shark Sanctuary

Marine protected areas (MPAs) have emerged as potentially important conservation tools for the conservation of biodiversity and mitigation of climate impacts. Among MPAs, a large percentage has been created with the implicit goal of protecting shark populations, including 17 shark sanctuaries which fully protect sharks throughout their jurisdiction. The Commonwealth of the Bahamas represents a long-term MPA for sharks, following the banning of commercial longlining in 1993 and subsequent designation as a shark sanctuary in 2011. Little is known, however, about the longterm behavior and space use of sharks within this protected area, particularly among reef-associated sharks for which the sanctuary presumably offers the most benefit. We used acoustic telemetry to advance our understanding of the ecology of such sharks, namely Caribbean reef sharks (Carcharhinus perezi) and tiger sharks (Galeocerdo cuvier), over two discrete islands (New Providence and Great Exuma) varying in human activity level, over 2 years. We evaluated which factors influenced the likelihood of detection of individuals, analyzed patterns of movement and occurrence, and identified variability in habitat selection among species and regions, using a dataset of 23 Caribbean reef sharks and 15 tiger sharks which were passively monitored in two arrays with a combined total of 13 acoustic receivers. Caribbean reef sharks had lower detection probabilities than tiger sharks, and exhibited relatively low habitat connectivity and high residency, while tiger sharks demonstrated wider roaming behavior across much greater space. Tiger sharks were associated with shallow seagrass habitats where available, but frequently transited between and connected different habitat types. Our data support the notion that large MPAs afford greater degrees of protection for highly resident species such as Caribbean reef sharks, shark, acoustic telemetry, marine protected area, MPA, seagrass, coral reef, Bahamas, Caribbea

Relationship between H.Pylori infection and clinicopathological features and prognosis of gastric cancer

<p>Abstract</p> <p>Background</p> <p>Aimed to assess the relationship between H.Pylori and the clinicopathological features and prognosis of gastric cancer by quantitative detection of H.Pylori.</p> <p>Methods</p> <p>157 patients were enrolled, all patients had a record of clinicopathological parameters. Specimens including the tumor and non-neoplastic were detected for H.Pylori by Real-Time PCR and analyzed clinical data retrospectively. Variables independently affecting prognosis were investigated by means of multivariate analysis using the Cox proportional hazards model.</p> <p>Results</p> <p>H.Pylori infection was greater in non-neoplastic tissue than the tumor tissue (p < 0.05), H.Pylori infection and its copies were related to the tumor site and N staging (p < 0.05). Overall survival (OS) in all 157 patients has no correlation with the H.Pylori infection status (p = 0.715). As to the patients who underwent a curative surgery, relapse-free survival (RFS) has no correlation with the H.Pylori infection status (p = 0.639). Among the H.Pylori positive patients, OS and RFS of those with higher copies were longer than in patients with low copies, but there was no significant statistical difference.</p> <p>Conclusions</p> <p>H.Pylori infection status and its copies were related to N staging. The OS and RFS in patients with positive H.Pylori status has no significant difference from the patients with negative H.Pylori status.</p

Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy

High activity of histone deacetylases (HDACs) causes epigenetic alterations associated with malignant cell behaviour. Consequently, HDAC inhibitors have entered late-phase clinical trials as new antineoplastic drugs. However, little is known about expression and function of specific HDAC isoforms in human tumours including prostate cancer. We investigated the expression of class I HDACs in 192 prostate carcinomas by immunohistochemistry and correlated our findings to clinicopathological parameters including follow-up data. Class I HDAC isoforms were strongly expressed in the majority of the cases (HDAC1: 69.8%, HDAC2: 74%, HDAC3: 94.8%). High rates of HDAC1 and HDAC2 expression were significantly associated with tumour dedifferentiation. Strong expression of all HDACs was accompanied by enhanced tumour cell proliferation. In addition, HDAC2 was an independent prognostic marker in our prostate cancer cohort. In conclusion, we showed that the known effects of HDACs on differentiation and proliferation of cancer cells observed in vitro can also be confirmed in vivo. The class I HDAC isoforms 1, 2 and 3 are differentially expressed in prostate cancer, which might be important for upcoming studies on HDAC inhibitors in this tumour entity. Also, the highly significant prognostic value of HDAC2 clearly deserves further study

Biomarkers of apoptosis

Within the era of molecularly targeted anticancer agents, it has become increasingly important to provide proof of mechanism as early on as possible in the drug development cycle, especially in the clinic. Selective activation of apoptosis is often cited as one of the major goals of cancer chemotherapy. Thus, the present minireview focuses on a discussion of the pros and cons of a variety of methodological approaches to detect different components of the apoptotic cascade as potential biomarkers of programmed cell death. The bulk of the discussion centres on serological assays utilising the technique of ELISA, since here there is an obvious advantage of sampling multiple time points. Potential biomarkers of apoptosis including circulating tumour cells, cytokeratins and DNA nucleosomes are discussed at length. However, accepting that a single biomarker may not have the power to predict proof of concept and patient outcome, it is clear that in the future more emphasis will be placed on technologies that can analyse panels of biomarkers in small volumes of samples. To this end the increased throughput afforded by multiplex ELISA technologies is discussed

Discrepancy between radiological and pathological size of renal masses

<p>Abstract</p> <p>Background</p> <p>Tumor size is a critical variable in staging for renal cell carcinoma. Clinicians rely on radiological estimates of pathological tumor size to guide patient counseling regarding prognosis, choice of treatment strategy and entry into clinical trials. If there is a discrepancy between radiological and pathological measurements of renal tumor size, this could have implications for clinical practice. Our study aimed to compare the radiological size of solid renal tumors on computed tomography (CT) to the pathological size in an Australian population.</p> <p>Methods</p> <p>We identified 157 patients in the Westmead Renal Tumor Database, for whom data was available for both radiological tumor size on CT and pathological tumor size. The paired Student's <it>t</it>-test was used to compare the mean radiological tumor size and the mean pathological tumor size. Statistical significance was defined as <it>P </it>< 0.05. We also identified all cases in which post-operative down-staging or up-staging occurred due to discrepancy between radiological and pathological tumor sizes. Additionally, we examined the relationship between Fuhrman grade and radiological tumor size and pathological T stage.</p> <p>Results</p> <p>Overall, the mean radiological tumor size on CT was 58.3 mm and the mean pathological size was 55.2 mm. On average, CT overestimated pathological size by 3.1 mm (<it>P </it>= 0.012). CT overestimated pathological tumor size in 92 (58.6%) patients, underestimated in 44 (28.0%) patients and equaled pathological size in 21 (31.4%) patients. Among the 122 patients with pT1 or pT2 tumors, there was a discrepancy between clinical and pathological staging in 35 (29%) patients. Of these, 21 (17%) patients were down-staged post-operatively and 14 (11.5%) were up-staged. Fuhrman grade correlated positively with radiological tumor size (<it>P </it>= 0.039) and pathological tumor stage (<it>P </it>= 0.003).</p> <p>Conclusions</p> <p>There was a statistically significant but small difference (3.1 mm) between mean radiological and mean pathological tumor size, but this is of uncertain clinical significance. For some patients, the difference leads to a discrepancy between clinical and pathological staging, which may have implications for pre-operative patient counseling regarding prognosis and management.</p

A relevant in vitro rat model for the evaluation of blood-brain barrier translocation of nanoparticles

Poly(MePEG2000cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their capacity to reach the rat central nervous system after intravenous injection. For insight into the transport of colloidal systems across the blood-brain barrier (BBB), we developed a relevant in vitro rat BBB model consisting of a coculture of rat brain endothelial cells (RBECs) and rat astrocytes. The RBECs used in our model displayed and retained structural characteristics of brain endothelial cells, such as expression of P-glycoprotein, occludin and ZO-1, and immunofluorescence studies showed the specific localization of occludin and ZO1. The high values of transendothelial electrical resistance and low permeability coefficients of marker molecules demonstrated the functionality of this model. The comparative passage of polyhexadecylcyanoacrylate and PEG-PHDCA nanoparticles through this model was investigated, showing a higher passage of PEGylated nanoparticles, presumably by endocytosis. This result was confirmed by confocal microscopy. Thanks to a good in vitro/in vivo correlation, this rat BBB model will help in understanding the mechanisms of nanoparticle translocation and in designing new types of colloidal carriers as brain delivery systems