Stereotactic Body Radiotherapy Versus Metastasectomy in Patients With Pulmonary Metastases From Soft Tissue Sarcoma.

The lung is the preferred site of metastasis from soft tissue sarcoma (STS). This systematic review aims to evaluate the outcomes of stereotactic body radiotherapy (SBRT) and metastasectomy (MTS) for the treatment of lung metastases from STS. A systematic review was carried out according to the PRISMA protocol. PubMed, Medline, EMBASE, Cochrane Library, Ovid and Web of Knowledge databases were searched for English-language articles to December 2018 using a predefined strategy. Retrieved studies were independently screened and rated for relevance. Data were extracted by two researchers. In total, there were 1306 patients with STS: 1104 underwent MTS and 202 had SBRT. The mean age ranged from 40 to 55.8 years in the MTS group and from 47.9 to 64 years in the SBRT group. The cumulative death rate was 72% (95% confidence interval 59-85%) in the MTS group and 56% (38-74%) in the SBRT group. The cumulative mean overall survival time was 46.7 months (36.4-57.0%) in the MTS group and 47.6 months (33.7-61.5%) in the SBRT group. The cumulative rate of patients alive with disease was 5% (2-9%) in the MTS group and 15% (6-36%) in the SBRT group. Finally, the cumulative rate of patients alive without disease in the two groups was 19% (9-29%) and 20% (10-50%), respectively. Our study showed that local treatment of pulmonary metastases from STS with SBRT, compared with surgery, was associated with a lower cumulative overall death rate and similar overall survival time and survival rates without disease. By contrast, SBRT was associated with a higher survival rate with disease than MTS. Large randomised trials are necessary to confirm these findings and to establish whether SBRT may be a reliable option for early stage disease.

The Dose Response Multicentre Investigation on Fluid Assessment (DoReMIFA) in critically ill patients.

BACKGROUND: The previously published "Dose Response Multicentre International Collaborative Initiative (DoReMi)" study concluded that the high mortality of critically ill patients with acute kidney injury (AKI) was unlikely to be related to an inadequate dose of renal replacement therapy (RRT) and other factors were contributing. This follow-up study aimed to investigate the impact of daily fluid balance and fluid accumulation on mortality of critically ill patients without AKI (N-AKI), with AKI (AKI) and with AKI on RRT (AKI-RRT) receiving an adequate dose of RRT. METHODS: We prospectively enrolled all consecutive patients admitted to 21 intensive care units (ICUs) from nine countries and collected baseline characteristics, comorbidities, severity of illness, presence of sepsis, daily physiologic parameters and fluid intake-output, AKI stage, need for RRT and survival status. Daily fluid balance was computed and fluid overload (FO) was defined as percentage of admission body weight (BW). Maximum fluid overload (MFO) was the peak value of FO. RESULTS: We analysed 1734 patients. A total of 991 (57 %) had N-AKI, 560 (32 %) had AKI but did not have RRT and 183 (11 %) had AKI-RRT. ICU mortality was 22.3 % in AKI patients and 5.6 % in those without AKI (p < 0.0001). Progressive fluid accumulation was seen in all three groups. Maximum fluid accumulation occurred on day 2 in N-AKI patients (2.8 % of BW), on day 3 in AKI patients not receiving RRT (4.3 % of BW) and on day 5 in AKI-RRT patients (7.9 % of BW). The main findings were: (1) the odds ratio (OR) for hospital mortality increased by 1.075 (95 % confidence interval 1.055-1.095) with every 1 % increase of MFO. When adjusting for severity of illness and AKI status, the OR changed to 1.044. This phenomenon was a continuum and independent of thresholds as previously reported. (2) Multivariate analysis confirmed that the speed of fluid accumulation was independently associated with ICU mortality. (3) Fluid accumulation increased significantly in the 3-day period prior to the diagnosis of AKI and peaked 3 days later. CONCLUSIONS: In critically ill patients, the severity and speed of fluid accumulation are independent risk factors for ICU mortality. Fluid balance abnormality precedes and follows the diagnosis of AKI.

Cumulative iron dose and resistance to erythropoietin.

INTRODUCTION: Optimizing anemia treatment in hemodialysis (HD) patients remains a priority worldwide as it has significant health and financial implications. Our aim was to evaluate in a large cohort of chronic HD patients in Fresenius Medical Care centers in Spain the value of cumulative iron (Fe) dose monitoring for the management of iron therapy in erythropoiesis-stimulating agent (ESA)-treated patients, and the relationship between cumulative iron dose and risk of hospitalization. METHODS: Demographic, clinical and laboratory parameters from EuCliD(®) (European Clinical Dialysis Database) on 3,591 patients were recorded including ESA dose (UI/kg/week), erythropoietin resistance index (ERI) [U.I weekly/kg/gr hemoglobin (Hb)] and hospitalizations. Moreover the cumulative Fe dose (mg/kg of bodyweight) administered over the last 2 years was calculated. Univariate and multivariate analyses were performed to identify the main predictors of ESA resistance and risk of hospitalization. Patients belonging to the 4th quartile of ERI were defined as hypo-responders. RESULTS: The 2-year iron cumulative dose was significantly higher in the 4th quartile of ERI. In hypo-responders, 2-year cumulative iron dose was the only iron marker associated with ESA resistance. At case-mix adjusted multivariate analysis, 2-year iron cumulative dose was an independent predictor of hospitalization risk. DISCUSSION: In ESA-treated patients cumulative Fe dose could be a useful tool to monitor the appropriateness of Fe therapy and to prevent iron overload. To establish whether the associations between cumulative iron dose, ERI and hospitalization risk are causal or attributable to selection bias by indication, clinical trials are necessary.

Role of Lefty in the anti tumor activity of human adult liver stem cells.

Recent studies demonstrated that factors derived from embryonic stem cells inhibit the tumorigenicity of a variety of cancer cell lines. Embryonic stem cell-secreted Lefty, an inhibitor of Nodal-signalling pathway, was implicated in reprogramming cancer cells. Whether adult stem cells exhibited similar properties has not been explored. The aim of the present study was to investigate whether the conditioned medium (CM) derived from adult stem cells influence in vitro and in vivo tumor growth by a Nodal-dependent pathway. In particular we compared the anti-tumor effect of CM from human liver stem cells (HLSC) with that of bone marrow-derived mesenchymal stem cells (MSC). We found that HLSC-CM inhibited the in vitro growth and promoted apoptosis in HepG2 cells that expressed a deregulated Nodal pathway. The effect of HLSC-CM was related to the presence of Lefty A in the CM of HLSC. Silencing Lefty A in HLSC or Lefty A blockade with a blocking peptide abrogated the anti-proliferative and pro-apoptotic effect of HLSC-CM. Moreover, the administration of human recombinant Lefty A protein mimicked the effect of HLSC-CM indicating that Nodal pathway is critical for the growth of HepG2. At variance of HLSC, bone marrow-derived MSC did not express and release Lefty A and the MSC-CM did not exhibited an anti-tumor activity in vitro, but rather stimulated proliferation of HepG2. In addition, the intra-tumor administration of HLSC-CM was able to inhibit the in vivo growth of HepG2 hepatoma cells implanted subcutaneously in SCID mice. At variance, HLSC-CM derived from Lefty A silenced HLSC was unable to inhibit tumor growth. In conclusion, the results of present study suggest that Lefty A may account for the tumor suppressive activity of HLSC as a result of an inhibition of the Nodal-signalling pathway by a mechanism similar to that described for embryonic stem cells.

Tumor-derived microvesicles and the cancer microenvironment.

Tumor cells release microvesicles (MVs) that may remain in the extracellular space in proximity to the cell of origin, or that may migrate to distant sites by entering biological fluids. Increasing evidence indicates that MVs are mediators of cell-to-cell communication which are able to deliver specific signals, both within the tumor microenvironment and in the long-range. MVs are able to transfer bioactive lipids and proteins, including oncogene products and receptors, from the cell of origin to recipient cell. In addition, MVs may induce epigenetic changes in recipient cells by transferring genetic information in the form of mRNA, microRNA and oncogenes. Several changes in the phenotype and function that occur in stromal cells within the cancer microenvironment have been ascribed to tumor cell-derived MVs. In this review we discuss the various biological actions of tumor-derived MVs and their potential role in tumor biology.

Endothelial progenitor cell-derived microvesicles improve neovascularization in a murine model of hindlimb ischemia.

Paracrine mediators released from endothelial progenitor cells (EPCs) have been implicated in neoangiogenesis following ischemia. Recently, we demonstrated that microvesicles (MVs) derived from EPCs are able to activate an angiogenic program in quiescent endothelial cells by a horizontal transfer of RNA. In this study we aim to investigate whether EPC-derived MVs are able to induce neoangiogenesis and to enhance recovery in a murine model of hindlimb ischemia. Hindlimb ischemia was induced in severe combined immunodeficient (SCID) mice by ligation and resection of the left femoral artery and mice were treated with EPC-derived MVs (MVs), RNase-inactivated MVs (RnaseMVs), fibroblast-derived MVs or vehicle alone as control (CTL). Since MVs contained the angiogenic miR-126 and miR-296, we evaluated whether microRNAs may account for the angiogenic activities by treating mice with MVs obtained from DICER-knock-down EPC (DICER-MVs). The limb perfusion evaluated by laserdoppler analysis demonstrated that MVs significantly enhanced perfusion in respect to CTL (0.50±0.08 vs 0.39±0.03, p<0.05). After 7 days, immunohistochemical analyses on the gastrocnemius muscle of the ischemic hindlimb showed that MVs but not fibroblast-MVs significantly increased the capillary density in respect to CTL (MVs vs CTL: 24.7±10.3 vs 13.5±6, p<0.0001) and (fibroblast-MVs vs CTL: 10.2±3.4 vs 13.5±6, ns); RNaseMVs and DICER-MVs significantly reduced the effect of MVs (RNaseMVs vs CTL: 15.7±4.1 vs 13.5±6, ns) (MVs vs DICER-MVs 24.7±10.3 vs 18.1±5.8, p <0.05), suggesting a role of RNAs shuttled by MVs. Morphometric analysis confirmed that MVs enhanced limb perfusion and reduced injury. The results of the present study indicate that treatment with EPC-derived MVs improves neovascularization and favors regeneration in severe hindlimb ischemia induced in SCID mice. This suggests a possible use of EPCs-derived MVs for treatment of peripheral arterial disease.

Body composition and heart rate variability to achieve dry weight and tolerance.

Autonomic dysfunction in patients with end- stage renal disease is associated with poor prognosis. Heart rate variability (HRV), determined by the standard deviation of the normal R- R interval, has been reported to be a useful evaluation of cardiac autonomic modulation. The relationship between HRV and hydration status (HS) can be analyzed by whole body bioimpedance spectroscopy. This allows a classification of patients according the combination of HS with predialysis systolic blood pressure. Differences in HRV can be studied in patients with high over hydration, but normal or low blood pressure, with respect to fluid-overloaded/hypertensive patients and normohydrated/normotensive patients. In conclusion, the assessment of the autonomic nervous system response to the hemodialysis treatment in end- stage renal disease patients, classified according to a reliable and quantitative measurement of their fluid overload, could permit better management of both arterial blood pressure and HS.

Second-generation autologous chondrocyte transplantation: MRI findings and clinical correlations at a minimum 5-year follow-up.

OBJECTIVE: To evaluate the clinical outcome of hyaluronan-based arthroscopic autologous chondrocyte transplantation at a minimum of 5 years of follow-up and to correlate it with the MRI evaluation parameters. METHODS: Fifty consecutive patients were included in the study and evaluated clinically using the Cartilage Standard Evaluation Form as proposed by ICRS and the Tegner score. Forty lesions underwent MRI evaluation at a minimum 5-year follow-up. For the description and evaluation of the graft, we employed the MOCART-scoring system. RESULTS: A statistically significant improvement in all clinical scores was observed at 2 and over 5 years. The total MOCART score and the signal intensity (3D-GE-FS) of the repair tissue were statistically correlated to the IKDC subjective evaluation. Larger size of the treated cartilage lesions had a negative influence on the degree of defect repair and filling, the integration to the border zone and the subchondral lamina integrity, whereas more intensive sport activity had a positive influence on the signal intensity of the repair tissue, the repair tissue surface, and the clinical outcome. CONCLUSION: Our findings confirm the durability of the clinical results obtained with Hyalograft C and the usefulness of MRI as a non-invasive method for the evaluation of the repaired tissue and the outcome after second-generation autologous transplantation over time.

Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats.

Several studies indicate that adult stem cells may improve the recovery from acute tissue injury. It has been suggested that they may contribute to tissue regeneration by the release of paracrine factors promoting proliferation of tissue resident cells. However, the factors involved remain unknown. In the present study we found that microvesicles (MVs) derived from human liver stem cells (HLSC) induced in vitro proliferation and apoptosis resistance of human and rat hepatocytes. These effects required internalization of MVs in the hepatocytes by an alpha(4)-integrin-dependent mechanism. However, MVs pre-treated with RNase, even if internalized, were unable to induce hepatocyte proliferation and apoptosis resistance, suggesting an RNA-dependent effect. Microarray analysis and quantitative RT-PCR demonstrated that MVs were shuttling a specific subset of cellular mRNA, such as mRNA associated in the control of transcription, translation, proliferation and apoptosis. When administered in vivo, MVs accelerated the morphological and functional recovery of liver in a model of 70% hepatectomy in rats. This effect was associated with increase in hepatocyte proliferation and was abolished by RNase pre-treatment of MVs. Using human AGO2, as a reporter gene present in MVs, we found the expression of human AGO2 mRNA and protein in the liver of hepatectomized rats treated with MVs. These data suggested a translation of the MV shuttled mRNA into hepatocytes of treated rats. In conclusion, these results suggest that MVs derived from HLSC may activate a proliferative program in remnant hepatocytes after hepatectomy by a horizontal transfer of specific mRNA subsets.

The epidemiology of cardiac surgery-associated acute kidney injury.

PURPOSE: To describe current knowledge on the epidemiology of cardiac surgery-associated acute kidney injury (CSA-AKI) and to formulate recommendations for clinical practice and a research agenda. METHODS: After a modified Delphi analysis by the Acute Dialysis Quality Initiative (ADQI), 4 questions on the epidemiology of CSA-AKI and recommendations for clinical practice and a research agenda were formulated and addressed. RESULTS: Existing studies on CSA-AKI use over 35 different definitions for CSA-AKI. In addition, there may be important differences in patient characteristics and procedures. This explains the significant variations in reported incidence. Most studies report on CSA-AKI as defined by the need for renal replacement therapy. However, even small decreases in kidney function are associated with a worsened outcome. The workgroup formulated the recommendation to use the AKIN consensus criteria for AKI. One should differentiate early CSA-AKI, caused by the procedure, and late CSA-AKI, associated with the procedure. There may be different clinical scenarios: acute on chronic CSA-AKI, AKI prior to CS, and AKI occurring post CS. Risk factors should be differentiated between pre-, intra-, and post-CS, and between patient-, process-, and procedure-related. Endpoints should include both short-term and long-term outcomes. CONCLUSIONS: Existing data on the epidemiology of CSA-AKI are difficult to compare due to variations in definition and patient cohort. A modified Delphi analysis resulted in a series of recommendations for future research on CSA-AKI.

Prometheus: from legend to the real liver support therapy.

BACKGROUND: A large number of patients develop liver disease that may evolve into progressive chronic failure. Artificial liver support systems (e.g., MARS and Prometheus) are considered in the framework of the steady increase in the number of patients who could possibly benefit from these blood purification devices. Albumin dialysis and adsorption are now two integrated concepts. The present know-how enabling us to appropriately modify several intrinsic characteristics of the adsorbents--e.g., their chemical nature, the particle and pore size distribution, as well as a larger surface offered to adsorption--has helped in better fine-tuning liver support systems to improve adsorption kinetics and flow characteristics specifically for the intended clinical application. These properties together with an improved biocompatibility have made possible the development of adsorptive techniques for which clearances and total removal rates of target compound would be unthinkable with conventional hemodialysis or hemofiltration. Several adsorptive techniques are already available commercially for the treatment of sepsis and septic shock and of acute liver failure, but controlled studies with clinical end points are still lacking.

Online clearance measurement in high-efficiency hemodiafiltration.

The measurement of ionic dialysance by conductivity variation is an established method in diffusive hemodialysis. To extend the validity of this method for use in highly convective therapies, such as online hemodiafiltration, we derived a new model for the measurement of ionic dialysance. This method was validated in a study involving 12 patients on pre- and postdilution online hemodiafiltration under various conditions. Clinically, there was a very good agreement between the dialysance determined by conductivity variation and blood side urea clearance. Neither the dilution modes nor the flow rate of the substitution fluid was found to significantly influence this agreement. Our results show that ionic dialysance can be easily and precisely measured by conductivity variation, and this provides an excellent surrogate for urea clearance even in highly convective therapies.

The biological response to online hemodiafiltration.

The biologic response to uremia and to the associated chronic inflammation is an active area of research. Among the different modalities developed in the technology field of chronic renal replacement, hemodialfiltration has evolved consistently. On-line production of substitution fluid by 'cold sterilization' of dialysis fluid by ultrafiltration gives access to virtually an unlimited amount of sterile and non-pyrogenic intravenous grade solution. Today, on line HDF is already a widespread, accepted treatment. Here, we will review the main mechanisms through which on line hemodialfiltration acts and the biological response observed in relation to the immune system dysfunction and the anemia associated to chronic kidney disease.

Microinflammation induces endothelial damage in hemodialysis patients: the role of convective transport.

Cardiovascular complications are a major cause of mortality in hemodialysis patients. On-line hemofiltration combines convective clearance for removing large solutes with diffusion to remove small solutes and is associated with a significant reduction of inflammation and improved patient survival. We compared on-line hemofiltration to high-flux hemodialysis (HF-HD) in patients in a sequential manner. At baseline, 15 stable patients on HF-HD as compared with five control subjects showed significant increases in CD14+CD16+ cells, endothelial microparticles, and endothelial progenitor cells (EPCs). After 4 months of on-line hemofiltration, the number of CD14+CD16+ cells, microparticles, and EPCs decreased. After returning to HF-HD for 4 months, all measured parameters returned to their respective baseline values. The number of CD14+CD16+ cells correlated with both endothelial microparticles and EPCs. We conclude that on-line hemofiltration attenuates endothelial dysfunction possibly by decreasing microinflammation. This effect may be directly caused by a modulatory effect of on-line hemofiltration on proinflammatory cells or by a complex interaction that encompasses a wider removal of uremic toxins.

Pulmonary nodules in osteosarcoma patients: differential diagnosis of central venous catheter-related infections in the lungs.

PURPOSE: The purpose of this study was to evaluate the differential diagnosis of pulmonary nodules by conventional radiography and computed tomography (CT) in osteosarcoma patients with central venous catheter. MATERIALS AND METHODS: Between March 1997 and December 2001 at our Department of Musculoskeletal Oncology, 231 patients with peripheral osteosarcoma received a central venous catheter to allow infusion therapy and blood sampling. The mean age of these patients was 16 years (range 4-63), and 90 were aged 15 years or younger. All patients underwent radiological investigation for tumour staging and comparison with the following study in accordance with the protocol in place at our Department of Oncology and Division of Diagnostic Imaging. RESULTS: Of a total of 231 patients, 13 (5.6%) developed an infection of the central venous line, with fever that was very high in some cases. In ten cases (4.3%), radiology showed damage to the alveolar interstitium typical of inflammatory forms, whereas in the remaining three (1.3%) it depicted nodular opacities, which required differentiation between lung metastases and septic emboli. After appropriate antibiotic and replacement of the central venous line, CT demonstrated disappearance of the lung nodules in all three patients, enabling a diagnosis of nodular septic embolism. CONCLUSIONS: Placement of a central venous catheter for infusion therapy, chemotherapy and blood sampling has improved the quality of life of cancer patients. The most common complications of the use of central venous catheters include infection and venous thrombosis whereas pulmonary septic emboli are rare.

Recent insights into the pathogenesis of severe sepsis.

OBJECTIVE: Severe sepsis remains the dominant challenge in the care of critically ill patients. Over the last 10 years a large body of research has modified our understanding of this condition. In this article, we review the evolution of our understanding of the molecular mechanisms responsible for the development of this clinical syndrome. DATA SOURCES: The authors undertook a critical review of the literature on the molecular basis of the pathogenesis of sepsis with particular emphasis on the role of cytokines, toll-like receptors, adhesion molecules, coagulation cascade molecules and the possible role of in-vitro experimental models of blood-endothelium interaction. SUMMARY OF REVIEW: Recent insights into the molecular mechanisms responsible for the pathogenesis of the severe sepsis syndrome suggest that pro- and anti- inflammatory pathways are simultaneously activated and interact in a dynamic way. Pro-inflammatory cytokines previously considered as targets for intervention have typically been already activated and de-activated by the time the clinical diagnosis is made and intervention is possible. Cellular activity involving white cell-endothelial interactions occur later, making them a more attractive option for therapeutic intervention. Immunological incompetence rather than over-activity may be the most common state of cell function in critically ill patients. CONCLUSIONS: Our understanding of the the pathogenesis of severe sepsis continues to grow. Expression of membrane surface molecules such as toll-like receptors, adhesion molecules and cytokine receptors induce a high degree of redundancy and amplification. Cell responsiveness is reduced in an attempt to circumvent the amplification loop. However, the ensuing interaction between the host and the pathogen(s) may lead to an immune deficiency, leaving the field open to further invasion by the original bacteria or to superimposed infection agents. Endothelium-white cell interactions might be an appropriate target for future interventions.

Extracorporeal treatments in sepsis: are there new perspectives?

Sepsis continues to provide a major challenge to clinicians. Despite vast advancements achieved in the understanding of its pathways and mechanisms, the incidence of sepsis is increasing and the mortality and morbidity rates remain high, generating a considerable burden to health budgets worldwide. Unfortunately, no definitive therapy yet exists that can successfully treat sepsis and its complications. At variance with targeting single mediators, therapeutic intervention aimed at the non-selective removal of pro- and anti-inflammatory mediators seems a rational concept and a possible key to successful extra-corporeal therapies. A further advantage may lie in the continuous nature of such therapy. With such continuous therapy, sequentially appearing peaks of systemic mediator overflow may be attenuated and persistently high plasma levels reduced. This theoretical framework is proposed as the underlying biological rationale for a series of innovative modalities in sepsis. In this editorial, we will review recent animal and human trials which lend support to this concept. We will also review the importance of treatment dose during continuous renal replacement therapy as a major factor affecting survival in critically ill patients with acute renal failure. We will also review novel information related to other blood purification techniques using largo pore membranes or plasma filtration with adsorbent perfusion. Although these approaches are still in the early stages of clinical testing, they are conceptually promising and might represent an important advance.

[Treatment of septic shock with the use of CPFA (associated plasma filtration and adsorption): impact on hemodynamics monitored with PiCCO ]. / Trattamento dello shock settico con l'impiego della CPFA (plasmafiltrazione e adsorbimento associate): impatto sull'emodinamica valutata con sistema PiCCO

BACKGROUND: Septic shock represents an emerging pathology and sepsis and its complications are the main cause of death in medical and surgical intensive care units. Single-target therapeutic trials failed to demonstrate any benefit, suggesting that the unselective removal of different mediators may be a more appropriate approach. METHODS: We evaluated a new technique (CPFA) combining a plasma-adsorption (with plasma filter and sorbent cartridge) with a traditional 'slow' extracorporeal treatment on 10 patients, 7 men and 3 women (mean age 53.8+/-16.3), all on mechanical ventilation, with septic shock and multiorgan failure. To identify easily comparable clinical data, the hemodynamic parameters of the patients were monitored with a recently developed, minimally invasive technology, Pulsion PiCCO . RESULTS: We obtained significant improvement of pre- versus post-treatment mean arterial pressure 77.2+/-12.5 vs. 83.3+/-14.1 mmHg (p<0.0001), cardiac index 4.03+/-0.89 vs. 3.46+/-0.82 L/m2/min (p<0.0001), indexed systemic vascular resistances 1388+/-496 vs. 1753+/-516 dynes x sec/cm5 (p<0.0001), PaO2/FiO2 ratio 204+/-87 vs. 232+/-81 (p<0.0001), and norepinephrine requirements 0.13+/-0.07 vs. 0 y/kg/min after a mean of 5.3+/-2.7 consecutive treatments. The survival at day 28 was 90%. Seven patients were discharged from the intensive care unit after a mean of 37.8+/-24 days (range 10-93). CONCLUSIONS: Our data suggest a promising role for CPFA in improving hemodynamics and correcting vasoparalysis in septic shock. Moreover, the noninvasive monitoring of hemodynamic parameters with PiCCO could become a useful tool for estimating the effect of treatment and gaining easily comparable data in different patients.