Implementation Of New Therapies Research Articles

Treatment and survival of Merkel cell carcinoma since 1993: A population-based cohort study in The Netherlands

Merkel cell carcinoma (MCC) is a rare and potentially lethal skin cancer. MCC is known for its potential rapid growth and its propensity to metastasize. To describe the incidence, treatment, and survival of MCC in a population-based setting. All MCCs diagnosed in The Netherlands between 1993 and 2016 were selected from the Netherlands Cancer Registry. Patient and tumor characteristics, therapy, and vital status were obtained. Cox proportional hazards were computed, and relative survival analyses were performed. Our cohort included 1977 patients with MCC. Incidence increased from 0.17 per 100,000 person-years in 1993 to 0.59 per 100,000 in 2016. The mean age at diagnosis was 75.5. Most MCCs (59.8%) were treated with surgery alone. Relative 5-year survival was low (63.0%) and did not improve. Mortality was higher among males (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.11-1.39), higher age (HR, 1.07; 95% CI, 1.06-1.07), and nodal (HR, 1.26; 95% CI, 1.08-1.48) and distant spread of disease (HR, 2.44; 95% CI, 1.99-2.99). We lacked data on cause of death, comorbidity, and pathologic margins, which may have led to misinterpretation of the data. This study shows continuously increasing incidence rates of MCC in The Netherlands. Survival after a diagnosis of MCC remained low. Our results emphasize the need for implementation of new therapies.

Neonatal hypertension: cases, causes, and clinical approach

Neonatal hypertension is increasingly recognized as dramatic improvements in neonatal intensive care, advancements in our understanding of neonatal physiology, and implementation of new therapies have led to improved survival of premature infants. A variety of factors appear to be important in determining blood pressure in neonates, including gestational age, birth weight, and postmenstrual age. Normative data on neonatal blood pressure values remain limited. The cause of hypertension in an affected neonate is often identified with careful diagnostic evaluation, with the most common causes being umbilical catheter-associated thrombosis, renal parenchymal disease, and chronic lung disease. Clinical expertise may need to be relied upon to decide the best approach to treatment in such patients, as data on the use of antihypertensive medications in this age group are extremely limited. Available data suggest that long-term outcomes are usually good, with resolution of hypertension in most infants. In this review, we will take a case-based approach to illustrate these concepts and to point out important evidence gaps that need to be addressed so that management of neonatal hypertension may be improved.

A Functional Approach to Precision Medicine Identifies Targeted Therapies for Acute Myeloid Leukemia

Identification of genetic heterogeneity in acute myeloid leukemia (AML) has provided a unique opportunity for the greater individualization of therapy. However the implementation of new therapies has lagged far behind the ability to initially recognize operationally important genetic lesions. Until we have further bridged this gap between the identification of genetic lesions and the resultant knowledge of effective therapies, alternative strategies for rapidly identifying candidate therapies can become an important tool for precision medicine. Since most agents, regardless of whether “cytotoxic” or “targeted” ultimately function by activating the mitochondrial apoptotic pathway, we hypothesized that a tool that measures mitochondrial sensitivity may serve as a broadly predictable biomarker. We developed a dynamic BH3 profiling (DBP) technique that measures early death signaling within 8-16 hours after exposure to drugs. Increased cell death signaling is reflected by increased mitochondrial sensitivity (i.e. increased priming) to standardized BH3 peptides mimicking pro-apoptotic proteins.To develop a personalized therapy for AML using DBP, we utilized 20 independent patient derived xenograft (PDX) models, established from de novo, primary refractory or relapsed (R/R) patients (available at http://www.PRoXe.org). Human myeloblasts from spleen and bone marrow of xenotransplanted NSG mice were exposed to 30 targeted and 3 standard of care drugs to determine mitochondrial responses. Unsupervised hierarchical clustering of ex-vivo DBP measurements across AML PDXs revealed several distinct clusters. Majority of targeted agents with an ability to induce priming in selective PDXs were enriched within a cluster, including kinase inhibitors, epigenetic modifiers, SMAC mimetic and chemotherapy drugs. In contrast, a discrete subcluster of drugs showed sensitivity across majority of PDXs, including BH3 mimetics, CDK9 inhibitors and HDAC inhibitors. Drugs with identical mechanism of action showed similar priming patterns across PDXs. Of note, 3 non-myeloid PDXs clustered distinctly from AML, an indication of differential priming responses owing to their cells of origin. AML PDXs developed from treatment naïve patients clustered adjacently and showed greater priming responses to a large number of drugs as opposed to PDXs from R/R patients that formed a discrete cluster. These data reveal that mitochondrial priming can stratify AML PDXs according to its predicted sensitivity to targeted agents.Next, we validated ability of DBP to predict in-vivo responses of single agent birinapant (SMAC mimetic), JQ-1 (BRD-4 inhibitor), quizartinib (FLT-3 inhibitor), and venetoclax (BCL-2 inhibitor) across 6 AML PDX models, prioritized based on their greatest range of priming responses. We found that birinapant was most efficacious nonetheless as expected from ex-vivo DBP studies, responses varied between different PDX models. Myeloblasts of those PDXs that showed the greatest drug-induced changes in apoptotic priming were indeed the PDXs with the highest in-vivo responses. When we compared the ability of DBP to identify sensitive PDXs with additional precision medicine tools such as genomics, we found that DBP was able to accurately predict quizartinib activity in PDXs expressing WT FLT-3, which would have been predicted to be unresponsive based on genomic analysis. Collectively, priming responses obtained from ex-vivo DBP was able to rank different PDX models according to their sensitivities to targeted agents (AUC of ROC curve 0.8731, p<0.005). To investigate if DBP can predict combination therapies in relapsed settings, we first developed resistant models of single agents and then repeated DBP. Myeloblasts from relapsing clone showed reduced overall mitochondrial priming and lacked acquisition of a new chemical dependency compared to initial clone. This suggests that targeting of pre-existing dependencies might be more crucial than therapy induced dependency for AML.In summary, our findings highlight that mitochondria-based measurements could identifying individualized therapy for a heterogeneous population and may serve as a as a powerful biomarker to identify the best responders to patient therapies. DisclosuresLetai:AbbVie, AstraZeneca, Novartis: Consultancy, Research Funding.

Cytauxzoonosis: Diagnosis and treatment of an emerging disease.

Cytauxzoonosis is a life-threatening hematoprotozoal disease with a rapidly progressive clinical course. Once considered a rare disease only relevant to a small geographic area, it is now recognized in more than about a third of the United States. The geographic range seems likely to increase with expansion of the range of the vector tick. Both disease diagnosis and treatment offer challenges. The acute illness is often recognized by characteristic parasitic cellular inclusions, but illness may occur before parasites can be identified, and parasitic inclusions may persist long after illness has resolved. Also, while infection was once considered nearly uniformly fatal, subclinical infections are now recognized. Disease prognosis has improved for many cats through implementation of new therapies, but some pathogens are resistant to these therapies and death from disease is still common. Currently, prevention strategies are limited to ectoparasite control. Cytauxzoonosis caused by Cytauxzoon felis is limited to the Americas, and is especially problematic in southeastern and south central USA. However, other Cytauxzoon species have been recognized in Europe and Asia. This review is aimed at veterinary practitioners and focuses on the diagnosis and treatment of cytauxzoonosis. Disease management is of crucial importance in endemic regions. Furthermore, the expanding geographic range of infection, and the possibility of parasite identification in chronically infected cats with a travel history, make understanding cytauxzoonosis relevant in non-endemic regions as well. The authors draw on evidence from prospective clinical trials, experimental infections, retrospective clinical studies and case reports, as well as their own personal experience with the diagnosis and treatment of cytauxzoonosis.

A classification of chronic pain for ICD-11.

A classification of chronic pain for ICD-11.

Who does it first? The uptake of medical innovations in the performance of thrombolysis on ischemic stroke patients in Germany: a study based on hospital quality data.

BackgroundSince 2000, systemic thrombolysis has been the only approved curative and causal treatment for acute ischemic stroke. In 2009, the guidelines of the German Society for Neurology were updated and the therapeutic window for performing thrombolysis was extended. The implementation of new therapies is influenced by many factors. We analyzed the factors at the organizational level that influence the implementation of thrombolysis in stroke patients.MethodsThe data published by the majority of German hospitals in their structured quality reports was assessed. We calculated a regression model in order to measure the influence of hospital/department-level characteristics (e.g., teaching status, ownership, location, and number of hospital beds) on the implementation of thrombolysis in 2006 (this is the earliest point in time that can be analyzed on this data basis). In order to measure the effect of the guideline update in 2009 on the thrombolysis rate (TR) change between 2008 and 2010, we performed a Wilcoxon signed-rank test and utilized a regression model.ResultsIn 2006, 61.5% of a total of 286 neurology departments performed systemic thrombolysis to treat ischemic strokes. The influencing factors for the use of systemic thrombolysis in 2006 were the existence of a stroke unit (+) and a hospital size of between 500 and 1,000 beds (−). A significant increase of the mean departmental TR (thrombolysis rate) from 6.7% to 9.2% between 2008 and 2010 was observed after the guideline update in 2009. For the departments performing thrombolysis in 2008 and 2010, our analysis could not show any additional influencing factors on a structural level that would explain the TR rise during the period 2008–2010.ConclusionsBecause ischemic stroke patients benefit from systemic thrombolysis, it is necessary to examine possible barriers at the organizational level that hinder the implementation. Our data shows that, organizational factors have an influence on the implementation of thrombolysis. However, the recent guideline update resulted in a TR rise that occurred at all hospitals, regardless of the measured structural conditions, as our analysis could not identify any structural factors that might have influenced the TR after the guideline update.

Review of Intermediate Uveitis.

The purpose of this article is to highlight evidence about the medical and surgical management of intermediate uveitis (IU). Updated understandings of the immunopathology of IU were reviewed in this retrospective literature review. Literature selection for this review was based on the PubMed database (National Library of Medicine) and OVID database (Wolters Kluwer). Articles deemed relevant were selected and highlighted. Intermediate uveitis is most often a benign form of uveitis. Since intermediate uveitis has been described in association with different systemic disorders, the initial diagnostic evaluation should serve to exclude masquerade syndromes and infectious diseases in which immunosuppression may be ineffective or contraindicated. Although the pathogenesis of intermediate uveitis is not fully understood, identification of proinflammatory molecules involved in the IU has contributed to the development and implementation of new therapies. Studies about the use of various immunosuppressants, biological agents and surgical treatment on IU have provided more evidence for managing IU. Nevertheless, corticosteroids remain the mainstay of treatment. The treatment options of intermediate uveitis are evolving, with the development of various immunosuppressants and biological agents. The management of intermediate uveitis should be tailored individually, based on specific causes of the disease and associated complications.

FACS Analysis of Stat3/5 Signaling Reveals Ligand Sensitivity As a Significant Prognostic Factor in Pediatric AML: A Children's Oncology Group Report

Abstract 938Pediatric acute myeloid leukemia (AML) remains a devastating disease with a relapse rate near 50%. Kinase inhibitors are being incorporated into treatments, yet the signaling abnormalities targeted by these drugs remain poorly understood. Pathways involving Stat3 and Stat5 are known to be aberrantly active in AML, and increased activity has been associated with chemoresistant disease and poor outcome. Our hypothesis is that analysis of Stat3/5 activation patterns will delineate signaling abnormalities, and thereby guide the development of targeted therapies. We performed FACS analysis of the Stat3/5 signaling pathways in 140 diagnostic bone marrow samples from patients on the AML study CCG 2961. After thawing, cells were rested in serum-free medium for 2 hr. We measured tyrosine-phosphorylated Stat3 (pY-Stat3), serine-phosphorylated Stat3 (pS-Stat3) and pY-Stat5 in unstimulated cells, cells stimulated with low (1 ng/ml), intermediate (10 ng/ml), or high (100 ng/ml) dose G-CSF, and cells stimulated with low (0.5 + 1), intermediate (5 + 10), or high (50 + 100) dose IL-6 + soluble IL-6 receptor alpha. Constitutively phosphorylated proteins were quantified as the percent of events in the positive gate in unstimulated cells. Constitutive pY-Stat3 and pY-Stat5 were found to be common and highly variable. The median percent of pY-Stat3+ events was 37.3% (range 0.1–91.8%); the median %pY-Stat5+ was 18.6% (range 0.5–86.5%). In contrast, pS-Stat3 was generally low (median 3.63%, range 0.1–78.2%). There was non-significant correlation between %pY-Stat3+ and %pY-Stat5+. There was a significant correlation between %pY-Stat3+ and %total Stat3+, with Pearson correlation coefficient R=0.523 (p<0.001). Constitutively activated Src (pY-Src) was generally low (median 4.2%), although there was a population with 20–40 %pY-Src+, which also had high constitutive %pY-Stat3, suggesting that aberrant Src activation may account for high basal pY-Stat3 in some cases. Ligand responses were expressed as the fold increase in mean fluorescence intensity over unstimulated cells (δMFI). There was a strong correlation between pY-Stat3 and pY-Stat5 δMFIs to G-CSF (R=0.91, p<0.001), suggesting overlap of the pathways from G-CSF to each STAT. Likewise, the pY-Stat3 δMFI to G-CSF significantly correlated with the pY-Stat3 δMFI to IL-6 (R=0.343, p<0.001), suggesting convergence of the pathways from each receptor to Stat3. G-CSF receptor expression positively correlated with the GCSF-induced pY-Stat3 δMFI (R=0.396, p<0.001), whereas gp130 (IL-6 receptor) expression negatively correlated with the IL-6-induced pY-Stat3 δMFI (R=-0.262, p<0.005). None of the constitutive or ligand-induced pStat measurements, pY-Src, total Stat3, or receptor expression alone were significant predictors of survival. However, we did identify patterns of ligand sensitivity that predicted outcome. Patients with G-CSF-sensitive AML cells, defined as a pY-Stat3 δMFI > 2 in response to the low or intermediate G-CSF dose (33% of patients in the cohort), had a superior 5 year event-free survival (EFS; 57.8 ± 15% v. 37.2 ± 10%, p=0.025). A similar trend was observed for IL-6 sensitivity (p=0.1). When pY-Stat3 sensitivities to G-CSF and IL-6 were considered together, patients whose blasts were equally sensitive to both ligands had the best 5 yr EFS (69 ± 20%). Patients whose blasts responded to G-CSF only, or were unresponsive to both, had intermediate outcomes (5 yr EFS 38.5 ± 16% and 41.8 ± 14%, respectively). Surprisingly, patients whose blasts responded to IL-6 only had the worst outcome, with a 5 yr EFS of 25 ± 22% (p=0.047). These ligand sensitivity results highlight the importance of understanding not only molecular changes in AML, but also functional aberrancies. For example, cases with low constitutive and ligand-induced Stat3 activation may be resistant to Stat3 pathway inhibitors, whereas cases with high basal pY-Src or aberrant IL-6 sensitivity may be effectively treated with inhibitors of these pathways. In summary, multiparameter FACS analysis of Stat3 and Stat5 activities provides biologic and prognostic insight into the role of signaling aberrancies in AML, and this knowledge will promote rational implementation of new therapies. Disclosures:No relevant conflicts of interest to declare.

The Effects of Insulin, Glucagon, Glutamate, and Glucose Infusion on Blood Glutamate and Plasma Glucose Levels in Naive Rats

Elevated levels of glutamate in brain fluids, in the context of several neurodegenerative conditions, are associated with a worsened neurological outcome. Because there is a clear relationship between brain glutamate levels and glutamate levels in the blood, and an association of the latter with stress, the purpose of this study was to investigate the effects of glucose, insulin, and glucagon on rat blood glutamate levels. Rats received either 1 mL/100 g of rat body weight (BW) intravenous isotonic saline (control), 150 mg/1 mL/100 g BW intravenous glucose, 75 mg/1 mL/100 g BW intravenous glutamate, 50 g/100 g BW intraparitoneal glucagon, or 0.2 UI/100 g BW intraparitoneal insulin. Blood samples were subsequently drawn at 0, 30, 60, 90, and 120 minutes for determination of blood glutamate and glucose levels. We observed a significant decrease in blood glutamate levels at 30 minutes after injection of glucose (P<0.05), at 30 and 60 minutes after injection of insulin (P<0.05), and at 90 and 120 minutes after injection of glucagon. Plasma glucose levels were elevated after infusion of glutamate and glucose but were decreased after injection of insulin. The results of this study demonstrate that glucose, insulin, and glucagon significantly reduce blood glutamate levels. The effect of insulin is immediate and transient, whereas the effect of glucagon is delayed but longer lasting, suggesting that the sensitivity of pancreatic glucagon and insulin-secreting cells to glutamate is dependent on glucose concentration. The results of this study provide insight into blood glutamate homeostasis and may assist in the implementation of new therapies for brain neuroprotection from excess glutamate.

Biweekly cetuximab and irinotecan as second-line therapy in patients with gastro-esophageal cancer previously treated with platinum

Until recently there has been no proven second-line therapy for patients with advanced gastro-esophageal cancer (GEC). Since 2004, Denmark has had a national health program where non-proven therapy can be offered to patients with advanced cancer, after approval by an expert panel appointed by the National Board of Health. This program has accelerated the introduction and implementation of new therapies in Denmark. Inspired by therapy in metastatic colorectal cancer, a combination of cetuximab and irinotecan (Cetiri) was chosen for second-line therapy in GEC patients. We report our experience with Cetiri as second-line therapy in patients with GEC. All patients had histologically confirmed GEC and all patients had progressive disease during or after first-line platinum-containing chemotherapy. The patients received cetuximab 500 mg/m(2) on day 1 and irinotecan 180 mg/m(2) on day 1 every 2nd week until progression or unacceptable toxicity. Toxicity was prospectively evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0. From December 2007 to February 2009, 50 consecutive patients received Cetiri as second-line therapy. Median performance status (PS) was 1. The median number of courses was seven. Seven patients (14%) had a partial response. Median progression-free survival (PFS) was 3.3 months and overall survival (OS) was 5.5 months; two patients are still alive without progressive disease. Major toxicities were: diarrhea (8%), fatigue (10%), neutropenia (16%), and febrile neutropenia (2%). Cetiri every two weeks is a convenient and well-tolerated second-line regimen in GEC patients. A promising effect was seen in patients with PS 0-1 and in patients who developed a rash.

Pesquisa bibliográfica dos sistemas de vigilância em ventilação mecânica: o estado da arte na enfermagem

One is about a bibliographical research that objectified specifically to analyze the production of knowledge with the ventilation mechanics and especial the ventilatórios alarms in the data base National Library of Medicine (MedLine) in the period of 1996 the 2006. The adopted methodology was the virtual search with the describer ventilation alarm (s). The sample was composed for four articles developed in the nursing and anestesiologia area. The analysis of articles was based on the following information: the delineation of the study, the size of the sample, periodic of publication and the association or not of the ventilatórios alarms with the care of nursing. In the anestesiologia, the ventilatórios alarms had been studied as assistant in the implementation of new therapies. In the nursing area the alarms appear under two aspects: the incidence of ventilatórios alarms in units of intensive cares and the influence of the actions of nursing ahead of the alarms. One concludes that the carried through productions are few on as it ahead acts the team of nursing of a ventilatório alarm and its importance in the assistance to the patient under ventilation mechanics.

Biweekly cetuximab and irinotecan as second-line therapy to patients with platinium-resistant gastroesophageal cancer

e15624 Background: There is no established 2nd line therapy for patients (pts) with advanced gastroesophageal (GE) cancer. In 2004, the Danish government initiated a national health programme for pts with advanced cancer. Non- proven therapy may be offered after approval by an expert panel appointed by the National Board of Health that subsequently finances the cost of treatment. This programme has had a major impact on the management of cancer pts in Denmark and has accelerated the introduction and implementation of new therapies. Inspired by the excellent results in colorectal cancer a combination of cetuximab and irinotecan (CetIri) was chosen for platinum-resistant GE cancer. While awaiting approval of a phase II protocol CetIri was offered at a single institution. We report our preliminary experience with biweekly CetIri as 2nd line therapy in pts with GE cancer. Methods: All pts had histologically confirmed GE cancer (adeno- or squamous cell carcinoma) and all pts had previously received first line platinum based therapy. Pts received CetIri (cetuximab 500 mg/m2and irinotecan 180 mg/m2day 1) every 2nd week until progression or unacceptable toxicity. Response rate was evaluated by the investigator according to RECIST every 8th week. Toxicity was prospectively evaluated according to NCIC-CTC 3.0. Results: From December 2007 to August 2008, 31 consecutive pts was treated with CetIri. Median age was 62 years (33–76). Median performance status was 1 (0–2). Localisation of primary was: Esophagus 10%, GE junction 64%, gastric 26%. Twenty-seven pts (87%) had adenocarcimona. Median number of cycles were 6 (1–21). Most important grade 2–4 toxicities were non-haematological toxicity as diarrhea (25%), nausea (21%) and vomiting (11%). Three pts (11%) had grade 3 leukopenia, 1 had febrile neutropenia. Two pts had PR. Median PFS was 3.2 months. Fourteen pts (45%) received at least 6 courses (3 month of therapy). After a median follow-up of 6 month 5 pts continue CetIri without sign of PD. Conclusions: Biweekly CetIri is a convenient and well-tolerated 2nd line regimen in pts with GE cancer. Predictive factors are needed to select which pts will benefit from therapy. A confirmatory phase II study is ongoing. [Table: see text]

Das tripelnegative/basale Mammakarzinom

Das Mammakarzinom wird zunehmend als eine heterogene Gruppe individueller Mammakarzinomsubtypen verstanden. Diese Subgruppen unterscheiden sich sowohl (molekular-)pathologisch als auch klinisch. Der basale/tripelnegative Subtyp zeichnet sich durch eine fehlende Expression des Östrogenrezeptors (estrogen receptor, ER), des Progesteronrezeptors (PR) und des Her-2-Onkoproteins aus. Patientinnen mit einem tripelnegativen Mammakarzinom sind gekennzeichnet durch eine schlechte Prognose trotz einer hohen Ansprechrate gegenüber der systemischen Chemotherapie. Insbesondere Patientinnen, die nach der Primärtherapie ein Rezidiv erleiden, haben eine äußerst schlechte Überlebensprognose, nicht zuletzt aufgrund mangelnder Therapiealternativen. Vor diesem Hintergrund ist die Optimierung bestehender Therapieformen sowie die Entwicklung neuer systemischer Therapien für Patientinnen dieses Mammakarzinomsubtyps von besonderer Wichtigkeit.

When and how should new therapies become routine clinical practice?

The process by which new therapies enter clinical practice is frequently suboptimal. Often, ideas for new therapies are generated by clinical observations or laboratory studies; therapies based on those ideas may enter clinical practice without any further scrutiny. As a consequence, some ineffective practices become widespread. This article proposes a six-stage protocol for the implementation of new therapies. Hypotheses about therapy based on preclinical research should be subject to clinical exploration and pilot studies prior to rigorous assessment with randomised clinical trials. If randomised clinical trials suggest that the intervention produces clinically important effects, further randomised studies can be conducted to refine the intervention. New interventions should not be recommended, or included in teaching curricula, or taught in continuing education courses until their effectiveness has been demonstrated in high-quality randomised clinical trials.

New generation pharmacotherapy in elderly multiple myeloma patients

Background: Observational databases have demonstrated that the overall prognosis of multiple myeloma patients has markedly improved over the past decade, yet the greatest strides have been attained in younger rather than older patients. Objective: To review recent clinical trials that include new generation agents (thalidomide, lenalidomide and bortezomib) and autologous stem cell transplantation in older multiple myeloma patients. Results: Conventional regimens such as melphalan plus prednisone can be improved with the addition of thalidomide or bortezomib: more patients attain complete and near-complete remission, and progression-free survival rates are nearly doubled. In addition, autologous hematopoietic stem cell transplantation studies show that this treatment approach can be used successfully in selected older myeloma patients in whom the toxicity profile of autotransplant and resulting overall survival may be similar to that obtained in the younger patient group. Conclusions: In the advanced-age population, implementation of new therapies results in significant benefits in older as well as younger patients.

Metastatic renal cell carcinoma: Results of a population-based study with 25 years follow-up

Background Renal cell carcinoma (RCC) is the sixth leading cause of death in developed countries. A third of all RCC patients are confronted with metastatic disease. Since their approval in 2005 and 2006 in the USA, new targeted therapies may lead to substantial progress. Thus, the aim of this cohort study was to present clinical characteristics and survival in metastatic RCC in a population-based sample before widespread implementation of these new therapies. Methods Patients (2264) with metastatic RCC registered between 1978 and 2005 in the cancer registry of Munich, Bavaria were analysed. Results Median survival and 5 year relative survival from the 1st metastases were 14.4 months and 21%, respectively. Median survival has slightly improved from 13.2 months in 1978–1987 to 15.6 months since 2002. Conclusion Survival of patients with metastatic RCC did not substantially improve within the last three decades. Assuming that new targeted therapies are successful in the treatment of metastatic RCC, population-based data like these can provide a basis for assessing the progress shown in clinical studies and for surveying critically the future implementation of new therapies in routine care.

The Implementation of New Therapies for Severe Sepsis: Some Questions Raised by “Early Goal‐directed Therapy, Corticosteroid, and Recombinant Human Activated Protein C for the Treatment of Severe Sepsis and Septic Shock in the Emergency Department”

The Implementation of New Therapies for Severe Sepsis: Some Questions Raised by “Early Goal‐directed Therapy, Corticosteroid, and Recombinant Human Activated Protein C for the Treatment of Severe Sepsis and Septic Shock in the Emergency Department”

The Implementation of New Therapies for Severe Sepsis: Some Questions Raised by "Early Goal-directed Therapy, Corticosteroid, and Recombinant Human Activated Protein C for the Treatment of Severe Sepsis and Septic Shock in the Emergency Department"

The Implementation of New Therapies for Severe Sepsis: Some Questions Raised by "Early Goal-directed Therapy, Corticosteroid, and Recombinant Human Activated Protein C for the Treatment of Severe Sepsis and Septic Shock in the Emergency Department"

Trends in der chirurgischen Intensivmedizin

For critically ill medical patients until the year 2000, increases in patient age and severity of disease but also acute prognosis have been described. Since then, further improvement appears possible. Several controlled studies have recently demonstrated that acute mortality may be further lowered by new adjuvant therapies such as aggressive glycemic control. However, it is still unknown whether demographic changes and progress in intensive care can be reproduced in surgical critically ill patients outside of a controlled trial setting. We performed a retrospective, observational cohort study using data prospectively collected from the surgical intensive care unit (ICU) of the LMU Department of Surgery in Munich, Germany, Grosshadern Campus, from March 1 1993 through February 28 2005. Since 1999 we have successively introduced a variety of new therapies to daily routine. A cohort of 5,495 patients was analysed. We identified reduced ICU mortality during the observation period, although age rose simultaneously and disease severity remained constant. Results from multivariate analysis suggest that improvements in prognosis essentially result from the implementation of new therapies after 2001. After adjusting for more than 20 covariables, treatment received after 2001 was identified as an independent factor linked with reduced risk of death. General demographic trends and progress in intensive care can be demonstrated also in unselected surgical cohorts. Furthermore, the results here confirm the efficacy of new therapeutic modifications in routine therapy.

Cost-effectiveness of Mandibular Two-implant Overdentures and Conventional Dentures in the Edentulous Elderly

Implementation of new therapies is usually governed by financial considerations, so efficacy studies should also include cost comparisons. The cost and effectiveness of mandibular conventional dentures (CD, n = 30) and two-implant overdentures (IOD, n = 30) were compared in elderly subjects. Effectiveness (Oral Health Impact Profile, OHIP-20) and cost were measured up to one year post-treatment. Data for subsequent years were estimated by the Delphi method. Using an average life expectancy of 17.9 years, the equalized annual costs (in Canadian dollars) were dollar 399 for CD and dollar 625 for IOD (p < 0.001), and the equalized annual values for the outcome (OHIP-20) were 47.0 for CD and 31.3 for IOD treatment (p < 0.05). These values translate into a yearly additional cost for IOD treatment of dollar 14.41 per OHIP-20 point. These results are key to the implementation of programs to provide this form of therapy for edentulous adults.