598 research outputs found
Clinical and biological effects of interleukin 12 in patients with renal cell carcinoma
Il-12 has a number of immunoregulatory properties indicating its therapeutic
potential against cancer. The encouraging anti-tumor effects, observed in a
variety of animal tumor models, have stimulated the development of Il-12 as a
single agent for systemic cytokine therapy of cancer in humans. Metastatic renal
cell cancer is one of the few human cancers that are more responsive to
immunotherapy than to conventional cytotoxic therapies. Therefore, a phase I
study of Il-12 was performed in patients with advanced renal cell cancer. The
choice of schedule and route of administration were based on experiments in
cynomolgus monkeys. Il-12 in s.c. doses of 0.1 to 1.0 Jlg /kg /day, three times a
week, was shown to modulate immune activity without provoking substantial
toxicity in these animals.
The objective of the study described in chapter 2 was to evaluate the safety
and tolerability of subcutaneous IL-12 in humans and establish the
pharmacokinetic profile. The observation of a non-linear relationship between
dose and drug exposure in animal models formed the rationale to study the
effects of a single and multiple doses of Il-12. In chapter 3 the
immunomodulatory activities of IL-12 in humans are described in detail, with
emphasis on the induction of secondary cytokines and the effects on circulating
leucocyte subset counts. Based on the observation that side effects decreased
upon repeated injections of IL-12, we specifically studied whether or not
immunomodulatory effects were downregulated in the course of multiple IL-12
injections with special attention for the role of the immunosuppressive cytokine
IL-10.
Chapter 4 describes a study of the effect of IL-12 on fibrinolysis and
coagulation in humans. This study was performed because several bleeding
episodes were reported in simultaneously performed clinical studies, whereas
studies in mice and non-human primates had shown that IL-12 induced
activation of coagulation and fibrinolysis.
Il-12 is a strong pro-inflammatory cytokine. Studies in patients and
experimental animals have demonstrated that endogenously produced IL-12
plays an important role in the toxic sequel of sepsis and endotoxemia. In these
situations, excessive activation of various components of the inflammatory
cascade contributes to the development of tissue injury and mortality. In chapter
5 we describe the in-vivo effects of different doses of subcutaneous Il-12 on
components of the inflammatory cascade. We specifically addressed the degranulation of neutrophils and the formation of secretory phospholipase Az, a
regulatory enzyme in the formation of eicosanoids.
The study described in chapter 2 was one of four phase I studies, that were
simultaneously performed in Europe and the US. Subsequent phase II studies in
patients with advanced renal cell cancer and ovarian cancer demonstrated
disappointing anti-tumor effects. The results described in chapter 3, together
with other pharmacodynamic studies, indicate that the lack of efficacy was
accompanied by, and probably related to, declining biological effects of IL-12 in
the course of repeated administrations at doses approaching the maximum
tolerated dose (MTD). Nevertheless, IL-12 remains a promising immunotherapeutic
agent because recent cancer vaccination studies in animal models
and humans have demonstrated its powerful adjuvant properties. Chapter 6
reviews the adjuvant properties of IL-12 and delineates how the immuneregulatory
properties of IL-12 described in the previous chapters may contribute
to the adjuvant effects. In addition, it is discussed how the studies presented in
this paper, together with other clinical studies of systemic IL-12, indicate that IL-
12 may exert optimal adjuvant effects only at low dose levels. Finally, the future
perspectives of IL-12 in the treatment of cancer are addressed
Testing the effects on information use by older versus younger women of modality and narration style in a hospital report card
BACKGROUND: Hospital report cards (HRCs) are usually presented in a textual and factual format, likely hampering information processing. OBJECTIVE: This study aimed to investigate the effects of audiovisual and narrative information in HRCs on user responses, and to test differences between older and younger women. DESIGN: A 2 (modality [textual vs. audiovisual])âĂâ3 (narration style [factual vs. process narrative vs. experience narrative]) online experiment was conducted. Information about breast cancer care was used as a case example. Age (younger [<65] vs. older [â„65]) was included as a potential effect modifier. SETTING AND PARTICIPANTS: A total of 631 diseaseânaĂŻve women (M (age)â=â56.06) completed an online survey. The outcomes were perceived cognitive load, satisfaction, comprehension, information recall and decisional conflict. Data were analysed using AN(C)OVAs. RESULTS: Audiovisual (vs. textual) information resulted in higher information satisfaction across age groups, but was associated with lower comprehension in older women. An experience narrative (vs. factual information) increased satisfaction with attractiveness and emotional support of the information only in older women. A threeâway interaction effect was found, suggesting that older women were most satisfied with the comprehensibility of audiovisual factual or textual process narrative information. Younger women were most satisfied with the comprehensibility of audiovisual process narrative or textual factual information. DISCUSSION AND CONCLUSION: Audiovisual and narrative information in an HRC showed beneficial effects on satisfaction measures. In particular, audiovisual information could be incorporated into HRCs to increase satisfaction with information. PUBLIC CONTRIBUTION: Lay persons helped in optimizing the visuals used in the stimulus materials by checking for clarity
Resilience of Alternative Stable States during the Recovery of Shallow Lakes from Eutrophication: Lake Veluwe as a Case Study
In this paper we analyze a long-term dataset on the recovery from eutrophication of Lake Veluwe (The Netherlands). Clear hysteresis was observed in a number of ecosystem variables: the route to recovery differed significantly from the route that led to loss of clear water. The macrophyte dominated state disappeared in the late 1960s at TP above 0.20mglâ1, whereas its return occurred at less than 0.10mgTPlâ1. Several regime shifts resulting in the occurrence of three alternative stable states were observed over a period of 30years. The turbid state showed resistance to change, despite a strong and prompt reduction in Chl-a following reduction of external P-loading. The most important component that determined hysteresis in the return to clear water was not internal P-loading, but a high level of nonalgal light attenuation (through sediment resuspension) maintained by the interaction between wind and benthivorous fish. Although Chara was able to re-colonize the most shallow parts of the lake, recovery stalled and for a number of years clear (above charophyte beds) and turbid (deeper parts of the lake) water co-existed, as a separate alternative state on route to full recovery. Lake-wide clear water was re-established after bream density had been reduced substantially. This allowed a return of zebra mussels to the lake, whose high filtration capacity helped in maintaining clear water. In this study, we were able to identify the main drivers of hysteresis and regime shifts, although formal demonstration of cause and effect was not possible on the basis of field data alone. We argue that resilience of the present clear water state of Lake Veluwe very much depends on sizable populations of a few keystone species, especially Chara (stoneworts) and Dreissena (zebra mussels), and that careful management of these species is equally important as control of nutrients. Lake management should strive to maintain and strengthen resilience of the ecosystem, and this should offer protection against a renewed collapse of the clear stat
A comparison of treatment allocation and survival between younger and older patients with HER2-overexpressing de novo metastatic breast cancer
Introduction: There have been several developments in the treatment of HER2-overexpressing metastatic breast cancer. However, pivotal trials mainly included younger and healthier patients, resulting in a lack of information about the benefits and harms of treatment for most older patients. The aim of this study was to provide an overview of the differences in treatment allocation and survival outcomes over time between younger and older patients with HER2-overexpressing metastatic breast cancer. Materials and Methods: All patients from the Netherlands Cancer Registry with de novo metastatic breast cancer between 2005 and 2021 were included. Patients were divided into three age groups: <65, 65â74, and â„ 75 years. Changes in treatment allocation were graphically depicted over time. Cox proportional hazard models were used to calculate overall survival and Poisson models for relative survival. Results: Overall, 2,722 patients were included. Between 2005 and 2021, the use of targeted therapy as first-line treatment increased for all age groups (<65 years from 33.8% to 90.6%, p < 0.001; 65â74 years from 29.2% to 86.5%, p = 0.001; â„75 years from 4.3% to 55.8%, p < 0.001). Use of chemotherapy as first-line treatment also increased for all age groups (<65 years from 73.5% to 89.8%, p < 0.001; 65â74 years from 50.0% to 78.4%, p = 0.01; â„75 years from 8.7% to 37.2%, p = 0.04). Although not statistically significant, the use of endocrine therapy, both as monotherapy and in combination with targeted therapy in the first line, decreased (<65 years 19.1% to 5.5%, p < 0.001; 65â74 years 25.0% to 13.5%, p = 0.03; â„75 years 65.2% to 37.2%, p = 0.16). Changes in relative and overall survival were similar and improved in all age groups, but most in the youngest age group (relative excess risk [RER] 0.93, 95% confidence interval [CI] 0.91â0.94 per year, p < 0.001), and least in patients â„75 (RER 0.96, 95% CI 0.93â0.98 per year, p = 0.001). Discussion: The use of first-line chemotherapy and targeted therapy increased in all age groups, while the use of endocrine therapy decreased over time. Nevertheless, the uptake of chemotherapy and targeted therapies was substantially slower in the oldest age group. Overall survival and relative survival improved for all age groups, but these improvements were smaller in the older age groups.</p
Patient Preferences for Treatment Outcomes in Oncology with a Focus on the Older Patient:A Systematic Review
SIMPLE SUMMARY: In oncology, treatment outcomes can be competing, which means that one treatment could benefit one outcome, like survival, and negatively influence another, like independence. The choice of treatment therefore depends on the patientâs preference for outcomes, which needs to be assessed explicitly. Especially in older patients, patient preferences are important. Our systematic review summarizes all studies that assessed patient preferences for various treatment outcome categories. A total of 28 studies with 4374 patients were included, of which only six studies included mostly older patients. Although quality of life was only included in half of the studies, overall quality of life (79%) was most frequently prioritized as highest or second highest, followed by overall survival (67%), progression- and disease-free survival (56%), absence of severe or persistent treatment side effects (54%), treatment response (50%), and absence of transient short-term side effects (16%). In shared decision-making, these results can be used by healthcare professionals to better tailor the information provision and treatment recommendations to the individual patient. ABSTRACT: For physicians, it is important to know which treatment outcomes are prioritized overall by older patients with cancer, since this will help them to tailor the amount of information and treatment recommendations. Older patients might prioritize other outcomes than younger patients. Our objective is to summarize which outcomes matter most to older patients with cancer. A systematic review was conducted, in which we searched Embase and Medline on 22 December 2020. Studies were eligible if they reported some form of prioritization of outcome categories relative to each other in patients with all types of cancer and if they included at least three outcome categories. Subsequently, for each study, the highest or second-highest outcome category was identified and presented in relation to the number of studies that included that outcome category. An adapted NewcastleâOttawa Scale was used to assess the risk of bias. In total, 4374 patients were asked for their priorities in 28 studies that were included. Only six of these studies had a population with a median age above 70. Of all the studies, 79% identified quality of life as the highest or second-highest priority, followed by overall survival (67%), progression- and disease-free survival (56%), absence of severe or persistent treatment side effects (54%), and treatment response (50%). Absence of transient short-term side effects was prioritized in 16%. The studies were heterogeneous considering age, cancer type, and treatment settings. Overall, quality of life, overall survival, progression- and disease-free survival, and severe and persistent side effects of treatment are the outcomes that receive the highest priority on a group level when patients with cancer need to make trade-offs in oncologic treatment decisions
Nationwide trends in chemotherapy use and survival of elderly patients with metastatic pancreatic cancer
Despite an aging population and underrepresentation of elderly patients in clinical trials, studies on elderly patients with metastatic pancreatic cancer are scarce. This study investigated the use of chemotherapy and survival in elderly patients with metastatic pancreatic cancer. From the Netherlands Cancer Registry, all 9407 patients diagnosed with primary metastatic pancreatic adenocarcinoma in 2005â2013 were selected to investigate chemotherapy use and overall survival (OS), using KaplanâMeier and Cox proportional hazard regression analyses. Over time, chemotherapy use increased in all age groups (<70Â years: from 26 to 43%, 70â74Â years: 14 to 25%, 75â79Â years: 5 to 13%, all PÂ <Â 0.001, and â„80Â years: 2 to 3% PÂ =Â 0.56). Median age of 2,180 patients who received chemotherapy was 63Â years (range 21â86Â years, 1.6% was â„80Â years). In chemotherapy-treated patients, with rising age (<70, 70â74, 75â79, â„80Â years), microscopic tumor verification occurred less frequently (91-88-87-77%, respectively, PÂ =Â 0.009) and OS diminished (median 25-26-19-16Â weeks, PÂ =Â 0.003). After adjustment for confounding factors, worse survival of treated patients â„75Â years persisted. Despite limited chemotherapy use in elderly age, suggestive of strong selection, elderly patients (â„75Â years) who received chemotherapy for metastatic pancreatic cancer exhibited a worse survival compared to younger patients receiving chemotherapy
Macrophyte assessment in European lakes: Diverse approaches but convergent views of 'good' ecological status
The European Water Framework Directive has been adopted by Member States to assess and manage the ecological integrity of surface waters. Specific challenges include harmonizing diverse assessment systems across Europe, linking ecological assessment to restoration measures and reaching a common view on âgoodâ ecological status. In this study, nine national macrophyte-based approaches for assessing ecological status were compared and harmonized, using a large dataset of 539 European lakes. A macrophyte common metric, representing the average standardized view of each lake by all countries, was used to compare national methods. This was also shown to reflect the total phosphorus (r2âŻ=âŻ0.32), total nitrogen (r2âŻ=âŻ0.22) as well as chlorophyll-a (r2âŻ=âŻ0.35â0.38) gradients, providing a link between ecological data, stressors and management decisions. Despite differing assessment approaches and initial differences in classification, a consensus was reached on how type-specific macrophyte assemblages change across the ecological status gradient and where ecological status boundaries should lie. A marked decline in submerged vegetation, especially Charophyta (characterizing âgoodâ status), and an increase in abundance of free-floating plants (characterizing âless than goodâ status) were the most significant changes along the ecological status gradient. Macrophyte communities of âgoodâ status lakes were diverse with many charophytes and several Potamogeton species. A large number of taxa occurred across the entire gradient, but only a minority dominated at âless than goodâ status, including filamentous algae, lemnids, nymphaeids, and several elodeids (e.g., Zannichellia palustris and Elodea nuttallii). Our findings establish a âguiding imageâ of the macrophyte community at âgoodâ ecological status in hard-water lakes of the Central-Baltic region of Europe
Risk prediction models for postoperative outcomes of colorectal cancer surgery in the older population - a systematic review
Background: An increasing number of patients with Colorectal Cancer (CRC) is 65 years or older. We aimed to systematically review existing clinical prediction models for postoperative outcomes of CRC surgery, study their performance in older patients and assess their potential for preoperative decision making.Methods: A systematic search in Pubmed and Embase for original studies of clinical prediction models for outcomes of CRC surgery. Bias and relevance for preoperative decision making with older patients were assessed using the CHARMS guidelines.Results: 26 prediction models from 25 publications were included. The average age of included patients ranged from 61 to 76. Two models were exclusively developed for 65 and older. Common outcomes were mortality (n = 10), anastomotic leakage (n = 7) and surgical site infections (n = 3). No prediction models for quality of life or physical functioning were identified. Age, gender and ASA score were common predictors; 12 studies included intraoperative predictors. For the majority of the models, bias for model development and performance was considered moderate to high.Conclusions: Prediction models are available that address mortality and surgical complications after CRC surgery. Most models suffer from methodological limitations, and their performance for older patients is uncertain. Models that contain intraoperative predictors are of limited use for preoperative decision making. Future research should address the predictive value of geriatric characteristics to improve the performance of prediction models for older patients. (C) 2020 The Authors. Published by Elsevier Ltd.Pathophysiology, epidemiology and therapy of agein
Loss of skeletal muscle density during neoadjuvant chemotherapy in older women with advanced stage ovarian cancer is associated with postoperative complications
Objective: To assess the association between loss of lumbar skeletal muscle mass and density during neoadjuvant chemotherapy (NACT) and postoperative complications after interval cytoreductive surgery (CRS) in older patients with ovarian cancer. Materials and methods: This multicenter, retrospective cohort study included patients aged 70 years and older with primary advanced stage ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV), treated with NACT and interval CRS. Skeletal muscle mass and density were retrospectively assessed using Skeletal Muscle Index (SMI) and Muscle Attenuation (MA) on routinely made Computed Tomography scans before and after NACT. Loss of skeletal muscle mass or density was defined as >2% decrease per 100 days in SMI or MA during NACT. Results: In total, 111 patients were included. Loss of skeletal muscle density during NACT was associated with developing any postoperative complication â€30 days after interval CRS both in univariable (Odds Ratio (OR) 3.69; 95% Confidence Interval (CI) 1.57â8.68) and in multivariable analysis adjusted for functional impairment and WHO performance status (OR 3.62; 95%CI 1.27â10.25). Loss of skeletal muscle density was also associated with infectious complications (OR 3.67; 95%CI 1.42â9.52) and unintended discontinuation of adjuvant chemotherapy (OR 5.07; 95%CI 1.41â18.19). Unlike loss of skeletal muscle density, loss of skeletal muscle mass showed no association with postoperative outcomes. Conclusion: In older patients with ovarian cancer, loss of skeletal muscle density during NACT is associated with worse postoperative outcomes. These results could add to perioperative risk assessment, guiding the decision to undergo surgery or the need for perioperative interventions
- âŠ