1,720,984 research outputs found
Rischio di progressione nella terapia di prima linea del carcinoma colorettale metastatico per guidare la rivalutazione di malattia: un'analisi di undici trial delle fondazioni AIO e GONO
No full textI pazienti con diagnosi di carcinoma del colon-retto metastatico (mCRC) sono indirizzati a un follow-up radiologico che consiste in una rivalutazione ogni circa 2-3 mesi. Tuttavia, questa indicazione è gravata da un basso livello di evidenza e non è basata sull'aggressività biologica e su come il rischio di progressione (PD) vari nel tempo.
Per fornire delle indicazioni sul follow-up radiologico più precise, abbiamo raccolto dati individuali di 2845 pazienti non resecati reclutati in undici trial clinici randomizzati delle fondazioni GONO e AIO, e ne abbiamo descritto la frequenza e il rischio degli eventi PD durante la terapia di prima linea.
In tutta la popolazione, la massima densità di eventi PD è stata di 7.4 mesi, due mesi prima della mediana della sopravvivenza libera da progressione (PFS, 9.4 mesi). Il rischio massimo di PD è stato 23% a 14 mesi nei pazienti RAS e BRAF wild-type (N=1702), 25% a 10 mesi nei pazienti RAS-mutati (N=964) e 35% a 8 mesi nei pazienti BRAF-mutati (N=179). L'ECOG-PS > 0, la presenza del tumore primitivo in sede, la sua localizzazione nel colon destro, la diagnosi di metastasi peritoneali e la mutazione di BRAF erano associate a un più alto rischio di PD nei primi 8 mesi di terapia. Un nomogramma costruito su queste caratteristiche è risultato consistente in una coorte di training (C-index: 0.64) e di validazione (C-index: 0.61), di 1339 e 1506 pazienti di trial differenti.
Questi dati suggeriscono che la distribuzione degli eventi di PD nel mCRC non è gaussiana e la valutazione radiologica dovrebbe concentrarsi fra i 6-10 mesi dall’inizio del trattamento di prima linea. Il nomogramma può essere uno strumento utile per individualizzare di follow-up radiologico sulla base delle caratteristiche del paziente.
Metastatic colorectal cancer (mCRC) patients undergo a radiological surveillance protocol usually consisting of a radiological reassessment every two or three months. Nonetheless, this recommendation is tackled by a low quality of evidence, and it is not tailored neither to biological aggressiveness nor to time-varying risk of disease progression.
With the purpose of providing an individualized approach to radiological restaging, we collected individual data of 2845 unresected mCRC patients recruited in eleven randomized clinical trial by AIO and GONO foundations. We calculated the frequency and risk of disease progression (PD) events for individual time points during therapy. In the overall population, the maximum density of PD events was observed at 7.4 months prior to the median PFS of 9.4 months. The highest risk of PD was 23% at 14 months in RAS/BRAF wild-type patients (n=1702), 25% at 10 months in RAS mutant patients (n=964) and 35% at 8 months in BRAF mutant patients (n=179). ECOG-PS > 0, right sidedness, initially unresected primary tumor, the presence of peritoneal metastases and BRAF mutation were associated with higher risk of PD at 8 months. A nomogram built on these features showed consistency across a training (C-index: 0.64) and a validation set (C-index:0.61) of 1339 and 1506 patients of different trials, respectively.
Based on our findings, the distribution of PD events in clearly unresectable mCRC patients is not gaussian and tumor reassessment should focus on the interval between 6-10 months from treatment start. The nomogram might be helpful to schedule radiologic re-assessments according to baseline characteristics and the expected duration of each treatment efficacy
Health-related quality of life in patients with RAS wild-type metastatic colorectal cancer treated with fluorouracil and folinic acid with or without panitumumab as maintenance therapy: a prespecified secondary analysis of the PanaMa (AIO KRK 0212) trial
No full texthttp://dx.doi.org/10.13039/501100018931 AIO Studien gGmb
Maintenance therapy with 5-fluoruracil/leucovorin (5FU/LV) plus panitumumab (pmab) or 5FU/LV alone in RAS wildtype (WT) metastatic colorectal cancer (mCRC) - the PANAMA trial (AIO KRK 0212).
No full text3503 Background: Planned discontinuation or stop-and-go use of oxaliplatin are established strategies in the systemic therapy of mCRC. Consequently, and irrespective of antibody use, 5FU/LV represents the standard backbone of most maintenance strategies. Unlike VEGF-targeted substances, there is limited evidence that EGFR-antibodies add efficacy to 5FU/LV maintenance in RAS wildtype ( RAS WT) mCRC patients. Methods: Following induction therapy with six cycles of 5FU/LV, oxaliplatin (FOLFOX) and pmab, the trial randomized maintenance therapy with 5FU/LV plus pmab vs. 5FU/LV alone in a 1:1 fashion in patients (pts) with RAS WT mCRC. The primary endpoint was PFS (progression-free survival: time from randomization until progression or death). With 218 events needed for PFS, the trial was designed to demonstrate superiority of the 5FU/LV+ pmab arm vs. 5FU/LV alone with a hazard ratio (HR) of 0.75, power of 80% and a significance level of 10%. Secondary endpoints included overall survival (OS), objective response to induction- and maintenance therapy as well as quality of life. The trial is registered with ClinicalTrials.gov, NCT01991873. Results: The full analysis set consists of 248 pts (125 pts 5FU/LV + pmab and 123 pts 5FU/LV) who were randomized and received maintenance therapy. Median age was 66 vs. 65 years, male patients were 69.6% vs. 63.4%, ECOG 0 was 56.8% vs. 60.2% in the respective trial arms (5FU/LV+ pmab vs. 5FU/LV). At data cut-off, with 218 events, PFS of maintenance therapy was improved with 5FU/LV+ pmab vs. 5FU/LV alone (8.8 (80% CI 7.6-10.2) months vs. 5.7 (80% CI 5.6-6.0) months, HR 0.72 (80%CI 0.60-0.85), p = 0.014). OS (event rate 54.4%) numerically favoured the 5FU/LV+ pmab arm (28.7 (95% CI 25.4-39.1) months) as compared to 5FU/LV alone (25.7 (95% CI 22.2-28.2) months), HR 0.84 (95% CI 0.60-1.18). Conclusion: In RAS WT mCRC, maintenance therapy with 5FU/LV+ pmab appears to be superior to 5FU/LV alone and should be regarded as standard of care maintenance regimen following induction therapy with FOLFOX plus pmab. Clinical trial information: NCT01991873.3503 Background: Planned discontinuation or stop-and-go use of oxaliplatin are established strategies in the systemic therapy of mCRC. Consequently, and irrespective of antibody use, 5FU/LV represents the standard backbone of most maintenance strategies. Unlike VEGF-targeted substances, there is limited evidence that EGFR-antibodies add efficacy to 5FU/LV maintenance in RAS wildtype ( RAS WT) mCRC patients. Methods: Following induction therapy with six cycles of 5FU/LV, oxaliplatin (FOLFOX) and pmab, the trial randomized maintenance therapy with 5FU/LV plus pmab vs. 5FU/LV alone in a 1:1 fashion in patients (pts) with RAS WT mCRC. The primary endpoint was PFS (progression-free survival: time from randomization until progression or death). With 218 events needed for PFS, the trial was designed to demonstrate superiority of the 5FU/LV+ pmab arm vs. 5FU/LV alone with a hazard ratio (HR) of 0.75, power of 80% and a significance level of 10%. Secondary endpoints included overall survival (OS), objective response to induction- and maintenance therapy as well as quality of life. The trial is registered with ClinicalTrials.gov, NCT01991873. Results: The full analysis set consists of 248 pts (125 pts 5FU/LV + pmab and 123 pts 5FU/LV) who were randomized and received maintenance therapy. Median age was 66 vs. 65 years, male patients were 69.6% vs. 63.4%, ECOG 0 was 56.8% vs. 60.2% in the respective trial arms (5FU/LV+ pmab vs. 5FU/LV). At data cut-off, with 218 events, PFS of maintenance therapy was improved with 5FU/LV+ pmab vs. 5FU/LV alone (8.8 (80% CI 7.6-10.2) months vs. 5.7 (80% CI 5.6-6.0) months, HR 0.72 (80%CI 0.60-0.85), p = 0.014). OS (event rate 54.4%) numerically favoured the 5FU/LV+ pmab arm (28.7 (95% CI 25.4-39.1) months) as compared to 5FU/LV alone (25.7 (95% CI 22.2-28.2) months), HR 0.84 (95% CI 0.60-1.18). Conclusion: In RAS WT mCRC, maintenance therapy with 5FU/LV+ pmab appears to be superior to 5FU/LV alone and should be regarded as standard of care maintenance regimen following induction therapy with FOLFOX plus pmab. Clinical trial information: NCT01991873
Panitumumab Plus Fluorouracil and Folinic Acid Versus Fluorouracil and Folinic Acid Alone as Maintenance Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Randomized PANAMA Trial (AIO KRK 0212)
No full textPURPOSE
The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer.
METHODS
Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov ( NCT01991873 ).
RESULTS
Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%).
CONCLUSION
In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Protection against hypothermic-induced damage in cultures of primary human hepatocytes
No full textZur Behandlung des akuten Leberversagens sind die therapeutischen Alternativen
zur Transplantation rar. Mögliche Ansätze bieten Dialysesysteme, oder
experimentelle Systeme auf Zellbasis wie die bioartifiziellen
Leberunterstützungssysteme. Ihre Praktikabilität hängt mit der Verfügbarkeit
von Zellkulturen eng zusammen. Es kommen hier sowohl Tumorzelllinien, als auch
prim¨are porcine oder humane Hepatozyten in Frage. Da bei primären humanen
Hepatozyten die Biokompatibilität am größten ist, sind sie als Zellquelle der
ersten Wahl anzusehen. Leider sind die Ressourcen an primären humanen
Hepatozyten gering, da sie in ausreichender Menge nur aus abgelehnten
Spenderorganen isoliert werden können und in vitro nicht proliferieren. Ein
Verfahren zur effektiven Nutzung und Lagerung dieser wertvollen Zellquelle ist
demnach von Nutzen. Eine mögliche Strategie ist die hypotherme Lagerung der
Zellkulturen bis zum Einsatz am Patienten. Leider hat die Hypothermie neben
dem gewünschten Effekt der Verzögerung von Altersprozessen auch schädigende
Wirkungen. Ziel dieser Studie ist, mit Hilfe eines speziellen
Hypothermiemediums Kulturen von primären humanen Hepatozyten während einer 24-
stündigen hypothermen Lagerung vor hypothermieinduzierten Schäden zu schützen.
Für diese Arbeit wurden primäre humane Hepatozytenkulturen von n=11 Spendern
verwendet. Die Isolierung erfolgte mittels Kollagenaseperfusionstechnik aus
nicht pathologischen Leberstücken von 10-60g, die im Rahmen von
Leberteilresektionen von dem eigentlichen Resektat abgetrennt wurden. Nach
einer 24-stündigen Kultur im Brutschrank mit Standardmedium wurden Proben
genommen. Für die zweiten 24 Stunden wurden die Kulturen in vier Gruppen
aufgeteilt. Zwei Gruppen blieben im Brutschrank, eine erhielt Standardmedium,
die andere das Testmedium (HLC1). Die beiden restlichen Gruppen wurden bei 4°C
inkubiert, wieder jeweils eine mit Standardmedium und eine mit HLC1. Nach
dieser Zeitspanne erfolgte die zweite Probenentnahme. Am dritten Kulturtag
wurden alle Gruppen wieder mit Standardmedium im Brutschrank inkubiert, um
Schäden zu detektieren, die typischerweise während der Wiedererwärmung
auftreten. Am Ende dieses Tages erfolgte die letzte Probenentnahme. Es wurden
für jeden Zeitpunkt und jede Versuchsgruppe unterschiedliche Parameter
analysiert (Gesamtprotein, LDH, AST, Harnstoff, Albumin, Zellaktivität) und am
Ende des Versuchs lichtmikroskopische Bilder der Zellkulturen angefertigt.
Nach der abschließenden Rekulturphase hat die ungeschützt in der Kälte
inkubierte Gruppe das niedrigste Niveau der Syntheseparameter und eine hohe
Aktivität von Enzymen im Kulturmedium, jeweils als Ausdruck einer massiven
Schädigung der Kulturen. Die geschützten Kaltkulturen weisen höhere
Enzymaktivitäten als die warme Standardkultur auf, in den Syntheseleistungen
sind allerdings keine signifikanten Unterschiede sichtbar. Die imWarmen mit
Hypothermiemedium inkubierten Zellen weisen massive Schäden und produzieren in
der Rekulturphase signifikant weniger Albumin und Harnstoff als die
kaltinkubierte Gruppe mit dem gleichen Medium. Die ungeschützte Kaltgruppe ist
in ihrem gesamten Profil im Vergleich mit der geschützten Kaltgruppe als klar
unterlegen anzusehen. Die geschützte Kaltgruppe kommt der Standardkultur
aufgrund ihrer guten Synthesefunktionen recht nahe. Die hier vorgestellten
Ergebnisse belegen, dass eine effektive Minderung der kälteinduzierten
Schädigung in Kulturen von primären humanen Hepatozyten durch den Einsatz von
HLC1 Medium im 24-Stunden-Modell möglich ist. Die geschützten Kulturen zeigen
sich nach Kaltinkubation den ungeschützen deutlich überlegen, erreichen aber
nicht ganz das Niveau der durchgehend warm inkubierten Zellkulturen. Die
Versuchsdauer ist in diesem Modell noch zu kurz gewählt und müsste für eine
effektive Nutzung des Verfahrens sicherlich verlängert werden. Es bieten sich
aber sowohl im Versuchsaufbau als auch pharmakologisch noch zahlreiche
Möglichkeiten und Maßnahmen zur Verbesserung des Kulturergebnisses an.While transplantation is the only curative therapy for most cases of acute
liver failure, the lack of donor organs encourages research towards
alternative therapeutic methods. Current approaches include cell based
bioartificial support systems or cell transplantation for bridging-to-
transplantation or even bridging-to-recovery. Since cultured primary human
hepatocytes loose metabolic function within the first weeks of culture,
methods for cell preservation are desireable. Cell cultivation under
hypothermic conditions presents a simple method to maintain cell metabolic
function over extended time periods. Hypothermia and subsequent rewarming is
known to have adverse effects on cell viability. Here we present results
showing protection of primary human hepatocytes exposed to hypothermia for 24
hours using medium specifically designed for hypothermic incubation. Cultures
of primary human hepatocytes isolated (n=11) by collagenase-perfusion were
cultured for three days in four different study groups. On days one and three
all cells were kept under standard culture conditions at 37°C. On day two the
experimental groups were kept at 4°C. Cells exposed to hypothermia were either
cultured in standard medium or in medium containing iron-chelators (i.e.
phenanthroline, 2`2-dipyridyl) and antioxidants such as glutathione,
L-carnosine and L-cysteine. Medium supernatant samples and protein samples
were taken daily from every study group and tested for albumin, urea, AST and
total protein content. Cells cultured in protective medium which were exposed
to hypothermia showed just 8% of the AST-activities in their medium
supernatant compared to the unprotected group during cold incubation. After
rewarming the protected cells secreted 30% more urea as the unprotected
cultures did and showed no significant difference confered to the standard
culture. Total protein levels on day three matched to day one were 86% in
standard cultures, 72% in protected and 53% in unprotected cold groups. These
results suggest that hypothermic stand-by cultures may offer an effective
method for the timely provision of primary human hepatocytes for clinical
application
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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