Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group

Background: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. Patients and methods: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m2 alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. Results: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX-CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX-CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX-CDDP [13 complete responses (CRs) and 26 partial responses (PRs)], versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX-CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05-2.03, P = 0.024). Conclusions: In comparison to single agent DOX, the combination of DOX-CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance statu

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Linee guida sul Taglio Cesareo (revisione Linee guida del 1999)

In molti paesi europei ed extra-europei si osserva un aumento dei parti che vengono assistiti con il taglio cesareo (TC), con frequenze che si collocano intorno al 25-30%. Anche nel Lazio si osserva un andamento simile: in un periodo di vent\u2019anni, dal 1985 al 2005, i TC sono aumentati dal 23% al 42,7% con un incremento pari all\u201985,7%. Confrontando questi valori con quelli di altre regioni italiane, il Lazio insieme alla Campania, Basilicata, Sicilia, Puglia, Molise e Calabria si colloca ai primi posti, mentre altre regioni come la Lombardia, il Veneto e la Toscana presentano una frequenza di TC notevolmente inferiore (al di sotto del 30%); il Friuli Venezia Giulia ha la frequenza di TC pi\uf9 bassa (22%). Valori cos\uec elevati non sembrano giustificati da una maggiore frequenza di quelle condizioni cliniche (ad esempio ritardo di crescita intrauterino o patologie della placenta) che, correttamente, possono rappresentare un\u2019indicazione ad assistere il parto con taglio cesareo. Anche escludendo dalla valutazione del fenomeno i cesarei ripetuti, che nel 2005 rappresentavano nella regione il 27,2% del totale dei cesarei, il tasso osservato di primi cesarei (35,3%) risulta ancora molto pi\uf9 elevato di quello di altri paesi e regioni italiane. C\u2019\ue8 inoltre da sottolineare che sia il Piano Sanitario Nazionale del 2006-2008 che quello precedente hanno indicato tra gli obiettivi da raggiungere la riduzione del ricorso al taglio cesareo. E\u2019 quindi opportuno valutare anche il contributo svolto da fattori \u201cnon clinici\u201d. Un\u2019analisi delle schede di nascita di tutti i parti effettuati nella regione ha evidenziato che, a parit\ue0 di condizioni cliniche della donna e del feto, la probabilit\ue0 di ricorso al TC \ue8 pi\uf9 alta del 35% nelle maternit\ue0 private convenzionate e del 64% in quelle completamente private rispetto a quella osservata nelle maternit\ue0 pubbliche. L\u2019effetto del punto nascita, che a sua volta \ue8 determinato da fattori organizzativi della struttura ed individuali dei singoli operatori, spiega parte della variabilit\ue0 osservata fra i singoli istituti. Da una analisi effettuata da Laziosanit\ue0, Agenzia di Sanit\ue0 Pubblica sulle nascite del 2003-2005 emerge una notevole diversit\ue0 nel ricorso al taglio cesareo, anche fra centri di pari livello di complessit\ue0. Nel 2005 negli ospedali pubblici i valori osservati erano compresi fra il 28% e il 64%; in quelli universitari, fra il 44% ed il 54%; nelle maternit\ue0 private accreditate, fra il 35% ed il 64%; e nelle maternit\ue0 completamente private, fra il 72% e l\u201986%. Tale variabilit\ue0 rimane confermata anche controllando per l\u2019effetto di fattori clinici. Le implicazioni di queste evidenze sono numerose: il fatto che una donna, a parit\ue0 di condizioni cliniche, possa ricevere cure differenti a seconda del \u201cluogo\u201d presso il quale viene assistita, pone importanti interrogativi sulla appropriatezza, efficacia ed eticit\ue0 della professione sanitaria. In questo contesto, la realizzazione di interventi finalizzati alla diffusione di pratiche diagnostiche e terapeutiche di documentata efficacia appare di estrema attualit\ue0 e rilevanza per la sanit\ue0 pubblica, per i singoli operatori e per l\u2019utenza. Le linee-guida sul TC che sono oggetto di questa pubblicazione, e che rappresentano un aggiornamento di quelle pubblicate nel 1999 e recepite dalla Giunta Regionale con DGR n. 2806 del 25/05/1999 costituiscono uno sforzo in questo senso. Vale la pena ricordare che le linee-guida sono \u201craccomandazioni di comportamento clinico, prodotte attraverso un processo sistematico, allo scopo di assistere medici e pazienti nel decidere quali siano le modalit\ue0 di assistenza pi\uf9 appropriate in specifiche circostanze cliniche\u201d. Non devono quindi essere considerate in alcun modo come \u201cpercorsi\u201d o protocolli diagnostico-terapeutici, ma possono essere un utile strumento per il miglioramento delle pratiche cliniche. Per una loro valutazione e implementazione si suggerisce ai Dirigenti di UOC di promuovere periodiche riunioni tra pari, all\u2019interno di ciascun punto nascita, finalizzate all\u2019attuazione di percorsi condivisi

Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma: a trial of the EORTC Gynaecological Cancer Group

The aim of this study was to investigate the efficacy and toxicity of carboplatin given as monotherapy in endometrial adenocarcinoma. Cisplatin is one of the most active drugs in gynaecological cancer types, but at the cost of an associated high toxicity. In this high-risk population of endometrial cancer patients, it is necessary to have chemotherapy regimens with a low toxicity. Patients eligible for this study were those with histologically-confirmed endometrial adenocarcinoma with evidence of recurrent and/or metastatic disease. Carboplatin was administered every 4 weeks as a first- (dose: 400 mg/m2) or second- (dose: 300 mg/m2) line chemotherapy. Of the 64 patients who entered the trial, 60 were eligible, 53 patients were evaluable for toxicity and 47 for efficacy. A total of 169 cycles of carboplatin was given with a median of 2 cycles per patient (range 1\u201311 cycles) to a median cumulative dose of 798 mg/m2 (range 290\u20133879 mg/m2). No grade 4 toxicity or toxic deaths occurred. White Blood Cell (WBC) toxicity grade 3 was noted five times, mainly in the radiotherapy pre-treated patients. Grade 3 non-haematological toxicity consisted mainly of nausea and vomiting (21%). There was a total of eight responses (3 Complete Responses (CR) and 5 Partial Responses (PR) with an overall response rate (ORR) of 13% (95% Confidence Interval (CI) 6\u201325). No responses occurred in patients treated with prior chemotherapy. In evaluable patients, the ORR in all patients (n=47) and in those receiving first-line chemotherapy (n=33) were, 17% (95% CI 8\u201331) and 24% (95% CI 11\u201342), respectively. After a median follow-up of 379 days, the median duration of response was 488 days (range 141\u20135303 days) with two very long responses in patients with a CR. Carboplatin has a low toxicity and is active in chemotherapy-naive advanced endometrial carcinoma patients. These results lead us to propose its use in association in first-line chemotherapy in recurrent or advanced endometrial carcinoma patients. The choice of the initial dose can be determined according to whether the patients have received prior radiotherapy treatment

Erratum: Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer GroupAnn Oncol 2003; 14: 441-448

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