Event-free survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell lymphoma treated with immunochemotherapy.

PURPOSE: Studies of diffuse large B-cell lymphoma (DLBCL) are typically evaluated by using a time-to-event approach with relapse, re-treatment, and death commonly used as the events. We evaluated the timing and type of events in newly diagnosed DLBCL and compared patient outcome with reference population data. PATIENTS AND METHODS: Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from 2002 to 2009. Patient outcomes were evaluated at diagnosis and in the subsets of patients achieving event-free status at 12 months (EFS12) and 24 months (EFS24) from diagnosis. Overall survival was compared with age- and sex-matched population data. Results were replicated in an external validation cohort from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France. RESULTS: In all, 767 patients with newly diagnosed DLBCL who had a median age of 63 years were enrolled onto the MER and NCCTG studies. At a median follow-up of 60 months (range, 8 to 116 months), 299 patients had an event and 210 patients had died. Patients achieving EFS24 had an overall survival equivalent to that of the age- and sex-matched general population (standardized mortality ratio [SMR], 1.18; P = .25). This result was confirmed in 820 patients from the GELA study and registry in Lyon (SMR, 1.09; P = .71). Simulation studies showed that EFS24 has comparable power to continuous EFS when evaluating clinical trials in DLBCL. CONCLUSION: Patients with DLBCL who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. EFS24 will be useful in patient counseling and should be considered as an end point for future studies of newly diagnosed DLBCL.

Immunocytochemical and pharmacological characterization of metabotropic glutamate receptors of the vestibular end organs in the frog.

Using immunocytochemistry and multiunit recording of afferent activity of the whole vestibular nerve, we investigated the role of metabotropic glutamate receptors (mGluR) in the afferent neurotransmission in the frog semicircular canals (SCC). Group I (mGluR1alpha) and group II (mGluR2/3) mGluR immunoreactivities were distributed to the vestibular ganglion neurons, and this can be attributed to a postsynaptic locus of metabotropic regulation of rapid excitatory transmission. The effects of group I/II mGluR agonist (1S,3R)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (ACPD) and antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG) on resting and chemically induced afferent activity were studied. ACPD (10-100 microM) enhanced the resting discharge frequency. MCPG (5-100 microM) led to a concentration-dependent decrease of both resting activity and ACPD-induced responses. If the discharge frequency had previously been restored by L-glutamate (L-Glu) in high-Mg2+ solution, ACPD elicited a transient increase in the firing rate in the afferent nerve suggesting that ACPD acts on postsynaptic receptors. The L-Glu agonists, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA), were tested during application of ACPD. AMPA- and NMDA-induced responses were higher in the presence than absence of ACPD, implicating mGluR in the modulation of ionotropic glutamate receptors. These results indicate that activation of mGluR potentiates AMPA and NMDA responses through a postsynaptic interaction. We conclude that ACPD may exert modulating postsynaptic effects on vestibular afferents and that this process is activity-dependent.

Désir de mort, désir de vie et fin de vie [Desire to die, desire to live at the end of life]

Since a couple of years, physicians are confronted with an increasing request of end of life patients asking for a dying facilitated process. The reasons for this are multiple and complex. Existential suffering, increased by depression, a feeling of loss of meaning or dignity and/or being a burden, seems to be a significant factor. Social isolation and physical symptoms seem to be only contributory. The identification of "protecting elements" such as spiritual well-being or a preserved sense of dignity offers new opportunities for care. Providing a space for dialogue by exploring the patient's expectations and fears, his knowledge of care options available at the end of life, his own resources and difficulties frequently contribute to decrease suffering.

Happy End

Treball presentat al Concurs 16 portes de Collserola - Porta 13 Trinitat

The early Miocene rotation of the Corso-Sardinian block. New paleomagnetic constraints for the end of the motion

The paleomagnetic investigations carried out in the 70's on Oligo-Miocene volcanics of Sardinia have demonstrated that the island was turned by 35-30 degrees clockwise from 33 Ma up to 3-1-20.5 Ma and rotated counterclockwise in a few million years [De Jong et al., 1969, 1973; Bobier et Coulon, 1970; Coulon et al., 1974; Manzoni, 1974, 1975; Bellon rr nl.. 1977: Edel et Lortscher, 1977; Edel, 1979, 1980]. Since then, the end of the rotation fixed at 19 Ma by Montigny er al. [1981] was the subject of discussions and several studies associating paleomagnetism and radiometric dating were undertaken [Assorgia er al., 1994: Vigliotti et Langenheim, 1995: Deino et al., 1997; Gattacceca rt Deino, 1999]. This is a contribution to this debate that is hampered by thr important secular variation recorded in the volcanics. The only way to get our of this problem is to sample series of successive flows as completely as possible, and to reduce the effect of secular variation by the calculation of means. Sampling was performed north of Bonorva in 5 pyroclastic flows that belong to the upper ignimbritic series SI2 according to Coulon rr nl. [1974] or LBLS according to Assorgia et al. [1997] (fig. I). Ar-40/Ar-39 dating of biotites from the debris flow (MDF) has yielded an age or 18.35 +/- 0.03 Ma [Dubois, 2000]. Five of the investigated sites are located beneath the debris flow ITV, TVB, TVD, SPM85, SPM86), one site was cured in the matrix of the debris flow (MDF) and one in 4 metric blocks included in the flow (DFC). Another site was sampled in the upper ash flow (PDM) that marks the end of the pyroclastic activity, just before the marine transgression. According to micropaleontological and radiometric dating this transgression has occurred between 18.35 and 17.6 Ma [Dubois, 2000]. After removal of a soft viscous component, the thermal demagnetization generally shows a univectorial behaviour of the remanent magnetization (fig. 2a). The maximum unblocking temperatures of 580-620 degrees (tab. I) and a rapid saturation below 100 mT (fig. 3) indicate that the carrier of the characteristic magnetization is magnetite. The exception comes: from the upper site PDM in which were found two characteristic components, one with a normal polarity and low unblocking temperatures up to 350 degreesC and one with a reversed polarity and maximum unblocking temperatures at 580-600 degreesC of magnetite. After calculation of a mean direction for each flow, the mean << Al >> direction 4 degrees /57 degrees (alpha (95) = 13 degrees) computed with the mean directions for the 5 flows may be considered as weakly affected by secular variation. But the results require a more careful examination. The declinations are N to NNW beneath the debris flow. NNW in the debris flow. and NNE (or SSW) above the debris flow, The elongated distribution of the directions obtained at sites TVB and TVD. scattered from the mean direction of TV to the mean direction of MDF is interpreted as due to partial overprinting during the debris How volcanic episode, The low temperature component PDMa is likely related to the alteration seen on thin sections and is also viewed as an overprint. As NNE/SSW directions occur as well below (mean direction << B >> : 5 degrees /58 degrees) as above the debris flow (PDMb : 200 degrees/-58 degrees). the NNW directions (<< C >> : 337 degrees /64 degrees) associated with the debris flow volcanism may be interpreted as resulting from a magnetic field excursion. According to the polarity scale of Cande and Kent [1992, 1995] and the radiometric age of MDF, the directions with normal polarity (TV, TVB, TVD, SPM85. SPM86a. MDF. DFC) may represent the period 5En. while the directions with reversed polarity PDMb and SPM86b were likely acquired during the period 5Dr. Using the mean << Al >> direction, the mean << B >>, or the PDM direction (tab. I). the deviation in declination with the direction of stable Europe 6.4 degrees /58.7 degrees (alpha (95) = 8 degrees) for a selection of 4 middle Tertiary poles by Besse et Courtillot [1991] or 7 degrees /56 degrees (alpha (95) = 3 degrees) for 19 poles listed by Edel [1980] can be considered as negligible. Using the results from the uppermost ignimbritic layer of Anglona also emplaced around 18.3 Ma [Odin rt al.. 1994]. the mean direction << E >> (3 degrees /51.5 degrees) leads to the same conclusion. On the contrary, when taking into account all dated results available for the period 5En (mean direction << D >> 353 degrees /56 degrees for 45 sites) (tab. II). the deviation 13 degrees is much more significant. As the rotation of Sardinia started around 21-20.5 Ma. the assumption of a constant velocity of rotation and the deviations of the Sardinia directions with respect to the stable Europe direction locate the end of the motion between 18.3 and 17.2 or 16.7 Ma (fig. 4). During the interval 18.35-17.5 Ma, the marine transgression took place. At the same period a NE-SW shortening interpreted as resulting from the collision of Sardinia with Apulia affected different parts of the island [Letouzey et al., 1982]. Consequently, the new paleomagnetic results and the tectono-sedimentary evolution are in favour of an end of the rotation at 17.5-18 Ma.

Medical futility at the end of life: the perspectives of intensive care and palliative care clinicians.

Objectives Medical futility at the end of life is a growing challenge to medicine. The goals of the authors were to elucidate how clinicians define futility, when they perceive life-sustaining treatment (LST) to be futile, how they communicate this situation and why LST is sometimes continued despite being recognised as futile. Methods The authors reviewed ethics case consultation protocols and conducted semi-structured interviews with 18 physicians and 11 nurses from adult intensive and palliative care units at a tertiary hospital in Germany. The transcripts were subjected to qualitative content analysis. Results Futility was identified in the majority of case consultations. Interviewees associated futility with the failure to achieve goals of care that offer a benefit to the patient's quality of life and are proportionate to the risks, harms and costs. Prototypic examples mentioned are situations of irreversible dependence on LST, advanced metastatic malignancies and extensive brain injury. Participants agreed that futility should be assessed by physicians after consultation with the care team. Intensivists favoured an indirect and stepwise disclosure of the prognosis. Palliative care clinicians focused on a candid and empathetic information strategy. The reasons for continuing futile LST are primarily emotional, such as guilt, grief, fear of legal consequences and concerns about the family's reaction. Other obstacles are organisational routines, insufficient legal and palliative knowledge and treatment requests by patients or families. Conclusion Managing futility could be improved by communication training, knowledge transfer, organisational improvements and emotional and ethical support systems. The authors propose an algorithm for end-of-life decision making focusing on goals of treatment.

Intrauterine growth restriction and absent or reverse end-diastolic blood flow in umbilical artery (Doppler class II or III): A retrospective study of short- and long-term fetal morbidity and mortality.

OBJECTIVE: Absent or reverse end-diastolic flow (Doppler II/III) in umbilical artery is correlated with poor perinatal outcome, particularly in intrauterine growth restricted (IUGR) fetuses. The optimal timing of delivery is still controversial. We studied the short- and long-term morbidity and mortality among these children associated with our defined management. STUDY DESIGN: Sixty-nine IUGR fetuses with umbilical Doppler II/III were divided into three groups; Group 1, severe early IUGR, no therapeutic intervention (n = 7); Group 2, fetuses with pathological biophysical profile, immediate delivery (n = 35); Group 3, fetuses for which expectant management had been decided (n = 27). RESULTS: In Group 1, stillbirth was observed after a mean delay of 6.3 days. Group 2 delivered at an average of 31.6 weeks and two died in the neonatal period (6%). In Group 3 after a mean delay of 8 days, average gestational age at delivery was 31.7 weeks; two intra uterine and four perinatal deaths were observed (22%). Long-term follow-up revealed no sequelae in 25/31 (81%) and 15/18 (83%), and major handicap occurred in 1 (3%) and 2 patients (11%), respectively, for Groups 2 and 3. CONCLUSION: Fetal mortality was observed in 22% of this high risk group. After a mean period of follow-up of 5 years, 82% of infants showed no sequelae. According to our management, IUGR associated with umbilical Doppler II or III does not show any benefit from an expectant management in term of long-term morbidity.

End of Life Conversations, October 2003

A short course designed for adult study groups Prepared by the Curriculum Task Force of the End-of-Life Care Coalition of Central Iowa

Patients' knowledge of Diabetes five years after the end of an educational program

We present a cross-sectional study that aims to describe the sociodemographic and clinical conditions of individuals with diabetes mellitus and to analyze their knowledge of treatment five years after the end of an educational program in which they took part. In 2010, 40 individuals who had participated in a diabetes educational program for 12 months in 2005 at a primary care service were interviewed. A form was used for data collection that included their knowledge of the notion, physiopathology, and treatment of the disease; exercise; nutrition; foot care; self-monitoring of capillary blood glucose at home; hypoglycemia; chronic complications; special situations; and family support. The results showed that the volunteers incorporated the information about the notion, physiopathology, and treatment of the disease; exercise; foot care; self-monitoring; care associated with hypoglycemia; chronic complications; and special situations. In contrast, nutrition and family support require further reinforcement. It is concluded that five years after the end of the educational program, the participants kept most of the information provided.

How Much Chemotherapy Are Patients With Advanced Pancreatic Cancer Receiving at the End of Life?

Background: Advanced pancreatic adenocarcinoma (APC) is a chemoresistant cancer with poor prognosis. We evaluated the use of chemotherapy in the last months of life.Methods: Retrospective analysis of patients with APC treated from 1993 to 2010 at the Oncology Institute of Southern Switzerland. Clinical and laboratory parameters starting from 28 days prior to the last administration of chemotherapy were recorded, including ECOG performance status, presence of ascites, haemoglobin (Hb), white blood cell (WBC) count, platelets, total bilirubin, albumin, LDH, C-reactive protein (C-rp) and Ca 19.9.Results: The characteristics of the 231 patients were: males/females 53%/47%; metastatic/locally advanced disease 80%/20%; median age 66 years (range 32−85). Median overall survival calculated from diagnosis was 6.1 months (95% CI: 5.1−7.2); death was due to disease progression in all cases. At last chemotherapy administration, ECOG performance status was 0−1 in 38% and 2−3 in 62%. Fifty-nine percent of pts received first-line chemotherapy only (gemcitabine in 70%; gemcitabine-based doublets or 5FU in 30%), whilst 32%, 8% and 1% had second- (5FU 37%; oxaliplatinbased doublets 57%; phase I trial 6%), third- and fourth-line therapy (single agent or phase I trial), respectively. The interval between last chemotherapy administration and death was <4 weeks in 24%, _4−12 weeks in 47% and >12 weeks in 29%. Table 1 summarizes the proportion of patients treated according to the interval between last chemotherapy and death refered to chemotherapy line. Median survival from last chemotherapy delivery to death was 7.5 weeks (95% CI 6.7−8.4). In univariate analysis, presence of ascites, elevated WBC, total bilirubin, LDH, C-rp and Ca 19.9, and reduced albumin were found to predict shorter survival (p < 0.05 for each). However, none of them was an independent predictor in the multivariate analysis.Conclusions: A significant proportion of patients with APC received chemotherapy in the last months of life. In our study, none of the clinical and laboratory parameters recorded 28 days priorto the last chemotherapy delivery were found to predict survival.

Factors influencing Intensive Care Units nurses in end-of-life decisions

OBJECTIVETo identify the factors that influence the Intensive Care Unit nurse in the decision-making process in end-of-life situations.METHODEthnographic case study, which used the theoretical framework of medical anthropology. Data were collected through semi-structured interviews with 10 nurses.RESULTSThe inductive thematic analysis enabled us to identify four themes:The cultural context of the Intensive Care Unit: decision-making in situations of end-of-life; Beliefs and subjectivity of care in end-of-life situations; Professional experience and context characteristics of end-of-life care situations; and Humanization practices in end-of-life situations: the patient and family centered care.CONCLUSIONProfessional maturity, the ability to transmit information and the ability to negotiate are directly related to the inclusion of nurses in the decision-making process.