Poor outcome of elderly patients with platinum-sensitive recurrent ovarian cancer: Results from the SOCRATES retrospective study

Background

Elderly patients with ovarian carcinoma have a poorer prognosis compared with their younger counterpart, and this depends in most cases on undertreatment. The aim of this study was to evaluate, retrospectively, the pattern of care and the prognosis of elderly patients with platinum-sensitive recurrent ovarian cancer. The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000-2002 in 37 Italian centres. Data were collected between April and September 2005.

Patients and methods

Patients with recurrent ovarian cancer with >6 months of platinum free interval were considered eligible. Four-hundred-ninety-three patient files were collected and 425 were considered eligible and analyzed. Ninety-four patients with age ≥70 years and 331 patients with age <70 years were analyzed.

Results

Recurrence free interval (RFI), PS, and number of disease sites were similar among the two groups. A lower proportion of elderly patients underwent secondary cytoreduction (8.9% compared to 23.9%; p = 0.0018). The mean number of chemotherapy lines received for recurrence was 2.7 and 2.5 in young and aged patients, respectively. Elderly patients received more frequently at second line single agent platinum than platinum-combination therapy or other non-platinum chemotherapy. The response rate to the second line chemotherapy was higher in younger patients than in the elderly population (CR + PR, younger: 67.2%; elderly: 46.5%; p = 0.0004). Median overall survival from recurrence was 30.7 months in the younger patients and 23.6 months in the elderly group (p = 0.0037). At multivariate analysis, number of disease sites (>1 vs. 1), performance status at recurrence (2-3 vs. 0-1), RFI (6-12 months vs. >12 months), age at recurrence, were independently associated with survival.

Conclusion

Elderly patients with platinum-sensitive recurrent ovarian cancer receive less surgery and chemotherapy. Response to chemotherapy is better in younger patients. Age is an unfavourable factor independently associated to a worst prognosis.     

Improving the Diagnostic Accuracy of Depression in Older Persons: The Depression in the Aged Female National Evaluation Cluster Randomized Trial

OBJECTIVES: To evaluate whether a training intervention can improve the ability of geriatricians to recognize depression in older persons.
DESIGN: Multicenter, cluster randomized clinical trial.
SETTING: Fourteen geriatric outpatient clinics in Italy, each representing the unit of randomization.
PARTICIPANTS: After training, a total of 1,914 outpatients aged 65 years and older in both arms, not on antidepressant at entry, were blindly evaluated by the clinic geriatrician, in charge of routine clinical management, and by a field researcher, who formally diagnosed depression by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), taken as the criterion standard.
INTERVENTION: After randomization, geriatricians belonging to the intervention arm were assigned to receive a residential 3-day educational program on depression. Those in the control arm received a generic course on disease management in elderly people.
MEASUREMENTS: Sensitivity and specificity of the diagnosis of depression made by geriatricians, compared with the DSM-IV diagnosis.
RESULTS: Sensitivity and specificity were significantly higher in trained than in untrained geriatricians (49 vs 35% and 91 vs 88%, respectively; P =.002 in marginal regression models). Effectiveness of training was confirmed, adjusting for age, sex, and cognitive performance ( P =.02).
CONCLUSION: The ability of geriatricians to diagnose depression in older outpatients can be improved with a specific training intervention. Improvement of diagnostic performance might translate into more-appropriate clinical management.     

Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity

We analyzed 21 children with leukemia receiving haploidentical hematopoietic stem cell transplantation (haplo-HSCT) from killer immunoglobulin (Ig)-like receptors (KIR) ligand-mismatched donors. We showed that, in most transplantation patients, variable proportions of donor-derived alloreactive natural killer (NK) cells displaying anti-leukemia activity were generated and maintained even late after transplantation. This was assessed through analysis of donor KIR genotype, as well as through phenotypic and functional analyses of NK cells, both at the polyclonal and clonal level. Donor-derived KIR2DL1(+) NK cells isolated from the recipient displayed the expected capability of selectively killing C1/C1 target cells, including patient leukemia blasts. Differently, KIR2DL2/3(+) NK cells displayed poor alloreactivity against leukemia cells carrying human leukocyte antigen (HLA) alleles belonging to C2 group. Unexpectedly, this was due to recognition of C2 by KIR2DL2/3, as revealed by receptor blocking experiments and by binding assays of soluble KIR to HLA-C transfectants. Remarkably, however, C2/C2 leukemia blasts were killed by KIR2DL2/3(+) (or by NKG2A(+)) NK cells that coexpressed KIR2DS1. This could be explained by the ability of KIR2DS1 to directly recognize C2 on leukemia cells. A role of the KIR2DS2 activating receptor in leukemia cell lysis could not be demonstrated. Altogether, these results may have important clinical implications for the selection of optimal donors for haplo-HSCT.     

Neurocognitive aging: prior memories hinder new hippocampal encoding

Normal aging is often accompanied by impairments in forming new memories, and studies of aging rodents have revealed structural and functional changes to the hippocampus that might point to the mechanisms behind such memory loss. In this article, we synthesize recent neurobiological and neurophysiological findings into a model of the information-processing circuit of the aging hippocampus. The key point of the model is that small concurrent changes during aging strengthen the auto-associative network of the CA3 subregion at the cost of processing new information coming in from the entorhinal cortex. As a result of such reorganization in aged memory-impaired individuals, information that is already stored would become the dominant pattern of the hippocampus to the detriment of the ability to encode new information.     

Consolidation effect of repeated processing of declarative knowledge in mental experiences during human sleep

Sleep may positively influence declarative memory through the processing, which transforms items of declarative knowledge into contents of mental sleep experience (MSE). A prediction from this general hypothesis is that the consolidation level should be higher for the output of items repeatedly processed and transformed into identical or very similar (so-called interrelated) contents of distinct MSEs of the same night rather than for the output of items presumably processed once (that is, all other, non-interrelated contents). Two experiments examined whether and how far the frequency and long-term retention of interrelated contents depend on the repeated processing of given items rather than on the experimental procedure applied for detection of interrelated contents. This procedure entails both multiple awakenings and a verbal report of MSE after awakening. Multiple awakenings could facilitate the re-access and elaboration of some contents into the subsequent (i.e. contiguous) MSE rather than non-contiguous MSEs; verbal reports could enhance the delayed recall of interrelated contents in as much as repeatedly encoded. The first experiment showed that interrelated contents were more frequent and better retained than both non-interrelated and pseudo-interrelated (i.e. by-chance similar or identical) contents, and even more in pairs of contiguous than non-contiguous MSEs collected from the first four periods of REM sleep on each experimental night. The second experiment showed that the frequency and retention rate of interrelated contents, while higher than those of non-interrelated and pseudo-interrelated contents, were not significantly different in pairs of MSEs which were verbally or mentally recalled after awakening provoked during the first four periods of REM sleep in each experimental night. Taken together, these findings indicate that the advantage provided by repeated processing during REM sleep for the consolidation of the output of items of declarative knowledge is conspicuous and largely independent from the experimental procedure, as this only slightly enhances the frequency and retention rate of interrelated contents.     

Electrophysiological actions of zonisamide on striatal neurons: Selective neuroprotection against complex I mitochondrial dysfunction

Since the anti-epileptic drug Zonisamide (ZNS) seems to exert beneficial effects in Parkinson's (PD) disease, we have investigated the electrophysiological effects of ZNS in a rat corticostriatal slice preparation. ZNS affected neither the resting membrane potential nor the input resistance of the putative striatal spiny neurons. In contrast, this drug depressed in a dose-dependent manner the current-evoked repetitive firing discharge with a EC₅₀ value of 16.38 μM. ZNS also reduced the amplitude of glutamatergic excitatory postsynaptic potentials (EPSPs) with a EC₅₀ value of 32.5 μM.Reduced activity of the mitochondrial respiratory chain, particularly complex I and II, is implicated in the pathophysiology of PD and Huntington's (HD) diseases, respectively. Thus, ZNS was also tested in two different in vitro neurotoxic models obtained by acutely exposing corticostriatal slices either to rotenone, a selective inhibitor of mitochondrial complex I, or to 3-nitropropionic acid (3-NP), an inhibitor of complex II. Additionally, we also investigated the effect of ZNS in an in vitro model of brain ischemia. Interestingly, low concentrations of ZNS (0.3, 1, 3 and 10 μM) significantly reduced the rotenone-induced toxicity protecting striatal slices from the irreversible loss of corticostriatal field potential (FP) amplitude via a GABA-mediated mechanism. Conversely, this drug showed no protection against 3-NP and ischemia-induced toxicity.Our data indicate that relatively high doses of ZNS are required to decrease striatal neuronal excitability while low concentrations of this drug are sufficient to protect striatum against mitochondrial impairment suggesting its possible use in the therapy of basal ganglia neurodegenerative diseases.     

Role of NMDA receptor in homocysteine-induced activation of Mitogen-Activated Protein Kinase and Phosphatidyl Inositol 3-Kinase pathways in cultured human vascular smooth muscle cells

Introduction

Exposure of vascular smooth muscle cells (VSMC) to homocysteine, at concentrations associated with an increased risk of cardiovascular events, enhances synthesis and secretion of Matrix Metalloproteinase-2 (MMP-2), which is involved in atherosclerotic plaque instabilization. This effect was prevented by inhibitors of Mitogen Activated Protein Kinase (MAPK) and Phosphatidylinositol 3-Kinase (PI3-K) pathways, allowing to hypothesize that homocysteine activates both these pathways, likely via a receptor-mediated mechanism. One possible receptor is N-methyl-D-aspartate receptor (NMDAr), which is expressed in VSMC and is involved in homocysteine effects in other cell types.

Materials and Methods

VSMC exposed to DL-homocysteine or NMDA (100 μmol/L for both; 5 min-8 hours), were investigated by measuring: i) phosphorylation of ERK1/2, p38MAPK (signaling molecules of MAPK pathway) and Akt and p70S6K (signaling molecules of PI3-K pathway) by western blot; ii) synthesis and secretion of MMP-2 (western blot); iii) activation of MMP-2 (gelatin zimography). To evaluate NMDAr involvement in the homocysteine effects, the experiments were repeated in the presence of a non-competitive NMDAr-antagonist MK-801 (50 μmol/L) or L-glycine (10 μmol/L), which inhibits NMDAr function by promoting its internalization.

Results

DL-homocysteine and NMDA time-dependently increased: i) the phosphorylation of ERK1/2, p38 MAPK, Akt and p70S6K (ANOVA, p < 0.0001); ii) the synthesis, secretion and activation of MMP-2. DL-homocysteine and NMDA effects were prevented by VSMC pre-incubation with MK-801 or high L-glycine concentrations.

Conclusions

In human VSMC homocysteine-at concentrations associated with increased cardiovascular risk- activates MAPK and PI3-K pathways and MMP-2 synthesis and secretion through NMDA receptor, a potential mechanism involved in intracellular signaling in response to homocysteine in VSMC.     

Everyday use of the computer mouse extends peripersonal space representation

Auditory and tactile stimuli are integrated within a limited space around the body to form an auditory peripersonal space (APPS). Here we investigate whether the APPS representation around the hand can be extended through the use of a common technological tool such as the computer mouse. When using a mouse, an action occurring in the space around the hand has a distal effect in the space defined by the computer screen; thus, the mouse virtually links near and far space. Does prolonged experience with the mouse durably extend APPS representation to the far space? We examined 16 habitual mouse users to determine whether a sound presented near the right hand or near the computer screen affected reaction times to a tactile target at the hand. When subjects sat in front of the computer, without holding the mouse, they responded faster to tactile stimuli when sounds were presented near the hand rather than near the screen, consistent with a normal segregation of APPS around the hand. In contrast, when subjects either actively used or even passively held the mouse, the difference between the effects of near and far sounds disappeared, thus showing an extension of the APPS toward the far space. This effect was selective for the effector used to operate the mouse: if tactile stimuli were presented on the left hand, rarely used to act upon the mouse, a sound presented near the hand speeded up reactions times when subjects both held and did not hold the mouse in their left hand.     

Improving language without words: first evidence from aphasia

The pervasiveness of word-finding difficulties in aphasia has motivated several theories regarding management of the deficit and its effectiveness. Recently, the hypothesis was advanced that instead of simply accompanying speech gestures participate in language production by increasing the semantic activation of words grounded in sensory-motor features, hence facilitating retrieval of the word form. Based on this assumption, several studies have developed rehabilitation therapies in which the use of gestures reinforces word recovery. Until now, however, no studies have investigated the beneficial effects of gesture observation in word retrieval.Here, we report whether a different modality of accessing action-motor representation interacts with language by promoting long lasting recovery of verb retrieval deficits in aphasic patients.Six aphasic participants with a selective deficit in verb retrieval participated in an intensive rehabilitation training that included three daily sessions over two consecutive weeks. Each session corresponded to a different rehabilitation procedure: (1) “action observation”, (2) “action observation and execution”, and (3) “action observation and meaningless movement”. In the four participants with lexical phonologically based disturbances, significant improvement of verb retrieval was found only with “action observation” and “action observation and execution”. No significant differences were present between the two procedures. Moreover, the follow-up testing revealed long-term verb recovery that was still present two months after the two treatments ended.In support of a multimodal representation of action, these findings univocally demonstrate that gestures interact with the speech production system, inducing long-lasting modification at the lexical level in patients with cerebral damage.