Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centre

Varicella-Zoster viruses associated with post-herpetic neuralgia induce sodium current density increases in the ND7-23 Nav-1.8 neuroblastoma cell line

Post-herpetic neuralgia (PHN) is the most significant complication of herpes zoster caused by reactivation of latent Varicella-Zoster virus (VZV). We undertook a heterologous infection in vitro study to determine whether PHN-associated VZV isolates induce changes in sodium ion channel currents known to be associated with neuropathic pain. Twenty VZV isolates were studied blind from 11 PHN and 9 non-PHN subjects. Viruses were propagated in the MeWo cell line from which cell-free virus was harvested and applied to the ND7/23-Nav1.8 rat DRG x mouse neuroblastoma hybrid cell line which showed constitutive expression of the exogenous Nav 1.8, and endogenous expression of Nav 1.6 and Nav 1.7 genes all encoding sodium ion channels the dysregulation of which is associated with a range of neuropathic pain syndromes. After 72 hrs all three classes of VZV gene transcripts were detected in the absence of infectious virus. Single cell sodium ion channel recording was performed after 72 hr by voltage-clamping. PHN-associated VZV significantly increased sodium current amplitude in the cell line when compared with non-PHN VZV, wild-type (Dumas) or vaccine VZV strains ((POka, Merck and GSK). These sodium current increases were unaffected by acyclovir pre-treatment but were abolished by exposure to Tetrodotoxin (TTX) which blocks the TTX-sensitive fast Nav 1.6 and Nav 1.7 channels but not the TTX-resistant slow Nav 1.8 channel. PHN-associated VZV sodium current increases were therefore mediated in part by the Nav 1.6 and Nav 1.7 sodium ion channels. An additional observation was a modest increase in message levels of both Nav1.6 and Nav1.7 mRNA but not Nav 1.8 in PHN virally infected cells

Vocabulary Learning in a Yorkshire Terrier: Slow Mapping of Spoken Words

Rapid vocabulary learning in children has been attributed to “fast mapping”, with new words often claimed to be learned through a single presentation. As reported in 2004 in Science a border collie (Rico) not only learned to identify more than 200 words, but fast mapped the new words, remembering meanings after just one presentation. Our research tests the fast mapping interpretation of the Science paper based on Rico's results, while extending the demonstration of large vocabulary recognition to a lap dog. We tested a Yorkshire terrier (Bailey) with the same procedures as Rico, illustrating that Bailey accurately retrieved randomly selected toys from a set of 117 on voice command of the owner. Second we tested her retrieval based on two additional voices, one male, one female, with different accents that had never been involved in her training, again showing she was capable of recognition by voice command. Third, we did both exclusion-based training of new items (toys she had never seen before with names she had never heard before) embedded in a set of known items, with subsequent retention tests designed as in the Rico experiment. After Bailey succeeded on exclusion and retention tests, a crucial evaluation of true mapping tested items previously successfully retrieved in exclusion and retention, but now pitted against each other in a two-choice task. Bailey failed on the true mapping task repeatedly, illustrating that the claim of fast mapping in Rico had not been proven, because no true mapping task had ever been conducted with him. It appears that the task called retention in the Rico study only demonstrated success in retrieval by a process of extended exclusion

Child categorization

Categorization is a process that spans all of development, beginning in earliest infancy yet changing as children's knowledge and cognitive skills develop. In this review article, we address three core issues regarding childhood categorization. First, we discuss the extent to which early categories are rooted in perceptual similarity versus knowledge-enriched theories. We argue for a composite perspective in which categories are steeped in commonsense theories from a young age but also are informed by low-level similarity and associative learning cues. Second, we examine the role of language in early categorization. We review evidence to suggest that language is a powerful means of expressing, communicating, shaping, and supporting category knowledge. Finally, we consider categories in context. We discuss sources of variability and flexibility in children's categories, as well as the ways in which children's categories are used within larger knowledge systems (e.g., to form analogies, make inferences, or construct theories). Categorization is a process that is intrinsically tied to nearly all aspects of cognition, and its study provides insight into cognitive development, broadly construed. WIREs Cogn Sci 2011 2 95–105 DOI: 10.1002/wcs.96 For further resources related to this article, please visit the WIREs websitePeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78491/1/96_ftp.pd

Is caching the key to exclusion in corvids? The case of carrion crows (Corvus corone corone)

Recently, two corvid species, food-caching ravens and non-caching jackdaws, have been tested in an exclusion performance (EP) task. While the ravens chose by exclusion, the jackdaws did not. Thus, foraging behaviour may affect EP abilities. To investigate this possibility, another food-caching corvid species, the carrion crow (Corvus corone corone), was tested in the same exclusion task. We hid food under one of two cups and subsequently lifted either both cups, or the baited or the un-baited cup. The crows were significantly above chance when both cups were lifted or when only the baited cup was lifted. When the empty cup was lifted, we found considerable inter-individual variation, with some birds having a significant preference for the un-baited but manipulated cup. In a follow-up task, we always provided the birds with the full information about the food location, but manipulated in which order they saw the hiding or the removal of food. Interestingly, they strongly preferred the cup which was manipulated last, even if it did not contain any food. Therefore, we repeated the first experiment but controlled for the movement of the cups. In this case, more crows found the food reliably in the un-baited condition. We conclude that carrion crows are able to choose by exclusion, but local enhancement has a strong influence on their performance and may overshadow potential inferential abilities. However, these findings support the hypothesis that caching might be a key to exclusion in corvids

First-line treatment for advanced ovarian cancer: paclitaxel, platinum and the evidence

Four large randomised trials of paclitaxel in combination with platinum against a platinum-based control treatment have now been published in full, representing around 88% (3588 out of 4057) of patients randomised into the eight known trials of this question. There is substantial heterogeneity in the results of these four trials. Four main explanations for this heterogeneity have been proposed: differences in the extent and timing of ‘crossover’ to taxanes in the control groups; differences in the types of patient included; differences in the effectiveness of the research regimens used; differences in the effectiveness of the control regimens used. In this study we examine whether any of these explanations is consistent with the pattern of results seen in these trials. Each explanation suggests that a particular characteristic of each trial was responsible for the results observed. For each explanation the trials were split into groups according to that characteristic, in order to partition the total heterogeneity into that seen ‘within’ and ‘between’ groups of trials. If a particular explanation was consistent with the pattern of results, we would expect to see relatively little heterogeneity within each group of trial results viewed in this way, with most of the heterogeneity being between groups which are dissimilar with respect to the key characteristic. Heterogeneity ‘within’ and ‘between’ groups was formally compared using the F-ratio. If any explanation appeared to be consistent with the results of the trials, it was considered whether the explanation was also consistent with other evidence available about these regimens. Only one explanation appeared to be consistent with the pattern of results seen in these trials, and that was differences in effectiveness of the control arms used in these trials. This suggests that the very positive results in favour of paclitaxel/cisplatin seen in two of the trials may have been due to the use of a suboptimal control arm. There is no direct evidence about the relative effectiveness of the control arms used in these trials, but indirect evidence is consistent with the conclusion that the cyclophosphamide/cisplatin regimen used in two of the trials may be less effective than the control regimens used in the other trials. Specific concerns about the choice of a cyclophosphamide/cisplatin control arm in the first of these trials to report were raised before the results of the other trials were known, i.e. before any heterogeneity had been observed. Further investigation of this question would be useful. In the meantime, given all of the randomised evidence on the efficacy and toxicity associated with the regimens used in these trials, we conclude that single agent carboplatin is a safe and effective first-line treatment for women with advanced ovarian cancer

Two-Item Sentence Comprehension by a Dog (Canis familiaris)

Syntax use by non-human animals remains a controversial issue. We present here evidence that a dog may respond to verbal requests composed of two independent terms, one referring to an object and the other to an action to be performed relative to the object. A female mongrel dog, Sofia, was initially trained to respond to action (point and fetch) and object (ball, key, stick, bottle and bear) terms which were then presented as simultaneous, combinatorial requests (e.g. ball fetch, stick point). Sofia successfully responded to object-action requests presented as single sentences, and was able to flexibly generalize her performance across different contexts. These results provide empirical evidence that dogs are able to extract the information contained in complex messages and to integrate it in directed performance, an ability which is shared with other linguistically trained animals and may represent a forerunner of syntactic functioning

Sustained platelet-sparing effect of weekly low dose paclitaxel allows effective, tolerable delivery of extended dose dense weekly carboplatin in platinum resistant/refractory epithelial ovarian cancer

Background: Platinum agents have shown demonstrable activity in the treatment of patients with platinum resistant, recurrent ovarian cancer when delivered in a "dose-dense" fashion. However, the development of thrombocytopenia limits the weekly administration of carboplatin to no greater than AUC 2. Paclitaxel has a well-described platelet sparing effect however its use to explicitly provide thromboprotection in the context of dose dense carboplatin has not been explored. Methods: We treated seven patients with platinum resistant ovarian cancer who had previously received paclitaxel or who had developed significant peripheral neuropathy precluding the use of further full dose weekly paclitaxel. Results: We were able to deliver carboplatin AUC 3 and paclitaxel 20 mg/m(2) with no thrombocytopenia or worsening of neuropathic side-effects, and with good activity. Conclusions: We conclude that this regimen may be feasible and active, and could be formally developed as a "platinum-focussed dose-dense scaffold" into which targeted therapies that reverse platinum resistance can be incorporated, and merits further evaluation

Extended weekly dose-dense paclitaxel/carboplatin is feasible and active in heavily pre-treated platinum-resistant recurrent ovarian cancer

There is increasing evidence of the efficacy of dose-dense therapy in the management of platinum-resistant/refractory ovarian cancer. We report our experience of extended weekly carboplatin and paclitaxel in this population group. Twenty patients with platinum-resistant/refractory ovarian cancer received carboplatin AUC 3 and paclitaxel 70 mg m−2 on day 1, 8, 15 q 4 weekly for six planned cycles. Toxicity was assessed using Common Toxicity Criteria. Response was evaluated using radiological and CA125 criteria. Median age was 61 years (range 40–74 years). Median number of prior therapies is three (range 1–8). Response rate was 60% by radiological criteria (RECIST) and 76% by CA125 assessment. Grade 3 toxicities consisted of neutropenia (29% of patients) and anaemia (5%). One patient experienced grade 4 neutropenia. No grade 3/4 thombocytopaenia was reported. Fatigue, nausea and peripheral neuropathy were the most frequent non-hematological side effects. Median progression-free survival was 7.9 months and overall survival was 13.3 months. The dynamics of response to dose-dense therapy were as rapid as with front-line therapy within the same patient. This dose-dense regimen can be extended to at least 18 weekly cycles over 6 months and is well tolerated with high response rates in heavily pre-treated, platinum-resistant ovarian cancer. It forms a highly active and tolerable cytotoxic scaffold to which molecular-targeted therapies can be added in platinum-resistant ovarian cancer