Patupilone (epothilone B) for recurrent glioblastoma: clinical outcome and translational analysis of a single-institution phase I/II trial.

BACKGROUND: Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multimodal treatment and have a median survival of 6-9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models. METHODS: This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m(2), every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers. RESULTS: Nine patients with a mean age of 54.6 ± 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5-17 months) and 45% (95% CI, 14-76), respectively. Median PFS was 1.5 months (95% CI, 1.3-1.7 months) and PFS6 was 22% (95% CI, 0-46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade ≤3 was seen in 2 patients (22%) at 8 months and grade 4 diarrhea in the 2nd patient (11%). Non-patupilone-related peri-operative complications occurred in 2 patients resulting in discontinuation of patupilone therapy. There were no neurocognitive changes 3 months after surgery compared to baseline. CONCLUSIONS: In recurrent GBM, patupilone can be given safely pre- and postoperatively. The drug accumulates in the tumor tissue. The treatment results in long-term PFS in some patients. Patupilone represents a valuable novel compound which deserves further evaluation in combination with radiation therapy in patients with GBM.

Impaired verbal memory in Parkinson disease: relationship to prefrontal dysfunction and somatosensory discrimination.

OBJECTIVE: To study the neurocognitive profile and its relationship to prefrontal dysfunction in non-demented Parkinson's disease (PD) with deficient haptic perception. METHODS: Twelve right-handed patients with PD and 12 healthy control subjects underwent thorough neuropsychological testing including Rey complex figure, Rey auditory verbal and figural learning test, figural and verbal fluency, and Stroop test. Test scores reflecting significant differences between patients and healthy subjects were correlated with the individual expression coefficients of one principal component, obtained in a principal component analysis of an oxygen-15-labeled water PET study exploring somatosensory discrimination that differentiated between the two groups and involved prefrontal cortices. RESULTS: We found significantly decreased total scores for the verbal learning trials and verbal delayed free recall in PD patients compared with normal volunteers. Further analysis of these parameters using Spearman's ranking correlation showed a significantly negative correlation of deficient verbal recall with expression coefficients of the principal component whose image showed a subcortical-cortical network, including right dorsolateral-prefrontal cortex, in PD patients. CONCLUSION: PD patients with disrupted right dorsolateral prefrontal cortex function and associated diminished somatosensory discrimination are impaired also in verbal memory functions. A negative correlation between delayed verbal free recall and PET activation in a network including the prefrontal cortices suggests that verbal cues and accordingly declarative memory processes may be operative in PD during activities that demand sustained attention such as somatosensory discrimination. Verbal cues may be compensatory in nature and help to non-specifically enhance focused attention in the presence of a functionally disrupted prefrontal cortex.

Broca's area: a supramodal hierarchical processor?

Despite the presence of shared characteristics across the different domains modulating Broca's area activity (e.g., structural analogies, as between language and music, or representational homologies, as between action execution and action observation), the question of what exactly the common denominator of such diverse brain functions is, with respect to the function of Broca's area, remains largely a debated issue. Here, we suggest that an important computational role of Broca's area may be to process hierarchical structures in a wide range of functional domains.

Awake surgery for glioma resection in eloquent areas--Zurich's experience and review--.

Awake surgery was performed in a series of 21 patients with gliomas in eloquent areas with the use of intraoperative electrical mapping. Gross total removal was performed in 18 patients. There was no operative mortality. Postoperative findings included no change in symptoms and signs in 10 patients, improvement of the preoperative deficit in 11 patients. Four patients had improved Karnofsky performance status (KPS) scores after surgery, 17 patients were stable, and no patient had lower KPS score. Extensive radical resection of gliomas prolongs the overall survival and improves the patient's quality of life. However, surgical resection of gliomas located within the sensorimotor or language areas remains a neurosurgical challenge in reducing eloquent neurological sequelae. Awake surgery with intraoperative functional mapping is a safe approach to maximize the extent of tumor removal and to minimize the resultant neurological deficits in the treatment of glioma involving the eloquent cortex.

Number representation deficit: a bilingual case of failure to access written verbal numeral representations.

This study reports the case of a Greek-German bilingual patient (S.V.) with specific deficit in Arabic number production from written German number words. S.V. was able to successfully complete the reverse task, i.e. to convert Arabic numerals into written or oral German number words. She also showed preserved ability to produce both German and Greek numbers and to accurately make oral magnitude judgments in both languages. However, when transcoding two-digit numbers from German written numerals to Arabic numbers she consistently reversed the digits. A series of in-house tasks were used to test her general abilities of number processing, i.e. number synesthesia and calculation. Moreover, a number magnitude comparison task was developed specifically for pairs of numbers with reverse digits and we found that out of pairs of numbers with reverse digits with magnitude less than 100, there exist 19 pair combinations for which distance and relative distance are not concordant. The results suggest that S.V.'s performance was significantly worse as the absolute distance between the numbers in the number pairs increased. These investigations are discussed in analogy with a grammatical rule problem related to absolute and relative distance effects.

Neural correlates for the acquisition of natural language syntax.

Some types of simple and logically possible syntactic rule never occur in human language grammars, leading to a distinction between grammatical and nongrammatical syntactic rules. Comparison of the neuroanatomical correlates underlying the acquisition of grammatical and nongrammatical rules can provide relevant evidence on the neural processes dedicated to language acquisition in a given developmental stage. Until present no direct evidence on the neural mechanisms subserving language acquisition at any developmental stage has been supplied. We used fMRI in investigating the acquisition of grammatical and nongrammatical rules in the specified sense in 14 healthy adults. Grammatical rules compared with nongrammatical rules specifically activated a left hemispheric network including Broca's area, as shown by direct comparisons between the two rule types. The selective role of Broca's area was further confirmed by time x condition interactions and by proficiency effects, in that higher proficiency in grammatical rule usage, but not in usage of nongrammatical rules, led to higher levels of activation in this area. These findings provide evidence for the neural mechanisms underlying language acquisition in adults.

A cross-linguistic data bank for oral picture naming in Dutch, English, German, French, Italian, Russian, Spanish, and Swedish (PEDOI).

The well established effect of word frequency on adult's picture naming performance is now called into question. This is particularly true for variables which are correlated with frequency, as is the case of age of word acquisition. Since the work of [Carrol and White, 1973] there is growing agreement among researchers to confer an important role in lexical access to this variable. Indeed, it has been shown ( [Hodgson and Ellis, 1998]) that for normal English-speaking adults only the variables 'age-of-acquisition' and 'name agreement' are independent predictors of naming success among the various variables considered. However, when brain-damaged subjects with and without degenerative pathologies are studied, word frequency and word length as well as concept familiarity all give significant effects ( [Hirsh and Funnell, 1995]; [Lambon Ralph et al., 1998]; [Nickels and Howard, 1995]). Finally, it has been suggested that the production of specific error types may be related to such variables. According to [Nickels and Howard, 1994] the production of semantic errors is specifically affected by 'imageability' and in the recent study by [Kremin et al., 2001] 'age of acquisition' predicts (frank) word finding difficulties.