Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial.

TLR-9 agonists are immunostimulating agents that have antitumor effects in animal models. A phase I trial was conducted to define the safety profile of subcutaneous injections, combined with intrathecally administration of CpG-28, a TRL 9 agonist, in patients with neoplastic meningitis (NM). Cohorts of 3-6 patients with NM were treated for 5 weeks with escalating doses of CpG-28. The primary endpoint was tolerance. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Twenty-nine patients were treated with CpG-28. The primary cancers were malignant glioma, lung carcinoma, breast cancer, melanoma or melanocytoma, ependymoma, and colorectal cancer. The median age was 56 years and median Karnovsky Performance status (KPS) was 70%. The treatment was well tolerated. Adverse effects that were possibly or probably related to the studied drug were grade 2 lymphopenia, anemia and neutropenia, local erythema at injection sites, fever and seizure. There were five serious adverse events: two confusions, two infections of ventricular devices and one grade 4 thrombopenia and neutropenia. The median PFS was 7 weeks and median OS was 15 weeks. Interestingly, the median survival was slightly (but not significantly) higher in the eight patients who were concomitantly treated with bevacizumab (19 weeks vs 15 weeks; P = 0.11). CpG-28 was well tolerated at doses up to 0.3 mg/kg subcutaneously and 18 mg intrathecally. Additional trials are warranted.

Steroid requirements during radiotherapy for malignant gliomas.

Radiotherapy (RT) is the standard treatment for high-grade gliomas. However, toxicity may develop during RT, such as brain edema or worsening of neurological symptoms. Surprisingly, no dedicated study had focused on steroid requirements during RT in adult patients with malignant gliomas. We evaluated prospectively all patients with malignant gliomas treated by RT in a single center from July 2006 to May 2009. Age, sex, initial Karnofsky performance status (KPS), tumor localization and histology, type of surgical resection, clinical target volume, total dose and duration of RT, concomitant treatment with temozolomide, and steroid dosage during RT and at 1 and 3 months after RT were recorded in all patients. Most of the 80 patients (70%) were already taking steroids before RT. Half of them (55%) required initiation or further steroids increase during RT. The median time to steroid increase was 8 days. Only 13% of patients remained free of steroids during RT, and the mean maximal dosage of prednisone was 55 ± 48 mg. At 3 months after RT, 29% of patients were free of steroids, and the mean prednisone dosage was 32 ± 50 mg. Unresected tumors and initial KPS ≤80% were the only variables associated with higher steroid requirements on multivariate analysis. In our series, almost all patients required steroids during RT. Poor initial KPS and biopsy were associated with higher steroid requirements.

Psychomotor slowing in mild cognitive impairment, Alzheimer's disease and lewy body dementia: mechanisms and diagnostic value.

BACKGROUND: Although psychomotor slowing is frequent in Alzheimer's disease (AD) and Lewy body dementia (LBD), its mechanism and diagnostic value have not been examined. OBJECTIVE: To (i) assess psychomotor speed in patients with mild cognitive impairment (MCI), AD and LBD, (ii) determine the underlying mechanisms, and (iii) examine whether psychomotor slowing constitutes a useful diagnostic marker. METHODS: Psychomotor speed was assessed in MCI (n = 11) and mild dementia due to AD (n = 23) or LBD (n = 18) and controls (n = 52) with visual inspection time (VIT), digital tapping, simple reaction time (SRT) and choice reaction time (CRT) tests. RESULTS: MCI did not differ from controls. Both dementia groups showed different patterns. In AD, VIT (p = 0.0001), tapping (p = 0.021), SRT (p = 0.0001) and decision time (p = 0.0001) were impaired as compared to controls. In LBD, VIT (p = 0.0001) was very impaired and correlated with visual hallucinations (p = 0.001); SRT lengthening (p = 0.0001) was related to attentional disorders (p = 0.0001). CONCLUSIONS: Psychomotor slowing of AD is due to slower perceptuomotor and decision processes. In LBD, psychomotor slowing is due to visual and attention disorders, and subtle visual disorders contribute to hallucinations. VIT and CRT are useful diagnostic markers.

Music as a mnemonic strategy to mitigate verbal episodic memory in Alzheimer's disease: Does musical valence matter?

Introduction: Music is increasingly used to improve cognition in clinical settings. However, it remains unclear whether its use as a mnemonic strategy is effective in Alzheimer's disease (AD). The present study aimed at determining whether a musical mnemonic might mitigate patients' learning of new verbal information and at exploring the effect of factors such as retention delay and emotional valence of the musical excerpt used. Method: 13 patients with AD and 26 healthy comparisons (HC) with a low musical expertise were included. They learned texts about everyday life themes that were either set to familiar instrumental music, which was positively- or negatively-valenced, or spoken only. Immediate and delayed recalls (after 10 min and 24 hours) were measured. Results: Main results showed that (i) HC demonstrated better verbal episodic memory performance than participants with AD; (ii) participants with AD encoded texts paired with positively-valenced music better than texts paired with negatively-valenced music; (iii) participants with AD recalled sung texts better than spoken texts (after 10 min and 24 hours), regardless of musical valence while HC displayed better recall for texts paired with positively-valenced music. Conclusions: Musical mnemonics may help people with AD learn verbal information that relates to their daily life, regardless the musical expertise of the patients. This result gives promising clinical insights showing that music processing is robust to brain damage in AD. Possible hypotheses explaining the effectiveness of musical mnemonics in AD regardless the musical valence are discussed (e.g., different processing between musical and spoken conditions; disappearance of the positivity bias and implications with respect to the underlying socio-emotional selectivity theory).

The TMA-93: A New Memory Test for Alzheimer's Disease in Illiterate and Less Educated People.

The present study aimed at validating the Memory Associative Test of the district of Seine-Saint-Denis (TMA)-93, a new test of episodic memory. The TMA-93 was proposed to mostly less educated and multicultural elderly population composed of 376 healthy controls (HC) and 94 patients with Alzheimer's disease (AD). The construct validity was checked by studying correlations with a widely used memory test (the Free and Cued Selective Reminding Test [FCSRT]) in the subsample of literate patients. Results showed that (i) all the TMA-93 scores of the patients with AD were lower than those of the HC, (ii) the TMA-93 total score identified patients with AD with a high sensitivity (88%) and very high specificity (97%), and (iii) the TMA-93 total score was strongly correlated with both free recall and total recall scores of the FCSRT. Taken together, results showed that the TMA-93 is a reliable tool to assess episodic memory in a multicultural, less educated, or illiterate population, with good construct validity for AD diagnostic accuracy.

TNI-93: A New Memory Test for Dementia Detection in Illiterate and Low-Educated Patients.

OBJECTIVE: To validate the TNI-93 test in illiterate and low-educated subjects by setting cutoff scores to discriminate non-demented and demented subjects in a clinical setting (CESILL) and verifying the adequacy of these cutoff scores in a population-based study (AMI cohort). METHOD: We used two study samples. First, a clinical setting (CESILL) comprising normal elderly participants and demented patients, mostly multicultural, low educated, or illiterate, was used to compute the cutoff scores of TNI-93 for the detection of dementia. Second, the AMI cohort, a population-based cohort of retired farmers living in a rural setting, was used as a replication study, to assess the detection properties of the cutoff scores in a different population composed mostly of low-educated older people. RESULTS: When combining the two scores, that is, free recall <6 or total recall <9, TNI-93 can detect dementia with a high sensitivity (87%) and specificity (96%), in the CESILL setting. These cutoff scores were roughly similar in the AMI cohort with high sensitivity (80% sensitivity) and specificity (81% specificity). In both study samples, the level of education had no effect on performance. CONCLUSIONS: The TNI-93 appears to be a good test to detect dementia. The absence of a significant effect of education level on the performances makes the TNI-93 a tool of choice in the screening of dementia in illiterate/low-educated subjects.

[Symptomatic management of brain metastasis]. / Prise en charge symptomatique des métastases cérébrales.

Indications and choice of antiepileptic drugs (AED), treatments for cerebral edema and prophylactic and curative treatments of thromboembolic complications of brain metastasis are discussed.

Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma.

Approximately 10% of patients with non-small cell lung cancer (NSCLC) have brain metastases at the time of diagnosis. When surgical resection is not possible, whole brain radiotherapy is the standard of care, with a cerebral response rate of approximately 30%. We report our experience with an upfront association of carboplatin and pemetrexed (areas under the curve, 5 and 500 mg/m(2), respectively), every 3 weeks, in 30 patients presenting with newly diagnosed brain metastases and NSCLC. Cerebral MRIs were performed every 6-9 weeks. The radiologic response rates were assessed according to Response Evaluation Criteria in Solid Tumors. Overall survival was also determined. Twenty-six patients were evaluable for response, and the objective cerebral response rate (complete and partial response) in the intent-to-treat population was 40% (12 of 30 patients). Event-free survival was 31 weeks, and median overall survival was 39 weeks. The upfront association of carboplatin plus pemetrexed allows simultaneous treatment of cerebral and systemic disease in patients with NSCLC with newly diagnosed brain metastases and appears to be particularly interesting in terms of radiologic response and overall survival. Further clinical studies are warranted.

[Clinical symptoms and symptomatic management of brain metastases]. / Métastases cérébrales : manifestations cliniques et traitements symptomatiques.

Cancer patients frequently develop brain metastases. Symptomatic treatments are important to stabilize these patients before an oncological procedure (usually radiotherapy, sometimes surgery or chemotherapy) can be started. These symptomatic treatments mainly rely on steroids to reduce the peritumoral edema; anti-epileptic drugs for patients who previously had seizures, and low-molecular-weight heparin for patients at risk of thrombo-embolic events.