Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma.

PURPOSE: This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. RESULTS: A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. CONCLUSION: Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.     

Tapping movements according to regular and irregular visual timing signals investigated with fMRI

Whole-head functional MR images were acquired while 10 subjects were asked to tap with their right index finger in synchrony with a visual stimulus appearing regularly with a frequency of 1.5 Hz, or irregularly with a mean frequency of 1.5 Hz. Performance data show that during regular tapping most taps were close to stimulus onset. However, when the subjects paced their tapping according to the irregular stimuli, most taps appeared about 300 ms after the onset of the pacing stimuli. Comparing the brain activations resulting from regular tapping with those from irregular tapping, we found increased activation in left precuneus only. Comparing irregular versus regular tapping shows increased activity in right cerebellar nuclei and vermis, left ventrolateral thalamus, left sensorimotor cortex, left and right pre-SMA and left SMA proper. These results show that during irregular pacing the motor areas are more strongly activated than during regular pacing. In addition, further neural systems are involved in the motor control during irregular pacing: cerebellar vermis and a cerebello-thalamo-cortical system. The latter is supposedly involved in error correction in the context of visually guided movements.     

The T393C polymorphism of the G alpha s gene (GNAS1) is a novel prognostic marker in bladder cancer.

The G protein G(alpha)s pathway is linked to proapoptotic signaling in cancer cell lines. To assess the role of the GNAS1 locus encoding G(alpha)s as a genetic factor for disease progression of transitional cell carcinoma (TCC) of the bladder, we genotyped the synonymous T393C polymorphism in 254 patients with TCC (minor allele frequency: 0.43) to examine a potential association between genotypes and disease progression. Using Kaplan-Meier estimates to calculate 5-year probabilities of follow-up, we could show that progression-free survival, metastasis-free survival, and cancer-specific survival was significantly increased in TT genotypes (56%, 84%, 82%) compared with CC genotypes (35%, 53%, 58%). In multivariate Cox proportional hazard analysis, the T393C polymorphism was an independent prognostic factor for clinical outcome. Homozygous CC patients were at highest risk for progression [odds ratio (OR), 1.94; P = 0.020], metastasis (OR, 3.49; P = 0.005), and tumor-related death (OR, 2.49; P = 0.031) compared with TT genotypes. Heterozygous patients had an intermediate risk compatible with a gene-dose effect. Real-time PCR analysis of urothelial tumor tissue as well as adipose and heart tissue revealed that G(alpha)s mRNA expression was highest in TT genotypes, indicating a proapoptotic effect in these genotypes. In conclusion, the GNAS1 T393C status associated with differential G(alpha)s mRNA expression is a novel independent prognostic marker for clinical outcome supporting a functional role of G(alpha)s in bladder cancer progression.     

Phase II study of oxaliplatin for treatment of patients with mucosa-associated lymphoid tissue lymphoma.

PURPOSE: Various chemotherapeutic regimens have been applied for treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, but no standard regimen has been identified to date. In view of the activity of oxaliplatin (L-OHP) in various types of lymphoma, we performed a phase II study to evaluate the activity of L-OHP for treatment of MALT lymphoma. The primary objective of this study was to determine the objective response rate according to WHO standard criteria. PATIENTS AND METHODS: A total of 16 patients with MALT lymphoma of various sites of origin (four of the ocular adnexa, five of the salivary glands, three of the stomach, two of the lung, and one of the colon and the breast) were administered L-OHP at a dose of 130 mg/m2 infused during 2 hours every 3 weeks. Restaging was performed every two cycles; treatment was continued until complete remission (CR) or for a maximum of six cycles in responders. RESULTS: Sixty-five cycles were administered (median, four; range, two to six); toxicity consisted of transient sensory neuropathy in eight patients and nausea/emesis WHO grade 2 in two patients, whereas hematologic adverse effects (thrombocytopenia and leukocytopenia grade 2) occurred in only one patient each. Fifteen patients responded to chemotherapy, with nine achieving CR (56%), six (37.5%) achieving partial response, and one achieving stable disease; the median time to response was 4 months (range; 2 to 4 months). CONCLUSION: These data suggest L-OHP is a highly active agent for treatment of MALT lymphoma. However, a longer follow-up is needed to judge whether these remissions are durable.     

Pneumatic compression hemodynamics in total hip arthroplasty

A crossover study was performed to evaluate the effect of several pneumatic compression devices and active dorsoplantar flexion in 10 patients who underwent total hip arthroplasty. Using the Acuson 128XP/10 duplex ultrasound unit with a 5-MHz linear array probe, peak venous velocity and venous volume were assessed above and below the greater saphenous vein and common femoral vein junction. A computer generated randomization table was used to determine the order of the test conditions. The pneumatic compression devices evaluated included two foot pumps, one foot and calf pump, one calf pump, and three calf and thigh pumps. Statistical analyses included analysis of variance and analysis of variance with covariance between devices and patients. The covariates tested were the baseline measurements and the order in which the devices were tested. Differences between devices relate in part to the frequency and rate of inflation and the location and type of compression. Pulsatile calf and foot and calf pneumatic compression with a rapid inflation time produced the greatest increase in peak venous velocity, whereas compression of the calf and thigh showed the greatest increase in venous volume. Because patient and nursing compliance is essential to the success of mechanical prophylaxis for thromboembolic disease, the more simple, yet efficacious, devices that are easier to apply and less cumbersome appear to have a greater likelihood of success. In the active and alert patient, active dorsoplantar flexion should be encouraged.     

Dopamine antagonists in anovulation?

Increased hypothalamic dopamine turnover may prevent the ovulatory LH peak by different mechanisms and may in this way result in anovulation. Ten patients with anovulatory menstrual cycles who had been treated with clomiphene citrate without success were given the dopaminolytic drug pimozide (Antalon) at a dose of 5 mg/day orally either from day 7 to day 11 (7 women; group 1) or from day 11 to day 15 of the menstrual cycle (4 women; group 2). One patient from group 2 ovulated during the treatment cycle. A further woman from this group exhibited an LH peak, but did not ovulate, whereas a slow increase of the circulating LH level was recorded in the remaining two patients. Systematic investigations should clarify whether introduction of dopaminolytic therapy in the treatment of hypothalamic anovulation may be justified.     

Resin infiltration of deproteinised natural occlusal subsurface lesions improves initial quality of fissure sealing

The aim of this ex vivo study was to evaluate the infiltration capability and rate of microleakage of a low-viscous resin infiltrant combined with a flowable composite resin (RI/CR) when used with deproteinised and etched occlusal subsurface lesions (International Caries Detection and Assessment System code 2). This combined treatment procedure was compared with the exclusive use of flowable composite resin (CR) for fissure sealing. Twenty premolars and 20 molars revealing non-cavitated occlusal carious lesions were randomly divided into two groups and were meticulously cleaned and deproteinised using NaOCl (2%). After etching with HCl (15%), 10 premolar and 10 molar lesions were infiltrated (Icon/DMG; rhodamine B isothiocyanate (RITC)-labelled) followed by fissure sealing (G-?nial Flo/GC; experimental group, RI/CR). In the control group (CR), the carious fissures were only sealed. Specimens were cut perpendicular to the occlusal surface and through the area of the highest demineralisation (DIAGNOdent pen, KaVo). Using confocal laser-scanning microscopy, the specimens were assessed with regard to the percentage of caries infiltration, marginal adaption and internal integrity. Within the CR group, the carious lesions were not infiltrated. Both premolar (57.9%± 23.1%) and molar lesions (35.3%± 22.1%) of the RI/CR group were uniformly infiltrated to a substantial extent, albeit with significant differences (P=0.034). Moreover, microleakage (n=1) and the occurrence of voids (n=2) were reduced in the RI/CR group compared with the CR group (5 and 17 specimens, respectively). The RI/CR approach increases the initial quality of fissure sealing and is recommended for the clinical control of occlusal caries.