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.     

Expression of Daxx sensitizes Jurkat T-cells to the apoptosis-inducing effect of chemotherapeutic agents.

BACKGROUND: The role of Daxx, in particular its ability to promote or hinder apoptosis, still remains controversial. In order to elucidate the functional relevance of Daxx in the extrinsic signaling of malignant lymphocytes Jurkat T-cells were stably transfected with a Daxx-expressing vector or with the respective Daxx-negative control vector. RESULTS: Assessing first the impact of Daxx expression on the rate of proliferation we demonstrate that overexpression of Daxx alone is not sufficient to alter proliferation in neoplastic lymphocytes. Nevertheless, expression of Daxx down-regulates anti-apoptotic Bcl-2 and up-regulates pro-apoptotic BID. In addition, Daxx-overexpressing Jurkat cells exhibit a decreased expression of the pro-caspase-8, -10, -9 and -3 and a concomitant increase of the inhibitors of apoptosis proteins survivin, XIAP, cIAP-1 and -2. We further demonstrate, that upon incubation with various chemotherapeutic agents these Daxx-induced molecular alterations sensitize Jurkat T-cells to the apoptosis-inducing effects of specific chemotherapeutic agents. CONCLUSIONS: We here outline the molecular changes elicited by Daxx on major components of the apoptotic cascade of malignant lymphocytes and demonstrate the capacity of Daxx to sensitize these cells to the apoptosis-inducing effect of various chemotherapeutic agents.     

Utricular dysfunction in patients with benign paroxysmal positional vertigo.

OBJECTIVE: The objective of this study was to test the hypothesis that utricular function is impaired in patients with idiopathic benign paroxysmal positional vertigo. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary dizziness clinic and vestibular research laboratory. PATIENTS: Twelve patients with unilateral idiopathic benign paroxysmal positional vertigo were examined 1 week and 1 month after successful treatment with positioning maneuvers and compared with 24 healthy subjects. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Otolith function was assessed with estimation of the subjective visual vertical and analysis of the torsional otolith-ocular reflex. Unilateral stimulation of the utricle was performed on a rotator that allowed eccentric lateral displacement of the patient during earth-vertical rotation with constant velocity. The otolith-ocular reflex was recorded with three-dimensional video-oculography. RESULTS: There was no difference in the estimation of the subjective visual vertical between patients and controls. The peak-to-peak amplitude of the otolith-ocular reflex torsional eye position was smaller in patients than in the control group. The gain of the unilateral otolith-ocular reflex was reduced in patients on both sides on first testing. After several weeks, only the affected labyrinth showed a reduced otolith-ocular reflex gain. CONCLUSION: Our findings document otolith dysfunction in patients with idiopathic benign paroxysmal positional vertigo possibly secondary to degeneration of the utricular macula. This finding may account for the transient mild imbalance and dizziness that some patients with benign paroxysmal positional vertigo experience even after resolution of positional vertigo.     

Intensity modulated radiation therapy with multileaf collimators of different leaf widths: a comparison of achievable dose distributions.

PURPOSE: A planning study to analyze the impact of different leaf widths on the achievable dose distributions with intensity modulated radiation therapy (IMRT). METHODS: Five patients (3 intra- and 2 extra-cranial) with projected planning target volume (PTV) sizes smaller than 10 cm by 10 cm were re-planned with four different multileaf collimators (MLC). Two internal collimators with an isocentric leaf width of 4 and 10 mm and two add-on collimators with an isocentric leaf width of 2.75 and were evaluated. The inverse treatment planning system KonRad (Siemens Medical Solutions) was used to create IMRT 'step & shoot' plans. For each patient the same arrangement of beams and the same parameters for the optimization were used for all MLCs. The beamlet size for all treatment plans was chosen to coincide with the leaf width of the respective MLC. To evaluate the treatment plans 3D dose distributions and dose volume histograms were analyzed. As indicators for the quality of the PTV dose distribution the minimum dose, maximum dose and the standard deviation were used. For the organs at risk (OAR) the equivalent uniform dose (EUD) was calculated. To measure the dose coverage of the PTV the volume (V(90)) that received doses higher than 90% of the prescribed dose was calculated where for the conformity the dose conformity index given by Baltas et al. was determined. RESULTS: The MLC with the smallest leaf width yields the best mean value of all five patients for the PTV coverage and for the conformity. For the MLCs with the same leaf width, the add-on MLC leads to superior treatment plans than the internal MLC. This is due to the sharper penumbra of the add-on MLC. The number of IMRT field segments to deliver increased by approximately a factor of two if 2. MLC leafs are used instead of the standard 10 mm leafs. In case of the para-spinal patients the EUD value for the spinal cord is only reduced slightly by using MLCs with leaf widths smaller than 5 mm. For the intra-cranial the EUD value for some organs improved with reduced leaf widths while for some organs the 10 mm MLC leafs give comparable values. CONCLUSION: As expected the MLC with the smallest leaf width always yields the best PTV coverage. Reducing the leaf width from 4 to 2.75 mm results in a slight enhancement of the PTV coverage. With the selected organ parameters no significant improvement for most OAR was found. The disadvantage of the reduction of the leaf width is the increasing number of segments due to the more complex fluence patterns and therefore an increased delivery time.     

Neoplastic human embryonic stem cells as a model of radiation resistance of human cancer stem cells

Studies have implicated that a small sub-population of cells within a tumour, termed cancer stem cells (CSCs), have an enhanced capacity for tumour formation in multiple cancers and may be responsible for recurrence of the disease after treatment, including radiation. Although comparisons have been made between CSCs and bulk-tumour, the more important comparison with respect to therapy is between tumour-sustaining CSC versus normal stem cells that maintain the healthy tissue. However, the absence of normal known counterparts for many CSCs has made it difficult to compare the radiation responses of CSCs with the normal stem cells required for post-radiotherapy tissue regeneration and the maintenance of tissue homeostasis. Here we demonstrate that transformed human embryonic stem cells (t-hESCs), showing features of neoplastic progression produce tumours resistant to radiation relative to their normal counterpart upon injection into immune compromised mice. We reveal that t-hESCs have a reduced capacity for radiation induced cell death via apoptosis and exhibit altered cell cycle arrest relative to hESCs in vitro. t-hESCs have an increased expression of BclXL in comparison to their normal counterparts and re-sensitization of t-hESCs to radiation upon addition of BH3-only mimetic ABT737, suggesting that overexpression of BclXL underpins t-hESC radiation insensitivity. Using this novel discovery platform to investigate radiation resistance in human CSCs, our study indicates that chemotherapy targeting Bcl2-family members may prove to be an adjuvant to radiotherapy capable of targeting CSCs.