Phase I study of GSK461364, a specific and competitive Polo-like Kinase 1 (PLK1) inhibitor in patients with advanced solid malignancies.

Purpose: GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted. Experimental Design: GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatment tumor biopsies. Results: Forty patients received GSK461364: 23 patients in schedule A and 17 in schedule B. Dose-limiting toxicities (DLT) in schedule A at 300 mg (2 of 7 patients) and 225 mg (1 of 8 patients) cohorts included grade 4 neutropenia and/or grade 3–4 thrombocytopenia. In schedule B, DLTs of grade 4 pulmonary emboli and grade 4 neutropenia occurred at 7 or more days at 100 mg dose level. Venous thrombotic emboli (VTE) and myelosuppression were the most common grade 3–4, drug-related events. Pharmacokinetic data indicated that AUC (area under the curve) and C max (maximum concentration) were proportional across doses, with a half-life of 9 to 13 hours. Pharmacodynamic studies in circulating tumor cells revealed an increase in phosphorylated histone H3 (pHH3) following drug administration. A best response of prolonged stable disease of more than 16 weeks occurred in 6 (15%) patients, including 4 esophageal cancer patients. Those with prolonged stable disease had greater expression of Ki-67, pHH3, and Plk1 in archived tumor biopsies. Conclusions: The final recommended phase II dose for GSK461364 was 225 mg administered intravenously in schedule A. Because of the high incidence (20%) of VTE, for further clinical evaluation, GSK461364 should involve coadministration of prophylactic anticoagulation.

Induction of tetraploidy through loss of p53 and upregulation of Plk1 by Human Papillomavirus type-16 E6

Cancer cells are insensitive to many signals that inhibit growth of untransformed cells. Here, we show that primary human epithelial cells expressing human papillomavirus (HPV) type-16 E6/E7 bypass arrest caused by the DNA-damaging drug adriamycin and become tetraploid. To determine the contribution of E6 in the context of E7 to the resistance of arrest and induction of tetraploidy, we used an E6 mutant unable to degrade p53 or RNAi targeting p53 for knockdown. The E6 mutant fails to generate tetraploidy; however, the presence of E7 is sufficient to bypass arrest while the p53 RNAi permits both arrest insensitivity and tetraploidy. We published previously that polo-like kinase 1 (Plk1) is upregulated in E6/E7-expressing cells. We observe here that abnormal expression of Plk1 protein correlates with tetraploidy. Using the p53 binding-defective mutant of E6 and p53 RNAi, we show that p53 represses Plk1, suggesting that loss of p53 results in tetraploidy through upregulation of Plk1. Consistent with this hypothesis, overexpression of Plk1 in cells generates tetraploidy but does not confer resistance to arrest. These results support a model for transformation caused by HPV-16 where bypass of arrest and tetraploidy are separable consequences of p53 loss with Plk1 required only for the latter effect.

Gamma Knife stereotactic radiosurgery for idiopathic trigeminal neuralgia. Clinical article

Object
Trigeminal neuralgia pain causes severe disability. Stereotactic radiosurgery is the least invasive surgical option for patients with trigeminal neuralgia. Since different medical and surgical options have different rates of pain relief and morbidity, it is important to evaluate longer-term outcomes.

Methods
The authors retrospectively reviewed outcomes in 503 medically refractory patients with trigeminal neuralgia who underwent Gamma Knife surgery (GKS). The median patient age was 72 years (range 26–95 years). Prior surgery had failed in 205 patients (43%). The GKS typically was performed using MR imaging guidance, a single 4-mm isocenter, and a maximum dose of 80 Gy.

Results
Patients were evaluated for up to 16 years after GKS; 107 patients had > 5 years of follow-up. Eighty-nine percent of patients achieved initial pain relief that was adequate or better, with or without medications (Barrow Neurological Institute [BNI] Scores I–IIIb). Significant pain relief (BNI Scores I–IIIa) was achieved in 73% at 1 year, 65% at 2 years, and 41% at 5 years. Including Score IIIb (pain adequately controlled with medication), a BNI score of I–IIIb was found in 80% at 1 year, 71% at 3 years, 46% at 5 years, and 30% at 10 years. A faster initial pain response including adequate and some pain relief was seen in patients with trigeminal neuralgia without additional symptoms, patients without prior surgery, and patients with a pain duration of = 3 years. One hundred ninety-three (43%) of 450 patients who achieved initial pain relief reported some recurrent pain 3–144 months after initial relief (median 50 months). Factors associated with earlier pain recurrence that failed to maintain adequate or some pain relief were trigeminal neuralgia with additional symptoms and = 3 prior failed surgical procedures. Fifty-three patients (10.5%) developed new or increased subjective facial paresthesias or numbness and 1 developed deafferentation pain; these symptoms resolved in 17 patients. Those who developed sensory loss had better long-term pain control (78% at 5 years).

Conclusions
Gamma Knife surgery proved to be safe and effective in the treatment of medically refractory trigeminal neuralgia and is of value for initial or recurrent pain management. Despite the goal of minimizing sensory loss with this procedure, some sensory loss may improve long-term outcomes. Pain relapse is amenable to additional GKS or another procedure.

MarcoPolo-R near earth asteroid sample return mission

MarcoPolo-R is a sample return mission to a primitive Near-Earth Asteroid (NEA) proposed in collaboration with NASA. It will rendezvous with a primitive NEA, scientifically characterize it at multiple scales,and return a unique sample to Earth unaltered by the atmospheric entry process or terrestrial weathering. MarcoPolo-R will return bulk samples (up to 2 kg) from an organic-rich binary asteroid to Earth for laboratory analyses, allowing us to: explore the origin of planetary materials and initial stages of habitable planet formation; identify and characterize the organics and volatiles in a primitive asteroid; understand the unique geomorphology, dynamics and evolution of a binaryNEA. This project is based on the previous Marco Polo mission study,which was selected for the Assessment Phase of the first round of Cosmic Vision. Its scientific rationale was highly ranked by ESA committees andit was not selected only because the estimated cost was higher than theallotted amount for an M class mission. The cost of Marco Polo-R will be reduced to within the ESA medium mission budget by collaboration withAPL (John Hopkins University) and JPL in the NASA program for coordination with ESA's Cosmic Vision Call. The baseline target is a binary asteroid (175706) 1996 FG3, which offers a very efficient operational and technical mission profile. A binary target also providesenhanced science return. The choice of this target will allow newinvestigations to be performed more easily than at a single object, andalso enables investigations of the fascinating geology and geophysics ofasteroids that are impossible at a single object. Several launch windows have been identified in the time-span 2020-2024. A number of otherpossible primitive single targets of high scientific interest have beenidentified covering a wide range of possible launch dates. The baselinemission scenario of Marco Polo-R to 1996 FG3 is as follows: a singleprimary spacecraft provided by ESA, carrying the Earth Re-entry Capsule, sample acquisition and transfer system provided by NASA, will be launched by a Soyuz-Fregat rocket from Kourou into GTO and using two space segment stages. Two similar missions with two launch windows, in 2021 and 2022 and for both sample return in 2029 (with mission durationof 7 and 8 years), have been defined. Earlier or later launches, in 2020 or 2024, also offer good opportunities. All manoeuvres are carried out by a chemical propulsion system. MarcoPolo-R takes advantage of three industrial studies completed as part of the previous Marco Polo mission (see ESA/SRE (2009)3, Marco Polo Yellow Book) and of the expertise of the consortium led by Dr. A.F. Cheng (PI of the NASA NEAR Shoemaker mission) of the JHU-APL, including JPL, NASA ARC, NASA LaRC, and MIT.

Spitzer observations of the asteroid-comet transition object and potential spacecraft target 107P (4015) Wilson-Harrington

Context: Near-Earth asteroid-comet transition object 107P/ (4015) Wilson-Harrington is a possible target of the joint European Space Agency (ESA) and Japanese Aerospace Exploration Agency (JAXA) Marco Polo sample return mission. Physical studies of this object are relevant to this mission, and also to understanding its asteroidal or cometary nature. Aims: Our aim is to obtain significant new constraints on the surface thermal properties of this object. Methods: We present mid-infrared photometry in two filters (16 and 22 μm) obtained with NASA's Spitzer Space Telescope on February 12, 2007, and results from the application of the Near Earth Asteroid Thermal Model (NEATM). We obtained high S/N in two mid-IR bands allowing accurate measurements of its thermal emission. Results: We obtain a well constrained beaming parameter (η = 1.39±0.26) and obtain a diameter and geometric albedo of D = 3.46±0.32 km, and pV = 0.059±0.011. We also obtain similar results when we apply this best-fitting thermal model to single-band mid-IR photometry reported by Campins et al. (1995, P&SS, 43, 733), Kraemer et al. (2005, AJ, 130, 2363) and Reach et al. (2007, Icarus, 191, 298). Conclusions: The albedo of 4015 Wilson-Harrington is low, consistent with those of comet nuclei and primitive C-, P-, D-type asteorids. We establish a rough lower limit for the thermal inertia of W-H of 60 Jm-2s-0.5 K-1 when it is at r = 1 AU, which is slightly over the limit of 30 Jm-2 s-0.5 K-1 derived by Groussin et al. (2009, Icarus, 199, 568) for the thermal inertia of the nucleus of comet 22P/Kopff.