A phase II trial of intraperitoneal EGEN-001, an IL-12 plasmid formulated with PEG–PEI–cholesterol lipopolymer in the treatment of persistent or recurrent epithelial ovarian,fallopian tube or primary peritoneal cancer: A Gynecologic Oncology Group study

Objective

The purpose of this phase II trial was to evaluate the toxicity and antitumor activity of EGEN-001 in platinum resistant recurrent ovarian cancer.

Methods

Eligible patients had weekly IP infusion of EGEN-001 at a dose of 24 mg/m². Toxicity and antitumor activity were evaluated using CTCAE and RESIST criteria, respectively. Co-primary endpoints were tumor response and survival without progression (PFS) for at least 6 months. Survival without progression before going onto a subsequent therapy (EFS) for at least six months was also considered.

Results

A total of 58 EGEN-001 cycles were administered to 20/22 enrolled patients (median 2 cycles, range 1–9). The most frequently associated adverse events related specifically to EGEN-001 treatment were grade 1/2 fatigue, fever, chills, abdominal pain, nausea, vomiting, anemia, thrombocytopenia, and leukopenia. Three of 20 EGEN-001 treated patients evaluable for toxicity elected to withdraw from the study motivated in part by grade 1 treatment related toxicities. There were no patients with partial or complete response (0%; 90% CI 0–10.9%). Seven (35%) of 16 patients evaluable for response had stable disease, and 9 (45%) had progressive disease. Six (30%) patients had a PFS of greater than six months, although three had gone off study and onto other therapies before six months. The estimated six-month EFS was 15%. The median PFS and OS were 2.89 and 9.17 months, respectively.

Conclusion

EGEN-001 at the dose and schedule evaluated was associated with some but limited activity and was seemingly less tolerated in platinum resistant recurrent ovarian cancer patients.     

A phase II trial of sunitinib in women with metastatic or recurrent endometrial carcinoma: A study of the Princess Margaret,Chicago and California Consortia

Objective

Treatment options remain limited for women with relapsed/metastatic endometrial cancer (EC). Angiogenesis is one of the major components of tumor progression and thus an attractive target. The aim of this phase II trial was to assess the efficacy and tolerability of sunitinib, an oral multitargeted receptor tyrosine-kinase inhibitor with antiangiogenic and antitumor activity in the treatment of recurrent EC.

Methods

We performed a multicenter, single arm, two-stage phase II study of sunitinib, 50 mg daily administered on a 4 weeks on–2 weeks off schedule. Eligibility criteria included recurrent/metastatic EC or carcinosarcoma with no more than one prior line of chemotherapy. The primary endpoint was objective response rate.

Results

34 women were enrolled; 33 received at least one dose of sunitinib and were included in the analyses. Six women (18.1%) had a partial response and six additional women (18.1%) stable disease. In total, ten patients (30.3%) had disease control for at least 6 months and of these, seven were controlled for more than one year. Median progression free and overall survival times were 3 months and 19.4 months, respectively. Adverse events related to treatment were frequent. At least one grade 3 toxicity occurred in 30 patients and dose reductions were required in 17 patients (52%). The most common grade 3 toxicities were fatigue, hypertension, palmar–plantar erythrodysesthesia, diarrhea and hematologic.

Conclusion

Sunitinib therapy showed promising activity in women with recurrent EC. Toxicity was seen frequently but was manageable. Anti-angiogenic agents warrant further investigation in EC to define which patients will derive the greatest benefit.     

Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer

Objective

The phosphatidylinositol-3 kinase/serine–threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor ridaforolimus were evaluated in this study.

Methods

This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40 mg for 5 consecutive days followed by a 2 day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting.

Results

31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9 and 26.5 months. An additional 18 patients showed disease stabilization (52.9%) for a median duration of 6.6 months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status.

Conclusion

Oral ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.     

Dynamics of quadrupedal locomotion of monkeys: implications for central control

We characterized the three-dimensional kinematics and dynamics of quadrupedal gait of young adult rhesus and cynomolgus monkeys while they walked with diagonal and lateral gaits at 0.4–1.0 m/s on a treadmill. Rigid bodies on the wrist, ankle, and back were monitored by an optical motion detection system (Optotrak). Kinematic data could be normalized using characteristic stride length, reducing variance due to different gait styles, to emphasize common characteristics of swing and stance parameters among animals. Mean swing phase durations fell as walking speed increased, but the swing phase durations increased at each walking velocity as a linear function of increases in amplitude, thereby following a main sequence relationship. The phase plane trajectories of the swing phases, i.e., plots of the relation of the rising and falling limb velocity to limb position in the sagittal (X–Z) plane, had unique dynamic characteristics. Trajectories were separable at each walking velocity and increases in swing amplitude were linearly related to peak swing velocities, thus comprising main sequences. We infer that the swing phase dynamics are set by central neural mechanisms at the onset of the swing phases according to the intended amplitude, which in turn is based on the walking velocity in the stance phases. From the many dynamic similarities between swing phases and rapid eye movements, we further suggest that the swing phases may be generated by neural mechanisms similar to those that produce saccades and quick phases of nystagmus from a signal related to sensed or desired walking velocity. Grants: This work was supported by National Institute of Health Grants EY11812, EY04148, DC05204, and EY01867.     

B cell elimination in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus.     

Frequency-plane analysis of normal and pathological ECG signals for disease identification

In this paper a frequency plane analysis of both normal and diseased ECG signals is performed specifically for disease identification. Image processing techniques are used to develop an automated data acquisition package of 12 lead ECG signals from paper records. A regeneration domain is also developed to check the captured pattern with the original wave shape. A QRS complex detector with an accuracy level ～98.4% in up to 30% signal to noise level is developed. Discrete Fourier transform (DFT) is performed to obtain the frequency spectrum of every ECG signal. Some interesting amplitude and phase response properties of chest lead V2, V3, V4, V6 and limb lead I, II, III, AVL, AVF are seen. Both amplitude and phase properties are different for normal and diseased subjects and can serve an important role in disease identification. A statistical analysis of amplitude property is carried out to show that this property is significantly different for normal and diseased subjects.     

Phase change material for thermotherapy of Buruli ulcer: modelling as an aid to implementation

A mathematical model was developed and validated to predict the thermal behaviour of a heat application device based on a phase change material (pcm) for the heat treatment of Mycobacterium ulcerans infection (Buruli ulcer). The thermal model allows the prediction of skin surface temperatures and an optimization of the amount of pcm with respect to discharge time. A first prototype of such a pcm bandage was manufactured and used in a proof-of-principal trial in Cameroon. The experimental data were analysed and yielded no difference in thermoregulatory response between people living in hot or moderate climate. Short-term maximum skin surface temperatures of 42°C are tolerable; the pcm bandage keeps the skin surface temperature above 40°C for about four to five hours. This makes such pcm bandages an ideal device for the heat treatment of Buruli ulcer. The pcm bandage is easy to apply, cheap, and thus is well suited for use in low-resource countries.     

Measurement of phase synchrony of coupled segmentation clocks

The temporal behavior of segmentation clock oscillations shows phase synchrony via mean field like coupling of delta protein restricting to nearest neighbors only, in a configuration of cells arranged in a regular three dimensional array. We found the increase of amplitudes of oscillating dynamical variables of the cells as the activation rate of delta-notch signaling is increased, however, the frequencies of oscillations are decreased correspondingly. Our results show the phase transition from desynchronized to synchronized behavior by identifying three regimes, namely, desynchronized, transition and synchronized regimes supported by various qualitative and quantitative measurements.     

Characterization of right or left ventricular contraction heterogeneity using Fourier phase analysis

The standard deviation of the first harmonic Fourier phase histogram is an indicator of the contraction heterogeneity of the heart ventricles. This approach has been applied to analyse tomographic blood pool (^99mTc) examinations in a group of 32 patients with angiographically verified mainly right (RV) but also left (LV) kinetic disorders in relation to severe ventricular arrhythmias and suspicion of arrhythmogenic right ventricular dysplasia (ARVD). The reference group consisted of ten patients with low probability of cardiac kinetic abnormalities.Thick tomographic slices including both ventricles have been reconstructed in the horizontal long axis orientation from a series of 32 gated projections recorded over a 360° rotation. Separately for each ventricle the Fourier phase histograms have been computed and characterized by their standard deviations (PSD). Normal values (mean±standard deviation, LV=11°±5°, RV=12°±5°) were significantly lower (P<0.01 and P<0.001) than those measured in abnormal cases (LV=19°±10° and RV=31°±17°).Detailed analysis of the data supports the hypothesis of a primary RV disease in ARVD, with secondary LV extension. PSD seems to be a good predictor of an organic cardiac disease underlying ventricular arrhythmias and may be used for screening the patients.This work has been supported by a contract of the National Health Insurance Office of France (Caisse Nationale d'Assurance Maladie des Travailleurs Salariés)