Florian Lenz

The PACOVAR-trial: A phase I/II study of pazopanib (GW786034) and cyclophosphamide in patients with platinum-resistant recurrent, pre-treated ovarian cancer

BackgroundThe prognosis of patients with recurrent, platinum-resistant epithelial ovarian cancer (EOC) is poor. There is no standard treatment available. Emerging evidence suggests a major role for antiangiogenic treatment modalities in EOC, in particular in combination with the metronomic application of low dose chemotherapy. The novel, investigational oral antiangiogenic agent pazopanib targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and c-kit is currently being studied in different tumour types and is already used as first line therapy in recurrent renal cell carcinoma. A combined therapy consisting of pazopanib and metronomic oral cyclophosphamide may offer a well-tolerable treatment option to patients with recurrent, pretreated EOC.Methods/designThis study is designed as a multicenter phase I/II trial evaluating the optimal dose for pazopanib (phase I) as well as activity and tolerability of a combination regimen consisting of pazopanib and metronomic cyclophosphamide in the palliative treatment of patients with recurrent, platinum-resistant, pre-treated ovarian cancer (phase II). The patient population includes patients with histologically or cytologically confirmed diagnosis of EOC, cancer of the fallopian tube or peritoneal cancer which is platinumresistant or -refractory. Patients must have measurable disease according to RECIST criteria and must have failed available standard chemotherapy. Primary objectives are determination of the optimal doses for pazopanib (phase I) and the overall response rate according to RECIST criteria (phase II). Secondary objectives are time to progression, overall survival, safety and tolerability. The treatment duration is until disease progression or intolerability of study drug regimen (with a maximum of 13 cycles up to 52 weeks per subject).DiscussionThe current phase I/II trial shall clarify the potential of the multitargeting antiangiogenic tyrosinkinaseinhibitor GW 786034 (pazopanib) in combination with oral cyclophosphamide as salvage treatment in patients with recurrent, pretreated ovarian cancer.Trial registrationClinicalTrials.gov: NCT01238770

Validation of a German version of the P-QOL Questionnaire

ObjectiveThe objective of this study was to validate the German version of the prolapse quality-of-life questionnaire (P-QOL).MethodsThe P-QOL questionnaire was translated into German and administered to women recruited from two gynecological outpatient clinics and seven gynecological practices. All women were examined in supine position using the Pelvic Organ Prolapse Quantification System of the International Continence Society. The validity was assessed by comparing symptom scores and quality-of-life scores between symptomatic and asymptomatic women.ResultsAccording to the English study, 140 symptomatic and 75 asymptomatic women were included. The total scores for each P-QOL domain were significantly different between symptomatic and asymptomatic women (p < 0.001). Seven symptom regarding questions showed significant differences (p < 0.05).ConclusionThe German version of P-QOL is a valid, reliable, and easily comprehensible instrument to assess quality of life and symptoms in German-speaking patients with urogenital prolapse.

Evolutionary phase space in driven elliptical billiards

We perform the first long-time exploration of the classical dynamics of a driven billiard with a four dimensional phase space. With increasing velocity of the ensemble we observe an evolution from a large chaotic sea with stickiness due to regular islands to thin chaotic channels with diffusive motion leading to Fermi acceleration. As a surprising consequence, we encounter a crossover, which is not parameter induced but rather occurs dynamically, from amplitude dependent tunable subdiffusion to universal normal diffusion in momentum space. In the high velocity case we observe particle focusing in phase space.

MRI findings before and after prolapse surgery

Background Therapeutical outcome after prolapse surgery is evaluated using a standardized grading system based on maximum prolapse extent, which might not provide the full picture of the patient’s subjective outcome. We therefore applied an evaluation method, which is detached from a grading system. Purpose To evaluate the impact of pelvic organ mobility in dynamic magnetic resonance imaging (MRI) before and after mesh-repair surgery in patients with symptomatic pelvic organ prolapse. Material and Methods To obtain measurements, we performed parasagittal T2-weighted turbo spin echo sequence at rest (TR, 3460 ms; TE, 85 ms; matrix, 512; slice thickness [ST], 5 mm), parasagittal T2-weighted true fast imaging with steady-state precession (TrueFISP) single-shot sequence during straining (TR, 397.4 ms; TE, 1.5 ms; matrix, 256; ST, 8 mm), and parasagittal T2-weighted TrueFISP sequence at maximum strain (TR, 4.3 ms; TE, 2.15 ms; matrix, 256; ST, 5 mm) at 1.5 T MRI. Pelvic organ prolapse (anatomical landmarks: bladder, cervix, pouch, rectum) was measured perpendicularly with reference to the pubococcygeal and the midpubic line. Pelvic organ mobility was defined as the difference between the measured distance at rest and at maximum strain for each anatomical landmark. All patients underwent mesh-repair procedure. Eighty patients could be included in this short-term follow-up study. Due to the physical diagnosis of pelvic organ prolapse, 51 underwent anterior mesh repair, 16 underwent posterior mesh repair, and 13 underwent total mesh repair. Surgery was performed by one surgeon, using mesh implants from several manufacturers. Results Median values of maximum organ prolapse for bladder, cervix, pouch, and rectum preoperatively were 2.54 cm, 0.33 cm, 2.47 cm, and 0.32 cm, respectively, and 12 weeks postoperatively 0.87 cm, −1.79 cm, 1.49 cm, and 0.49 cm, respectively. Highly significant improvement (P < 0.001) of pelvic organ mobility was observed in the treated compartment at 4- and 12-week follow-up. Physical evaluation 12 weeks after mesh-repair showed an asymptomatic POP-Q stage I, if any. Conclusion Dynamic MRI is useful in visualizing the maximum extent of pelvic organ prolapse, as the evaluation of pelvic organ mobility documents the intraindividual therapeutic outcome detached from a grading system based on maximal prolapse values.

Short-range clinical, dynamic magnetic resonance imaging and P-QOL questionnaire results after mesh repair in female pelvic organ prolapse

OBJECTIVE To evaluate clinical, quality-of-life (QoL) and dynamic magnetic resonance imaging (dMRI) results in patients with pelvic organ prolapse (POP) preoperatively, and 4 and 12 weeks after anterior and/or posterior mesh repair. STUDY DESIGN Thirty-six patients (mean age 65 years) with symptomatic pelvic floor descent underwent mesh repair. The prolapse was quantified using the POP-Q system. Before surgery as well as 4 and 12 weeks after surgery, the pelvic organ positions were measured on dynamic magnetic resonance imaging during Valsalva manoeuvre in relation to the pubococcygeal and mid-pubic lines to assess surgery outcome. Patients also completed the P-QOL questionnaire to evaluate subjective changes at each visit. RESULTS Four and 12 weeks after surgery patients showed improvement of the POP on clinical examination and on dynamic MRI. The latter demonstrated high significance (p<0.001) especially in bladder and vaginal cuff/cervix positions during maximal straining. All quality-of-life domains and some symptom questions of the P-QOL questionnaire significantly improved (p<0.05) 12 weeks after surgery. CONCLUSION Significant anatomical and quality-of-life improvement was demonstrated after anterior and/or posterior mesh repair for POP using dynamic MRI and the P-QOL questionnaire.

Resonant population transfer in the time-dependent quantum elliptical billiard

We analyze the quantum dynamics of the time-dependent elliptical billiard using the example of a certain breathing mode. A numerical method for the time propagation of an arbitrary initial state is developed based on a series of transformations, thereby removing the time dependence of the boundary conditions. The time evolution of the energies of different initial states is studied. The maximal and minimal energies that are reached during the time evolution show a series of resonances as a function of the applied driving frequency. At these resonances, higher (or lower) lying states are periodically populated, leading to the observed change in energy. The resonances occur when the driving frequency or a multiple of it matches the mean energetic difference between the two involved states exactly. This picture is confirmed by a few-level Rabi-like model with periodic couplings, reproducing the key results of our numerical study.

Directed transport and localization in phase-modulated driven lattices

We explore the dynamics of noninteracting particles loaded into a phase-modulated one-dimensional lattice formed by laterally oscillating square barriers. Tuning the parameters of the driven unit cell of the lattice selected parts of the classical phase space can be manipulated in a controllable manner. We find superdiffusion in position space for all parameters regimes. A directed current of an ensemble of particles can be created through locally breaking the spatiotemporal symmetries of the time-driven potential. Magnitude and direction of the current are tunable. Several mechanisms for transient localization and trapping of particles in different wells of the driven unit cell are presented and analyzed.

Scattering dynamics of driven closed billiards

We investigate the classical scattering dynamics of the driven elliptical billiard. Two fundamental scattering mechanisms are identified and employed to understand the rich behavior of the escape rate. A long-time algebraic decay which can be tuned by varying the driving amplitude is established. Pulsed escape rates and decelerated escaping particles are generic properties of the harmonically breathing billiard. This suggests time-dependent billiards as prototype systems to study the nonequilibrium evolution of classical ensembles encountering a multitude of scattering processes off driven targets.

Patterned deposition of particles in spatio-temporally driven lattices

We present and analyze mechanisms for the patterned deposition of particles in a spatio-temporally driven lattice. The working principle is based on the breaking of the spatio-temporal translation symmetry, which is responsible for the equivalence of all lattice sites, by applying modulated phase shifts to the lattice sites. The patterned trapping of the particles occurs in confined chaotic seas, created via the ramping of the height of the lattice potential. Complex density profiles on the length scale of the complete lattice can be obtained by a quasi-continuous, spatial deformation of the chaotic sea in a frequency modulated lattice.

Formation of density waves via interface conversion of ballistic and diffusive motion

We develop a mechanism for the controlled conversion of ballistic to diffusive motion and vice versa. This process takes place at the interfaces of domains with different time-dependent forces in lattices of laterally oscillating barrier potentials. As a consequence, long-time transient oscillations of the particle density are formed, which can be converted to permanent density waves by an appropriate tuning of the driving forces. The proposed mechanism opens the perspective of an engineering of the nonequilibrium dynamics of particles in inhomogeneously driven lattices.