Search

Background: Cytotoxic chemotherapy is the mainstay of treatment in metastatic triple negative breast cancer (TNBC), a phenotype predictive of poor survival. Similarly, ovarian cancer is the leading cause of death from gynecologic malignancies and shares genomic similarities with TNBC. New treatment paradigms are needed for people with these malignancies. CDK4/6 (CDKi) and histone deacetylase (HDACi) inhibitors are promising treatment approaches in breast cancer though neither has been successfully translated as monotherapy in TNBC. HDACi have single-agent activity against TNBC in vivo, possibly through decreasing epithelial mesenchymal transition, migration, and metastases. CDKi cause cell cycle arrest and tumor regression in TNBC models. HDACi increase inhibitors of cell cycle progression including RB1, CDKN1A, CDKN1C, CDKN2B, and CDKN2D in TNBC in vitro. We hypothesized that HDACi would increase the sensitivity of breast cancer to CDKi. RIB + BEL demonstrated growth inhibition in TNBC cell lines with synergy seen at multiple doses. RIB and BEL are expected to be safe in combination. BEL has no effect on CYP3A4, the main metabolizing enzyme for RIB. Although RIB can inhibit CYP3A4, which partially metabolizes BEL, BEL is primarily metabolized by UGT1A1. Although both drugs can cause myelosuppression, thrombocytopenia occurs more often with BEL and leukopenia with RIB. The primary objective is to assess the maximum tolerated dose of RIB and BEL in combination. Secondary objectives include safety and efficacy. Exploratory objectives include development of a predictive biomarker, exploration of subclonal structure and phenotypic pathway activation through serial biopsies, and efficacy within RB1 mutation status subgroups. We hypothesized that RIB plus BEL will be well-tolerated and demonstrate activity in people with metastatic TNBC or recurrent ovarian cancer. Methods: This open-label, multi-center, phase I study follows a modified 3+3 dose escalation design allowing independent escalation of the dose of each of the agents with a 10 person expansion cohort at the Recommended Phase 2 Dose (RP2D). Dose escalation will be open to patients with TNBC or ovarian cancer and only TNBC will be enrolled at dose expansion. The first cohort uses RIB 200 mg daily and BEL 600 mg/m2 daily on days 1-5 of a 28 day cycle. Tumor is assessed at baseline and every 8 weeks. Biopsies occur at screening and cycle 2 day 15 to establish a predictive biomarker panel that will be validated with future study. Patients ≥ 18 years of age who have measurable and metastatic or unresectable disease are included. Patients previously treated with a CDKi or HDACi are excluded. Additional exclusion criteria include use of valproic acid during the study or within 5 days of the first dose of BEL, prolonged QTc, grade ≥2 unresolved diarrhea, or new or progressive brain metastases. Statistical analysis of safety data will be descriptive. Efficacy will be reported in the study population as well as in RB1 mutation status subgroups. PFS will be estimated using Kaplan-Meier methods. Cox regression will be used to determine if there is a relationship between biomarker predictor and PFS. The estimated duration for accrual is 18 months with patient participation of around 36 months. Enrollment began January 2021 with 2 patients currently enrolled. Clinical Trial registry Number: NCT04315233 Citation Format: Shashank Sama, Kristen Kelley, Christos Vaklavas, Andrea Bild, Kenneth Boucher, John Lamb, Julia Lehman, Philip Moos, Theresa Werner, Adam Cohen. A phase I/Ib trial of the CDK4/6 antagonist ribociclib (RIB) and the HDAC inhibitor belinostat (BEL) in patients with metastatic triple negative breast cancer and recurrent ovarian cancer with response prediction by genomics (CHARGE) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-19-07.

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10–200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = 62). Maximum tolerated dose was determined as 150 mg daily. Dose-limiting toxicity was reported in 4/28 evaluable phase 1 patients (three at 200 mg, one at 80 mg). In phase 1b, 120 mg was defined as the recommended dose due to tolerability. Treatment-related adverse events (TRAEs) were experienced by 174/193 patients (90.2%); grade ≥ 3 TRAEs in 103 patients (53.4%). Most common TRAEs were diarrhea, fatigue, hypertension and nausea; TRAEs led to treatment discontinuation in 26 patients (13.5%) and death in one patient. Sitravatinib was steadily absorbed and declined from plasma with a terminal elimination half-life of 42.1–51.5 h following oral administration. Overall objective response rate was 11.8% in phase 1b, 13.2% in patients with non-small cell lung cancer (NSCLC) and 4.2% in patients with NSCLC with prior checkpoint inhibitor experience. Sitravatinib demonstrated manageable safety and modest clinical activity in solid tumors. NCT02219711 (first posted August 14, 2014).

The article offers a much-needed impulse to the debate on humanitarian military interventions, which is characterized by conceptual confusion and a lack of comparative research. Based on a comprehe...

A deficiency in the implementation of current radiation protection is the determination of the ambient dose equivalent H*(10) and the directional dose equivalent H´(0.07) in pulsed radiation fields. Conventional dosimeter systems are not suitable for measurements in photon fields comprising short radiation pulses, which consequently leads to high detector loads in short time periods. Nevertheless, due to the implementation of advanced medical accelerators for cancer therapy, new medical diagnostic devices as well as various laser machining systems, there is an urgent need for suitable dosimeter systems for real time dosimetry. In this paper, a detector concept based on an organic scintillator and a full digital data analysis with the aim of developing a portable, battery powered measurement system is presented.

The ultimate goal of radiotherapy using external beams is to maximize the dose delivered to the tumor while minimizing the radiation given to surrounding healthy critical organs. Prompt Gamma Spectroscopy (PGS) has been proposed for range control of particle beams along with the determination of the elemental composition of irradiated tissues. We aim at developing a PGS system for the German Cancer Research Center – DKFZ that takes advantage of the superior selectivity of Helium and Carbon beams accelerated at the Heidelberg Ion-Beam Therapy Center. Preliminary tests with protons accelerated with an IBA C230 cyclotron located at the Universitäts Protonen Therapie Dresden were performed at OncoRay – National Center for Radiation Re-search in Oncology. We present results obtained with a PGS system composed of CeBr3 detectors (Ø 2’’ × 2’’) and (Ø 1.5’’ × 3’’) coupled to a Hamamatsu R13089 photomulti-plier tube and plugged to a Target U100 Spectrometer. Such system provides accurate time-of-flight measurements to increase the signal-to-noise ratio relative to neutron-induced background. First measurements resulted from the irradiation of PMMA and water phantoms, and graphite and aluminum bricks. Several PG energy lines ranging from 0.511 MeV up to 8 MeV were identified and compared with reference re-sults. Two further experiments consisted in irradiating PMMA phantoms in a slit- and semi-collimated configuration with mono-energetic proton beams of 165 MeV and 224 MeV, respectively. Results acquired by means of trans-versal PGS at different phantom depths, ranging from 6 cm before the Bragg peak (BP) to 3.5 cm beyond the BP in 5 mm steps with a 1 cm slit collimation (tungsten) showed a slight decrease of PG yields after the BP. Similar measurements with a semi-opened collimation configuration demonstrated a steeper decrease of PG yields after the BP.

In proton therapy, patients benefit from the precise deposition of the dose in the tumor volume due to the interaction of charged particles with matter. Currently, the determination of the beam range in the patient’s body during the treatment is not a clinical standard. This lack causes broad safety margins around the tumor, which limits the potential of proton therapy. To overcome this obstacle, different methods are under investigation aiming at the verification of the proton range in real time during the irradiation. One approach is the prompt gamma-ray timing (PGT) method, where the range of the primary protons is derived from time-resolved profiles (PGT spectra) of promptly emitted gamma rays, which are produced along the particle track in tissue. After verifying this novel technique in an experimental environment but far away from treatment conditions, the translation of PGT into clinical practice is intended. Therefore, new hardware was extensively tested and characterized using short irradiation times of 70 ms and clinical beam currents of 2 nA. Experiments were carried out in the treatment room of the University Proton Therapy Dresden. A pencil beam scanning plan was delivered to a target without and with cylindrical air cavities of down to 5 mm thickness. The range shifts of the proton beam induced due to the material variation could be identified from the corresponding PGT spectra, comprising events collected during the delivery of a whole energy layer. Additionally, an assignment of the PGT data to the individual pencil beam spots allowed a spot-wise analysis of the variation of the PGT distribution mean and width, corresponding to range shifts produced by the different air cavities. Furthermore, the paper presents a comprehensive software framework which standardizes future PGT analysis methods and correction algorithms for technical limitations that have been encountered in the presented experiments., publishedVersion

Prompt γ-ray imaging with a knife-edge shaped slit camera provides the possibility of verifying proton beam range in tumor therapy. Dedicated experiments regarding the characterization of the camera system have been performed previously. Now, we aim at implementing the prototype into clinical application of monitoring patient treatments. Focused on this goal of translation into clinical operation, we systematically addressed remaining challenges and questions. We developed a robust energy calibration routine and corresponding quality assurance protocols. Furthermore, with dedicated experiments, we determined the positioning precision of the system to 1.1 mm (2σ). For the first time, we demonstrated the application of the slit camera, which was intentionally developed for pencil beam scanning, to double scattered proton beams. Systematic experiments with increasing complexity were performed. It was possible to visualize proton range shifts of 2-5 mm with the camera system in phantom experiments in passive scattered fields. Moreover, prompt γ-ray profiles for single iso-energy layers were acquired by synchronizing time resolved measurements to the rotation of the range modulator wheel of the treatment system. Thus, a mapping of the acquired profiles to different anatomical regions along the beam path is feasible and additional information on the source of potential range shifts can be obtained. With the work presented here, we show that an application of the slit camera in clinical treatments is possible and of potential benefit.

In-vivo range verification has been a hot topic in particle therapy for about two decades. In spite of vast efforts made by research groups all over the world, clinical devices and procedures for routinely monitoring the range of therapeutic particle beams in the patient’s body and to ensure their correspondence with the treatment plan are not yet available. The paper reviews recent approaches with focus on prompt-gamma based methods of proton range verification and points to challenges that have not been discussed with the necessary depth and rigor in many (even recent) publications: First, the macro time structure of treatment beams in common proton therapy facilities requires detection systems with extreme load tolerance, throughput capability, and stability against load leaps. Second, the time period available for verifying the range of a single pencil beam spot is of the order of milliseconds, which limits the number of prompt gamma events that can be detected and processed. In view of these constraints it might be favorable to waive tight event selection by collimation or coincidence conditions as applied in most prompt-gamma based range verification techniques considered so far, and to move on to straight detection with uncollimated detectors combined with a multi-feature analysis deploying all pieces of information comprised in a registered event. Energy deposition, timing, and energy sharing between the involved detector segments in case of Compton-scattering or pair production are parameters bearing information on the beam track that could be extracted in a comprehensive analysis. This would maximize the number of valid events on the expense of ‘information sharpness’, but could eventually increase the total yield of information exploitable for range verification. Some aspects of such a strategy have already been realized with the Prompt Gamma-Ray Timing (PGT) and the Prompt Gamma Peak Integration (PGPI) techniques proposed recently. Data analysis schemes for a more generalized approach have not yet been developed, but the hardware to be used can already be sketched: Prompt gamma rays should be detected with scintillation detector modules consisting of single pixels with individual light readouts and independent electronic channels, similar to those developed for PET-MR. Prompt gamma-ray detection in this context is, however, much more demanding with respect to dynamic range, energy resolution, load acceptance, and stability. The corresponding requirements represent a challenge for the detector physics community.

In-situ range verification of ion beams during dose delivery is a key for further improving the precision and reducing side effects of radiotherapy with particle beams. The detection and analysis of prompt gamma rays with respect to their emission points, emission time, and emission energy can provide corresponding means. Prompt gamma-ray imaging (PGI) has already been used for range verification in patient treatments with proton beams. The prompt gamma-ray timing (PGT) technique promises range verification at lower hardware expense with simpler detection systems superseding heavy collimators. After proving the principle, this technique is now being translated to the treatment room. The paper presents latest experimental results obtained with clinically applicable PGT hardware in irradiations of plexiglass targets in pencil beam scanning (PBS) mode with proton beams at clinical dose rates. The data were acquired with multiple PGT detection units while the distal layer of an artificial 1 Gy dose cube treatment plan was repeatedly delivered to a solid PMMA target that sometimes comprised a cylindrical air cavity of 5, 10, or 20 mm depth. The corresponding local range shifts were clearly detected and visualized by analyzing position or variance of the prompt gamma-ray timing peaks in PGT spectra assigned to the individual PBS spots. In this context, a major challenge concerning all prompt-gamma based techniques is examined and discussed: collecting the event statistics that is needed for range verification of single pencil beam spots at an accuracy level of a few millimeters.

Proton therapy is an advantageous treatment modality compared to conventional radiotherapy. In contrast to photons, charged particles have a finite range and can thus spare organs at risk. Additionally, the increased ionization density in the so-called Bragg peak close to the particle range can be utilized for maximum dose deposition in the tumour volume. Unfortunately, the accuracy of the therapy can be affected by range uncertainties, which have to be covered by additional safety margins around the treatment volume. A real-time range and dose verification is therefore highly desired and would be key to exploit the major advantages of proton therapy. Prompt gamma rays, produced in nuclear reactions between projectile and target nuclei, can be used to measure the proton's range. The prompt gamma-ray timing (PGT) method aims at obtaining this information by determining the gamma-ray emission time along the proton path using a conventional time-of-flight detector setup. First tests at a clinical accelerator have shown the feasibility to observe range shifts of about 5 mm at clinically relevant doses. However, PGT spectra are smeared out by the bunch time spread. Additionally, accelerator related proton bunch drifts against the radio frequency have been detected, preventing a potential range verification. At OncoRay, first experiments using a proton bunch monitor (PBM) at a clinical pencil beam have been conducted. Elastic proton scattering at a hydrogen-containing foil could be utilized to create a coincident proton-proton signal in two identical PBMs. The selection of coincident events helped to suppress uncorrelated background. The PBM setup was used as time reference for a PGT detector to correct for potential bunch drifts. Furthermore, the corrected PGT data were used to image an inhomogeneous phantom. In a further systematic measurement campaign, the bunch time spread and the proton transmission rate were measured for several beam energies between 69 and 225 MeV as well as for variable momentum limiting slit openings. We conclude that the usage of a PBM increases the robustness of the PGT method in clinical conditions and that the obtained data will help to create reliable range verification procedures in clinical routine.

Range verification is a very important point in order to fully exploit the physical advantages of protons compared to photons in cancer irradiation. Recently, a simple method has been proposed which makes use of the time of flight of protons in tissue and the promptly emitted secondary photons along the proton path (Prompt Gamma Timing, PGT). This has been considered so far for monoenergetic pencil beams only. In this work, it has been studied whether this technique can also be applied in passively formed irradiation fields with a so called spread out Bragg peak. Time correlated profiles could be recorded, which show a trend that is consistent with theoretical predictions.

Cell transplantation and stem cell therapy are promising approaches for regenerative medicine and are of interest to researchers and clinicians worldwide. However, currently, no imaging technique that allows three-dimensional in vivo inspection of therapeutically administered cells in host tissues is available. Therefore, we investigate magnetomotive optical coherence tomography (MM-OCT) of cells labeled with magnetic particles as a potential noninvasive cell tracking method. We develop magnetomotive imaging of mesenchymal stem cells for future cell therapy monitoring. Cells were labeled with fluorescent iron oxide nanoparticles, embedded in tissue-mimicking agar scaffolds, and imaged using a microscope setup with an integrated MM-OCT probe. Magnetic particle-induced motion in response to a pulsed magnetic field of 0.2 T was successfully detected by OCT speckle variance analysis, and cross-sectional and volumetric OCT scans with highlighted labeled cells were obtained. In parallel, fluorescence microscopy and laser speckle reflectometry were applied as two-dimensional reference modalities to image particle distribution and magnetically induced motion inside the sample, respectively. All three optical imaging modalities were in good agreement with each other. Thus, magnetomotive imaging using iron oxide nanoparticles as cellular contrast agents is a potential technique for enhanced visualization of selected cells in OCT.

Recent studies in animal models provided proof-of-principle evidence for cell transplantation as a potential future therapeutic approach for retinal pathologies in humans such as Retinitis pigmentosa or age-related macular degeneration. In this case, donor cells are injected into the eye in order to protect or replace degenerating photoreceptors or retinal pigment epithelium. However, currently there is no three-dimensional imaging technique available that allows tracking of cell migration and integration into the host tissue under in vivo conditions. Therefore, we investigate about magnetomotive optical coherence tomography (OCT) of substances labeled with iron oxide nanoparticles as a potential method for noninvasive, three-dimensional cell tracking in the retina. We use a self-developed spectral domain OCT system for high-resolution imaging in the 800 nm-wavelength region. A suitable AC magnetic field for magnetomotive imaging was generated using two different setups, which consist of an electrically driven solenoid in combination with a permanent magnet, and a mechanically driven all-permanent magnet configuration. In the sample region the maximum magnetic flux density was 100 mT for both setups, with a field gradient of 9 T/m and 13 T/m for the solenoid and the allpermanent magnet setup, respectively. Magnetomotive OCT imaging was performed in elastic tissue phantoms and single cells labeled with iron oxide nanoparticles. Particle-induced sub-resolution movement of the elastic samples and the single cells could successfully be detected and visualized by means of phase-resolved Doppler OCT analysis. Therefore, this method is a potential technique to enhance image contrast of specific cells in OCT.