Ultrasound and Microbubbles Mediated Bleomycin Delivery in Feline Oral Squamous Cell Carcinoma-An In Vivo Veterinary Study.

To investigate the feasibility and tolerability of ultrasound and microbubbles (USMB)-enhanced chemotherapy delivery for head and neck cancer, we performed a veterinary trial in feline companion animals with oral squamous cell carcinomas. Six cats were treated with a combination of bleomycin and USMB therapy three times, using the Pulse Wave Doppler mode on a clinical ultrasound system and EMA/FDA approved microbubbles. They were evaluated for adverse events, quality of life, tumour response and survival. Furthermore, tumour perfusion was monitored before and after USMB therapy using contrast-enhanced ultrasound (CEUS). USMB treatments were feasible and well tolerated. Among 5 cats treated with optimized US settings, 3 had stable disease at first, but showed disease progression 5 or 11 weeks after first treatment. One cat had progressive disease one week after the first treatment session, maintaining a stable disease thereafter. Eventually, all cats except one showed progressive disease, but each survived longer than the median overall survival time of 44 days reported in literature. CEUS performed immediately before and after USMB therapy suggested an increase in tumour perfusion based on an increase in median area under the curve (AUC) in 6 out of 12 evaluated treatment sessions. In this small hypothesis-generating study, USMB plus chemotherapy was feasible and well-tolerated in a feline companion animal model and showed potential for enhancing tumour perfusion in order to increase drug delivery. This could be a forward step toward clinical translation of USMB therapy to human patients with a clinical need for locally enhanced treatment.

Comparison between de novo and metachronous metastatic breast cancer: the presence of a primary tumour is not the only difference-a Dutch population-based study from 2008 to 2018.

PURPOSE: The aim of this study was to compare characteristics and survival of patients with de novo and metachronous metastatic breast cancer. METHODS: Data of patients with metastatic breast cancer were obtained from the Netherlands Cancer Registry. Patients were categorized as having de novo metastatic breast cancer (n = 8656) if they had distant metastases at initial presentation, or metachronous metastatic disease (n = 2374) in case they developed metastases within 5 or 10 years after initial breast cancer diagnosis. Clinicopathological characteristics and treatments of these two groups were compared, after which multiple imputation was performed to account for missing data. Overall survival was compared for patients treated with systemic therapy in the metastatic setting, using Kaplan Meier curves and multivariable Cox proportional hazards models. The hazard ratio for overall survival of de novo versus metachronous metastases was assessed accounting for time-varying effects. RESULTS: Compared to metachronous patients, patients with de novo metastatic breast cancer were more likely to be ≥ 70 years, to have invasive lobular carcinoma, clinical T3 or T4 tumours, loco-regional lymph node metastases, HER2 positivity, bone only disease and to have received systemic therapy in the metastatic setting. They were less likely to have triple negative tumours and liver or brain metastases. Patients with de novo metastases survived longer (median 34.7 months) than patients with metachronous metastases (median 24.3 months) and the hazard ratio (0.75) varied over time. CONCLUSIONS: Differences in clinicopathological characteristics and survival between de novo and metachronous metastatic breast cancer highlight that these are distinct patients groups.

The Effect of Microbubble-Assisted Ultrasound on Molecular Permeability across Cell Barriers.

The combination of ultrasound and microbubbles (USMB) has been applied to enhance drug permeability across tissue barriers. Most studies focused on only one physicochemical aspect (i.e., molecular weight of the delivered molecule). Using an in vitro epithelial (MDCK II) cell barrier, we examined the effects of USMB on the permeability of five molecules varying in molecular weight (182 Da to 20 kDa) and hydrophilicity (LogD at pH 7.4 from 1.5 to highly hydrophilic). Treatment of cells with USMB at increasing ultrasound pressures did not have a significant effect on the permeability of small molecules (molecular weight 259 to 376 Da), despite their differences in hydrophilicity (LogD at pH 7.4 from -3.2 to 1.5). The largest molecules (molecular weight 4 and 20 kDa) showed the highest increase in the epithelial permeability (3-7-fold). Simultaneously, USMB enhanced intracellular accumulation of the same molecules. In the case of the clinically relevant anti- C-X-C Chemokine Receptor Type 4 (CXCR4) nanobody (molecular weight 15 kDa), USMB enhanced paracellular permeability by two-fold and increased binding to retinoblastoma cells by five-fold. Consequently, USMB is a potential tool to improve the efficacy and safety of the delivery of drugs to organs protected by tissue barriers, such as the eye and the brain.

Ultrasound-Mediated Drug Delivery With a Clinical Ultrasound System: In Vitro Evaluation.

Chemotherapy efficacy is often reduced by insufficient drug uptake in tumor cells. The combination of ultrasound and microbubbles (USMB) has been shown to improve drug delivery and to enhance the efficacy of several drugs in vitro and in vivo, through effects collectively known as sonopermeation. However, clinical translation of USMB therapy is hampered by the large variety of (non-clinical) US set-ups and US parameters that are used in these studies, which are not easily translated to clinical practice. In order to facilitate clinical translation, the aim of this study was to prove that USMB therapy using a clinical ultrasound system (Philips iU22) in combination with clinically approved microbubbles (SonoVue) leads to efficient in vitro sonopermeation. To this end, we measured the efficacy of USMB therapy for different US probes (S5-1, C5-1 and C9-4) and US parameters in FaDu cells. The US probe with the lowest central frequency (i.e. 1.6 MHz for S5-1) showed the highest USMB-induced intracellular uptake of the fluorescent dye SYTOX™ Green (SG). These SG uptake levels were comparable to or even higher than those obtained with a custom-built US system with optimized US parameters. Moreover, USMB therapy with both the clinical and the custom-built US system increased the cytotoxicity of the hydrophilic drug bleomycin. Our results demonstrate that a clinical US system can be used to perform USMB therapy as efficiently as a single-element transducer set-up with optimized US parameters. Therefore, future trials could be based on these clinical US systems, including validated US parameters, in order to accelerate successful translation of USMB therapy.

Phase I feasibility study of Magnetic Resonance guided High Intensity Focused Ultrasound-induced hyperthermia, Lyso-Thermosensitive Liposomal Doxorubicin and cyclophosphamide in de novo stage IV breast cancer patients: study protocol of the i-GO study.

INTRODUCTION: In breast cancer, local tumour control is thought to be optimised by administering higher local levels of cytotoxic chemotherapy, in particular doxorubicin. However, systemic administration of higher dosages of doxorubicin is hampered by its toxic side effects. In this study, we aim to increase doxorubicin deposition in the primary breast tumour without changing systemic doxorubicin concentration and thus without interfering with systemic efficacy and toxicity. This is to be achieved by combining Lyso-Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox, Celsion Corporation, Lawrenceville, NJ, USA) with mild local hyperthermia, induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU). When heated above 39.5°C, LTLD releases a high concentration of doxorubicin intravascularly within seconds. In the absence of hyperthermia, LTLD leads to a similar biodistribution and antitumour efficacy compared with conventional doxorubicin. METHODS AND ANALYSIS: This is a single-arm phase I study in 12 chemotherapy-naïve patients with de novo stage IV HER2-negative breast cancer. Previous endocrine treatment is allowed. Study treatment consists of up to six cycles of LTLD at 21-day intervals, administered during MR-HIFU-induced hyperthermia to the primary tumour. We will aim for 60 min of hyperthermia at 40°C-42°C using a dedicated MR-HIFU breast system (Profound Medical, Mississauga, Canada). Afterwards, intravenous cyclophosphamide will be administered. Primary endpoints are safety, tolerability and feasibility. The secondary endpoint is efficacy, assessed by radiological response.This approach could lead to optimal loco-regional control with less extensive or even no surgery, in de novo stage IV patients and in stage II/III patients allocated to receive neoadjuvant chemotherapy. ETHICS AND DISSEMINATION: This study has obtained ethical approval by the Medical Research Ethics Committee Utrecht (Protocol NL67422.041.18, METC number 18-702). Informed consent will be obtained from all patients before study participation. Results will be published in an academic peer-reviewed journal. TRIAL REGISTRATION NUMBERS: NCT03749850, EudraCT 2015-005582-23.

New Developments in Imaging for Sentinel Lymph Node Biopsy in Early-Stage Oral Cavity Squamous Cell Carcinoma.

Sentinel lymph node biopsy (SLNB) is a diagnostic staging procedure that aims to identify the first draining lymph node(s) from the primary tumor, the sentinel lymph nodes (SLN), as their histopathological status reflects the histopathological status of the rest of the nodal basin. The routine SLNB procedure consists of peritumoral injections with a technetium-99m [99mTc]-labelled radiotracer followed by lymphoscintigraphy and SPECT-CT imaging. Based on these imaging results, the identified SLNs are marked for surgical extirpation and are subjected to histopathological assessment. The routine SLNB procedure has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). However, an infamous limitation arises in situations where SLNs are located in close vicinity of the tracer injection site. In these cases, the hotspot of the injection site can hide adjacent SLNs and hamper the discrimination between tracer injection site and SLNs (shine-through phenomenon). Therefore, technical developments are needed to bring the diagnostic accuracy of SLNB for early-stage OSCC to a higher level. This review evaluates novel SLNB imaging techniques for early-stage OSCC: MR lymphography, CT lymphography, PET lymphoscintigraphy and contrast-enhanced lymphosonography. Furthermore, their reported diagnostic accuracy is described and their relative merits, disadvantages and potential applications are outlined.

Spatial heterogeneity of nanomedicine investigated by multiscale imaging of the drug, the nanoparticle and the tumour environment.

Genetic and phenotypic tumour heterogeneity is an important cause of therapy resistance. Moreover, non-uniform spatial drug distribution in cancer treatment may cause pseudo-resistance, meaning that a treatment is ineffective because the drug does not reach its target at sufficient concentrations. Together with tumour heterogeneity, non-uniform drug distribution causes "therapy heterogeneity": a spatially heterogeneous treatment effect. Spatial heterogeneity in drug distribution occurs on all scales ranging from interpatient differences to intratumour differences on tissue or cellular scale. Nanomedicine aims to improve the balance between efficacy and safety of drugs by targeting drug-loaded nanoparticles specifically to tumours. Spatial heterogeneity in nanoparticle and payload distribution could be an important factor that limits their efficacy in patients. Therefore, imaging spatial nanoparticle distribution and imaging the tumour environment giving rise to this distribution could help understand (lack of) clinical success of nanomedicine. Imaging the nanoparticle, drug and tumour environment can lead to improvements of new nanotherapies, increase understanding of underlying mechanisms of heterogeneous distribution, facilitate patient selection for nanotherapies and help assess the effect of treatments that aim to reduce heterogeneity in nanoparticle distribution. In this review, we discuss three groups of imaging modalities applied in nanomedicine research: non-invasive clinical imaging methods (nuclear imaging, MRI, CT, ultrasound), optical imaging and mass spectrometry imaging. Because each imaging modality provides information at a different scale and has its own strengths and weaknesses, choosing wisely and combining modalities will lead to a wealth of information that will help bring nanomedicine forward.

Central nervous system localisation of chronic lymphocytic leukaemia, description of two very distinct cases and a review of the literature.

Central nervous system (CNS) localisation of chronic lymphocytic leukaemia (CLL) can induce various neurological symptoms. Unfamiliarity with this manifestation causes diagnostic delay. We present two cases of leptomeningeal CLL. These cases and our literature review emphasise that CNS localisation of CLL should be considered in patients with any neurological symptom, irrespectively of the stage and systemic activity of CLL.

GUIDE, a structured pre-dialysis programme that increases the use of home dialysis.

BACKGROUND: Despite the many advantages it offers, the percentage of dialysis patients that receive home dialysis [peritoneal dialysis (PD) or home haemodialysis (HHD)] in the Netherlands has declined over the last decade. Pre-dialysis education could stimulate the use of home dialysis. This article presents the results of the pre-dialysis programme GUIDE, with regard to the following question: Does the implementation of a structured pre-dialysis programme with a home-focused approach increase the number of pre-dialysis patients that choose and receive home dialysis? METHODS: The GUIDE process starts when a patient has an eGFR of 15 mL/min/1.73 m2. The process begins with a home visit from a case manager and the completion of questionnaires by the patient, the case manager and the nephrologist. A multidisciplinary meeting (MDM) is held to determine a specific patient profile (or treatment recommendation). This is followed by patient education, a second MDM and finally the selection of the treatment by the patient and the nephrologist. This retrospective observational study describes the selection process of all patients that received a treatment recommendation between 12 September 2013 and 18 December 2014 at Meander Medical Centre. Data were collected by file research and analysis of questionnaires. RESULTS: One hundred and two patients were included. They started the process at a mean eGFR of 12.3 mL/min/1.73 m2. Home dialysis was recommended for 62.8% of the patients who were advised to have dialysis treatment. Of the patients that opted for dialysis, 34.2% chose PD and 8.2% chose HHD; 22.9% started home dialysis as their first therapy, compared with 17.6% in the months before implementation of GUIDE. Finally, 32.1% of the patients that received dialysis therapy received home dialysis. In the months before GUIDE, an average of just 19.5% of the patients that received dialysis received home dialysis. CONCLUSIONS: In comparison to historical data, the pre-dialysis programme GUIDE increases the number of patients that choose and receive home dialysis.