Rachel Bar-Shalom

Bio: Rachel Bar-Shalom is an academic researcher from Shaare Zedek Medical Center. The author has contributed to research in topics: Prodrug & Image resolution. The author has an hindex of 2, co-authored 5 publications receiving 10 citations.

Chemo-Radiotherapy of Oligometastases of Colorectal Cancer With Pegylated Liposomal Mitomycin-C Prodrug (Promitil): Mechanistic Basis and Preliminary Clinical Experience.

Abstract: Hypo-fractionated radiotherapy and stereotactic body radiotherapy are viable options for treatment of oligometastases. A prodrug of mitomycin-C is under clinical testing as a pegylated liposomal formulation (Promitil) with an improved safety profile over mitomycin-C. Promitil was offered to two patients with oligometastases from colorectal cancer as radiosensitizer. Each derived durable clinical benefit from Promitil administered immediately prior to and following irradiation. Transient toxicity to normal tissues of moderate to severe degree was observed. Promitil appears to have potential clinical value in this setting. HIGHLIGHTS - Delivery of radio-sensitizing drugs with pegylated (long-circulating) liposomes is a pharmacologically rational approach which remains largely clinically untested.- A mitomycin-c prodrug delivered by pegylated liposomes (Promitil) is activated by thiol groups, which are produced in excess by radiation-damaged cells, thus potentiating the radio-sensitizing effect of Promitil.- Two durable clinical responses in patient with colorectal oligometastases to Promitil and radiotherapy suggest that this approach may be of value in cancer chemo-radiotherapy.

Gamma Radiation Imaging System via Variable and Time-Multiplexed Pinhole Arrays.

Abstract: Biomedical planar imaging using gamma radiation is a very important screening tool for medical diagnostics. Since lens imaging is not available in gamma imaging, the current methods use lead collimator or pinhole techniques to perform imaging. However, due to ineffective utilization of the gamma radiation emitted from the patient’s body and the radioactive dose limit in patients, poor image signal to noise ratio (SNR) and long image capturing time are evident. Furthermore, the resolution is related to the pinhole diameter, thus there is a tradeoff between SNR and resolution. Our objectives are to reduce the radioactive dose given to the patient and to preserve or improve SNR, resolution and capturing time while incorporating three-dimensional capabilities in existing gamma imaging systems. The proposed imaging system is based on super-resolved time-multiplexing methods using both variable and moving pinhole arrays. Simulations were performed both in MATLAB and GEANT4, and gamma single photon emission computed tomography (SPECT) experiments were conducted to support theory and simulations. The proposed method is able to reduce the radioactive dose and image capturing time and to improve SNR and resolution. The results and method enhance the gamma imaging capabilities that exist in current systems, while providing three-dimensional data on the object.

Posttreatment FDG-Avid Splenic Lesions in DLBCL and HD: Clinical and Radiographic Characteristics for Risk Assessment.

Abstract: Residual end of treatment (EOT) FDG-avid lesions are often due to infectious or inflammatory process and not due to refractory lymphoma. Nonetheless, such lesions prompt diagnostic and therapeutic interventions. We evaluate clinical and radiological characteristics of patients with EOT FDG-avid splenic lesions. Comparing metabolic volume (MV) ratio between EOT to interim, showed a marked difference between false positive and true positive lesions (0.5 vs 3.6, P = 0.02). EOT SUVmax was also significantly different between the groups (7 vs. 19, P = 0.02). We suggest EOT/interim-MV ratio as a tool to identify patients at low risk of refractory disease allowing non-invasive surveillance.

Time Multiplexed Pinholes Array based Imaging in the Gamma and X-ray Spectral Range

Abstract: Validation and optimization of lensless radiation imaging technique for gamma and x-ray systems based on variable coded aperture is presented. The system can also provide depth information and 3D images with improved SNR and sensitivity.

Limiting surveillance imaging for patients with lymphoma in remission: a mixed methods study leading to a Choosing Wisely recommendation

Abstract: Background Under the ‘Choosing Wisely’ (CW) framework, professional organisations internationally have advocated limiting imaging for asymptomatic patients following curative cancer therapy, based on limited value and high cost. F18-fluorodeoxyglucose (FDG) positron emission tomography-CT (PET/CT) was widely adopted locally for surveillance lymphoma imaging after 2004. Objectives Prior to ratification of a local CW recommendation to limit surveillance imaging in lymphoma, we aimed to assess: (A) performance characteristics of surveillance FDG-PET/CT; (B) rates, clinical consequences and costs of false positives (FP); and (C) patients and professionals’ attitudes towards overuse. Methods Mixed methods (quantitative and qualitative) study. We analysed surveillance FDG-PET/CT results of two patient cohorts (n1=215 Hodgkin lymphoma and non-Hodgkin lymphoma; n2=203 Hodgkin lymphoma only). FPs were defined by negative biopsy or clinical follow-up. We held focus group discussions and in-depth interviews eliciting attitudes of 26 patients and 11 clinicians, respectively. Results FPs were observed in 25.1% (95% CI 20.5 to 30.5) per scan—cohort 1, and 41.7% (95% CI 37.9 to 45.6) per patient—cohort 2, engendering frequent additional testing. Specific characteristics and location of findings altered the FP rate. The estimated cost per relapse detected was $50 000 (cohort 2). Patients sought reassurance via surveillance imaging, which they considered highly accurate, yet stressful. Aware of radiation risks, they were largely unconcerned about consequences of FPs. Confidence in the treating physicians was an important factor in patients’ acceptance of forgoing imaging. Clinicians, frequently under patient pressure to order imaging, generally believed that it did not affect prognosis (with important exceptions), welcomed professional guidelines, but rejected regulatory restrictions on its use. Conclusion Acceptance of CW recommendations to limit overuse may be enhanced by quantitative data on consequences and costs of surveillance imaging, supplemented by qualitative data on patient and physician attitudes.

Understanding nanoparticle endocytosis to improve targeting strategies in nanomedicine

Abstract: Nanoparticles (NPs) have attracted considerable attention in various fields, such as cosmetics, the food industry, material design, and nanomedicine. In particular, the fast-moving field of nanomedicine takes advantage of features of NPs for the detection and treatment of different types of cancer, fibrosis, inflammation, arthritis as well as neurodegenerative and gastrointestinal diseases. To this end, a detailed understanding of the NP uptake mechanisms by cells and intracellular localization is essential for safe and efficient therapeutic applications. In the first part of this review, we describe the several endocytic pathways involved in the internalization of NPs and we discuss the impact of the physicochemical properties of NPs on this process. In addition, the potential challenges of using various inhibitors, endocytic markers and genetic approaches to study endocytosis are addressed along with the principal (semi) quantification methods of NP uptake. The second part focuses on synthetic and bio-inspired substances, which can stimulate or decrease the cellular uptake of NPs. This approach could be interesting in nanomedicine where a high accumulation of drugs in the target cells is desirable and clearance by immune cells is to be avoided. This review contributes to an improved understanding of NP endocytic pathways and reveals potential substances, which can be used in nanomedicine to improve NP delivery.

Update on pharmacotherapy for ocular surface squamous neoplasia

Abstract: The most frequently encountered non-pigmented tumor of the ocular surface is ocular surface squamous neoplasia (OSSN). Over the past two decades, the pharmacological management of OSSN has grown, with topical 5-fluorouracil, mitomycin, and interferon alpha 2b all being successfully used to treat this disease. Other agents, such as anti-vascular endothelial growth factor (VEGF), retinoic acid, cidofovir and Aloe vera, have less frequently been used in the treatment of OSSN. This review will discuss these pharmacologic agents, summarizing available data and presenting the approach to the treatment of these tumors.

Conjugating Aptamer and Mitomycin C with Reductant-Responsive Linker Leading to Synergistically Enhanced Anticancer Effect.

Abstract: Mitomycin C (MMC) has been using for the treatment of a variety of digestive tract cancers. However, its nonspecific DNA-alkylating ability usually causes severe side effects, thus largely limiting its clinical applications. The utilization of an efficient active targeted drug delivery technique would address this issue. Accordingly, we report the design and development of aptamer-mitomycin C conjugates that use different cross-linking chemistry. The targeted delivery ability and cytotoxicity of these conjugates were carefully studied. It is worth noting that a linker-dependent cytotoxicity effect was observed for these conjugates. The use of a reductant-sensitive disulfide bond cross-linking strategy resulted in significantly enhanced cytotoxicity of MMC against the target cancer cell lines. Importantly, this cytotoxicity enhancement was suited to different types of aptamers, demonstrating the success of our design. Mechanistic studies of the enhanced cytotoxicity effect indicated that the target recognition, specific binding, and receptor-mediated internalization of aptamer were also critical for the observed effect.

Critical considerations for targeting colorectal liver metastases with nanotechnology.

Abstract: Colorectal cancer remains a significant cause of morbidity and mortality worldwide. Half of all patients develop liver metastases, presenting unique challenges for their treatment. The shortcomings of conventional chemotherapy has encouraged the use of nanomedicines; the application of nanotechnology in the diagnosis and treatment of disease. In spite of technological improvements in nanotechnology, the complexity of biological systems hinders the prospect of nanomedicines being applied in cancer therapy at the present time. This review highlights current biological barriers and discusses aspects of tumor biology together with the physicochemical features of the nanocarrier, that need to be considered in order to develop effective nanotherapeutics for colorectal cancer patients with liver metastases. It becomes clear that incorporating an interdisciplinary approach when developing nanomedicines should assure appropriate disease-driven design and that this will form a critical step in improving their clinical translation. This article is characterized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.