Implementation of a dose calculation algorithm based on Monte Carlo simulations for treatment planning towards MRI guided ion beam therapy

Magnetic resonance guidance in particle therapy has the potential to improve the current performance of clinical workflows. However, the presence of magnetic fields challenges the current algorithms for treatment planning. To ensure proper dose calculations, compensation methods are required to guarantee that the maximum deposited energy of deflected beams lies in the target volume. In addition, proper modifications of the intrinsic dose calculation engines, accounting for magnetic fields, are needed. In this work, an algorithm for proton treatment planning in magnetic fields was implemented in a research treatment planning system (TPS), matRad. Setup-specific look up tables were generated using a validated MC model for a clinical proton beamline (62.4 – 215.7 MeV) interacting with a dipole magnet (B = 0–1 T). The algorithm was successfully benchmarked against MC simulations in water, showing gamma index (2%/2mm) global pass rates higher than 96% for different plan configurations. Additionally, absorbed depth doses were compared with experimental measurements in water. Differences within 2% and 3.5% in the Bragg peak and entrance regions, respectively, were found. Finally, treatment plans were generated and optimized for magnetic field strengths of 0 and 1 T to assess the performance of the proposed model. Equivalent treatment plans and dose volume histograms were achieved, independently of the magnetic field strength. Differences lower than 1.5% for plan quality indicators (D_2%, D_50%, D_90%, V_95% and V_105%) in water, a TG119 phantom and an exemplary prostate patient case were obtained. More complex treatment planning studies are foreseen to establish the limits of applicability of the proposed model.     

Geometry optimisation of graphite energy degrader for proton therapy

Introduction: Cyclotron-based proton therapy facilities use an energy degrader of variable thickness to deliver beams of the different energies required by a patient treatment plan; scattering and straggling in the degrader give rise to an inherent emittance increase and subsequent particle loss in the downstream energy-selection system (ESS). Here we study alternative graphite degrader geometries and examine with Monte-Carlo simulations the induced emittance growth and consequent particle transmission.Methods: We examined the conventional multiple-wedge degrader used in the Paul Scherrer Institute PROSCAN proton therapy system, the equivalent parallel-sided degrader, and a single block degrader of equivalent thickness. G4Beamline Monte-Carlo tracking of protons was benchmarked against measurements of the existing degrader for proton energies from 75 to 230 MeV, and used to validate simulations of the alternative geometries.Results: Using a careful calculation of the beam emittance growth, we determined that a single-block degrader placed close to the collimators of the ESS is expected to deliver significantly larger transmission, up to 17% larger at 150 MeV. At the lowest deliverable of 75 MeV there is still a clear improvement in beam transmission.Conclusions: Whilst dose rates are not presently limited on the PROSCAN system at higher energies, a single-block degrader offers the ability to access either lower energies for treatment or a larger dose rate at 75 MeV in case transmission optimisation is desired. Single-block degraders should be considered for the delivery of low-energy protons from a cyclotron-based particle therapy system.     

New insights into small‐cell lung cancer development and therapy

Small‐cell lung cancer (SCLC) accounts for approximately 15% of lung cancer cases; however, it is characterized by easy relapse and low survival rate, leading to one of the most intractable diseases in clinical practice. Despite decades of basic and clinical research, little progress has been made in the management of SCLC. The current standard first‐line regimens of SCLC still remain to be cisplatin or carboplatin combined with etoposide, and the adverse events of chemotherapy are by no means negligible. Besides, the immunotherapy on SCLC is still in an early stage and novel studies are urgently needed. In this review, we describe SCLC development and current therapy, aiming at providing useful advices on basic research and clinical strategy.     

The use of three-dimensional model construction of virtual technology in orthopedic treatment

ObjectiveThe objective of this study is to explore the construction of a digital three-dimensional model of virtual technology that plays an auxiliary role in orthopedic treatment.MethodsThree fracture patients were selected, with no abnormality was observed in bone examination, no musculoskeletal disease in the past; and spiral CT scan of the spine and pelvis, upper limbs, and lower limbs was performed. The virtual technology was used to build a digital 3D model, mainly using the editing software Mimics10.0 software. In addition, the virtual three-dimensional model was verified by virtual surgery, data storage security, work efficiency of the model, model validity, three-dimensional characteristics of the model, the interaction mode of the model, and the data accuracy of the model were studied.ResultsThe digital 3D model was successfully established by Mimics10.0 software. The data fitting efficiency was very high. The data storage security of the 3D model was greatly improved compared with the 2D model, and the work efficiency was improved by at least 50%. There was also a significant change in the accuracy and interaction of data acquisition. Therefore, the detection of digital 3D model work through virtual surgery simulation fully demonstrated the positive auxiliary role of 3D model in orthopedic treatment.ConclusionThe digital 3D model based on Mimics10.0 software is efficient and accurate in obtaining data. It is very effective for subsequent adjuvant therapy in the field of orthopedics, reducing the probability of misdiagnosis by doctors, saving time and improving efficiency, reducing patient's physical pain and unnecessary economic expenses.     

Combined ipilimumab and nivolumab first‐line and after BRAF‐targeted therapy in advanced melanoma

The combination of ipilimumab and nivolumab is a highly active systemic therapy for metastatic melanoma but can cause significant toxicity. We explore the safety and efficacy of this treatment in routine clinical practice, particularly in the setting of serine/threonine‐protein kinase B‐Raf (BRAF)‐targeted therapy. Consecutive patients with unresectable stage IIIC/IV melanoma commenced on ipilimumab and nivolumab across 10 tertiary melanoma institutions in Australia were identified retrospectively. Data collected included demographics, response and survival outcomes. A total of 152 patients were included for analysis, 39% were treatment‐naïve and 22% failed first‐line BRAF/MEK inhibitors. Treatment‐related adverse events occurred in 67% of patients, grade 3–5 in 38%. The overall objective response rate was 41%, 57% in treatment‐naïve and 21% in BRAF/MEK failure patients. Median progression‐free survival was 4.0 months (95% CI, 3.0–6.0) in the whole cohort, 11.0 months (95% CI, 6.0‐NR) in treatment‐naïve and 2.0 months (95% CI, 1.4–4.6) in BRAF/MEK failure patients. The combination of ipilimumab and nivolumab can be used safely and effectively in a real‐world population. While first‐line efficacy appears comparable to trial populations, BRAF‐mutant patients failing prior BRAF/MEK inhibitors show less response.     

Distinct genomic traits of acral and mucosal melanomas revealed by targeted mutational profiling

The incidence of melanoma is rising globally including China. Comparing to Caucasians, the incidence of non‐cutaneous melanomas is significantly higher in Chinese. Herein, we performed genomic profiling of 89 Chinese surgically resected primary melanomas, including acral (n = 54), cutaneous (n = 22), and mucosal (n = 13), by hybrid capture‐based next‐generation sequencing. We show that mucosal melanomas tended to harbor more pathogenic mutations than other types of melanoma, though the biological significance of this finding remains uncertain. Chromosomal arm‐level alterations including 6q, 9p, and 10p/q loss were highly recurrent in all subtypes, but mucosal melanoma was significantly associated with increased genomic instability. Importantly, 7p gain significantly correlated with unfavorable clinical outcomes in non‐cutaneous melanomas, representing an intriguing prognostic biomarker of those subtypes. Furthermore, focal amplification of 4q12 (KIT, KDR, and PDGFRα) and RAD51 deletion were more abundant in mucosal melanoma, while NOTCH2 amplification was enriched in acral melanoma. Additionally, cutaneous melanomas had higher mutation load than acral melanomas, while mucosal melanomas did not differ from other subtypes in mutation burden. Together, our data revealed important features of acral and mucosal melanomas in Chinese including distinctive driver mutation pattern and increased genomic instability. These findings highlight the possibilities of combination therapies in the clinical management of melanoma.     

Advancing Aptamers as Molecular Probes for Cancer Theranostic Applications—The Role of Molecular Dynamics Simulation

Theranostics cover emerging technologies for cell biomarking for disease diagnosis and targeted introduction of drug ingredients to specific malignant sites. Theranostics development has become a significant biomedical research endeavor for effective diagnosis and treatment of diseases, especially cancer. An efficient biomarking and targeted delivery strategy for theranostic applications requires effective molecular coupling of binding ligands with high affinities to specific receptors on the cancer cell surface. Bioaffinity offers a unique mechanism to bind specific target and receptor molecules from a range of non‐targets. The binding efficacy depends on the specificity of the affinity ligand toward the target molecule even at low concentrations. Aptamers are fragments of genetic materials, peptides, or oligonucleotides which possess enhanced specificity in targeting desired cell surface receptor molecules. Aptamer–target binding results from several inter‐molecular interactions including hydrogen bond formation, aromatic stacking of flat moieties, hydrophobic interaction, electrostatic, and van der Waals interactions. Advancements in Systematic Evolution of Ligands by Exponential Enrichment (SELEX) assay has created the opportunity to artificially generate aptamers that specifically bind to desired cancer and tumor surface receptors with high affinities. This article discusses the potential application of molecular dynamics (MD) simulation to advance aptamer‐mediated receptor targeting in targeted cancer therapy. MD simulation offers real‐time analysis of the molecular drivers of the aptamer‐receptor binding and generate optimal receptor binding conditions for theranostic applications. The article also provides an overview of different cancer types with focus on receptor biomarking and targeted treatment approaches, conventional molecular probes, and aptamers that have been explored for cancer cells targeting.     

Overexpression of ER Protein Processing and Apoptosis Regulator Genes in Human Embryonic Kidney 293 Cells Improves Gene Therapy Vectors Production

Gammaretroviral and lentiviral vectors (γ‐RV and LV) are among the most used vectors in gene therapy. Currently, human embryonic kidney (HEK) 293 cells, the manufacture platform of choice for these vectors, provide low transducing particle yields, challenging their therapeutic applications and commercialization. This work studies metabolic pathways, focusing on endoplasmic reticulum (ER) protein processing and anti‐apoptotic mechanisms, influencing vector productivity in HEK 293 cell substrates. To that end, four candidate genes—protein disulfide isomerase family A member 2 gene, heat shock protein family A (Hsp70) member 5 gene, X‐box binding protein 1 gene (ER protein processing), and B‐cell lymphoma 2 protein gene (anti‐apoptotic)—are individually stably expressed in the cells. How their overexpression level influence vector yields is analyzed by establishing cell populations with incremental genomic copies of each. γ‐RV volumetric productivity increases up to 97% when overexpressing ER protein processing genes. LV volumetric production increases 53% when overexpressing the anti‐apoptotic gene. Improvements are associated with higher cell specific productivities and dependent on gene overexpression level, highlighting the importance of fine‐tuning gene expression. Overall, this work discloses gene engineering targets enabling efficient gene therapy product manufacture showing that ER protein processing and anti‐apoptotic pathways are pivotal to producer cell performance.     

Design and synthesis of a folate-receptor targeted diazepine-ring-opened pyrrolobenzodiazepine prodrug conjugate

Pyrrolobenzodiazepines (PBDs) and their dimers (bis-PBDs) have emerged as some of the most potent chemotherapeutic compounds and are currently under development as novel payloads in antibody-drug conjugates (ADCs). However, when used as stand-alone therapeutics or as warheads for small molecule drug conjugates (SMDCs), dose-limiting toxicities are often observed. As an elegant solution to this inherent problem, we designed and synthesized a diazepine-ring-opened bis-PBD prodrug (pro-PBD-PBD) folate conjugate lacking the one of the two imine moieties found in the corresponding free bis-PBD. Upon entering a targeted cell, cleavage of the linker system, including the hydrolysis of an oxazolidine moiety, results in the formation of a reactive intermediate which possesses a newly formed aldehyde as well as an aromatic amine. A fast and spontaneous intramolecular ring-closing reaction subsequently takes place as the aromatic amine adds to the aldehyde with the loss of water to give the imine, and as a result, the diazepine ring, thereby delivering the bis-PBD to the targeted cell. The in vitro and in vivo activity of this conjugate has been evaluated on folate receptor positive KB cells. Sub-nanomolar activity with good specificity and high cure rates with minimal toxicity have been observed.