Total Body Irradiation for Hematopoietic Stem Cell Transplantation: What Can We Agree on?

Total body irradiation (TBI), used as part of the conditioning regimen prior to allogeneic and autologous hematopoietic cell transplantation, is the delivery of a relatively homogeneous dose of radiation to the entire body. TBI has a dual role, being cytotoxic and immunosuppressive. This allows it to eliminate disease and create "space" in the marrow while also impairing the immune system from rejecting the foreign donor cells being transplanted. Advantages that TBI may have over chemotherapy alone are that it may achieve greater tumour cytotoxicity and better tissue penetration than chemotherapy as its delivery is independent of vascular supply and physiologic barriers such as renal and hepatic function. Therefore, the so-called "sanctuary" sites such as the central nervous system (CNS), testes, and orbits or other sites with limited blood supply are not off-limits to radiation. Nevertheless, TBI is hampered by challenging logistics of administration, coordination between hematology and radiation oncology departments, increased rates of acute treatment-related morbidity and mortality along with late toxicity to other tissues. Newer technologies and a better understanding of the biology and physics of TBI has allowed the field to develop novel delivery systems which may help to deliver radiation more safely while maintaining its efficacy. However, continued research and collaboration are needed to determine the best approaches for the use of TBI in the future.

A mixed-integer linear programming optimization model framework for capturing expert planning style in low dose rate prostate brachytherapy.

Low dose rate (LDR) brachytherapy is a minimally invasive form of radiation therapy, used to treat prostate cancer, and it involves permanent implantation of radioactive sources (seeds) inside of the prostate gland. Treatment planning in brachytherapy involves a decision making process for the placement of the sources in order to deliver an effective dose of radiation to cancerous tissue in the prostate while sparing the surrounding healthy tissue. Such a decision making process can be modeled as a mixed-integer linear programming (MILP) problem. In this paper, we introduce a novel MILP optimization model framework for interstitial LDR prostate brachytherapy designed to explicitly mimic the qualities of treatment plans produced manually by expert planners. Our approach involves incorporating a unique set of clinically important constraints, called spatial constraints, into the optimization model. Computational results for an initial model reflecting clinical practice at our cancer center show that the treatment plans produced largely capture the spatial and dosimetric characteristics of manual plans created by expert planners.

Scientific overview on CSCI-CITAC Annual General Meeting and 2017 Young Investigators' Forum.

The 2017 Annual General Meeting of the Canadian Society of Clinician Investigators (CSCI) and Clinician Investigator Trainee Association of Canada/Association des Cliniciens-Chercheurs en Formation du Canada (CITAC/ACCFC) was a national Annual General Meeting (AGM) held in Toronto, Ontario November 20-22, 2017, in conjunction with the University of Toronto Clinician Investigator Program Research Day. The theme for this year's meeting was "Roll up your sleeves-How to manage your physician scientist career", emphasizing lectures and workshops that were designed to provide tools for being proactive and successful in career planning. The keynote speakers were Dr. Rod McInnes (McGill University and Canadian Institutes of Health Research Acting President), who was the Distinguished Scientist Award recipient, Dr. David Goltzman (McGill University), who was the 2017 Henry Friesen Award recipient, Dr. Gillian Hawker (University of Toronto), Dr. Mike Sapieha (Université de Montréal), who was the 2017 Joe Doupe Award recipient, and Dr. Alex MacKenzie (Children's Hospital of Eastern Ontario Research Institute, University of Ottawa). The workshops, focusing on career development for clinician scientists, were hosted by Dr. Lisa Robinson, Dr. Nicola Jones, Kevin Vuong, Fran Brunelle, Dr. Jason Berman and Dr. Alan Underhill. Further to this, the Young Investigators' Forum encompasses presentations from scientist-clinician trainees from across the country. All scientific abstracts are summarized in this review. There were over 100 abstracts showcased at this year's meeting during the highlighted poster sessions, with six outstanding abstracts selected for oral presentations during the President's Forum.

Initial clinical assessment of "center-specific" automated treatment plans for low-dose-rate prostate brachytherapy.

PURPOSE: To report results of an initial pilot study assessing iodine-125 prostate implant treatment plans created automatically by a new seed-placement method. METHODS AND MATERIALS: A novel mixed-integer linear programming method incorporating spatial constraints on seed locations in addition to standard dose-volume constraints was used to place seeds. The approach, described in detail elsewhere, was used to create treatment plans fully automatically on a retrospective basis for 20 patients having a wide range of prostate sizes and shapes. Corresponding manual plans used for patient treatment at a single institution were combined with the automated plans, and all 40 plans were anonymized, randomized, and independently evaluated by five clinicians using a common scoring tool. Numerical and clinical features of the plans were extracted for comparison purposes. RESULTS: A full 51% of the automated plans were deemed clinically acceptable without any modification by the five practitioners collectively versus 90% of the manual plans. Automated plan seed distributions were for the most part not substantially different from those for the manual plans. Two observed shortcomings of the automated plans were seed strands not intersecting the prostate and strands extending into the bladder. Both are amenable to remediation by adjusting existing spatial constraints. CONCLUSIONS: After spatial and dose-volume constraints are set, the mixed-integer linear programming method is capable of creating prostate implant treatment plans fully automatically, with clinical acceptability sufficient to warrant further investigation. These plans, intended to be reviewed and refined as necessary by an expert planner, have the potential to both save planner time and enhance treatment plan consistency.

Matrilin-3 as a putative effector of C-type natriuretic peptide signaling during TGF-ß induced chondrogenic differentiation of mesenchymal stem cells.

C-type natriuretic peptide (CNP) signaling has been implicated as an important regulator of chondrogenic differentiation during endochondral bone development. This preliminary study further investigated the putative effectors and/or targets of CNP signaling in transforming growth factor (TGF)-ß induced in vitro chondrogenic differentiation of mesenchymal stem cells (MSCs). Previously characterized human trabecular bone derived MSCs were induced either with only TGF-ß1 or with a combination of TGF-ß1 and CNP in micromass culture for 10 or 20 days. Genome wide gene expression profile changes in between these two groups were analyzed on day-10 or day-20 of culture. Results revealed that there were only 7 genes, whose expression change was fourfolds or higher in TGF-ß1 and CNP fed group in comparison to only TGF-ß1 fed group. The up-regulated genes included matrilin-3 (MATN3), engulfment and cell motility 1 (ELMO1), CD24, and DCN1, defective in cullin neddylation 1, domain containing 1 (DCUN1D1). The down-regulated genes, on the other hand, included LIM domain kinase 2 (LIMK2), Ewing sarcoma breakpoint region 1, and guanine nucleotide binding protein (G protein), gamma 12 (GNG12). The up-regulation of MATN3 was confirmed on the basis of RT-PCR. The known literature on both CNP signaling and MATN3 function in chondrogenesis match with each other and suggest MATN3 as a putative effector and/or target of CNP signaling during this process.

Bisphosphonate-derivatized liposomes to control drug release from collagen/hydroxyapatite scaffolds.

A drug delivery system was developed by combining composite scaffolds made up of collagen and hydroxyapatite (Col/HA) with bisphosphonate (BP)-derivatized liposomes. The Col/HA scaffold was prepared by a freeze-drying method to yield a porous scaffold. The liposomes were composed of distearoylphosphocholine, cholesterol, distearoylphosphoethanolamine-poly(ethylene glycol) (DSPE-PEG), and a bone-binding bisphosphonate (BP) attached to the DSPE-PEG (DSPE-PEG-BP). By taking advantage of the specific interaction between the liposomal BP and the HA incorporated into the scaffold, the BP-decorated liposomes (BP-liposomes) were shown to display a strong affinity to Col/HA scaffolds. Three different model drugs, carboxyfluorescein (CF), doxorubicin (DOX), and lysozyme (LYZ) were entrapped in liposomes; there were no differences in drug release from the liposomes whether the liposomes were BP decorated or not. Whereas unencapsulated drugs and drugs encapsulated in PEG-liposomes displayed rapid release from the scaffolds, the drugs entrapped in BP-liposomes showed a slower release from the Col/HA scaffolds. We conclude that the proposed system can prolong the in situ residence of model drugs and has the potential to provide a sustained drug release platform in bone regeneration and repair.