Embracing the Practical Aspects of Theranostics With Prostate-Specific Membrane Antigen-Targeted Lutetium-177.

Treatment options for men with metastatic castration-resistant prostate cancer are rapidly changing. In addition to novel anti-androgens and taxane-based chemotherapy, radiopharmaceuticals are having an increasing role. Although calcium-mimetic theranostics have been in use for years, newer approaches use molecularly targeted radiation therapy by conjugating isotopes to prostate-specific membrane antigen (PSMA) and in so doing directly target prostate cancer cells; 177Lutetium-PSMA-617 is perhaps the best-known member of this new class. Expanding our capacity to deliver targeted beta-emitters requires additional planning and equipment. Having delivered close to 200 doses of 177Lutetium-PSMA-617 at our center, we offer practical advice about patient selection, radiation safety, treatment administration, and toxicity monitoring. Although this blueprint is not the only way to expand a theranostics program beyond Radium-223, we offer our institutional experience with 177Lutetium-PSMA-617 as an example to programs seeking to expand their radiopharmaceutical programs. We must rise to meet the patient-driven demand for these innovative and effective therapies.

Cell-shaped silicon-on-insulator microdosimeters: characterization and response to 239PuBe irradiations.

This work tested the feasibility of a silicon-on-insulator microdosimeter, which mimics the size and shape of specific cells within the human body, to determine dose equivalent from neutron irradiation. The microdosimeters were analyzed in terms of their basic diode characteristics, i.e., leakage current as a function of bias voltage. Lineal energy spectra were acquired using two different converter layers placed atop the microdosimeter: a tissue-substitute converter made from high-density polyethylene, and a boron converter consisting of epoxy coated with boron powder. The spectra were then converted into absorbed dose and dose equivalent. Experimental results were compared to Monte Carlo simulations of the neutron irradiations, revealing good agreement. Uncertainty in the dose equivalent determinations was 7.5% when using the cell-shaped microdosimeter with the tissue-substitute converter and 13.1% when using the boron converter. This work confirmed that the SOI approach to cell-mimicking microdosimetry is feasible.

Investigating Mutations to Reduce Huntingtin Aggregation by Increasing Htt-N-Terminal Stability and Weakening Interactions with PolyQ Domain.

Huntington's disease is a fatal autosomal genetic disorder characterized by an expanded glutamine-coding CAG repeat sequence in the huntingtin (Htt) exon 1 gene. The Htt protein associated with the disease misfolds into toxic oligomers and aggregate fibril structures. Competing models for the misfolding and aggregation phenomena have suggested the role of the Htt-N-terminal region and the CAG trinucleotide repeats (polyQ domain) in affecting aggregation propensities and misfolding. In particular, one model suggests a correlation between structural stability and the emergence of toxic oligomers, whereas a second model proposes that molecular interactions with the extended polyQ domain increase aggregation propensity. In this paper, we computationally explore the potential to reduce Htt aggregation by addressing the aggregation causes outlined in both models. We investigate the mutation landscape of the Htt-N-terminal region and explore amino acid residue mutations that affect its structural stability and hydrophobic interactions with the polyQ domain. Out of the millions of 3-point mutation combinations that we explored, the (L4K E12K K15E) was the most promising mutation combination that addressed aggregation causes in both models. The mutant structure exhibited extreme alpha-helical stability, low amyloidogenicity potential, a hydrophobic residue replacement, and removal of a solvent-inaccessible intermolecular side chain that assists oligomerization.

Initial analysis of Pro-Qura: a multi-institutional database of prostate brachytherapy dosimetry.

PURPOSE: The study aimed to analyze the Pro-Qura database in terms of patient implant sequence number for each institution to determine evidence for a dosimetric learning curve. METHODS AND MATERIALS: In the Pro-Qura database, 2833 of a total of 4614 postplans from 57 brachytherapists were analyzed for evidence of a dosimetric learning curve. The median time between implant and postimplant CT scan was 30 days. I-125 was used in 2123 patients (1687 monotherapy and 536 boost) and Pd-103 in 710 patients (367 monotherapy and 343 boost). Preimplant prostate volume was 35.3 and 32.9 cm3 in the I-125 and Pd-103 cohorts, respectively. The mean I-125 seed activity was 0.32 and 0.26 mCi for monotherapy and boost, whereas for Pd-103 the mean seed activity was 1.59 and 1.27 mCi, respectively. Postimplant dosimetry was performed in a standardized fashion by overlaying the preimplant ultrasound and the postimplant CT scan. Criteria for implant adequacy included a D90 >90% and a V100 >80% for both isotopes. An adequate V150 was defined as <60% for I-125 and <75% for Pd-103. RESULTS: The mean V100 and D90 were 88.9% and 101.9% of prescription dose, respectively. When analyzed in terms of patient sequence number for each institution, the mean V100 for the first 10 patients was 87.4% and increased to 88.6% for patients 11-20 (p = 0.036). Similarly, the mean D90 for the first 10 patients was 98.9%, whereas for the second cohort of 10 patients the mean D90 increased to 102.2% (p = 0.001). In terms of mean V100 and D90, there was minimal further change for subsequent 10 patient institutional groupings of patient sequence numbers. For the first 10 cases, 27.2% were deemed "too cool" (V100 <80% and/or D90 <90%). Approximately 16% of all implants were deemed "too hot" (D90 >140% or V150 >60% for I-125 or >75% for Pd-103). CONCLUSIONS: Although a learning curve exists for prostate brachytherapy, high-quality brachytherapy is achievable in approximately 75-80% of patients treated at community centers.