Treatment outcome and identification of factors influencing overall survival after Lu-177-PSMA-617 radioligand therapy in metastatic prostate cancer

Objective To examine the clinical benefit of Lu-177-PSMA-617 radioligand therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods Between November 2014 and December 2018, a total of 56 consecutive patients (median age 69.5 years; range 55–84 years) with mCRPC were included in this retrospective analysis. Patients received between 1 and 4 therapy cycles with a mean activity of 6.8 GBq per cycle. Biochemical response was evaluated using Prostate Cancer Working Group Criteria 3 (PCWG 3). Survival was assessed using Kaplan-Meier estimates and Cox proportional hazards regression analysis. This retrospective study was approved by the local ethics committee. Results A total of 139 treatment cycles with Lu-177-PSMA-617 were performed. A decline of 50% or more of prostate-specific antigen (PSA) level occurred in 54% and a PSA decline of any amount in 65% of patients. The estimated median overall survival (OS) was 16 months, in the chemotherapy subgroup 14 months. A longer OS was associated with a PSA-decline ≥50%, more than 2 cycles of therapy, cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l]. These identified predictors remained significant on uni- and multivariate Cox regression analysis. Moreover, 40% of the patients who were non-responders after the first therapy cycle turned into responders after the second one. Conclusion PSA-decline ≥50%, a cumulative activity >15 GBq and an initial alkaline phosphatase ≤ 220 [U/l] were identified as key predictors of prolonged OS in patients with mCRPC. In contrast rapid clinical deterioration mostly due to skeletal carcinomatosis resulted in early treatment failure.

A Simple and Novel Approach to Study Kinetics and Estimate Radiation doses from Internally Administered Radiopharmaceuticals using An External dose Measurement System

Various methods have been reported to study radiotracer kinetics and make internal dosimetry feasible in the routine clinical nuclear medicine practice. The aim of the present study was to quantify cumulative activity and organ doses using an indigenously designed and fabricated external dose measurement system. The measurement was demonstrated on patients undergoing whole-body (WB) 18F-FDG (Fluorine-18-fluorodeoxyglucose) direct positron emission tomography/computed tomography investigations. An external dose measurement system comprising of an ionisation chamber-survey meter and the movable focussing collimator was used to quantify the uptake of 18F-FDG in liver and brain. Cumulative activity and normalised cumulative activity in these organs were calculated. The results were validated by performing measurements on a phantom uniformly filled with known activity of 18F-FDG.The difference in the absorbed dose estimated with and without collimator was statistically significant (p < 0.05). The external dose measurement technique is relatively novel, convenient and reliable for the assessment of internal absorbed dose of organs.

Safety and efficacy of repeat Y90 radioembolization to the same hepatic arterial territory

Objective: To study the efficacy and safety of repeat transarterial radioembolization (TARE) to similar hepatic arterial territories. Methods: Between 3/2011 and 4/2019, 26 patients (25 males and 1 Female, Mean Age: 65 yo, SD: 11.7 yo, Range: 18–83.0 yo) received TARE with Y90 glass microspheres to treat recurrent or residual primary disease in similar hepatic arterial lobe or segments. Tumor response was evaluated by imaging using the modified-RECIST criteria. Incidence of RILD and adverse events were categorized by a standardized scale using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results: Mean cumulative activity after the first treatment was 2.50 GBq (SD:1.04 GBq, Range:0.61–4.93 GBq) and second treatment was 2.27 GBq (SD:1.01 GBq, Range:0.92–5.46 GBq). Mean interval time between initial and repeat treatments was 9.6 months (Range: 1–53 months). Tumor responses were complete, partial, or progression in 73% (n = 19/26), 23% (n = 6/26), and 4% (n = 1/26) in repeat treatment patients, respectively. The incidence of RILD was 0%. Toxicity after first and second treatment was seen in 19% (n = 5/26) & 23% (n = 6/26) patients, respectively, and were all of CTCAE Grade 2. No significant predictors of treatment toxicity for repeat treatment were identified except increased MELD score (p = 0.04). Kaplan-Meier survival analysis in patients with repeat treatment showed a median survival of 15.0 months (95% CI 8.8–21.1 months) and 19.0 months (95% CI 8.1–29.9 months) in patients who only received one treatment with a p value of 0.485. Conclusion: Repeat TARE with glass microspheres was an effective and safe treatment strategy for disease management in patients with residual or recurrent disease to the similar hepatic arterial territories without any major treatment related toxicity. Advances in knowledge: Although safety and efficacy of repeat radioembolism has been studied, no study has focused on repeat treatment to similar hepatic arterial territories. The current study shows that repeat treatment to the same hepatic arterial territory is as safe as single treatment to the same territory.

Labeling of ethylenediamine tetramethylene phosphonate with 153Sm and 177Lu,Comparison Study

Background 177Lu and 153Sm are perspective radionuclides in terms of applying to nuclear medicine. High-energy beta particles and the relative half-life of the radionuclide are used to achieve an effective palliative treatment of bone metastases. Materials and methods The absorbed doses in different organs and tissues of 177Lu and 153Sm in ionic form and labeled with EDTMP are determined by IDAC-Dose 2.1 (Internal Dose Assessment by Computer) software and WinAct software which used to calculate cumulative activity. 177Lu and 153Sm are lanthanide radionuclide which actively accumulates in liver and bone when used in ionic form. In the case of labeling with EDTMP, the distribution and elimination of the drug occur according to the kinetics of a carrier, EDTMP. The using of osteotropic (Describing any drug etc. that is attracted to, and targets bone) complex allows creating a large dose in the pathological areas and minimizing damages in healthy organs and tissues. Results The effective dose per administered activity is 0.189 mSv/MBq for 177Lu-ionic form, 0.232 mSv/MBq for 153Sm-ionic form and 0.242 mSv/MBq for 177Lu-EDTMP and 0.139 mSv/MBq for 153sm-EDTMP. Conclusion 177Lu and 153Sm labeled with EDTMP are decreasing the liver dose absorption and increasing the bone surface absorption for more effective treatment and minimize side effects.

Calculation of Absorption Dose Value using MIRD Method with Cobalt 57 MIBI for Four Body Organs

MIRD has developed methods, assumptions, models, and mathematical formulae for estimating internal radiation doses from the injected radiopharmaceuticals into the body. This study aims to determine the radiopharmaceutical distribution of Cobalt 57 MIBI in patients identified as having breast cancer by using an oncology examination with MIRD method on 4 patient's organs with some time variations. The four organs of the patient's body are the heart, thyroid, kidney, and liver. The MIRD method developed to calculate the absorption dose of each organ is the product of the cumulative activity and the S factor of each organ studied. The results showed that the highest uptake dose in these patients was in the thyroid and kidney organs, and then followed by the heart and liver. These results indicate that the thyroid and kidney organs are the most vulnerable organs by the method of injecting radiopharmaceutical doses into the body of breast cancer patients.

Transcription imparts architecture, function, and logic to enhancer units

Distal enhancers remain one of the least understood regulatory elements with pivotal roles in development and disease. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites (TSSs) are robust predictors of enhancer activity with higher resolution and specificity than histone modifications. We show that active enhancer units are precisely delineated by active TSSs, validate that these boundaries are sufficient to capture enhancer function, and confirm that core promoter sequences are required for this activity. Finally, we assay pairs of adjacent units and find that their cumulative activity is best predicted by the strongest unit within the pair. Synthetic fusions of enhancer units demonstrate that adjacency imposes winner-takes-all logic, revealing a simple design for a maximum-activity filter of enhancer unit outputs. Together, our results define fundamental enhancer units and a principle of non-cooperativity between adjacent units.

Mapping human cell phenotypes to genotypes with single-cell genomics

The cumulative activity of all of the body’s cells, with their myriad interactions, life histories, and environmental experiences, gives rise to a condition that is distinctly human and specific to each individual. It is an enduring goal to catalog our human cell types, to understand how they develop, how they vary between individuals, and how they fail in disease. Single-cell genomics has revolutionized this endeavor because sequencing-based methods provide a means to quantitatively annotate cell states on the basis of high-information content and high-throughput measurements. Together with advances in stem cell biology and gene editing, we are in the midst of a fascinating journey to understand the cellular phenotypes that compose human bodies and how the human genome is used to build and maintain each cell. Here, we will review recent advances into how single-cell genomics is being used to develop personalized phenotyping strategies that cross subcellular, cellular, and tissue scales to link our genome to our cumulative cellular phenotypes.

Long-term Outcomes in a Large Randomized Trial of HIV-1 Salvage Therapy: 96-Week Results of AIDS Clinical Trials Group A5241 (OPTIONS)

Background Short-term (48-week) results of the OPTIONS trial showed that nucleoside reverse transcriptase inhibitors (NRTIs) can be safely omitted from salvage therapy as long as the regimen has a cumulative activity of >2 active antiretroviral medications. The long-term durability of this approach and outcomes in persons who have more-extensive HIV-1 drug resistance are uncertain. Methods Participants with virologic failure and anticipated antiretroviral susceptibility received an optimized regimen and were randomized to omit or add NRTIs. A separate group with more resistance (cumulative activity ≤2 active agents) received an optimized regimen including NRTIs. Results At week 96, among 360 participants randomized to omit or add NRTIs, 70% and 65% had HIV-1 RNA <200 copies/mL, respectively. Virologic failure was uncommon after week 48. Younger age and starting fewer new antiretroviral medications were associated with higher odds of virologic failure. In the highly resistant group, 53% had HIV-1 RNA <200 copies/mL at week 96. Conclusions HIV-1 salvage therapy can safely omit NRTIs without compromising efficacy or durability of response as long as the new regimen has a cumulative activity of >2 active drugs. Younger people and those receiving fewer new antiretrovirals require careful monitoring. Even among individuals with more-extensive resistance, most achieve virologic suppression. Clinical Trials Registration NCT00537394.