An Integrated Liquid Biopsy Analysis for Comprehensive Investigation of Uveal Melanoma

https://openworks.mdanderson.org/sumexp23/1107/thumbnail.jp

Reproductive patterns in the Baluchistan gerbil, Gerbillus nanus (Rodentia: Muridae), from western Saudi Arabia : the role of rainfall and temperature

There is little information pertaining to the reproductive biology of the Baluchistan gerbil (Gerbillus nanus) despite a broad distribution throughout the Middle East. In the current study, body mass, reproductive–tract morphometrics plus gonadal histology and endocrine profiles of males and females were studied over 12 consecutive months in a field population of Baluchistan gerbils from the western region of Saudi Arabia in an attempt to gain insights into a) the environmental zeitgeber(s) that correlate with reproduction as well as b) to assess if reproduction is seasonal or aseasonal in this species. With the exception of testosterone all male reproductive indicators varied seasonally and were lower during winter than the rest of the year and most increased with rainfall. In contrast, ovarian mass and volume as well as immature follicle counts showed no seasonal patterns and were independent of rainfall or temperature. First pregnancies were observed in late spring coinciding with the increased progesterone concentrations and peaked in summer. This was accompanied by seasonal peaks in the number of Graafian follicles and corpora lutea in females and these parameters were significantly correlated with temperature, but not rainfall In the Arabian Peninsula male, but not female Baluchistan gerbils show seasonal recrudescence and this appears to be correlated largely to rainfall.The Deanship of Scientific Research at the King Saud University through the research group project (No. RGP_VPP_020)http://www.elsevier.com/locate/jaridenvhj201

Seasonal reproduction in the Arabian spiny mouse, Acomys dimidiatus (Rodentia : Muridae) from Saudi Arabia : the role of rainfall and temperature

In deserts where unpredictable rainfall arises and a large variation in temperature occurs, this poses severe energetic and water related constraints on reproduction in small mammals and makes the use of photoperiod as cue for reproduction unreliable. In the present study, the gonad morphometrics, gonadal histology and endocrine profiles of the Arabian spiny mouse (Acomys dimidiatus) were studied over 12 consecutive months in a field population from western Saudi Arabia in an attempt to assess the seasonality of reproduction and gain insights into the environmental cues that may trigger reproduction in this species. Although sperm was present throughout the year, most reproductive parameters exhibited a seasonal pattern with a minimum in winter in both sexes and pregnancies were observed from spring to autumn. Whereas testes volume, the number of corpora lutea and progesterone levels were correlated with temperature, all other reproductive parameters were correlated with rainfall. Thus, it appears that A. dimidiatus ceases to breed during winter and uses rainfall as an environmental cue to initiate reproduction in the study area. However, the species appears to have the ability to reproduce throughout the year, if favourable conditions arise.Research Chairs Program, Deanship of Scientific Research at the King Saud University. HH Prince Bandar Bin Saud Al-Saud President, Saudi Wildlife Authority.National Research Foundation (grant no. 64756) and the University of Pretoria.http://www.elsevier.com/locate/jaridenv2017-01-31hb201

Pilot Study of Circulating Tumor Cells in Early-Stage and Metastatic Uveal Melanoma

Nearly 50% of uveal melanoma (UM) patients develop metastatic disease, and there remains no current standard assay for detection of minimal residual disease. We conducted a pilot study to check the feasibility of circulating tumor cell (CTC) detection in UM. We enrolled 40 patients with early or metastatic UM of which 20 patients had early-stage disease, 19 had metastatic disease, and one was not evaluable. At initial blood draw, 36% of patients had detectable CTCs (30% in early-stage vs. 42% in metastatic), which increased to 54% at data cutoff (40% in early-stage vs. 68% in metastatic). Five early-stage patients developed distant metastases, 60% (3/5) had detectable CTCs before radiographic detection of the metastasis. Landmark overall survival (from study enrollment) at 24 months was statistically lower in CTC-positive vs. negative early-stage UM (p < 0.05). Within this small dataset, the presence of CTCs in early-stage UM predicted an increased risk of metastatic disease and was associated with worse outcomes

1534 Clinical activity of SD-101 with immune checkpoint inhibition (ICI) in metastatic uveal melanoma liver metastasis (MUM-LM) from the PERIO-01 Phase 1 trial

BackgroundMUM-LM are resistant to ICIs for several reasons including the prevalence of myeloid-derived suppressor cells (MDSCs). PFS has been limited, even with approved therapies such as tebentafusp (median 3.3 months) with grade 3/4 AE rates typically >30%. TLR9 agonists are capable of MDSC polarization but drug delivery has historically been limited using an intra-tumoral approach. Pressure-enabled drug delivery (PEDDTM) of SD-101, a TLR9 agonist, has the potential to overcome these barriers to improve outcomes.MethodsPERIO-01 is a phase 1 trial of hepatic arterial SD-101 via PEDD in MUM-LM (NCT04935229), with dose-escalation cohorts as monotherapy (Cohort A), with nivolumab (Cohort B), or nivolumab + ipilimumab (Cohort C). SD-101 is delivered over 2 outpatient cycles, with 3 weekly doses/cycle.Results53 patients received at least one dose of SD-101: 13 in Cohort A, 25 in Cohort B, and 15 in Cohort C. Median age was 65 and 45% were female. 70% received prior MUM-LM treatment, and 8 (15%) received tebentafusp. Fifteen participants (28%) had LM >5cm and 18 (44%) had >10 LMs. One patient experienced partial response (Cohort B 4 mg) that is ongoing at 258 days. Six additional patients had decreases in target lesion size (SD), 3 ongoing at a median follow-up of 168 days. Across dose levels, median PFS was highest in Cohort B (2 mg) at 11.7 months, and disease control rate of 86% (6/7 SD). Serious grade 3/4 treatment-related AEs (TRAEs) to SD-101 or ICI were documented in 8% of subjects: 0% in Cohort A, 4% in Cohort B, and 20% in Cohort C, with an overall Grade 3/4 TRAE rate of 21%. PEDD of SD-101 resulted in reductions in LM monocytic MDSC (mMDSC) by immunofluorescence, along with decreased expression of ARG1, CD163, and FASN. We also observed evidence of immune activation in LM with increased CD4+ and CD8+ T cells, decreased Treg, and increased IFNg and IFNa2 gene expression. These were associated with evidence of systemic immune activation peripherally characterized by increased proliferating CD8+ T and NK cells, and increased IP-10, TNFa, IFNg, IL-2R, and IL-18. Among 25 patients with evaluable ctDNA data, 68% had a decrease relative to peak, with complete clearance in 28%.ConclusionsDelivery of SD-101 by PEDD plus systemic ICI in MUM-LM patients results in clinical activity with median PFS of 11.7 months, MDSC re-programming, and evidence of peripheral and intra-tumoral immune activation. Phase 2 of PERIO-01 is planned for expansion of the optimal dose.Trial RegistrationNCT04935229Ethics ApprovalThe study was IRB approved at all sites and participants signed written informed consen