South Genetic Group From O'ahu, Hawai'i Santos, Scott R; Hui, Livable Hawai'i Kai; Yamamoto, Mike N ...
Pacific science,
07/2022, Letnik:
76, Številka:
3
Journal Article
Recenzirano
The anchialine ecosystem, comprised of coastal landlocked habitats containing brackish water, experiences tidal fluctuations due to simultaneous underground connections with the sea and terrestrial ...aquifer system. Anthropogenic impacts have led to substantial habitat degradation and loss, potentially making the anchialine ecosystem and its biota one of Hawai'i's most threatened. Prior analyses of mitochondrial (mtDNA) cytochrome oxidase subunit I (COI) sequences from the Hawaiian anchialine atyid shrimp Halocaridina rubra revealed a potential cryptic species complex with strong regional endemism. This study hypothesized that a Halocaridina population discovered in 2018 in southeast O'ahu, an area with no historically documented anchialine habitats but where a specimen was collected in 1998, represents a unique lineage or genetic group endemic to the region. Comparison of newly generated mtDNA COI sequences to previous ones identified the population as belonging to the South O'ahu lineage of Halocaridina. However, fixed mutations and significant genetic differentiation distinguish it from the closely related 'Ewa genetic group of southwest O'ahu. Given this, we propose the new Maunalua genetic group for Halocaridina from southeast O'ahu, with an apparent split between groups occurring at approximately the Holocene-Pleistocene Epoch boundary, corresponding well to the geological age of where the new population was discovered. Notably, the 1998 specimen shared the same distinctive coloration as the Maunalua and 'Ewa genetic groups, implying inclusion within the South O'ahu lineage. Conservation efforts should consider the currently recognized 15 Halocaridina genetic groups since they represent unique units from all others in both their genetics and geographic distribution. Keywords: anchialine, crustacean, evolution, Hawai'i, Halocaridina, invertebrate, phylogeography
Background
Characterization of circulating tumor DNA (ctDNA) has been integrated into clinical practice. Although labs have standardized validation procedures to develop single locus tests, the ...efficacy of on‐site plasma‐based next‐generation sequencing (NGS) assays still needs to be proved.
Materials and Methods
In this retrospective study, we profiled DNA from matched tissue and plasma samples from 75 patients with cancer. We applied an NGS test that detects clinically relevant alterations in 33 genes and microsatellite instability (MSI) to analyze plasma cell‐free DNA (cfDNA).
Results
The concordance between alterations detected in both tissue and plasma samples was higher in patients with metastatic disease. The NGS test detected 77% of sequence alterations, amplifications, and fusions that were found in metastatic samples compared with 45% of those alterations found in the primary tumor samples (p = .00005). There was 87% agreement on MSI status between the NGS test and tumor tissue results. In three patients, MSI‐high ctDNA correlated with response to immunotherapy. In addition, the NGS test revealed an FGFR2 amplification that was not detected in tumor tissue from a patient with metastatic gastric cancer, emphasizing the importance of profiling plasma samples in patients with advanced cancer.
Conclusion
Our validation experience of a plasma‐based NGS assay advances current knowledge about translating cfDNA testing into clinical practice and supports the application of plasma assays in the management of oncology patients with metastatic disease. With an in‐house method that minimizes the need for invasive procedures, on‐site cfDNA testing supplements tissue biopsy to guide precision therapy and is entitled to become a routine practice.
Implications for Practice
This study proposes a solution for decentralized liquid biopsy testing based on validation of a next‐generation sequencing (NGS) test that detects four classes of genomic alterations in blood: sequence mutations (single nucleotide substitutions or insertions and deletions), fusions, amplifications, and microsatellite instability (MSI). Although there are reference labs that perform single‐site comprehensive liquid biopsy testing, the targeted assay this study validated can be established locally in any lab with capacity to offer clinical molecular pathology assays. To the authors' knowledge, this is the first report that validates evaluating an on‐site plasma‐based NGS test that detects the MSI status along with common sequence alterations encountered in solid tumors.
This report describes the concordance between circulating tumor DNA and matched tumor tissue molecular profiles, discusses interpretation of observed discordant data, and illustrates applications through clinical cases. It is the first known report to evaluate the performance of an on‐site plasma‐based next‐generation sequencing test to detect microsatellite instability status along with common sequence alterations in the context of its clinical utility and therapeutic applications in precision oncology.
•Bone pain is the leading patient-reported outcome in contemporary trials of advanced prostate cancer; however, preapproval studies have not addressed a therapeutic agent's ability to palliate pain ...in a manner to use for regulatory approval.•A multicenter, phase II clinical trial examining the use of radium-223 enrolled 29 patients with metastatic castration-resistant prostate cancer and a Brief Pain Inventory score of greater than 3, with primary end point defined as a greater than 30decrease decline in the Brief Pain Inventory score by week 8 and confirmed at week 12•The primary end point was met in 43% of patients, easily satisfying the protocol-defined threshold for expansion to a second phase, but accrual was slow and did not proceed to the second phase.•This prospective trial was the first examining radium-223 in pain palliation using standard doses and contemporary pain end points radium-223, and demonstrated radium-223’s ability to palliate pain in a clinically meaningful manner in nearly one-half of enrolled patients
Prostate Cancer Working Group 3 and FDA guidelines recommend a standardized approach to pain assessment in preapproval trials. No prior trial has examined pain palliation of Radium-223 using standard dosing and contemporary PRO pain-assessment tools.
In this multicenter phase II trial, patients with Brief Pain Inventory (BPI) ≥3 were eligible for Radium-223 per its label. Primary endpoint was a 30% decrease in BPI Worst Pain from baseline to Week 8, sustained at Week 12 without escalation of medication on the World Health Organization (WHO) analgesic ladder. Secondary endpoints included changes in Brief Fatigue Inventory (BFI) Worst fatigue and BPI pain interference. If six of 27 subjects (22%) met the primary endpoint, the trial would expand by another 36 subjects.
Twenty-nine subjects were accrued. Nine of 29 (31%) subjects met the primary endpoint, with 21 (72%) evaluable for the primary endpoint. Among responders: median worst pain declined 62% (range 36–100) at Week 8 and 63% (range 38–100) at Week 12; median reduction of pain interference with general activity and sleep at Week 12 was 62% (range 18–100) and 53% (range 8–100) respectively; median reduction in worst fatigue of 45% (range 10–85) at Week 12.
In the first prospective trial using standard Ra-223 doses, contemporary pain endpoints and PRO collection tools, Ra-223 palliated pain, reduced fatigue, and improved pain interference. The pain response rate easily exceeded the requirements for expansion to the second phase, but the trial was closed due to slow accrual.
In this multicenter phase II trial- the first to prospectively examine Radium-223's pain palliation in mCRPC using standard dosing and contemporary endpoints- the primary endpoint (>30% decline in BPI scoring by week 8, confirmed at week 12) was met in 31% patients. Although this satisfied the protocol-defined threshold for expansion, accrual was slow and did not proceed to second phase.
Quantitation of androgen receptor variant (AR-V) expression in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) has great potential for ...treatment customization. However, the absence of a uniform CTC isolation platform and consensus on an analytical assay has prevented the incorporation of these measurements in routine clinical practice. Here, we present a single-CTC sensitive digital droplet PCR (ddPCR) assay for the quantitation of the two most common AR-Vs, AR-V7, and AR-v567es, using antigen agnostic CTC enrichment. In a cohort of 29 mCRPC patients, we identify AR-V7 in 66% and AR-v567es in 52% of patients. These results are corroborated using another gene expression platform (NanoString
) and by analysis of RNA-Seq data from patients with mCRPC (SU2C- PCF Dream Team). We next quantify AR-V expression in matching EpCAM-positive vs EpCAM-negative CTCs, as EpCAM-based CTC enrichment is commonly used. We identify lower AR-V prevalence in the EpCAM-positive fraction, suggesting that EpCAM-based CTC enrichment likely underestimates AR-V prevalence. Lastly, using single CTC analysis we identify enrichment for AR-v567es in patients with neuroendocrine prostate cancer (NEPC) indicating that AR-v567es may be involved in lineage plasticity, which warrants further mechanistic interrogation.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) may play important roles in prostate cancer (PCa) progression. Specifically, LH expression in PCa tissues has been associated with ...metastatic disease with a poor prognosis, while FSH has been shown to stimulate prostate cell growth in hormone-refractory PCa cell lines. Gonadotropin-realizing hormone (GnRH) analogues are common agents used for achieving androgen deprivation in the treatment for PCa. GnRH analogues include LH-releasing hormone (LHRH) agonists and GnRH antagonists, both of which exhibit distinct mechanisms of action that may be crucial in terms of their overall clinical efficacy. LHRH agonists are typically used as the primary therapy for most patients and function via a negative-feedback mechanism. This mechanism involves an initial surge in testosterone levels, which may worsen clinical symptoms of PCa. GnRH antagonists provide rapid and consistent hormonal suppression without the initial surge in testosterone levels associated with LHRH agonists, thus representing an important therapeutic alternative for patients with PCa. The concentrations of testosterone and dihydrotestosterone are significantly reduced after treatment with both LHRH agonists and GnRH antagonists. This reduction in testosterone concentrations to castrate levels results in significant, rapid, and consistent reductions in prostatic-specific antigen, a key biomarker for PCa. Evidence suggests that careful maintenance of testosterone levels during androgen deprivation therapy provides a clinical benefit to patients with PCa, emphasizing the need for constant monitoring of testosterone concentrations throughout the course of therapy.
What's known on the subject? and What does the study add?
Upstaging to non‐organ‐confined (NOC) disease is frequent at the time of radical cystectomy for urothelial carcinoma of the bladder (UCB). ...Pre‐surgical models that can accurately predict which patients are likely to have more extensive disease are sparse.
The present study developed an accurate nomogram for the prediction of NOC‐UCB based on a cohort of patients with clinically organ‐confined disease. Adoption of such a tool into daily clinical decision‐making may lead to more appropriate integration of perioperative chemotherapy, thereby potentially improving survival in patients with UCB.
Objective
To create an accurate pre‐cystectomy decision‐making tool that allows for the accurate identification of patients with clinically organ‐confined urothelial carcinoma of the bladder (UCB) who have non‐organ‐confined UCB (NOC‐UCB) at cystectomy, as identification of patients with UCB most likely to benefit from neoadjuvant chemotherapy (NACTx) is hampered by inaccurate clinical staging.
Patients and Methods
A prospectively maintained single‐institution database containing 201 patients who underwent cystectomy and pelvic lymph node (LN) dissection without NACTx for UCB was analysed.
Predictive variables for NOC‐UCB included, among others, age, gender, transurethral resection of bladder tumour (TURBT) findings (stage, grade, histology, size, presence of carcinoma in situ, lymphovascular invasion LVI, multifocality), history of intravesical therapy, time from TURBT to cystectomy, and cross‐sectional imaging findings.
Results
Clinical stage distribution was 19 patients with Ta, 15 with Tis, 67 with T1, and 100 with T2.
At the time of cystectomy, NOC‐UCB and LN‐positive disease were found in 71 (35%) and 38 (19%) of patients, respectively; 81 (40%) of patients had NOC‐UCB (≥pT3/Nany or pTany/N+).
Tumour stage (P trend <0.001), presence of LVI (odds ratio OR 5.2; P = 0.02), and radiographic evidence of NOC‐UCB or hydronephrosis (OR 3.2; P = 0.01) were independently associated with ≥pT3 Nany UCB.
Tumour stage (P trend < 0.001) and presence of LVI (OR 6.64; P = 0.01) were independently associated with (≥pT3/Nany or pTany/N+) UCB.
A nomogram to predict (≥pT3/Nany or pTany/N+) based on all three variables was highly accurate (area under the curve 0.828) and well calibrated, deviating <8% from ideal prediction. Decision curve analysis showed net benefit across all threshold probabilities.
Conclusions
NOC‐UCB can be predicted with high accuracy by integrating standard clinicopathological factors with imaging information.
This model may help to identify patients with NOC‐UCB who may benefit from NACTx.
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