259 Background: Aggressive variant prostate cancer (AVPC) is a subtype of metastatic castrate-resistant prostate cancer (mCRPC) characterized by several high-risk features. AVPC is associated with poorer overall survival and has limited response to androgen receptor targeted therapy, although it often shows some responsiveness to chemotherapy. In this study, we evaluated the outcomes of AVPC patients who received Prostate-Specific Membrane Antigen (PSMA) radioligand therapy (RLT). Methods: This retrospective study included 201 mCRPC patients who received Lutetium-177, [ 177 Lu]-PSMA RLT at two academic centers. Patients were classified as having AVPC based on the presence of at least one of the following eight criteria: exclusive visceral metastases (n=1), predominantly lytic bone metastasis (n=1), bulky lymphadenopathy or pelvic mass (≥5 cm) (n=4), low PSA (≤10 ng/mL) at initial presentation plus high-volume (≥20) bone metastases (n=0), serum CEA and/or LDH levels twice the upper limit of normal at the time of treatment (n=5), a short interval (≤6 months) to CRPC (n=7), small cell/neuroendocrine carcinoma morphology (n=5), and the presence of two or more genomic defects among TP53, RB1, and PTEN (n=13). Results: Of the 201 patients, 34 (16.9%) were classified as having AVPC (Table). The PSA50 response rate was 55% in the AVPC group and 60% in the non-AVPC group. The median overall survival (OS) (median time from the start of therapy to the last follow-up or death) was 171 days for the AVPC group and 282 days for the non-AVPC group. Although, the Kaplan-Meier plot only suggested a trend toward worse survival in AVPC patients compared to non-AVPC patients, the difference did not reach statistical significance (log-rank test p-value = 0.179). Conclusions: Our study suggests patients with AVPC may benefit from PSMA RLT and should be considered for this treatment if they are eligibly. Further studies are needed for a better understanding of this patient population. Details of patients. AVPC Non AVPC N=201 34 167 Age 1 (mean, year) 64.38 64.09 PSA 2 (mean, ng/mL) 331 251 PSA 3 (mean, ng/mL) 717 504 PSA50 (%) 55 60 OS/FU (median, day) 171 282 1 Age at the time of therapy. 2 Baseline PSA at diagnosis. 3 Most recent PSA prior to therapy.

Background

Sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, inhibits the mitogen-activated protein kinase pathway that is activated in most uveal melanoma tumors. This phase II study was conducted by the SWOG cooperative group to evaluate the efficacy of sorafenib in combination with carboplatin and paclitaxel (CP) in metastatic uveal melanoma.

Methods

Twenty-five patients with stage IV uveal melanoma who had received 0-1 prior systemic therapy were enrolled. Treatment included up to 6 cycles of carboplatin (AUC = 6) and paclitaxel (225 mg/m(2)) administered IV on day 1 plus sorafenib (400 mg PO twice daily), followed by sorafenib monotherapy until disease progression. The primary endpoint was objective response rate (ORR); a two-stage design was used with the study to be terminated if no confirmed responses were observed in the first 20 evaluable patients. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS).

Results

No confirmed objective responses occurred among the 24 evaluable patients (ORR = 0% [95% CI: 0-14%]) and the study was terminated at the first stage. Minor responses (tumor regression less than 30%) were seen in eleven of 24 (45%) patients. The median PFS was 4 months [95% CI: 1-6 months] and the 6-month PFS was 29% [95% CI: 13%-48%]. The median OS was 11 months [95% CI: 7-14 months].

Conclusion

In this study, the overall efficacy of CP plus sorafenib in metastatic uveal melanoma did not warrant further clinical testing when assessed by ORR, although minor tumor responses and stable disease were observed in some patients.

Trial registration

ClinicalTrials.govNCT00329641.

Abstract Background Our ultimate goal is to detect the entire human microbiome, in health and in disease, in a single reaction tube, and employing only commercially available reagents. To that end, we adapted molecular inversion probes to detect bacteria using solely a massively multiplex molecular technology. This molecular probe technology does not require growth of the bacteria in culture. Rather, the molecular probe technology requires only a sequence of forty sequential bases unique to the genome of the bacterium of interest. In this communication, we report the first results of employing our molecular probes to detect bacteria in clinical samples. Results While the assay on Affymetrix GenFlex Tag16K arrays allows the multiplexing of the detection of the bacteria in each clinical sample, one Affymetrix GenFlex Tag16K array must be used for each clinical sample. To multiplex the clinical samples, we introduce a second, independent assay for the molecular probes employing Sequencing by Oligonucleotide Ligation and Detection. By adding one unique oligonucleotide barcode for each clinical sample, we combine the samples after processing, but before sequencing, and sequence them together. Conclusions Overall, we have employed 192 molecular probes representing 40 bacteria to detect the bacteria in twenty-one vaginal swabs as assessed by the Affymetrix GenFlex Tag16K assay and fourteen of those by the Sequencing by Oligonucleotide Ligation and Detection assay. The correlations among the assays were excellent.

Bulk deconvolution with single-cell/nucleus RNA-seq data is critical for understanding heterogeneity in complex biological samples, yet the technological discrepancy across sequencing platforms limits deconvolution accuracy. To address this, we utilize an experimental design to match inter-platform biological signals, hence revealing the technological discrepancy, and then develop a deconvolution framework called DeMixSC using this well-matched, that is, benchmark, data. Built upon a novel weighted nonnegative least-squares framework, DeMixSC identifies and adjusts genes with high technological discrepancy and aligns the benchmark data with large patient cohorts of matched-tissue-type for large-scale deconvolution. Our results using two benchmark data sets of healthy retinas and ovarian cancer tissues suggest much-improved deconvolution accuracy. Leveraging tissue-specific benchmark data sets, we applied DeMixSC to a large cohort of 453 age-related macular degeneration patients and a cohort of 30 ovarian cancer patients with various responses to neoadjuvant chemotherapy. Only DeMixSC successfully unveiled biologically meaningful differences across patient groups, demonstrating its broad applicability in diverse real-world clinical scenarios. Our findings reveal the impact of technological discrepancy on deconvolution performance and underscore the importance of a well-matched data set to resolve this challenge. The developed DeMixSC framework is generally applicable for accurately deconvolving large cohorts of disease tissues, including cancers, when a well-matched benchmark data set is available.

PURPOSE: Castration-sensitive prostate cancer (CSPC) is a complex and heterogeneous condition encompassing a range of clinical presentations. As new approaches have expanded management options, clinicians are left with myriad questions and controversies regarding the optimal individualized management of CSPC. MATERIALS AND METHODS: The US Prostate Cancer Conference (USPCC) multidisciplinary panel was assembled to address the challenges of prostate cancer management. The first annual USPCC meeting included experts in urology, medical oncology, radiation oncology, and nuclear medicine. USPCC co-chairs and session moderators identified key areas of controversy and uncertainty in prostate cancer management and organized the sessions with multidisciplinary presentations and discussion. Throughout the meeting, experts responded to questions prepared by chairs and moderators to identify areas of agreement and controversy. RESULTS: The USPCC panel discussion and question responses for CSPC-related topics are presented. Key advances in CSPC management endorsed by USPCC experts included the development and clinical utilization of gene expression classifiers and artificial intelligence (AI) models for risk stratification and treatment selection in specific patient populations, the use of advanced imaging modalities in patients with clinically localized unfavorable intermediate or high-risk disease and those with biochemical recurrence, recommendations of doublet or triplet therapy for metastatic CSPC (mCSPC), and consideration of prostate and/or metastasis-directed radiation therapy in select patients with mCSPC. CONCLUSIONS: CSPC is a diverse disease with many therapeutic options and the potential for adverse outcomes associated with either undertreatment or overtreatment. Future studies are needed to validate and clinically integrate novel technologies, including genomics, AI, and advanced imaging, to optimize outcomes among patients with CSPC.

BACKGROUND: Management strategies for metastatic castration-resistant prostate cancer (mCRPC) have rapidly shifted in recent years. As novel imaging and therapeutic approaches have made their way to the clinic, providers are encountering increasingly challenging clinical scenarios, with limited guidance from the current literature. MATERIALS AND METHODS: The US Prostate Cancer Conference (USPCC) is a multidisciplinary meeting of prostate cancer experts intended to address the many challenges of prostate cancer management. At the first annual USPCC meeting, areas of controversy and consensus were identified during a 2-day meeting that included expert presentations, full-panel discussions, and postdiscussion responses to questions developed by the USPCC cochairs and session moderators. RESULTS: This narrative review covers the USPCC expert discussion and perspectives relevant to mCRPC, including neuroendocrine/aggressive-variant prostate cancer (NEPC/AVPC). Areas of broad agreement identified among USPCC experts include the benefits of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with BRCA1/2 mutations, the use of radioligand therapy in patients with prostate-specific membrane antigen (PSMA)-positive mCRPC, and the need for clinical trials that address real-world clinical questions, including the performance of novel therapies when compared with modern standard-of-care treatment. Ongoing areas of controversy and uncertainty included the appropriateness of PARP inhibitors in patients with non-BRCA1/2 mutations, the optimal definition of PSMA positivity, and systemic therapies for patients with NEPC/AVPC after progression on platinum-based therapies. CONCLUSIONS: The first annual USPCC meeting identified several areas of controversy in the management of mCRPC, highlighting the urgent need for clinical trials designed to facilitate treatment selection and sequencing in this heterogeneous disease state.