Assessment of Zonular Integrity in Phakic Eyes Following Pars Plana Vitrectomy Using Ultrasound Biomicroscopy: A Prospective Paired Eye Comparative Study.

PURPOSE: To assess zonular integrity in phakic patients post vitrectomy using ultrasound biomicroscopy (UBM). DESIGN: Prospective, comparative, nonrandomized, double-masked, paired eye study. METHODS: We used ultrasound biomicroscopy (UBM) to evaluate phakic patients with a history of unilateral pars-plana vitrectomy. INCLUSION CRITERIA: (1) phakic patients with history of pars plana vitrectomy in one eye as the only procedure; (2) normal unoperated fellow eye; and (3) complete gas or air resolution from the vitreous cavity at the time of UBM assessment. EXCLUSION CRITERIA: (1) monocular patients; (2) history of intraoperative lenticular trauma; (3) the use of silicone oil tamponade; (4) history of trauma or pseudoexfoliation in either eye; (5) history of other ocular conditions that can affect the integrity of zonules, such as uveitis or ectopia lentis; (6) eyes with extreme myopia or long axial length (> -8.00 D or >30.0 mm); (7) history of intravitreal injection in either eye; (8) age <18 years. TECHNIQUE: A high-frequency (50 MHz) UBM device was used by a masked technician to obtain radial section images from zonular bundles at 8 different clock positions. Image quality was assessed in real time, captured, and saved. Two experienced masked observers (H.C. and C.B.) then assessed the quality of the images and graded the zonular findings. Only patients with adequate studies have been included. A unique grading system that was specifically devised for this study was used as the following: (0) clear, well-defined zonule(s); (1) uneven, disrupted zonules or stretched zonules; and (2) extensive loss of zonules. Each clock hour was graded according to this system and the total score was then calculated for each eye. In the primary outcome, 2 main groups were analyzed: vitrectomized eyes and healthy contralateral nonvitrectomized eyes. The mean total UBM score (TUS) from each group was compared and analyzed. RESULTS: Thirty-five patients were recruited into this study. Eleven patients were male and 24 were female. The mean age was 66.3 years. Thirty patients had vitrectomy for vitreomacular interface disorders (either macular hole or epiretinal membrane), 1 patient had vitreous hemorrhage and the remaining 4 patients had rhegmatogenous retinal detachments. With regard to tamponade agents, SF6 was used in 21 (60%) patients, air in 9 (26%) patients, and C3F8 in 5 (14%) patients. The mean TUS in the vitrectomized eyes was 2.28 (SD 1.83) vs 2.24 (SD 1.77) in the nonvitrectomized eyes (P = .9531). Overall, in the comparative analysis of mean scores based on 2 graders' assessments for each clock position in vitrectomized and nonvitrectomized eyes, there were no significant differences noted between the groups. CONCLUSION: This study found no evidence for a difference in the mean total UBM score in eyes following vitrectomy when compared to their contralateral healthy, nonvitrectomized eyes. This likely indicates that vitrectomy may not affect the integrity of zonules in phakic patients, at least for patients with vitreomacular interface disorders undergoing uncomplicated surgery.

The evolution of metastatic upper tract urothelial carcinoma through genomic-transcriptomic and single-cell protein markers analysis.

The molecular characteristics of metastatic upper tract urothelial carcinoma (UTUC) are not well understood, and there is a lack of knowledge regarding the genomic and transcriptomic differences between primary and metastatic UTUC. To address these gaps, we integrate whole-exome sequencing, RNA sequencing, and Imaging Mass Cytometry using lanthanide metal-conjugated antibodies of 44 tumor samples from 28 patients with high-grade primary and metastatic UTUC. We perform a spatially-resolved single-cell analysis of cancer, immune, and stromal cells to understand the evolution of primary to metastatic UTUC. We discover that actionable genomic alterations are frequently discordant between primary and metastatic UTUC tumors in the same patient. In contrast, molecular subtype membership and immune depletion signature are stable across primary and matched metastatic UTUC. Molecular and immune subtypes are consistent between bulk RNA-sequencing and mass cytometry of protein markers from 340,798 single cells. Molecular subtypes at the single-cell level are highly conserved between primary and metastatic UTUC tumors within the same patient.

Survival and characteristics of retinopathy of prematurity in micro-premature infants.

OBJECTIVE: To describe the risk and nature of retinopathy of prematurity (ROP) in micro-premature infants (≤26 weeks' gestational age [GA]). METHODS: Retrospective analysis of prospectively collected data from infants born at 22-26 weeks' GA over a 5-year period. RESULTS: A total of 502 infants were identified, of whom 414 survived to discharge (82.5%). The Vermont Oxford Network database documented clinical follow-up data and ROP outcomes for all 414 patients; complete ROP clinical records were available for 294 of the infants who survived (70.8%). Forty infants were born between 22 and 23 weeks' GA (group A, 13.6%), and 254 were born between 24 and 26 weeks' GA (group B, 86.4%). Survival for group A infants was worse than that of group B infants (66.2% vs 85.4%; p < 0.01). Survival of group A infants improved during the study period (R2 = 0.625). Overall, 59.9% of infants developed any ROP and 8.5% developed type 1 ROP. Group A infants were more likely to develop ROP (90.0% vs 48.6%; p < 0.01) and type 1 ROP (30.0% vs 5.1%; p < 0.01) than group B infants. Group A infants developed ROP at an earlier age (32 + 6 weeks vs 33 + 3 weeks; p = 0.02) and were more likely to have zone I disease on presentation (65.0% vs 20.5%; p < 0.01), but there was no difference in the corrected gestational age of peak severity of ROP (35 + 2 weeks vs 34 + 5 weeks; p = 0.36). CONCLUSION: The most premature infants, born at 22-23 weeks' GA, develop ROP at an earlier age, are more likely to present with posterior disease, and have a high risk of disease requiring treatment.

Immunogenomic Landscape of Neuroendocrine Prostate Cancer.

PURPOSE: Patients with neuroendocrine prostate cancer (NEPC) are often managed with immunotherapy regimens extrapolated from small-cell lung cancer (SCLC). We sought to evaluate the tumor immune landscape of NEPC compared with other prostate cancer types and SCLC. EXPERIMENTAL DESIGN: In this retrospective study, a cohort of 170 patients with 230 RNA-sequencing and 104 matched whole-exome sequencing data were analyzed. Differences in immune and stromal constituents, frequency of genomic alterations, and associations with outcomes were evaluated. RESULTS: In our cohort, 36% of the prostate tumors were identified as CD8+ T-cell inflamed, whereas the remaining 64% were T-cell depleted. T-cell-inflamed tumors were enriched in anti-inflammatory M2 macrophages and exhausted T cells and associated with shorter overall survival relative to T-cell-depleted tumors (HR, 2.62; P < 0.05). Among all prostate cancer types in the cohort, NEPC was identified to be the most immune depleted, wherein only 9 out of the 36 total NEPC tumors were classified as T-cell inflamed. These inflamed NEPC cases were enriched in IFN gamma signaling and PD-1 signaling compared with other NEPC tumors. Comparison of NEPC with SCLC revealed that NEPC had poor immune content and less mutations compared with SCLC, but expression of checkpoint genes PD-L1 and CTLA-4 was comparable between NEPC and SCLC. CONCLUSIONS: NEPC is characterized by a relatively immune-depleted tumor immune microenvironment compared with other primary and metastatic prostate adenocarcinoma except in a minority of cases. These findings may inform development of immunotherapy strategies for patients with advanced prostate cancer.

Molecular Evolution of Classic Hodgkin Lymphoma Revealed Through Whole-Genome Sequencing of Hodgkin and Reed Sternberg Cells.

The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells in classic Hodgkin lymphoma (cHL) limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Using this approach, we now report the whole-genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events leading to cHL. We identified alterations in driver genes not previously described in cHL, APOBEC mutational activity, and the presence of complex structural variants including chromothripsis. We found that high ploidy in cHL is often acquired through multiple, independent chromosomal gains events including whole-genome duplication. Evolutionary timing analyses revealed that structural variants enriched for RAG motifs, driver mutations in B2M, BCL7A, GNA13, and PTPN1, and the onset of AID-driven mutagenesis usually preceded large chromosomal gains. This study provides a temporal reconstruction of cHL pathogenesis. SIGNIFICANCE: Previous studies in cHL were limited to coding sequences and therefore not able to comprehensively decipher the tumor complexity. Here, leveraging cHL whole-genome characterization, we identify driver events and reconstruct the tumor evolution, finding that structural variants, driver mutations, and AID mutagenesis precede chromosomal gains. This article is highlighted in the In This Issue feature, p. 171.

Prognostic Features of Preoperative OCT in Retinal Detachments: A Systematic Review and Meta-analysis.

TOPIC: To evaluate the prognostic association between preoperative features seen on OCT imaging and postoperative visual acuity (VA) outcomes in rhegmatogenous retinal detachments (RRDs). CLINICAL RELEVANCE: Currently, there is limited literature on the prognostic value of preoperative RRD OCT features. METHODS: A literature search was conducted on Ovid MEDLINE, Ovid Embase, and Cochrane CENTRAL from inception to September 15, 2022. A meta-analysis was performed using a random-effects model. Quality of studies and evidence were assessed using the Joanna Briggs Institute tools and the Grading of Recommendations, Assessment, Development and Evaluation framework, respectively. RESULTS: A total of 1671 eyes of 1670 patients from 29 observational studies were included. Of these, 89% of eyes had a macula-off RRD at presentation. The mean average duration of detachment was 15 ± 10 days. Most eyes (62%) underwent pars plana vitrectomy. Six preoperative OCT features were analyzed: height of retinal detachment (HRD) at the fovea, central macular thickness (CMT), disruption of the ellipsoid zone (EZ) and/or external limiting membrane (ELM), intraretinal cystic cavities (ICCs), outer retinal corrugations (ORCs), and macular detachment. A greater HRD was weakly associated with postoperative VA (Pearson correlation r = 0.35; 95% confidence interval [CI], 0.20-0.48; P < 0.01), and there was no change in this association throughout the postoperative follow-up period. The CMT was not associated with postoperative VA. Eyes with disruption of the EZ and/or ELM had a postoperative VA worse by 0.35 logarithm of the minimum angle of resolution (logMAR) (95% CI, 0.15-0.54; P < 0.01) or 3 Snellen lines. Eyes with ICCs had a postoperative VA worse by 0.14 logMAR (95% CI, 0.01-0.26; P < 0.01) or 2 Snellen lines. Eyes with ORCs did not have a significantly different postoperative VA than eyes without ORCs. Eyes with macular detachment had a postoperative VA worse by 0.15 logMAR (95% CI, -0.31 to 0.00; P = 0.02) or 2 Snellen lines. Overall, the quality of studies ranged from moderate to good (73%-100%). All associations had a low quality of evidence, with CMT being of very low quality. CONCLUSION: Despite the low quality of evidence, a greater HRD, disruption of the EZ and/or ELM, presence of ICCs, and macular detachment were associated with a poor postoperative VA. We propose a standardized nomenclature for consistency and accuracy in reporting preoperative RRD OCT features for future studies. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Whole-genome characterization of myoepithelial carcinomas of the soft tissue.

Myoepithelial carcinomas (MECs) of soft tissue are rare and aggressive tumors affecting young adults and children, but their molecular landscape has not been comprehensively explored through genome sequencing. Here, we present the whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing findings of two MECs. Patients 1 and 2 (P1, P2), both male, were diagnosed at 27 and 37 yr of age, respectively, with shoulder (P1) and inguinal (P2) soft tissue tumors. Both patients developed metastatic disease, and P2 died of disease. P1 tumor showed a rhabdoid cytomorphology and a complete loss of INI1 (SMARCB1) expression, associated with a homozygous SMARCB1 deletion. The tumor from P2 showed a clear cell/small cell morphology, retained INI1 expression and strong S100 positivity. By WES and WGS, tumors from both patients displayed low tumor mutation burdens, and no targetable alterations in cancer genes were detected. P2's tumor harbored an EWSR1::KLF15 rearrangement, whereas the tumor from P1 showed a novel ASCC2::GGNBP2 fusion. WGS evidenced a complex genomic event involving mainly Chromosomes 17 and 22 in the tumor from P1, which was consistent with chromoplexy. These findings are consistent with previous reports of EWSR1 rearrangements (50% of cases) in MECs and provide a genetic basis for the loss of SMARCB1 protein expression observed through immunohistochemistry in 10% of 40% of MEC cases. The lack of additional driver mutations in these tumors supports the hypothesis that these alterations are the key molecular events in MEC evolution. Furthermore, the presence of complex structural variant patterns, invisible to WES, highlights the novel biological insights that can be gained through the application of WGS to rare cancers.

Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer.

Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets.

In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell-like (SCL) subtype driven by activator protein-1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.

Utility of multimodality molecular profiling for pediatric patients with central nervous system tumors.

Background: As our molecular understanding of pediatric central nervous system (CNS) tumors evolves, so too do diagnostic criteria, prognostic biomarkers, and clinical management decision making algorithms. Here, we explore the clinical utility of wide-breadth assays, including whole-exome sequencing (WES), RNA sequencing (RNA-seq), and methylation array profiling as an addition to more conventional diagnostic tools for pediatric CNS tumors. Methods: This study comprises an observational, prospective cohort followed at a single academic medical center over 3 years. Paired tumor and normal control specimens from 53 enrolled pediatric patients with CNS tumors underwent WES. A subset of cases also underwent RNA-seq (n = 28) and/or methylation array analysis (n = 27). Results: RNA-seq identified the driver and/or targetable fusions in 7/28 cases, including potentially targetable NTRK fusions, and uncovered possible rationalized treatment options based on outlier gene expression in 23/28 cases. Methylation profiling added diagnostic confidence (8/27 cases) or diagnostic subclassification endorsed by the WHO (10/27 cases). WES detected clinically pertinent tier 1 or tier 2 variants in 36/53 patients. Of these, 16/17 SNVs/INDELs and 10/19 copy number alterations would have been detected by current in-house conventional tests including targeted sequencing panels. Conclusions: Over a heterogeneous set of pediatric tumors, RNA-seq and methylation profiling frequently yielded clinically relevant information orthogonal to conventional methods while WES demonstrated clinically relevant added value primarily via copy number assessment. Longitudinal cohorts comparing targeted molecular pathology workup vs broader genomic approaches including therapeutic selection based on RNA expression data will be necessary to further evaluate the clinical benefits of these modalities in practice.

The genomic landscape of metastatic clear cell renal cell carcinoma after systemic therapy.

Primary clear cell renal cell carcinoma (ccRCC) has been previously characterized, but the genomic landscape of metastatic ccRCC is largely unexplored. Here, we performed whole exome sequencing (WES) in 68 samples from 44 patients with ccRCC, including 52 samples from a metastatic site. SETD2, PBRM1, APC and VHL were the most frequently mutated genes in the metastatic ccRCC cohort. RBM10 and FBXW7 were also among the 10 most frequently mutated genes in metastatic tissues. Recurrent somatic copy number variations (CNV) were observed at the previously identified regions 3p25, 9p21 and 14q25, but also at 6p21 (CDKN1A) and 13q14 (RB1). No statistically significant differences were found between samples from therapy-naïve and pretreated patients. Clonal evolution analyses with multiple samples from 13 patients suggested that early appearance of CNVs at 3p25, 9p21 and 14q25 may be associated with rapid clinical progression. Overall, the genomic landscapes of primary and metastatic ccRCC seem to share frequent CNVs at 3p25, 9p21 and 14q25. Future work will clarify the implication of RBM10 and FBXW7 mutations and 6p21 and 13q14 CNVs in metastatic ccRCC.

Molecular Evaluation of Low-grade Low-stage Endometrial Cancer With and Without Recurrence.

Low-grade, low-stage endometrioid carcinomas (LGLS EC) demonstrate 5-yr survival rates up to 95%. However, a small subset of these tumors recur, and little is known about prognostic markers or established mutation profiles associated with recurrence. The goal of the current study was to identify the molecular profiles of the primary carcinomas and the genomic differences between primary tumors and subsequent recurrences. Four cases of LGLS EC with recurrence and 8 cases without recurrence were evaluated via whole-exome sequencing. Three of the 4 recurrent tumors were evaluated via Oncomine Comprehensive Assay. The resulting molecular profiles of the primary and recurrent tumors were compared. Two of the 3 recurrent cases showed additional mutations in the recurrence. One recurrent tumor included an additional TP53 mutation and the other recurrent tumor showed POLE and DDR2 kinase gene mutation. The POLE mutation occurred outside the exonuclease domain. PIK3CA mutations were detected in 4 of 4 primary LGLS EC with recurrence and in 3 of 8 disease-free cases. LGLS EC with recurrence showed higher MSIsensor scores compared with LGLS without recurrence. The level of copy number gains in LGLS EC with recurrence was larger than LGLS EC without recurrence. This pilot study showed 1 of 3 recurrent cases gained a mutation associated with genetic instability (TP53) and 1 of them also acquired a mutation in the DDR2 kinase, a potential therapeutic target. We also noted a higher level of copy number gains, MSIsensor scores and PIK3CA mutations in the primary tumors that later recurred.

Functional comparison of exome capture-based methods for transcriptomic profiling of formalin-fixed paraffin-embedded tumors.

The availability of fresh frozen (FF) tissue is a barrier for implementing RNA sequencing (RNA-seq) in the clinic. The majority of clinical samples are stored as formalin-fixed, paraffin-embedded (FFPE) tissues. Exome capture platforms have been developed for RNA-seq from FFPE samples. However, these methods have not been systematically compared. We performed transcriptomic analysis of 32 FFPE tumor samples from 11 patients using three exome capture-based methods: Agilent SureSelect V6, TWIST NGS Exome, and IDT XGen Exome Research Panel. We compared these methods to the TruSeq RNA-seq of fresh frozen (FF-TruSeq) tumor samples from the same patients. We assessed the recovery of clinically relevant biological features. The Spearman's correlation coefficients between the global expression profiles of the three capture-based methods from FFPE and matched FF-TruSeq were high (rho = 0.72-0.9, p < 0.05). A significant correlation between the expression of key immune genes between individual capture-based methods and FF-TruSeq (rho = 0.76-0.88, p < 0.05) was observed. All exome capture-based methods reliably detected outlier expression of actionable gene transcripts, including ERBB2, MET, NTRK1, and PPARG. In urothelial cancer samples, the Agilent assay was associated with the highest molecular subtype concordance with FF-TruSeq (Cohen's k = 0.7, p < 0.01). The Agilent and IDT assays detected all the clinically relevant fusions that were initially identified in FF-TruSeq. All FFPE exome capture-based methods had comparable performance and concordance with FF-TruSeq. Our findings will enable the implementation of RNA-seq in the clinic to guide precision oncology approaches.

Validation of a Circulating Tumor DNA-Based Next-Generation Sequencing Assay in a Cohort of Patients with Solid tumors: A Proposed Solution for Decentralized Plasma Testing.

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.

Targeting the epichaperome as an effective precision medicine approach in a novel PML-SYK fusion acute myeloid leukemia.

The epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.

Patient-derived xenografts and organoids model therapy response in prostate cancer.

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.

Molecular medicine tumor board: whole-genome sequencing to inform on personalized medicine for a man with advanced prostate cancer.

PURPOSE: Molecular profiling of cancer is increasingly common as part of routine care in oncology, and germline and somatic profiling may provide insights and actionable targets for men with metastatic prostate cancer. However, all reported cases are of deidentified individuals without full medical and genomic data available in the public domain. PATIENT AND METHODS: We present a case of whole-genome tumor and germline sequencing in a patient with advanced prostate cancer, who has agreed to make his genomic and clinical data publicly available. RESULTS: We describe an 84-year-old Caucasian male with a Gleason 10 oligometastastic hormone-sensitive prostate cancer. Whole-genome sequencing provided insights into his tumor's underlying mutational processes and the development of an SPOP mutation. It also revealed an androgen-receptor dependency of his cancer which was reflected in his durable response to radiation and hormonal therapy. Potentially actionable genomic lesions in the tumor were identified through a personalized medicine approach for potential future therapy, but at the moment, he remains in remission, illustrating the hormonal sensitivity of his SPOP-driven prostate cancer. We also placed this patient in the context of a large prostate-cancer cohort from the PCAWG (Pan-cancer Analysis of Whole Genomes) group. In this comparison, the patient's cancer appears typical in terms of the number and type of somatic mutations, but it has a somewhat larger contribution from the mutational process associated with aging. CONCLUSION: We combined the expertise of medical oncology and genomics approaches to develop a molecular tumor board to integrate the care and study of this patient, who continues to have an outstanding response to his combined modality treatment. This identifiable case potentially helps overcome barriers to clinical and genomic data sharing.

Impact of the COVID-19 pandemic on characteristics of retinal detachments: the Canadian experience.

OBJECTIVE: To describe the impact of the coronavirus disease 2019 (COVID-19) pandemic on the characteristics of retinal detachments (RD) at a tertiary centre. DESIGN: Retrospective consecutive case series. PARTICIPANTS: One hundred and ninety eyes of 188 patients with primary, rhegmatogenous RD. METHODS: Patients with RD who presented over a 1-year period (September 14, 2019 to September 13, 2020). The relationship between demographic, anatomic, and visual acuity parameters were compared before and after onset of the pandemic using generalized estimating equations. MAIN OUTCOME MEASURES: Macular status and corrected distance visual acuity on presentation. RESULTS: One hundred and eighty-seven eyes, divided into 2 cohorts: pre-COVID (n = 100 September 14, 2019 to March 13, 2020) and post-COVID (n = 87, March 14, 2020 to September 13, 2020). Of the eyes, 63.2% (n = 87) presented with macular detachment in the post-COVID group compared with 45% (n = 100) in the pre-COVID group (odds ration [OR], 2.14; 95% confidence interval [CI],1.19-3.86; p = 0.011). As well, eyes in the pre-pandemic cohort had significantly fewer detached quadrants on initial examination (OR, 0.53; 95% CI, 0.30-0.93; p = 0.026). Patients in the post-COVID group had a significantly worse corrected distance visual acuity at baseline (mean difference [MD] = -0.35 logMAR, 95% CI, -0.60 to -0.09; p = 0.008), but not at 1 month or at final follow-up. No differences were seen between groups with respect to demographics, lens status, treatment, time to presentation, or chronicity. Pneumatic retinopexy was the most commonly performed procedure in both cohorts, with a 71.5% success rate. CONCLUSIONS: Closures after the COVID-19 pandemic affected the characteristics of RDs at presentation with respect to macular detachment, extent of RD, and presenting visual acuity. At final follow-up, final visual acuity and anatomic outcomes were similar between the 2 groups. These data are helpful for future patient education, triaging, and treatment decision making.