Serial Biopsies Research Articles

Predictive value of the resistance of the probe to pass through the lesion in the diagnosis of peripheral pulmonary lesions using radial probe endobronchial ultrasound with a guide sheath.

Transbronchial lung biopsy guided by radial probe endobronchial ultrasonography with a guide sheath (EBUS-GS-TBLB) is becoming a significant approach for diagnosing peripheral pulmonary lesions (PPLs). We aimed to explore the clinical value of the resistance of the probe to pass through the lesion in the diagnosis of PPLs when performing EBUS-GS-TBLB, and to determine the optimum number of EBUS-GS-TBLB. We performed a prospective, single-center study of 126 consecutive patients who underwent EBUS-GS-TBLB for solid and positive-bronchus-sign PPLs where the probe was located within the lesion from September 2019 to May 2022. The classification of probe resistance for each lesion was carried out by two bronchoscopists independently, and the final result depended on the bronchoscopist responsible for the procedures. The primary endpoint was the diagnostic yield according with the resistance pattern. The secondary endpoints were the optimum number of EBUS-GS-TBLB and factors affecting diagnostic yield. Procedural complications were also recorded. The total diagnostic yield of EBUS-GS-TBLB was 77.8%, including 83.8% malignant and 67.4% benign diseases (P=0.033). Probe resistance type II displayed the highest diagnostic yield (87.5%), followed by type III (81.0%) and type I (61.1%). A significant difference between the diagnostic yield of malignant and benign diseases was detected in type II (P = 0.008), whereas others did not. Although most of the malignant PPLs with a definitive diagnosis using EBUS-GS-TBLB in type II or type III could be diagnosed in the first biopsy, the fourth biopsy contributed the most sufficient biopsy samples. In contrast, considerably limited tissue specimens could be obtained for each biopsy in type I. The inter-observer agreement of the two blinded bronchoscopists for the classification of probe resistance was excellent (κ = 0.84). The probe resistance is a useful predictive factor for successful EBUS-GS-TBLB diagnosis of solid and positive-bronchus-sign PPLs where the probe was located within the lesion. Four serial biopsies are appropriate for both probe resistance type II and type III, and additional diagnostic procedures are needed for type I.

Combining amino acid PET and MRI imaging increases accuracy to define malignant areas in adult glioma

Accurate determination of the extent and grade of adult-type diffuse gliomas is critical to patient management. In clinical practice, contrast-enhancing areas of diffuse gliomas in magnetic resonance imaging (MRI) sequences are usually used to target biopsy, surgery, and radiation therapy, but there can be discrepancies between these areas and the actual tumor extent. Here we show that adding 18F-fluoro-ethyl-tyrosine positron emission tomography (FET-PET) to MRI sequences accurately locates the most malignant areas of contrast-enhancing gliomas, potentially impacting subsequent management and outcomes. We present a prospective analysis of over 300 serial biopsy specimens from 23 patients with contrast-enhancing adult-type diffuse gliomas using a hybrid PET-MRI scanner to compare T2-weighted and contrast-enhancing MRI images with FET-PET. In all cases, we observe and confirm high FET uptake in early PET acquisitions (5–15 min after 18F-FET administration) outside areas of contrast enhancement on MRI, indicative of high-grade glioma. In 30% cases, inclusion of FET-positive sites changes the biopsy result to a higher tumor grade.

Defatting of Human Livers During Long-Term e x situ Normothermic Perfusion: Novel Strategy to Rescue Discarded Organs for Transplantation.

To develop a protocol for the defatting of steatotic liver grafts during long-term ex situ normothermic machine perfusion. Despite the alarming increase in donor organ shortage, the highly prevalent fatty liver grafts are often discarded due to the risk of primary nonfunction. Effective strategies preventing such outcomes are currently lacking. An exciting new avenue is the introduction of ex situ normothermic machine perfusion (NMP), enabling a liver to remain fully functional for up to 2 weeks and providing a unique window of opportunity for defatting before transplantation. Over a 5-year period, 23 discarded liver grafts and 28 partial livers from our resection program were tested during ex situ normothermic machine perfusion. The steatosis degree was determined on serial biopsies by expert pathologists, and triglyceride contents were measured simultaneously. Of 51 liver grafts, 20 were steatotic, with up to 85% macrovesicular steatosis, and were perfused for up to 12 days. Ten livers displayed marked (5 of which almost complete) loss of fat, while the other 10 did not respond to long-term perfusion. Successful defatting was related to prolonged perfusion, automated glucose control, circadian nutrition, and L-carnitine/fenofibrate supplementation. Pseudopeliotic steatosis and the associated activation of Kupffer/stellate cells were unexpected processes that might contribute to defatting. Synthetic and metabolic functions remained preserved for most grafts until perfusion ended. Ex situ long-term perfusion effectively reduces steatosis while preserving organ viability and may in the future allow transplantation of primarily unusable high-risk grafts, significantly increasing the number of organs available for transplantation.

Is Active Surveillance Too Active?

Many prostate cancer active surveillance protocols mandate serial monitoring at defined intervals, including but certainly not limited to serum PSA (often every 6months), clinic visits, prostate multiparametric MRI, and repeat prostate biopsies. The purpose of this article is to evaluate whether current protocols result in excessive testing of patients on active surveillance. Multiple studies have been published in the past several years evaluating the utility of multiparametric MRI, serum biomarkers, and serial prostate biopsy for men on active surveillance. While MRI and serum biomarkers have promise with risk stratification, no studies have demonstrated that periodic prostate biopsy can be safely omitted in active surveillance. Active surveillance for prostate cancer is too active for some men with seemingly low-risk cancer. The use of multiple prostate MRIs or additional biomarkers do not always add to the prediction of higher-grade disease on surveillance biopsy.

Histological Analysis of Serial Renal Biopsy Specimens from Children with Immunoglobulin A Nephropathy Not Treated with Immunosuppressants.

Although pediatric immunoglobulin A nephropathy (IgAN) is considered to have a good prognosis, few studies have investigated histological changes over time in IgAN. Serial renal biopsies were performed during the course of the disease and histological changes were observed in patients who did not receive immunosuppressive treatment. To our knowledge, this is the first report of two or more histological evaluations of renal biopsies from patients with pediatric IgAN who did not receive immunosuppressive drugs. Forty-two patients with biopsy-proven IgAN who did not receive immunosuppressive agents and underwent serial renal biopsies were followed in our hospital between 1990 and 2003. This retrospective study evaluated findings from renal biopsy specimens and medical records. Analysis of histological findings showed that 19 of 42 patients improved and 16 showed exacerbation of mesangial proliferation. Seven patients showed no obvious histological changes. Of the improved cases, 11 showed spreading of chronic lesions, and there was a significant difference between patients with and without segmental glomerular sclerosis or adhesion at the first biopsy. Of the exacerbated cases, only 5 of 16 patients showed strong active lesions at the first renal biopsy. Histological changes were investigated in pediatric IgAN patients not receiving immunosuppressive treatment. The results suggest that, even if mesangial hypercellularity improves, chronic lesions may spread during the natural history of the disease. Predicting histological changes by using findings from renal biopsies performed early after onset is difficult; therefore, patients should be carefully followed.

Trajectories of liver fibrosis and gene expression profiles in NAFLD associated with diabetes.

Understanding the mechanisms linking steatosis to fibrosis is needed to establish a promising therapy against nonalcoholic fatty liver disease (NAFLD). This study aims to clarify clinical features and hepatic gene expression signatures that predict and contribute to liver fibrosis development during the long-term real-world histological course of NAFLD subjects with and without diabetes. A pathologist scored 342 serial liver biopsy samples from 118 subjects clinically diagnosed with NAFLD during a 3.8 years (SD 3.45, maximum 15 years) course of clinical treatment (UMIN; Clinical Trials Registry, no. UMIN000035231). At the initial biopsy, 26 subjects had simple fatty liver, and 92 had nonalcoholic steatohepatitis (NASH). In the trend analysis, the Fibrosis-4 index (P < 0.001) and its components at baseline predicted the future fibrosis progression. In the generalized linear mixed model, an increase in HbA1c, but not BMI, was significantly associated with fibrosis progression (0.17 [0.009-0.326]; P = 0.038) for NAFLD subjects with diabetes. In gene set enrichment analyses, the pathways involved in hepatocytes zone 3, central liver sinusoidal endothelial cell (LSEC), stellate cells, and plasma cells were coordinately altered in association with fibrosis progression and HbA1c elevation. Therefore, in NAFLD subjects with diabetes, HbA1c elevation is significantly associated with liver fibrosis progression, independent of weight gain, which may be a valuable therapeutic target to prevent the pathological progression of NASH. Gene expression profiles suggest that diabetes-induced hypoxia and oxidative stress injure LSEC injury in zone 3, which may mediate inflammation and stellate cell activation, leading to liver fibrosis.

Consistency of Artificial Intelligence (AI)-based Diagnostic Support Software in Short-term Digital Mammography Reimaging After Core Needle Biopsy.

To evaluate the consistency in the performance of Artificial Intelligence (AI)-based diagnostic support software in short-term digital mammography reimaging after core needle biopsy. Of 276 women who underwent short-term (<3 mo) serial digital mammograms followed by breast cancer surgery from Jan. to Dec. 2017, 550 breasts were included. All core needle biopsies for breast lesions were performed between serial exams. All mammography images were analyzed using a commercially available AI-based software providing an abnormality score (0-100). Demographic data for age, interval between serial exams, biopsy, and final diagnosis were compiled. Mammograms were reviewed for mammographic density and finding. Statistical analysis was performed to evaluate the distribution of variables according to biopsy and to test the interaction effects of variables with the difference in AI-based score according to biopsy. AI-based score of 550 exams (benign or normal in 263 and malignant in 287) showed significant difference between malignant and benign/normal exams (0.48 vs. 91.97 in first exam and 0.62 vs. 87.13 in second exam, P<0.0001). In comparison of serial exams, no significant difference was found in AI-based score. AI-based score difference between serial exams was significantly different according to biopsy performed or not (-0.25 vs. 0.07, P = 0.035). In linear regression analysis, there was no significant interaction effect of all clinical and mammographic characteristics with mammographic examinations performed after biopsy or not. The results from AI-based diagnostic support software for digital mammography was relatively consistent in short-term reimaging even after core needle biopsy.

Relapse Timing Is Associated With Distinct Evolutionary Dynamics in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is cured in more than 60% of patients, but outcomes remain poor for patients experiencing disease progression or relapse (refractory or relapsed DLBCL [rrDLBCL]), particularly if these events occur early. Although previous studies examining cohorts of rrDLBCL have identified features that are enriched at relapse, few have directly compared serial biopsies to uncover biological and evolutionary dynamics driving rrDLBCL. Here, we sought to confirm the relationship between relapse timing and outcomes after second-line (immuno)chemotherapy and determine the evolutionary dynamics that underpin that relationship. Outcomes were examined in a population-based cohort of 221 patients with DLBCL who experienced progression/relapse after frontline treatment and were treated with second-line (immuno)chemotherapy with an intention-to-treat with autologous stem-cell transplantation (ASCT). Serial DLBCL biopsies from a partially overlapping cohort of 129 patients underwent molecular characterization, including whole-genome or whole-exome sequencing in 73 patients. Outcomes to second-line therapy and ASCT are superior for late relapse (>2 years postdiagnosis) versus primary refractory (<9 months) or early relapse (9-24 months). Diagnostic and relapse biopsies were mostly concordant for cell-of-origin classification and genetics-based subgroup. Despite this concordance, the number of mutations exclusive to each biopsy increased with time since diagnosis, and late relapses shared few mutations with their diagnostic counterpart, demonstrating a branching evolution pattern. In patients with highly divergent tumors, many of the same genes acquired new mutations independently in each tumor, suggesting that the earliest mutations in a shared precursor cell constrain tumor evolution toward the same genetics-based subgroups at both diagnosis and relapse. These results suggest that late relapses commonly represent genetically distinct and chemotherapy-naïve disease and have implications for optimal patient management.

Detecting ALK, ROS1, and RET fusions and the METΔex14 splicing variant in liquid biopsies of non-small-cell lung cancer patients using RNA-based techniques.

ALK, ROS1, and RET fusions and MET∆ex14 variant associate with response to targeted therapies in non-small-cell lung cancer (NSCLC). Technologies for fusion testing in tissue must be adapted to liquid biopsies, which are often the only material available. In this study, circulating-free RNA (cfRNA) and extracellular vesicle RNA (EV-RNA) were purified from liquid biopsies. Fusion and MET∆ex14 transcripts were analyzed by nCounter (Nanostring) and digital PCR (dPCR) using the QuantStudio® System (Applied Biosystems). We found that nCounter detected ALK, ROS1, RET, or MET∆ex14 aberrant transcripts in 28/40 cfRNA samples from positive patients and 0/16 of control individuals (70% sensitivity). Regarding dPCR, aberrant transcripts were detected in the cfRNA of 25/40 positive patients. Concordance between the two techniques was 58%. Inferior results were obtained when analyzing EV-RNA, where nCounter often failed due to a low amount of input RNA. Finally, results of dPCR testing in serial liquid biopsies of five patients correlated with response to targeted therapy. We conclude that nCounter can be used for multiplex detection of fusion and MET∆ex14 transcripts in liquid biopsies, showing a performance comparable with next-generation sequencing platforms. dPCR could be employed for disease follow-up in patients with a known alteration. cfRNA should be preferred over EV-RNA for these analyses.

Abstract A029: Whole genome and transcriptome analysis of paired metastatic biopsies identified resistance mechanisms in castration-resistant prostate cancer

Abstract Background: Androgen receptor signaling inhibitors (ARSIs), including abiraterone and enzalutamide, are widely used to treat prostate cancer. However, resistance inevitably develops, and subsequent treatment options remain limited. Prior studies of resistant tumors identified genetic mechanisms of ARSI resistance converging on AR, including its gene and enhancer amplifications, as well as mutations and structural variants involving the ligand-binding domain. Additionally, a phenotypic switch from AR-driven adenocarcinoma to AR-independent neuroendocrine carcinoma is well recognized and thought to be mediated by epigenetic reprogramming. Genomic analysis of paired metastatic biopsies before and after ARSIs offers a unique opportunity to systematically define resistance mechanisms, but such data are limited, in part due to difficulty obtaining serial biopsies. Methods: We obtained paired metastatic biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) before the initiation of an ARSI and at disease progression while on the ARSI. We performed whole-genome sequencing (WGS) and RNA-seq on these samples and conducted bioinformatic and statistical analyses contrasting pairs pre- vs. post-ARSI to search for genetic and transcriptomic alternations associated with ARSI resistance. Results: We generated WGS data for 45 paired biopsies and concurrent RNA-seq data for 35 pairs. WGS analysis identified further copy number gain in the genomic region spanning AR and its known upstream enhancer in multiple patients, driven by tandem duplications, and associated with increased AR expression. Overlaying publicly available chromatin immunoprecipitation sequencing data of transcription factors known to be important in prostate cancer (AR, FOXA1, and HOXB13) and the enhancer marker H3K27ac, we identified putative novel enhancers both upstream and downstream of AR and plan to further assess their effects on AR expression in cell lines. Paired WGS analysis also identified genes with mutations newly arising post-ARSI, yet with only limited recurrence suggesting intertumor heterogeneity. Interestingly, our paired RNA-seq analysis identified SSTR1, whose expression was consistently and significantly decreased in most ARSI-resistant samples. In a separate retrospective analysis of a cohort of 123 patients, we found that low SSTR1 expression was associated with worse overall survival, and patient survival was improved with post-biopsy ARSIs only when SSTR1 expression was high. SSTR1 encodes somatostatin receptor type 1, and its activation by endogenous somatostatin or exogenous somatostatin analogues exerts an anti-proliferative effect in cells expressing SSTR1, consistent with our observation of its downregulation in resistant tumors. Conclusions: Whole genome and transcriptome analysis of paired metastatic biopsies identified amplification of putative novel AR enhancers and decreased SSTR1 expression involved in ARSI resistance that warrant further investigation in additional patients and experimental systems. Citation Format: Xiaolin Zhu, Daniël Vis, Martin Sjöström, Raunak Shrestha, Jeroen Kneppers, Tesa Severson, Yanyun Zhu, Meng Zhang, Arian Lundberg, Thaidy Moreno Rodriguez, Alana Weinstein, Haolong Li, Adam Foye, Rahul Aggarwal, Andries M Bergman, Eric Small, Wilbert Zwart, David Quigley, Michiel van der Heijden, Felix Feng. Whole genome and transcriptome analysis of paired metastatic biopsies identified resistance mechanisms in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A029.

GS-001 - Primary results from MAESTRO-NASH a pivotal phase 3 52-week serial liver biopsy study in 966 patients with NASH and fibrosis

GS-001 - Primary results from MAESTRO-NASH a pivotal phase 3 52-week serial liver biopsy study in 966 patients with NASH and fibrosis

Phase III FIRE-4 study (AIO KRK-0114): Influence of baseline liquid biopsy results in first-line treatment efficacy of FOLFIRI/cetuximab in patients with tissue RAS-WT mCRC.

3507 Background: FIRE-4 (AIO KRK-0114) is performed in RAS wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, arm A patients continued FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with 5-FU/FA plus bevacizumab (5-FU/Bev) was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab may prolong PFS. Within the translational protocol, serial baseline liquid biopsy were taken to analyze RAS and BRAF mutations. Methods: Within this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued until progression or intolerable toxicity. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with 5-FU/FA plus bevacizumab (5mg/kg) until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Liquid Biopsies were analyzed by RAS BEAMing and BRAF ddPCR technology. Results: From August 2015 to January 2021, 673 patients were randomized, and liquid biopsies of 540 patients were evaluable at baseline. Of those, 70 (13%) were RAS mutant and 38 (7%) BRAFV600E mutant at baseline. Patients with a detectable RASmut had a significant shorter PFS and OS when compared to RASwt patients (PFS: 9.0mo vs. 11.5mo; p &lt; 0.001; OS: 22.1mo vs 33.6mo; p &lt; 0.001). Whereas, for RASwt patients no difference for both arms with respect to PFS and OS could be observed, RASmut patients (n = 70) had a clear trend towards shorter survival in the standard FOLFIRI cetuximab arm (PFS: 6.4mo vs. 10.1mo, p = 0.54; OS: 24.9mo vs. 16.3mo, p = 0.10). Patients with a BRAF mutation in liquid biopsy had median survival times as expected for BRAF mutant patients (PFS = 5.5mo; OS = 12.0mo). In the standard arm, with a continuous administration of cetuximab, the conversion rate from RASwt to RASmut was significantly higher at progression than in the switch maintenance arm. Conclusions: Liquid biopsy detected RAS mutation in 13% of patients deemed RASwt based on tissue analyses. These patients show outcome characteristics expected for RAS mutant patients (median PFS of 9.0 months and median OS of 22 months). The study thus shows the clinical relevance of liquid biopsy in the verification of RAS mutational status. Clinical trial information: NCT02934529 .

The PRIME-CUT study: A single-arm phase 2 study of ADT with PD-1 blockade and docetaxel in men with metastatic hormone-sensitive prostate cancer.

e17089 Background: Overall survival of patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) is improved with androgen deprivation therapy (ADT) and treatment intensification. Initially, ADT induces a robust and functional immune infiltrate into the tumor microenvironment (TME), with upregulation of immune checkpoint molecules. These effects diminish as castration-resistant prostate cancer (CRPC) invariably develops. We report the first results of the phase 2 PRIME-CUT study (modulating the PRostate cancer Immune MicroEnvironment with ChemoimmUnoTherapy for metastatic prostate cancer). Methods: Eligible pts had newly diagnosed mHSPC, ECOG performance status (PS) 0 or 1, serum testosterone levels &gt; 150 ng/dL, agreed to undergo serial metastatic tumor biopsies, and had not received ADT in the prior 6 months. Treatment consisted of ADT (degarelix 240 mg subcutaneously (SC) for one dose, followed by leuprolide 22.5 mg SC every 12 weeks) followed by anti-PD-1 antibody (cemiplimab 350 mg IV every 3 weeks) beginning four weeks after ADT initiation. With the intent of immune priming, a two-cycle lead-in of anti-PD-1 therapy was administered prior to standard of care docetaxel (75 mg/m2 every 3 weeks for six cycles). Participants received ADT and cemiplimab until study completion (52 weeks) or until a lack of clinical benefit or intolerable side effects. The primary endpoint was the rate of undetectable PSA at 6 months after chemotherapy initiation (week 37) and compared to the historical rate from the phase III CHAARTED trial (32%). Subjects were monitored for toxicity using a Bayesian adaptive study design with an early stopping rule for toxicity. Results: The study completed accrual of 20 pts (median age 62 years) from Columbia University Irving Medical Center in Aug 17, 2022. Among them, 7 self-identified race as Black and 12 self-identified their ethnicity as Hispanic. Baseline PSA ranged from 8.15 to &gt; 5000 ng/dL (median 2513.1 ng/dL). Site of metastatic disease included: 17/20 bone, 12/20 lymph nodes, 11/20 visceral organs. Overall, 14 of 20 patients received at least 4 cycles of docetaxel. Of the 12 patients that were still on-study at 37 weeks, 2 had an undetectable PSA, and 4 additional pts had PSA &lt; 1.0 ng/dL. Twelve pts experienced ≥ Grade 3 adverse events (AEs), 6 AEs were attributed to study intervention including cytopenias (3), hypotension (1), pneumonitis (1), and stenosis of gastrointestinal stoma (1). Unfortunately, two patients deceased on-study (myocardial infarction after 13 weeks, severe SARS-CoV-2 infection after 19 weeks). Conclusions: The Prime-Cut study did not meet its primary endpoint. However, PSA kinetics and results from the pre-planned correlative science demonstrate ongoing role for immunotherapeutic approaches in mHSPC. No new safety signals were observed. Clinical trial information: NCT03951831 .

A phase (Ph) I/II trial of abiraterone acetate in combination with tildrakizumab (anti-IL23 monoclonal antibody) in patients with metastatic castration-resistant prostate cancer (mCRPC).

TPS5105 Background: Tumor-infiltrating inflammatory myeloid cells promote prostate cancer (PC) growth and therapeutic resistance. Myeloid inflammatory cells release interleukin-23 (IL-23) to fuel tumor growth via JAK2-STAT3 signalling and facilitate tumor-promoting T helper 17 (TH17) differentiation in PC models in vivo. IL-23 blockade reverses resistance to AR-targeting in vivo; we hypothesise that targeting IL-23 can be an effective therapeutic strategy for CRPC. Tildrakizumab, an anti-IL-23 (p19) monoclonal antibody, is FDA/EMA approved for treating moderate-severe psoriasis. In progress is the first clinical trial to combining IL-23 and AR signalling blockade in humans. Methods: This is an open-label, single-arm, Ph 1/2, dose-escalation and expansion study evaluating safety and tolerability of tildrakizumab and abiraterone acetate combination therapy in patients with mCRPC. Eligible patients must have progressed on androgen deprivation therapy, plus abiraterone and/or enzalutamide. The Ph 1 trial will adopt a one-stage Bayesian Continual Reassessment Method design exploring escalating doses of 4-weekly, IV tildrakizumab (100 mg, 300 mg, and 600 mg), in combination with standard fixed doses of abiraterone acetate and methylprednisolone, with the aim of determining the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Depending on the number of responses observed, tolerable dose levels may be expanded up to 10 patients after review by the Safety Review Committee (SRC). The RP2D and MTD determination will be based on the rate of toxicity and efficacy, reviewed by the SRC. Once RP2D is determined, the Ph 2 study will enrol up to 25 response-evaluable patients using a Simon’s two-stage design. Primary endpoint of the Ph 2 trial is overall response rate. Adverse events are assessed according to CTCAE v5. Tumor response is determined according to RECIST v1.1, confirmed PSA decline of at least 50%, and/or CTC conversion. PK analyses is being performed for both drugs to identify potential drug-drug interactions. PD analyses is being performed on archival and serial tumour biopsies and blood samples to investigate putative predictive biomarkers and confirm on-target and downstream effector modulation. The trial began enrolling in January 2021 in the United Kingdom and Switzerland. As of January 22th 2023, 12 patients were included in the study. Clinical trial information: NCT04458311 .

Synuclein α accumulation mediates podocyte injury in Fabry nephropathy.

Current therapies for Fabry disease are based on reversing intra-cellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosome dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease remains unclear. First, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/CAS9-mediated α-Galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified alpha-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.

Liquid biopsy-informed precision oncology study to evaluate utility of plasma genomic profiling for therapy selection.

TPS1616 Background: Liquid biopsies have enabled a transformation in the management of patients with cancer as they have the potential to detect, characterize, and monitor tumor burden. However, the increasing complexity involved in the integration of genomic data into clinical practice has presented challenges with the practical implementation of liquid biopsies in clinical cancer care. To address these challenges, multidisciplinary teams comprised of experts within oncology, genetics, pathology, and informatics have created Molecular Tumor Boards (MTBs), which can improve clinical outcomes for cancer patients by efficiently utilizing the technologies created by the rapidly expanding precision oncology industry. Nevertheless, there remains a gap in the optimal implementation and interpretation of these diagnostic findings to maximize patient outcomes and access to standard of care therapies and clinical trials. Methods: We instigated a prospective observational liquid biopsy-informed precision oncology study, in which patients with metastatic solid tumors will be matched with genotype-driven therapies via serial liquid biopsies (NCT05585684). Liquid biopsy-derived genotypes will be generated through a clinical NGS assay (PGDX Plasma Focus) and will be annotated by an automated ensemble approach for variant actionability assessment, developed by the Johns Hopkins MTB, followed by a treatment recommendation. Key eligibility criteria include patients ≥18 years old, with ECOG performance status of 0-1 and with metastatic disease that have relapsed or progressed after standard of care first-line therapies or patients for which first-line standard of care therapeutic options are not expected to yield a clinical response. The primary objectives of the trial focus on feasibility of the approach and evaluating the fraction of patients with actionable mutations, for which the MTB recommendation is enacted upon. Unique to this study, a recommendation to not pursue genotype-targeted therapy is equally considered for personalized clinical decision making. Secondary objectives are to investigate whether enacting upon MTB recommendations improves progression-free and overall survival and perform a comparative analysis with tumor-based NGS. Exploratory objectives are to determine if serial molecular profiling after initiation of systemic treatment is sufficient to determine therapeutic response, compare with RECIST radiographic response and determine whether changes in liquid biopsy dynamics correlate with progression-free and overall survival. This study will enroll 150 patients with solid tumors, including lung, esophageal, breast, and head and neck cancer and mesothelioma to evaluate the clinical utility of liquid biopsy genomic profiling. Patient accrual for this study initiated in February 2023. Clinical trial information: NCT05585684 .

LBP-17 - Artificial intelligence to measure fibrosis change on liver biopsy in MAESTRO-NASH a phase 3 52-week serial liver biopsy study in 966 patients with NASH treated with resmetirom or placebo

LBP-17 - Artificial intelligence to measure fibrosis change on liver biopsy in MAESTRO-NASH a phase 3 52-week serial liver biopsy study in 966 patients with NASH treated with resmetirom or placebo

Phase I study of NEROFE and doxorubicin in KRAS-mutated ST2-positive solid tumors.

TPS2667 Background: KRAS-mutated tumors are notoriously difficult to treat clinically with targeted therapies. Recent advances targeting KRAS G12C with sotorasib and adagrasib are encouraging but limited to a small subset of patients. NEROFE is a 14 amino acid peptide which inhibits suppression of tumorigenicity 2 (ST2; member of the interleukin 1 [IL-1] receptor family and IL-33 receptor), a novel immune checkpoint present on tumor cells and tumor-associated macrophages. ST2 blockade with NEROFE has been shown to transform an immunosuppressive tumor microenvironment into an immune-stimulatory microenvironment. NEROFE also has been shown to induce microRNA miR-217 which downregulates KRAS and MAPK1/2 gene expression in preclinical models. When combined with low-dose doxorubicin, NEROFE has a synergistic effect on inducing apoptosis in KRAS-mutated, ST2-positive cell lines and xenograft models. Methods: This is a phase I trial of NEROFE given at 48 mg/m2 (dose level [DL] -1), 96 mg/m2 (DL1), 192 mg/m2 (DL2), or 288 mg/m2 (DL3) IV weekly with doxorubicin 8 mg/m2 IV weekly. A standard 3+3 dose escalation/de-escalation is used. The primary objective is to determine the recommended phase II dose. Patients are eligible if they have an advanced solid tumor with a KRAS mutation and ST2-positivity (via immunohistochemistry [IHC], centrally confirmed with pre-screening allowed). Patients must have measurable disease amenable to serial biopsy. Patients must have had progression or intolerance to all standard therapies or must decline available standard therapy. Pharmacokinetic profiles will be analyzed from serial blood draws pre- and 1, 2, 4, 6, and 24 hours post-infusion on cycle 1 day and cycle 2 day 1. Pre- and on-treatment tumor biopsies are mandatory. Correlative studies include IHC for ST2 expression, immune cell infiltration and blood-based analyses of KRAS mRNA, miR-217, and cytokines. Enrollment to DL1 began in Q1 2023 (NCT05661201). Clinical trial information: NCT05661201 .

Phase II trial of BXCL701 and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (EXPEL-PANC).

TPS4194 Background: Pancreatic ductal adenocarcinoma (PDAC) has limited therapeutic options and is thought to be a “cold” tumor that does not respond to immunotherapy, due to a tumor microenvironment (TME) consisting of a desmoplastic stroma and poor T cell infiltrate. BXCL701 is an oral synthetic dipeptide that competitively inhibits dipeptidyl peptidases DPP4, DPP8, DPP9 and fibroblast activation protein (FAP). BXCL701 exerts antitumor activity via inhibition of DPP8/9, which is associated with induction of proinflammatory cytokines, as well as inhibition of FAP, which disrupts tumor-stromal interactions. Preclinical xenograft models demonstrate synergy between BXCL701 and an anti-PD-1 monoclonal antibody, reducing tumor growth and promoting an increase in intratumoral CD4+ and CD8+ T cells and NK cells. The combination of BXCL701 and pembrolizumab is already being studied in a phase II trial in patients with prostate cancer (NCT03910660) and a multi-cohort basket study (NCT04171219). Methods: This is a phase II trial of BXCL701 administered at 0.2 mg PO BID days 1-7 and 0.3 mg BID days 8-14 during cycle 1 (21 days) followed by 0.3 mg BID days 1-14 every 21 days in all subsequent cycles, given with pembrolizumab 200 mg IV every 21 days (all cycles). The primary objective is to determine the 18-week progression-free survival rate (PFS18weeks) in patients with metastatic PDAC treated in the second-line setting. We estimate that historical 2nd-line PFS18weeks is 30% or less; using a Simon’s two-stage (minimax) design, a type I error rate of 0.05 and power of 80% when the true response rate of 50%, we will need 19 patients in stage 1 and 20 in stage 2 (a total of 39). We plan to enroll 43 patients to account for a predicted 10% drop out of unevaluable patients. Eligible patients must have metastatic PDAC and disease progression or intolerance to only 1 line of therapy for metastatic disease, without exposure to prior immunotherapy. Patients must have measurable disease amenable to serial biopsies. Correlative pharmacodynamic studies include imaging mass cytometry to examine 34 markers of the PDAC TME in tissue biopsies, as well as blood-based analyses of KRAS circulating tumor DNA, circulating markers of fibrosis, and IL-6. Enrollment began in Q1 2023. Clinical trial information: NCT05558982 .

A brief mind-body intervention to reduce pain and anxiety during prostate needle biopsy: A randomized, controlled trial with two-staged consent.

e17092 Background: Prostate biopsy is among the most common oncologic procedures performed annually. A substantial proportion of patients experience significant morbidity related to biopsy, including pain, anxiety, and discomfort which may discourage follow-up biopsy crucial for identifying progression or discourage enrollment in active surveillance programs that require serial biopsy. Guided meditation significantly reduces pain and anxiety during breast biopsy. We developed a brief mind-body intervention that could easily integrate into general practice for patients during prostate biopsy and compared patient-reported outcomes after biopsy with and without this intervention. Methods: We conducted a clinically-integrated randomized controlled trial (MSK IRB 18-089) of a brief mind-body intervention during prostate biopsy compared to usual care. All adult patients offered biopsy were eligible. Patients randomized to the intervention were offered both a pre-biopsy mind-body exercise and guided mindfulness meditation during biopsy via headphones. The primary outcome of interest was any severe patient-reported pain, anxiety, discomfort, or tolerability on a visual-analog scale (0-10). We compared the proportion of men in each arm reporting a severe score (7-10) on any of the four scales using Fisher’s exact test. The pre-specified clinically relevant improvement justifying integration into clinical practice was 15%. We compared means separately using ANCOVA with randomization stratum (first vs. prior biopsy) as a covariate. Results: 238 patients (119 per arm) enrolled. 102 in the intervention arm and 94 in the usual care arm proceeded to biopsy and completed the questionnaire. A total of 37/94 (39%) and 38/102 (37%) patients in the usual care and the intervention arms, respectively, reported severe scores in any of the four domains, a difference of 2.1% (95% confidence interval -13, 17%, p = 0.8). The upper bound of the confidence interval includes the pre-specified clinically relevant difference. There was no evidence of a difference in mean post-biopsy anxiety (p = 0.3), discomfort (p = 0.09), pain (p = 0.4) or tolerability scores (p = 0.2), Table. Conclusions: There was no difference in patient reported outcomes between a mind-body intervention and usual care for prostate biopsy. Though the upper bound of the 95% confidence interval included the clinically relevant difference in severe scores, the difference in means for each outcome suggests a clinically meaningful benefit for this brief mindfulness intervention is unlikely. [Table: see text]