Abstract Purpose: Metastatic castration-resistant prostate cancer (mCRPC) has limited treatment options and a poor prognosis. Recently, PSMA-targeted alpha particle therapy agents using Actinium-225 (225Ac) have shown promising results for prostate cancer treatment, but a significant fraction of patients with advanced mCRPC demonstrate loss of PSMA expression. We have previously reported that PSMA-null and PSMA-positive tumors can be detected and treated effectively with CD46-targeted radiopharmaceuticals. This study evaluates the CD46-targeting PET imaging agent [89Zr]DFO-YS5 and the radioimmunotherapy agent [225Ac]Macropa-PEG4-YS5 in disseminated prostate cancer tumors. Experimental Design: Microtumor lesions, primarily observed in the liver, kidneys, and lungs, were successfully detected with [89Zr]DFO-YS5 PET imaging. We used disseminated 22Rv1 tumors for biodistribution studies, dosimetry assessments, and therapeutic efficacy evaluations of [225Ac]Macropa-PEG4-YS5. Results: Quantitative digital alpha-particle autoradiography revealed high radiation dose deposition from [225Ac]Macropa-PEG4-YS5 in microtumors compared to surrounding liver tissues, although in larger lesions (>1 mm diameter) the dose distribution was heterogeneous. Early treatment of smaller disseminated tumors with uniform radiation dose was more effective in ablating tumors and promoting survival. In late-stage lesions of large size, heterogeneous dose deposition limited therapeutic efficacy, requiring higher administered activity to achieve a complete response. Conclusions: Our findings highlight that [225Ac]Macropa-PEG4-YS5 holds the potential for clinical translation for metastatic prostate cancer and reinforces the value of microdosimetry in understanding the efficacy of and resistance to targeted alpha therapy.
Lung transplant recipients undergo bronchoalveolar lavage (BAL) to detect antecedents of chronic lung allograft dysfunction (CLAD), but routine assessment of BAL cytology is controversial. We hypothesized that inflammation on BAL cytology would predict CLAD-free survival.In a single-center retrospective cohort, associations between cytology results and clinical characteristics were compared using generalized-estimating equation-adjusted regression. The association between BAL inflammation and CLAD or death risk was assessed using time-dependent Cox models.In 3365 cytology reports from 451 subjects, inflammation was the most common finding (6.2%, 210 cases), followed by fungal forms (5.3%, 178 cases, including 24 cases of suspected Aspergillus). Inflammation on BAL cytology was more common in procedures for symptoms (8.5%) versus surveillance (3.2%, p < .001). Inflammation on cytology was associated with automated neutrophil and lymphocyte counts, acute cellular rejection, infection, and portended a 2.2-fold hazard ratio (CI 1.2-4.0, p = .007) for CLAD or death. However, inflammation by cytology did not inform CLAD-free survival risk beyond automated BAL cell counts (p = .57).Inflammation on BAL cytology is clinically significant, suggesting acute rejection or infection and increased risk of CLAD or death. However, other indicators of allograft inflammation can substitute for much of the information provided by BAL cytology.
88 Background: A growing body of literature suggests that the presence of cribriform pattern (CP) in prostate biopsy specimens portends worse outcomes. Furthermore, CP tumors have been found to harbor a myriad of genomic alterations associated with more aggressive disease. We sought to examine the association between CP and Genomic Prostate Score (GPS) and how this association helps predict adverse pathology (AP) at radical prostatectomy (RP) in patients initially managed with active surveillance (AS). Methods: Using the UCSF Urologic Outcomes Database (UODB), we identified 180 AS patients who underwent GPS testing and subsequently RP. Biopsy specimens were re-reviewed centrally to confirm Gleason grade. AP was defined as GS ≥ 4+3, pT3/4, or pN1 on surgical pathology. Clinical and demographic characteristics were compared by CP status using t-tests and chi-squared tests. Cox proportional hazards regression was performed to identify factors associated with AP after adjusting for age, PSA density (log), percentage of positive biopsy cores, biopsy source (UCSF versus outside), and year of diagnosis. Additional models included the base covariates plus presence of CP, GPS, and both CP and GPS. Results: For the cohort, mean age was 60.7 years (SD 7.1) with median PSA of 5.3 ng/ml (interquartile range, IQR 4.2-6.9) at diagnosis. Median PSAD was 0.14 (IQR 0.10-0.20). Among 180 patients, 27 (15%) had CP at biopsy. Mean GPS was significantly higher in CP+ compared to CP- patients (35, SD 12.7 versus 27, SD13.7, p < 0.01), and a greater proportion of CP+ patients had AP compared to CP- (59% versus 54%, p < 0.01). On multivariate analysis, CP was associated with AP (HR 1.9, 95% CI 1.1-3.4, p = 0.02), but significance was lost after adjusting for GPS (p = 0.19). Conclusions: The presence of CP at biopsy was statistically significantly associated with higher GPS. While both were associated with AP at RP, CP was not associated with AP independent of GPS, suggesting an interaction or commonality between these factors not previously explored.
// Cristina L. Abrahams 1 , Xiaofan Li 1 , Millicent Embry 1 , Abigail Yu 1 , Stellanie Krimm 1 , Sarah Krueger 2 , Nancy Y. Greenland 3 , Kwun Wah Wen 3 , Chris Jones 3 , Venita DeAlmeida 1 , Willy A. Solis 1 , Shannon Matheny 1 , Toni Kline 1 , Alice Y. Yam 1 , Ryan Stafford 1 , Arun P. Wiita 3 , Trevor Hallam 1 , Mark Lupher 1 and Arturo Molina 1 1 Sutro Biopharma, Inc., South San Francisco, California, USA 2 MI Bioresearch, Ann Arbor, MI, USA 3 Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA Correspondence to: Arturo Molina, email: amolina@sutrobio.com Keywords: CD74; antibody-drug conjugate; multiple myeloma; xenograft models; STRO-001 Received: November 22, 2018 Accepted: December 04, 2018 Published: December 28, 2018 ABSTRACT STRO-001 is a site-specific, predominantly single-species, fully human, aglycosylated anti-CD74 antibody-drug conjugate incorporating a non-cleavable linker-maytansinoid warhead with a drug-antibody ratio of 2 which was produced by a novel cell-free antibody synthesis platform. We examined the potential pharmacodynamics and anti-tumor effects of STRO-001 in multiple myeloma (MM). CD74 expression was assessed in MM cell lines and primary bone marrow (BM) MM biopsies. CD74 mRNA was detectable in CD138+ enriched plasma cells from 100% (892/892) of patients with newly diagnosed MM. Immunohistochemistry confirmed CD74 expression in 35/36 BM biopsies from patients with newly diagnosed and relapsed/refractory MM. Cytotoxicity assays demonstrated nanomolar STRO-001 potency in 4/6 MM cell lines. In ARP-1 and MM.1S tumor-bearing mice, repeat STRO-001 dosing provided significant antitumor activity with eradication of malignant hCD138+ BM plasma cells and prolonged survival. In a luciferase-expressing MM.1S xenograft model, dose-dependent STRO-001 efficacy was confirmed using bioluminescent imaging and BM tumor burden quantification. Consistent with the intended pharmacodynamic effect, STRO-001 induced dose-responsive, reversible B-cell and monocyte depletion in cynomolgus monkeys, up to a maximum tolerated 10 mg/kg, with no evidence of off-target toxicity. Collectively, these data suggest that STRO-001 is a promising therapeutic agent for the treatment of MM.
Abstract Background Fine‐needle aspiration (FNA) biopsy is increasingly used for the diagnosis of hepatocellular masses. Because distinguishing well differentiated hepatocellular carcinoma (HCC) from other well differentiated hepatocellular lesions (e.g., large regenerative nodules or focal nodular hyperplasia) requires an assessment of architectural features, this may be challenging on FNA when intact tissue fragments are not sampled. Poorly differentiated HCC and intrahepatic cholangiocarcinoma (ICC) may exhibit overlapping pathologic features. Molecular testing can be helpful, because mutations in TERT promoter and CTNNB1 (β‐catenin) are characteristic of HCC, whereas mutations in BAP1 , IDH1/IDH2 , and PBRM1 may favor ICC. The goal of this study was to assess the role of next‐generation sequencing (NGS) in further subclassifying indeterminate liver lesions sampled by FNA. Methods A retrospective review of liver cytology cases with NGS on cell block material was performed. Age, radiologic features, background hepatic disease and treatment, outcome, and NGS data were obtained from the electronic medical record. Results Twelve FNA biopsies that had cell blocks from clinically suspected primary hepatic masses were identified. The presence of a TERT promoter mutation supported a diagnosis of HCC for one well differentiated neoplasm. For three patients, the presence of mutations, such as IDH1 , CDKN2A/CDKN2B , and BRAF , supported a diagnosis of ICC. Of the eight poorly differentiated carcinomas, NGS helped refine the diagnosis in six of eight cases, with one HCC, three ICCs, and two that had combined HCC‐ICC, with two cases remaining unclassified. Conclusions Molecular diagnostics can be helpful to distinguish HCC and ICC on FNA specimens, although a subset of primary hepatic tumors may remain unclassifiable.
Aims Tumour content in prostatic biopsies is an important indicator of prostate cancer volume and patient prognosis. Consequently, guidelines typically recommend reporting it as a percentage or linear length (mm). This study aimed to determine the current practices for reporting tumour content in prostatic biopsies and evaluated the consistency among pathologists in diagnosing 10 standard biopsy cases of prostate cancer to assess interobserver variability. Methods and results A web‐based survey gathered data on demographics, experience and attitudes regarding the reporting of prostate cancer and its extent in biopsies. Virtual microscopy allowed analysis of 10 biopsy cases, each consisting of a single slide of prostate cancer. Self‐reports from 304 participants recruited via the International Society of Urological Pathology and the German Society of Pathology were analysed. Most participants (43.4%) reported tumour extent as percentage of the biopsy core, 37.6% reported percentages and mm and 18.3% reported mm exclusively. The methods used to determine percentages showed an unexpected spread of choices, leading to considerable variability in results. Additionally, 40.8% of participants took part in the practical segment of the survey. The reported measures of tumour extent confirmed a notable interobserver variability, which was significantly higher for reported percentages. Conclusion A high rate of interobserver variability in reporting tumour content in prostatic biopsies was found. This matter is especially critical for patients who are candidates for active surveillance. Reporting absolute measures of tumour content has the advantage of lower variability in comparison to percentages.
