Background While enumeration of circulating tumor cells (CTCs) has shown some clinical value, the pool of CTCs contains a mixture of cells which contains additional information that can be extracted. Our group sub-classified CTCs by shape features focusing on nuclear size and related this to clinical information. Methods A total of 148 blood samples were obtained from 57 PC patients across the spectrum of metastatic states: no metastasis, non-visceral metastasis, and visceral metastasis. CTCs captured and enumerated on NanoVelcro Chips were subjected to pathologic review including nuclear size. The distribution of nuclear sizes was analyzed using a Gaussian Mixture Model. Correlations were made between CTC subpopulations and metastatic status. Results Statistical modeling of nuclear size distribution revealed 3 distinct subpopulations: large-nuclear (lnCTC), small-nuclear (snCTC), and very-small-nuclear CTCs (vsnCTCs). snCTC + vsnCTC identified patients with metastatic disease. vsnCTC counts alone, however, were elevated in patients with visceral metastases when compared to those without (0.36 ± 0.69 vs. 1.95 ± 3.77 cells/mL blood, p < 0.001). Serial enumerations suggested the emergence of vsnCTCs occurred prior to the detection of visceral metastases. Conclusions There are morphologic subsets of CTCs that can be identified by fundamental pathologic approaches, such as nuclear size measurement. This observational study strongly suggests that they contain relevant information on disease status. In particular, the detection of vsnCTCs correlated with the presence of visceral metastases and should be formally explored as a putative blood-borne biomarker to identify patients at risk for developing this clinical evolution of PC.
BACKGROUND Fyn is a kinase that is upregulated in a subset of metastatic castration-resistant prostate cancer. Saracatinib potently inhibits Fyn activation. We have noted a relationship between Fyn expression and directional motility, a cellular process related to metastasis. As such we hypothesized that treatment with saracatinib would increase the time required to develop new metastatic lesions. METHODS Patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel were eligible for enrollment. This study was executed as a randomized discontinuation trial. During a lead-in phase of two 28-Day cycles, all patients received saracatinib. Afterward, patients with radiographically stable disease were randomized to either saracatinib or placebo. Patients continued treatment until evidence of new metastasis. RESULTS Thirty-one patients were treated. Only 26% of patients had stable disease after 8 weeks and thus proceeded to randomization. This required early termination of the study for futility. The 70% of patients who progressed after the lead-in phase exhibited expansion of existing lesions or decompensation due to clinical progression without new metastatic lesions. Fatigue was reported in more than 25% of patients (all grades) with only two patients experiencing grade 3 toxicity. Other grade 3 adverse events included dehydration, thrombocytopenia, and weakness. CONCLUSIONS This study was unable to determine if saracatinib had potential as metastasis inhibitor. Metastasis inhibition by saracatinib may still be viable in an earlier time in the disease history.
Mantle cell lymphoma is a mature B-cell neoplasm composed of small to medium-sized atypical lymphocytes and has a characteristic t(11;14)(q13;q32) translocation, with a variably aggressive and overall incurable course. More aggressive histologic variants have been described, as well as rare cases of transformation to other large cell lymphomas. Here, we describe a novel case of large cell blastic transformation of mantle cell lymphoma/leukemia at presentation with unusual immunophenotypic and cytogenetic features, most consistent with B-lymphoblastic leukemia. Morphologic findings include sheets of large blasts replacing the bone marrow, as well as occasional small to medium-sized atypical lymphocytes in the background. The blasts express CD19, PAX5, CD10, Cyclin D1, and TdT but are negative for CD5, CD20, and BCL2 by immunophenotyping. Cytogenetic studies show a complex karyotype with t(11;14), monosomy 13, gains of 8q, and MYC gene rearrangement and amplification among other changes. This unique case of blastic TdTpositive B-cell leukemia arising from mantle cell lymphoma may represent transformation with complex cytogenetic abnormalities including "double hit" changes. This distinctive presentation may expand our understanding of the biology behind mantle cell lymphoma progression.
Background Circulating tumor cells (CTCs) are an emerging biomarker in prostate cancer (PC). Most efforts have focused on enumeration, we and others have identified subsets within this pool of cells which may be clinically informative. Using the highly sensitive NanoVelcro technology for CTC isolation and fluorescence microscopy, our group sub-classified CTCs by nuclear size and focused on the correlation with sites of metastatic disease in advanced PC patients. Methods Blood samples were obtained from PC patients across the spectrum of metastatic states, i.e. no metastasis, non-visceral (osseous/lymph node) metastasis, and visceral metastasis. The patients were divided into training and validation cohorts. CTCs were captured from the blood and enumerated on NanoVelcro Chips. These were then subjected to pathologic review for cellular morphology and nuclear size. The distribution of nuclear sizes was analyzed using a Gaussian Mixture Model to sub-classify the CTCs. Correlations were made between CTC subpopulations and metastatic status. Individual CTCs were isolated by laser-capture microdissection for subsequent characterization focusing on cellular markers and transcriptomic signatures in comparison between vsnCTC and other CTC subpopulations. Results Statistical analysis and modeling of nuclear size distribution revealed 3 distinct subpopulations in the training cohort: large-nuclear CTCs (lnCTC), small-nuclear CTCs (snCTC), and very-small-nuclear CTCs (vsnCTCs). While the lnCTC subpopulation alone failed to distinguish metastatic disease from non-metastatic disease, snCTC + vsnCTC counts could make that distinction. Furthermore, vsnCTC counts were elevated in PC patients with visceral metastases when compared to those without visceral metastases (0.5 ± 0.5 versus 3.1 ± 5.2 cells/mL of blood, p = 0.005). This difference remained statistically significant in the validation cohort (0.6 ± 1.0 versus 3.5 ± 4.0 cells/mL of blood, p = 0.007). Serial enumerations for individual patients showed the emergence of vsnCTCs prior to detection of newly developed visceral lesions. The recurrence of vsnCTC in patients under treatment is also associated with radiographic progression of existing visceral lesions through therapy. Molecular characterization of vsnCTCs reveals differential expression of genes related to neuroendocrine, stem cell, and androgen biology. Conclusions Subsets of CTCs contain information on PC disease status when analyzed with pathologic approaches, such as nuclear size measurement. In particular, the detection of vsnCTCs correlated with the presence of visceral metastatic lesions and should be explored as a potential biomarker to identify patients at risk for developing this more aggressive form of PC. Citation Format: Jie-Fu Chen, Hao Ho, Jake Lichterman, Yi-Tsung Lu, Yang Zhang, Mitch A. Garcia, Shang-Fu Chen, An-Jou Liang, Haiyen E. Zhau, Shuang Hou, Rafi S. Ahmed, Daniel J. Luthringer, Jiaoti Huang, Ker-Chau Li, Leland WK Chung, Zunfu Ke, Hsian-Rong Tseng, Edwin M. Posadas. Sub-classification of prostate cancer circulating tumor cells (CTCs) by nuclear size reveals very-small nuclear CTCs in patients with visceral metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3473. doi:10.1158/1538-7445.AM2015-3473
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