Citations

AbstractRobotic surgical techniques are now being applied in the setting of retroperitoneal lymphadenectomy (RPLND) for testicular cancer. While laparoscopic RPLND has not been widely accepted, reports of robot assisted RPLND (RARPLND) are emerging. This manuscript will review the application of RPLND for testicular cancer, evolution of minimally invasive techniques, the controversies, and current status of RARPLND. J. Surg. Oncol. 2015;112:736–740. © 2015 Wiley Periodicals, Inc.

Abstract Monoclonal antibodies that target the programmed death-1 (PD-1)–programmed death ligand-1 (PD-L1) axis have antitumor activity against multiple cancers. The presence of sarcomatoid differentiation in renal cell carcinoma (RCC) is associated with resistance to targeted therapy and poor responses to IL2 immunotherapy. Given the aggressive nature of RCC with sarcomatoid differentiation and the exclusion of sarcomatoid histology from metastatic RCC clinical trials, less is understood regarding selection of therapies. Here, we characterized the PD-1/PD-L1 axis in RCC with sarcomatoid differentiation. We directly compared two PD-L1 antibodies and found concordance of PD-L1 positivity in 89% of tested RCCs with sarcomatoid differentiation. Coexpression of PD-L1 on neoplastic cells and the presence of PD-1–positive tumor-infiltrating lymphocytes were identified in 50% (13 of 26) of RCCs with sarcomatoid differentiation. In contrast, only 1 of 29 clear cell RCCs (3%) had concurrent expression of PD-L1 and PD-1 (P = 0.002). Our study suggests that RCC with sarcomatoid differentiation may express PD-1/PD-L1 at a higher percentage than RCC without sarcomatoid differentiation, and patients with these tumors may be good candidates for treatment with anti–PD-1/PD-L1 therapies. Cancer Immunol Res; 3(12); 1303–7. ©2015 AACR.

Abstract Introduction Recent advances in stereotactic radiosurgery (SRS) have improved clinical outcomes in patients with limited intracranial metastases. As a result of this high-dose radiation delivery to a focal area within the brain, tissue structural and functional changes within the treatment field are often difficult to distinguish from local tumor recurrence based on conventional imaging techniques. Here, we demonstrate that elevation of circulating cells of myeloid origin, the key regulators of inflammation and immune responses, can serve as a potential surrogate marker to differentiate radiation-induced tissues changes from local tumor recurrence. Materials and Methods We retrospectively identified 96 patients who were initially treated with Gamma-knife radiosurgery at MD Anderson Cancer Center from 2009-2013 for brain metastases, and subsequently underwent surgical resection of previous irradiated lesions after presenting with clinical symptoms and radiographic findings suggestive of tumor progression. All surgical specimens were centrally reviewed by neuropathology. Pre-operative circulating blood cell profiles were analyzed for monocytic, granulocytic and lymphocytic sub-populations. Results A total of 11 and 85 patients who underwent surgical resection after prior SRS for brain metastasis were pathologically confirmed to have radiation-induced changes or tumor recurrence, respectively. Among patients with confirmed recurrence vs. those with radiation-induced changes, the number of circulating immature granulocytes (mean = 0.093 × 103ul−1 vs 0.032 × 103ul−1, p = 0.075) and monocytes (mean = 0.632 × 103ul−1 vs 0.401 × 103ul−1, p = 0.007) were elevated when compared to patients with radiation-induced changes (combined: mean = 0.71 × 103ul−1 vs 0.43 × 103ul−1, p = 0.002). No statistically significant differences were observed among mature granulocytic or lymphocytic populations between the two groups. Receiver operating characteristic analysis showed significant discriminative utility of pre-operative myeloid cell count when compared to reference line of no discrimination (AUC = 0.774, p = 0.003). The cut-point for myeloid cell population was found be > = 0.5 × 103ul−1, which corresponds to a detection sensitivity of 73.3% and specificity of 72.7% for tumor recurrence. Conclusion Bone marrow cells of myeloid origin play important roles in mediate acute inflammatory reactions and in regulating adaptive immunity. We showed here that certain primitive cells of myeloid lineage may potentially be used to aid the differentiation of tumor recurrence from radiation-induced changes in patients who had SRS for brain metastasis. The identification of potential circulating biomarkers that can complement traditional imaging to distinguish the two distinct pathological entities has significant implications in the management of these patients. Note: This abstract was not presented at the meeting. Citation Format: Wen Jiang, Yvo Rodriguez, Nicolas S. Boehling, Sujit S. Prabhu, Betty Y.S. Kim, Patrick Hwu, Erik P. Sulman, Paul D. Brown, Jing Li. Circulating myeloid precursor profile as potential marker to differentiate radiation changes from tumor recurrence after brain stereotactic radiosurgery. [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 532. doi:10.1158/1538-7445.AM2015-532

ABSTRACT Introduction: The aim of this study was to create reference values for jitter measured with concentric needle electrodes. Methods: Operators worldwide contributed recordings from orbicularis oculi (OO), frontalis (FR), and extensor digitorum (ED) muscles in healthy controls. Criteria for acceptable signal quality were agreed upon in advance. Fifteen or 20 recordings of acceptable quality from each muscle were required for voluntary and electrical stimulation recordings, respectively. Results: Recordings from 59 to 92 subjects were obtained for each muscle and activation type. Outlier limits for mean consecutive difference and individual jitter data for voluntary activation were: OO, 31 and 45 µs; FR, 28 and 38 µs; ED, 30 and 43 µs; and for electrical stimulation they were: OO, 27 and 36 µs; FR, 21 and 28 µs; ED, 24 and 35 µs. Conclusion: Reference jitter values from concentric needle electrode recordings were developed from signals of defined quality while seeking to avoid creating supernormal values. Muscle Nerve 53: 351–362, 2016

Abstract Introduction: Identification of causal DNA copy number variations (CNVs) is critical to the understanding of cancer development and progression, and is important clinically for accurate prognosis and efficient treatment. T-cell lymphomas are replete with amplifications and deletions that result in over- and under-expression of genes. Array comparative genomic hybridization (aCGH) has been the technology of choice to detect CNVs but recently, it has been proposed that mate-pair Next Generation Sequencing (mpNGS) can produce similar results. Here, we report a comparison between the two techniques. Methods: We have developed an algorithm based on extreme value theory to identify CNVs across the genome at high resolution from mate-pair NGS data. The algorithm is based on plotting the distribution of read-counts in windows across the genome, and detecting deletions and gains by finding the windows that differ significantly from the distribution of the normal part of the genome. We compared this algorithm with aCGH data to detect CNVs. We ran five cases of T-cell lymphoma with both techniques and compared the results using concordance statistics. Results: With 50kb lower cutoff for a CNV, mpNGS detected 98% of the cumulative deleted genome and 94% of the amplified/gained genome that were called by aCGH. Most of the discordant CNVs that were detected by only aCGH were in regions of repetitive areas where mapping fails. Conversely, aCGH detected 75% of the cumulative deleted genome and 74% of the amplified/gained genome that were called by mpNGS. Conclusion: A detailed comparison of these techniques showed that both have pros and cons. In general, mpNGS can detect most CNVs detected by aCGH, as long as they are more than 50KB. Additionally, mpNGS offers confirmatory data, particularly for deletions, based on detection of aberrant mate pairs that map to the rejoined ends of deleted regional. Finally, the mate-pair technology can also detect balanced translocations and can also predict fusion genes. Citation Format: George Vasmatzis, Andrew L. Feldman, Sarah H. Johnson, Erik C. Thorland, Rafael Fonseca, Esteban Braggio, Troy J. Gliem. Copy number detection using genomics technologies: A comparison between aCGH and NGS. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3572. doi:10.1158/1538-7445.AM2014-3572

Abstract Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer responsible for ∼80% of kidney cancer cases. Circulating tumor cells (CTCs) are emerging as an important prognostic and predictive biomarker in several types of metastatic cancers. However, methods for CTC detection that target only EpCAM and/or cytokeratin (CK) to enrich CTCs, may fail to recognize the CTCs in clear cell RCC (ccRCC) because ccRCC lacks expression of EpCAM. The objective of this study was to develop a new technology capable of detecting CTCs including those with a mesenchymal phenotype in metastatic RCC. Methods: Blood samples from patients affected by metastatic RCC were provided by Mayo Clinic Arizona and analyzed by Creatv MicroTech. CellSieveTM microfilters, which have 7 µm diameter pores in a uniform array, with 160,000 pores in a 9 mm diameter area, were used for separation of CTCs in the blood specimen. 7.5 mL of whole blood was diluted in the prefixation buffer and filtered through the microfilter. Clinical immunohistochemical markers for RCC such as CD10 and vimentin were used to identify candidate CTCs. The cells collected on the filter were fixed, permeabilized, and stained with DAPI and fluorescent antibodies specific to CD10, vimentin, and CD45. The assay protocol was developed using three RCC cell lines, 786-O, Caki-1, and Caki-2, and validated using blood samples from patients with metastatic RCC. Results: The capture efficiencies for 786-O, Caki-1, and Caki-2 cell lines were determined to be 98%, 98% and 97%, respectively. On-filter antibody staining revealed heterogeneous expressions of vimentin and CD10 in RCC cells. Patient samples were collected in duplicate CellSaveTM tubes and processed one day later. A CD10+/vimentin+/CD45- cell population was detected in blood samples with enumeration ranging from 4 to 86 cells/7.5 mL of blood. We found that the RCC CTC profile was distinct from other types of cancers. The typical CTCs display abnormal morphology, including large nuclei (typically 15-30 µm in size), irregular cell size and shape, and high nucleus-to-cytoplasm ratio. Although CD10 and vimentin antibodies have cross-reactivity with white blood cells (WBC), the CTCs could be distinguished from WBC based on morphology, cell size and CD45- staining. Conclusions: We demonstrated that the CellSieveTM microfiltration assay is a very simple and efficient method to isolate a CD10+/vimentin+/CD45- cell population from patients affected by metastatic ccRCC. Future studies include fluorescence in situ hybridization to confirm loss of 3p, a molecular event that occurs in >90% of ccRCC. We are also analyzing blood samples from patients treated with tyrosine kinase inhibitors to determine if cell enumeration is predictive of response to treatment. This technology might greatly facilitate detection of EpCAM negative ccRCC CTCs. The clinical significance of these unusual, large, rod-shaped, naked nuclei require further molecular characterization. Citation Format: Peixuan Zhu, Thai Ho, Erik P. Castle, Richard W. Joseph, Melissa L. Stanton, Shuhong Li, Daniel Adams, Olga V. Makarova, Platte T. Amstutz, Cha-Mei Tang. Isolation and identification of circulating tumor cells in renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3081. doi:10.1158/1538-7445.AM2014-3081

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