Browsing by Author "Cheng, Liang"
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Item A deep learning framework for automated classification of histopathological kidney whole-slide images(Elsevier, 2022-04-18) Abdeltawab, Hisham A.; Khalifa, Fahmi A.; Ghazal, Mohammed A.; Cheng, Liang; El-Baz, Ayman S.; Gondim, Dibson D.; Pathology and Laboratory Medicine, School of MedicineBackground: Renal cell carcinoma is the most common type of malignant kidney tumor and is responsible for 14,830 deaths per year in the United States. Among the four most common subtypes of renal cell carcinoma, clear cell renal cell carcinoma has the worst prognosis and clear cell papillary renal cell carcinoma appears to have no malignant potential. Distinction between these two subtypes can be difficult due to morphologic overlap on examination of histopathological preparation stained with hematoxylin and eosin. Ancillary techniques, such as immunohistochemistry, can be helpful, but they are not universally available. We propose and evaluate a new deep learning framework for tumor classification tasks to distinguish clear cell renal cell carcinoma from papillary renal cell carcinoma. Methods: Our deep learning framework is composed of three convolutional neural networks. We divided whole-slide kidney images into patches with three different sizes where each network processes a specific patch size. Our framework provides patchwise and pixelwise classification. The histopathological kidney data is composed of 64 image slides that belong to 4 categories: fat, parenchyma, clear cell renal cell carcinoma, and clear cell papillary renal cell carcinoma. The final output of our framework is an image map where each pixel is classified into one class. To maintain consistency, we processed the map with Gauss-Markov random field smoothing. Results: Our framework succeeded in classifying the four classes and showed superior performance compared to well-established state-of-the-art methods (pixel accuracy: 0.89 ResNet18, 0.92 proposed). Conclusions: Deep learning techniques have a significant potential for cancer diagnosis.Item A Simplified Diagnostic Approach on TFE3 Gene Fusion-Associated Renal Cell Carcinoma(Allen Press, 2020-11-04) Akgul, Mahmut; Cheng, Liang; Idrees, Muhammad; Urology, School of MedicineItem Aberrant ERG expression associates with downregulation of miR‐4638‐5p and selected genomic alterations in a subset of diffuse large B‐cell lymphoma(Wiley, 2019-10) Zhang, Shanxiang; Wang, Lin; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineERG (avian v‐ets erythroblastosis virus E26 oncogene homolog), an oncoprotein in prostate carcinoma and Ewing's sarcoma is associated with poor prognosis in patients with acute myeloid leukemia and T lymphoblastic leukemia. However little is known about ERG in lymphoma. Here we studied ERG in diffuse large B‐cell lymphoma (DLBCL) by immunohistochemistry, fluorescence in situ hybridization (FISH), genome‐wide microRNA (miRNA) expression profiling, real‐time reverse‐transcriptase polymerase chain reaction (RT‐PCR) and whole exome sequencing (WES). Approximately 30% of de novo DLBCLs (37 of 118) expressed ERG (ERG+). ERG expression showed no significant correlation with DLBCL cell‐of‐origin classification, patient's age, sex, nodal, or extranodal disease status, tumor expression of p53 or p63. There was no ERG rearrangement in 10 randomly selected ERG+ DLBCLs by FISH. Forty‐three miRNAs showed significant differential expression between ERG+ and ERG− DLBCLs. Downregulation of miR‐4638‐5p was confirmed by real‐time RT‐PCR. WES not only confirmed known gene mutations in DLBCLs but also revealed multiple novel gene mutations in POLA1, E2F1, PSMD8, AXIN1, GAB2, and GNB2L1, which occur more frequently in ERG+ DLBCLs. In conclusion, our studies demonstrated aberrant ERG expression in a subset of DLBCL, which is associated with downregulation of miR‐4638‐5p. In comparison with ERG‐negative DLBCL, ERG+ DLBCL more likely harbors mutations in genes important in cell cycle control, B‐cell receptor‐mediated signaling and degradation of β‐catenin. Further clinicopathological correlation and functional studies of ERG‐related miRNAs and pathways may provide new insight into the pathogenesis of DLBCL and reveal novel targets for better management of patients with DLBCL.Item Acoustofluidic assembly of primary tumor-derived organotypic cell clusters for rapid evaluation of cancer immunotherapy(BMC, 2023-02-04) Wu, Zhuhao; Ao, Zheng; Cai, Hongwei; Li, Xiang; Chen, Bin; Tu, Honglei; Wang, Yijie; Lu, Rongze Olivia; Gu, Mingxia; Cheng, Liang; Lu, Xin; Guo, Feng; Medicine, School of MedicineCancer immunotherapy shows promising potential for treating breast cancer. While patients may have heterogeneous treatment responses for adjuvant therapy, it is challenging to predict an individual patient’s response to cancer immunotherapy. Here, we report primary tumor-derived organotypic cell clusters (POCCs) for rapid and reliable evaluation of cancer immunotherapy. By using a label-free, contactless, and highly biocompatible acoustofluidic method, hundreds of cell clusters could be assembled from patient primary breast tumor dissociation within 2 min. Through the incorporation of time-lapse living cell imaging, the POCCs could faithfully recapitulate the cancer-immune interaction dynamics as well as their response to checkpoint inhibitors. Superior to current tumor organoids that usually take more than two weeks to develop, the POCCs can be established and used for evaluation of cancer immunotherapy within 12 h. The POCCs can preserve the cell components from the primary tumor due to the short culture time. Moreover, the POCCs can be assembled with uniform fabricate size and cell composition and served as an open platform for manipulating cell composition and ratio under controlled treatment conditions with a short turnaround time. Thus, we provide a new method to identify potentially immunogenic breast tumors and test immunotherapy, promoting personalized cancer therapy.Item Activating KRAS Mutations in Arteriovenous Malformations of the Brain: Frequency and Clinicopathologic Correlation(Elsevier, 2019) Priemer, David S.; Vortmeyer, Alexander O.; Zhang, Shaobo; Chang, Hsim Yee; Curless, Kendra L.; Cheng, Liang; Pathology and Laboratory Medicine, School of MedicineArteriovenous malformations (AVM) of the brain are considered congenital. Most AVMs are presumably sporadic, however rare familial cases occur and they may be observed in certain genetic disorders. We sought to determine the frequency of KRAS mutations and their association with clinicopathologic characteristics. We searched our neuropathology database from 2014–2017 for resected AVMs of the brain or dura mater. Twenty-one AVMs were tested (12 females, 9 males; average age: 32 years). KRAS mutations were found in 6/21 cases (28.5%). Five mutations were p.G12 V, and one p.G12C. The KRAS-mutant group contained 4 females and 2 males, with an average age of 28 years, compared to 34 years in the non-mutant group (P = .54). The average AVM size in the KRAS-mutant group was 3.9 cm, compared to 3.1 cm in the non-mutant group (P = .52). There were no histologic differences between KRAS-mutant and non-mutant cases. In summary, KRAS mutations occur in almost one third of brain AVMs. KRAS p.G12 V was the most common mutation identified. We also demonstrate the first reported instance of a KRAS p.G12C mutation in a brain AVM. The mean age of patients with KRAS-mutant AVMs was lower than the non-mutant group, and the mean size larger. Histologic characteristics were equally distributed between KRAS-mutant and non-mutant groups.Item Adjuvant therapy in renal cell carcinoma: is it the right strategy to inhibit VEGF?(AME Publishing, 2021-03) Mollica, Veronica; Rizzo, Alessandro; Di Nunno, Vincenzo; Santoni, Matteo; Cheng, Liang; Lopez-Beltran, Antonio; Scarpelli, Marina; Cimadamore, Alessia; Montironi, Rodolfo; Massari, Francesco; Pathology and Laboratory Medicine, School of MedicineDespite several clinical trials have assessed different agents in the adjuvant setting, renal cell carcinoma (RCC) still remains a disease orphan of an effective adjuvant treatment. In fact, systemic therapies targeting angiogenesis that have been observed to be effective in metastatic setting failed to show an improvement in terms of clinical outcomes when used ad adjuvant treatments. In this study, we performed a meta-analysis of 5 randomized clinical trials to assess the impact of tyrosine kinase inhibitors (TKIs) targeting angiogenesis after surgery: ASSURE, S-TRAC, PROTECT, ATLAS, SORCE. Among the 6,531 patients assessed, we confirmed the lack of efficacy of adjuvant treatments in terms of disease-free survival (DFS) (pooled-HR 0.93, 95% CI, 0.84–1.02, P=0.16) and overall survival (OS) (pooled-HR 0.98, 95% CI, 0.88–1.09, P=0.54). To the best of our knowledge, we still ignore why some treatments active in the metastatic setting do not show similar efficacy as adjuvant treatment. Exploring possible reasons of this apparently conflicting results is important as it may offer new insights that should be evaluated in next generation adjuvant trials. Immune checkpoint inhibitors (ICIs) have reported significant results—as monotherapy or in combinations with other anticancer agents—in metastatic setting, and the results of trials evaluating these agents in the adjuvant setting are awaited.Item Alternative lengthening of telomeres (ALT) influences survival in soft tissue sarcomas: a systematic review with meta-analysis(BMC, 2019-03-14) Lawlor, Rita T.; Veronese, Nicola; Pea, Antonio; Nottegar, Alessia; Smith, Lee; Pilati, Camilla; Demurtas, Jacopo; Fassan, Matteo; Cheng, Liang; Luchini, Claudio; Pathology and Laboratory Medicine, School of MedicineAlternative lengthening of telomeres (ALT) is a telomerase-independent mechanism used by a broad range of neoplasms to maintain telomere length, permitting uncontrolled replication during their progression. ALT has been described in different types of sarcoma, but a comprehensive analysis of its clinical significance is still lacking. Therefore, we provide here the first meta-analysis on this topic. METHODS: We searched SCOPUS and PubMed through July 2018 to identify all studies that investigated the prognostic role of ALT in sarcomas. We considered the risk of death (risk ratio, RR) calculated as the number of death vs. total participants during follow-up in ALT+ versus ALT- patients as the primary outcome. The secondary outcome was the hazard ratio (HR), adjusted for the maximum number of covariates available, using ALT- patients as reference. RESULTS: Eight articles comprising a total of 551 patients with sarcomas (226 ALT+ and 325 ALT-) were selected. The ALT+ group showed a higher mitotic count and a higher tumor grade compared with the ALT- group (p < 0.01). Furthermore, we demonstrate a strong impact of ALT on survival. In fact, ALT+ patients showed a statistically significant higher risk of death than ALT- patients, when also considering data from multivariate analyses (RR = 1.50; 95% CI: 1.15-1.96; p = 0.003; HR = 2.02; 95% CI: 1.22-3.38; p = 0.007). CONCLUSIONS: Our results indicate that ALT is associated with an increased risk of death in patients with sarcoma. In these neoplasms, ALT should be taken into account for a precise prognostic stratification and design of potential therapeutic strategies.Item Ambient ionization mass spectrometric analysis of human surgical specimens to distinguish renal cell carcinoma from healthy renal tissue(Springer, 2016-08) Alfaro, Clint M.; Jarmusch, Alan K.; Pirro, Valentina; Kerian, Kevin S.; Masterson, Timothy A.; Cheng, Liang; Cooks, R. Graham; Urology, School of MedicineTouch spray - mass spectrometry (TS-MS) is an ambient ionization technique (ionization of unprocessed samples in the open air) that may find intraoperative applications in quickly identifying the disease state of cancerous tissues and in defining surgical margins. In this study, TS-MS was performed on fresh kidney tissue (~1–5 cm3), within one hour of resection, from 21 human subjects afflicted by renal cell carcinoma (RCC). The preliminary diagnostic value of TS-MS data taken from freshly resected tissue was evaluated. Principal component analysis (PCA) of the negative ion mode (m/z 700–1000) data provided separation between RCC (16 samples) and healthy renal tissue (13 samples). Linear discriminant analysis (LDA) on the PCA compressed data estimated sensitivity (true positive rate) and specificity (true negative rate) of 98% and 95%, respectively, based on histopathological evaluation. The results indicate that TS-MS might provide rapid diagnostic information in spite of the complexity of unprocessed kidney tissue and the presence of interferences such as urine and blood. Desorption electrospray ionization imaging (DESI-MSI) in the negative ionization mode was performed on the tissue specimens after TS-MS analysis as a reference method. The DESI imaging experiments provided phospholipid profiles (m/z 700–1000) that also separated RCC and healthy tissue in the PCA space, with PCA-LDA sensitivity and specificity of 100% and 89%, respectively. The TS and DESI loading plots indicated that different ions contributed most to the separation of RCC from healthy renal tissue (m/z 794 [PC 34:1+Cl]− and 844 [PC 38:4+Cl]− for TS vs. m/z 788 [PS 36:1-H]− and 810 [PS 38:4-H]− for DESI), while m/z 885 ([PI 38:4-H]−) was important in both TS and DESI. The prospect, remaining hurdles, and future work required for translating TS-MS into a method of intraoperative tissue diagnosis is discussed.,Item Anaplastic Lymphoma Kinase Immunocytochemistry on Cell-Transferred Cytologic Smears of Lung Adenocarcinoma(Karger, 2015-03) Zhang, Chen; Randolph, Melissa L.; Jones, Kelly J.; Cramer, Harvey M.; Cheng, Liang; Wu, Howard H.; Department of Pathology and Laboratory Medicine, IU School of MedicineBackground: Anaplastic lymphoma kinase (ALK) immunohistochemical staining on formalin-fixed paraffin-embedded tissue or cell blocks (CB) has been reported as an effective alternative to fluorescence hybridization in situ (FISH) for the detection of ALK gene rearrangement. However, CB frequently lack adequate cellularity even when the direct smears are cellular. This study aims to assess the utility of ALK immunocytochemical (ICC) staining on direct smears using the cell transfer (CT) technique for the detection of ALK rearrangement. Methods: Fine-needle aspiration (FNA) cases of lung adenocarcinoma in which the ALK status had been determined by FISH on CB or a concurrent biopsy were identified. ICC staining for ALK was performed on alcohol-fixed Papanicolaou-stained direct smears using the CT technique. ALK immunoreactivity was evaluated using a modified semiquantitative scale. Results were compared with those of FISH. Results: A total of 47 FNA specimens were included. Five of 7 FISH-positive cases showed positive ALK ICC staining (71.4%), and 39 of 40 FISH-negative cases were negative on ALK ICC staining (97.5%). The overall correlation between ALK ICC and FISH was 93.6%. Conclusion: ICC performed on FNA smears using the CT technique is an alternative method for the assessment of ALK rearrangement, especially when CB lack adequate cellularity.Item Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications(MDPI, 2020-12) Aurilio, Gaetano; Cimadamore, Alessia; Mazzucchelli, Roberta; Lopez-Beltran, Antonio; Verri, Elena; Scarpelli, Marina; Massari, Francesco; Cheng, Liang; Santoni, Matteo; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of MedicineAround 80–90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient’s response to androgen ablation therapy is variable, and 20–30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.