Publications by authors named "Zaibo Li"

112 Publications

Quantitative Image Analysis for Tissue Biomarker Use: A White Paper From the Digital Pathology Association.

Appl Immunohistochem Mol Morphol 2021 Mar 17. Epub 2021 Mar 17.

GlaxoSmithKline-R&D, Cellular Biomarkers, Collegeville, PA The Ohio State University, Columbus, OH Visiopharm, Hoersholm, Denmark Translational Safety and Bioanalytical Sciences, Amgen Research, Amgen Inc. Moffitt Cancer Center, Tampa, FL Roche Tissue Diagnostics, Tucson, AZ Genentech, South San Francisco, CA PathAI, Boston, MA Johns Hopkins School of Medicine, Baltimore, MD Indica Labs, Albuquerque, NM Yale University School of Medicine, New Haven, CT Department of Pathology, University of Michigan, Ann Arbor, MI.

Tissue biomarkers have been of increasing utility for scientific research, diagnosing disease, and treatment response prediction. There has been a steady shift away from qualitative assessment toward providing more quantitative scores for these biomarkers. The application of quantitative image analysis has thus become an indispensable tool for in-depth tissue biomarker interrogation in these contexts. This white paper reviews current technologies being employed for quantitative image analysis, their application and pitfalls, regulatory framework demands, and guidelines established for promoting their safe adoption in clinical practice.
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http://dx.doi.org/10.1097/PAI.0000000000000930DOI Listing
March 2021

Breast HER2 Intratumoral Heterogeneity as a Biomarker for Improving HER2-Targeted Therapy.

Crit Rev Oncog 2020 ;25(3):233-240

Wexner Medical Center at The Ohio State University, Ohio, USA.

Development of HER2-targeted therapy drugs, particularly trastuzumab, demonstrated significant improvement of clinical outcomes among HER2 positive breast cancer patients during the last two decades. The exact biological mechanism of HER2 gene amplification occurrence remains unsolved. HER2 gene amplification and/or HER2 protein overexpression are the primary predictors for selecting invasive breast cancer patients as candidates for anti-HER2 agent-based chemotherapy protocol. However, HER2-targeted therapy is not completely successful: as it is well-documented, only one half of HER2 positive breast cancer patients achieve a pathological complete response after such a precision therapy. In the past, various HER2 drug resistance mechanisms were proposed for explaining incomplete the efficacy with anti-HER2 drugs. Recent studies suggested that HER2 intratumoral heterogeneity (ITH) determined by a concomitant HER2 gene and protein analyses are a significant primary resistance mechanism to HER2-targeted therapy. Recent discovery of undocumented "nonclassic" HER2-positive tumor cells with the amplified HER2 gene but no HER2 protein overexpression redefined HER2 ITH. The HER2 ITH consists of two groups of tumor heterogeneity subtypes: (1) genetic ITH (a mixture of HER2 negative tumor cells and classic HER2 positive tumor cells) and (2) nongenetic ITH (a mixture of classic HER2 positive tumor cells and nonclassic HER2 positive tumor cells). The mechanism underlining these nonclassic HER2 positive tumor cells with the amplified HER2 gene, but no HER2 protein overexpression, is unknown. Investigation of impaired HER2 and/or protein translation in these tumor cells could lead to a further improvement of cancer therapy by identifying new therapeutic targets for patients with HER2 ITH.
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http://dx.doi.org/10.1615/CritRevOncog.2020036150DOI Listing
January 2020

A solitary brain metastasis as the only site of recurrence of HR positive, HER2 negative breast cancer: a case report and review of the literature.

J Med Case Rep 2021 Jan 7;15(1). Epub 2021 Jan 7.

Division of Medical Oncology, The Ohio State University Wexner Medical Center, 1310D Lincoln Tower, 1800 Cannon Dr., Columbus, OH, 43210, USA.

Background: Breast cancer is one of the most common causes of brain metastases. However, the presence of isolated central nervous system (CNS) metastatic disease early in the course of disease relapse is a rare event in cases of hormone receptor positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer.

Case Presentation: We summarize the clinical course of a pre-menopausal, 39-year old Caucasian female with history of operable, hormone receptor positive, HER2 negative breast cancer who was initially treated with curative-intend therapy but who unfortunately developed solitary metastatic lesion in the left thalamus. A biopsy of the lesion confirmed the presence of hormone receptor positive, HER2 negative metastatic breast cancer. Patient's CNS metastases continued to progress without any evidence of metastatic disease outside of the central nervous system and she eventually passed away about 5 years after the date of her initial diagnosis and 18 months following the diagnosis with brain metastasis.

Conclusion: Based on our case, although rare, patients with treated, operable, hormone receptor positive, HER2 negative breast cancer can present with solitary brain metastasis as the only sign of disease recurrence.
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http://dx.doi.org/10.1186/s13256-020-02615-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789360PMC
January 2021

Breast Fine-Needle Aspiration Practice in 2019: Results of a College of American Pathologists National Survey.

Arch Pathol Lab Med 2020 Dec 22. Epub 2020 Dec 22.

The Department of Pathology, Ohio State University Medical Center, Columbus (Li).

Context.—: The College of American Pathologists surveys provide national benchmarks of pathology practice for laboratories.

Objective.—: To investigate breast fine-needle aspiration (FNA) biopsy practice in domestic and international laboratories in 2019.

Design.—: We analyzed data from the College of American Pathologists Breast FNA Practice Supplemental Questionnaire that was distributed to laboratories participating in the 2019 College of American Pathologists Non-Gynecologic Cytopathology Education Program.

Results.—: Sixty-one percent (499 of 816) of respondent laboratories routinely evaluated breast FNAs. Cystic lesions were the most common indication, and radiologists primarily performed FNAs in most settings. Forty-five percent (220 of 491) of laboratories performed ancillary studies on breast FNA samples, but 33.8% (70 of 207) did not report fixation time for breast biomarker studies. Only 54.5% (271 of 497) of laboratories had a standardized reporting system and only 16.8% (82 of 488) were aware of the International Academy of Cytology Yokohama Breast FNA Biopsy Cytology Reporting System. There were significant differences among different types of institutions in several aspects of breast FNA practice, including frequency of concurrent FNA and core needle biopsy for the same lesion, primary personnel who performed the FNA, etc. Significant differences existed between domestic and international laboratories in slide preparation, ancillary studies, fixation time reporting, standardized/descriptive diagnosis, and International Academy of Cytology Yokohama Reporting System awareness.

Conclusions.—: This is the first survey from the College of American Pathologists Cytopathology Committee to investigate breast FNA practices. The data reveal significant differences in breast FNA practice among different types of institutions and between domestic and international laboratories, and provide a baseline for future breast FNA studies in a variety of practice settings.
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http://dx.doi.org/10.5858/arpa.2020-0408-CPDOI Listing
December 2020

ESR1 genetic alterations and their association with clinicopathologic characteristics in advanced breast cancer: a single academic institution experience.

Hum Pathol 2021 Jan 4;107:80-86. Epub 2020 Nov 4.

Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, OH, USA. Electronic address:

Estrogen receptor (ER) alpha, a ligand-dependent nuclear transcription factor encoded by the ESR1 gene, is expressed in 70% of breast carcinomas (BCs) and is used as a target for endocrine-based therapies. However, some patients develop resistance to endocrine-based therapies due to ESR1 mutation, which leads to constitutive activation in the absence of ligand. We retrospectively analyzed 223 clinically advanced BCs using the FoundationOne CDX assay and found 13.9% (31/223) of cases had ESR1 genetic alterations (26 mutations and 5 amplifications). All ESR1 mutations occurred within the ligand binding domain, with the most prevalent being Y537S (42.3%) and D538G (38.5%), and all ESR1-mutated cases had a history of aromatase inhibitor use. No significant difference in clinicopathologic features was identified between ESR1-mutated and ESR1-amplified cases except higher frequency of HER2 positivity and TP53 mutations in ESR1-amplified cases. The prevalence of ESR1 mutations in ER-positive BCs was 19.1% (26/136). In comparison to ESR1-nonmutated ER-positive cases, ESR1-mutated cases demonstrated significantly higher percentage of tumor cells with ER and progesterone receptor expression, an increased tendency for overall distant metastasis and liver metastasis, higher frequency of FGF3/4/19 mutations, lower frequency of TP53 mutation, but no difference in overall survival and metastatic/recurrent intervals. In conclusion, our findings suggest that development of ESR1 mutations are selected for under the influence of estrogen deprivation, and a positive correlation between ESR1 mutations and ER protein expression may exist.
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http://dx.doi.org/10.1016/j.humpath.2020.10.007DOI Listing
January 2021

Interobserver agreement in programmed cell death-ligand 1 immunohistochemistry scoring in nonsmall cell lung carcinoma cytologic specimens.

Diagn Cytopathol 2021 Feb 26;49(2):219-225. Epub 2020 Oct 26.

Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, Ohio, USA.

Background: The evaluation of PD-L1 expression in nonsmall cell lung carcinoma (NSCLC) is becoming increasingly important given the effectiveness of PD-L1 inhibitors. Although cytologic specimens have been shown to be compatible with surgical specimens to evaluate PD-L1 immunohistochemistry (IHC), evidence of the reproducibility of PD-L1 in cytologic specimens is lacking. The aim of this study is to evaluate interobserver agreement in PD-L1 IHC in cytologic specimens.

Methods: PD-L1 IHC was performed on 86 NSCLC cytology specimens using Dako PD-L1 IHC 22C3 pharmDx. The digitally scanned whole slide images (WSI) were read by five pathologists. Each case was given a Tumor Proportion Score (TPS) and the results were compared between the observers. The interobserver concordance was assessed using 1% and 50% as cutoffs.

Results: TPSs were highly correlated among observers (Spearman correlation coefficient, 0.86-0.94). Using greater than 1% as a cutoff, interobserver agreement measured by Fleiss Kappa was 0.74 for all pathologists and Cohen's Kappa coefficient ranged from 0.49 to 0.83, consistent with moderate to substantial agreement. With a cutoff of greater than 50%, Fleiss Kappa was 0.79 for all pathologists and the kappa values ranged from 0.63 to 0.90, consistent with substantial to almost perfect agreement. Several pitfalls were identified by reviewing discordant cases, including staining in macrophages, stromal cells, and intratumoral heterogeneity.

Conclusion: Our data suggest that TPS of PD-L1 IHC on cytology specimens is reproducible, with a better agreement when using 50% as the cutoff value. However, special attention is required when the TPS is near the 1% cutoff.
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http://dx.doi.org/10.1002/dc.24651DOI Listing
February 2021

HER2 immunohistochemistry staining positivity is strongly predictive of tumor response to neoadjuvant chemotherapy in HER2 positive breast cancer.

Pathol Res Pract 2020 Nov 10;216(11):153155. Epub 2020 Aug 10.

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, United States. Electronic address:

Background: The current recommendation is to reflex test HER2 immunohistochemistry (IHC) equivocal breast cancer cases with fluorescence in situ hybridization (FISH) analysis. Either IHC 3+ or FISH positive cancers are considered HER2 positive (HER2+) and treated with HER2 targeted therapy. This study examined the predictive value of HER IHC or FISH positivity in tumor response to HER2 targeted therapy.

Methods: Biopsies of 76 HER2+ breast cancer cases were evaluated. All patients were treated with neoadjuvant HER2 targeted therapy and chemotherapy. Tumor response was evaluated on the excisional specimens. Cancers with complete pathologic response (pCR) or MD Anderson residual cancer burden-I (RCB-I) were classified as responders and cancers with RCB-II/III as non-responders. Clinicopathologic parameters were correlated with response.

Results: In univariate analysis, small tumor size, low nuclear grade, high Ki67, HER2 IHC 3+, homogenous strong HER2 IHC staining, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with pCR/RCB-I. In multivariate analysis, homogenous strong HER2 IHC staining pattern was significantly associated with pCR/RCB-I. The receiver operating characteristics (ROC) model showed either high HER2/CEP17 ratio or HER2 copy number individually was predictive of tumor response.

Conclusion: HER2 IHC staining pattern is significantly associated with tumor response to neoadjuvant chemotherapy, reiterating the importance of HER2 IHC evaluation. The ROC model shows either high HER2/CEP17 ratio or high HER2 copy number individually is predictive of tumor response to neoadjuvant HER2 targeted therapy in HER2+ breast cancer.
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http://dx.doi.org/10.1016/j.prp.2020.153155DOI Listing
November 2020

Magee Equations™ and response to neoadjuvant chemotherapy in ER+/HER2-negative breast cancer: a multi-institutional study.

Mod Pathol 2021 01 13;34(1):77-84. Epub 2020 Jul 13.

John A. Burns University of Hawaii Cancer Center, Honolulu, HI, USA.

Magee Equations™ (ME) are multivariable models that can estimate oncotype DX recurrence score. One of the equations, Magee Equation 3 (ME3) which utilizes only semi-quantitative receptor results has been shown to provide chemopredictive value in the neoadjuvant setting in a single institutional study. This multi-institutional study (seven institutions contributed cases) was undertaken to examine the validity of ME3 in predicting response to neoadjuvant chemotherapy in estrogen receptor positive, HER2-negative breast cancers. Stage IV cases were excluded. The primary endpoint was the pathologic complete response (pCR) rate in different categories of ME3 scores calculated based on receptor results in the pre-therapy core biopsy. A total of 166 cases met the inclusion criteria. The patient age ranged from 24 to 83 years (median 53 years). The average pre-therapy tumor size was 3.9 cm, and axillary lymph nodes were confirmed positive by pre-therapy core biopsy in 85 of 166 cases (51%). The pCR rate according to ME3 scores was 0% (0 of 64) in ME3 < 18, 0% (0 of 46) in ME3 18-25, 14% (3 of 21) in ME3 > 25 to <31, and 40% (14 of 35) in ME3 score 31 or higher (p value: <0.0001). There were no distant recurrences and no deaths in the 17 patients with pCR. In the remaining 149 cases with residual disease, ME3 score of >25 was significantly associated with shorter distant recurrence-free survival and showed a trend for shorter breast cancer-specific survival. The results of this multi-institutional study are similar to previously published data from a single institution (PMID: 28548119) and confirm the chemo-predictive value of ME3 in the neoadjuvant setting. In addition, ME3 may provide prognostic information in patients with residual disease which should be further evaluated.
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http://dx.doi.org/10.1038/s41379-020-0620-2DOI Listing
January 2021

Features, Outcomes, and Management Strategies of Male Breast Cancer: A Single Institution Comparison to Well-Matched Female Controls.

Eur J Breast Health 2020 Jul 20;16(3):201-207. Epub 2020 May 20.

Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, USA.

Objective: The primary objective of this study was to delineate differences in management, overall and distant disease-free survival in males diagnosed with breast cancer and treated at The Ohio State University Comprehensive Cancer Center as compared to comprehensively matched female subjects. Secondary objectives included assessment of clinical and histopathologic features and recurrence score, as measured by Oncotype DX and the modified Magee equation #2.

Materials And Methods: This single institution retrospective study compared male and comprehensively matched female patients (1:2) with stage I-III breast cancer between 1994 and 2014. Recurrence risk was estimated using a modified Magee equation. Overall survival and distant disease-free survival were estimated and compared using Kaplan-Meier and Log-rank methods.

Results: Forty-five male breast cancer patients were included (stage I: 26.7%; stage II: 53.3%; stage III: 20.0%; hormone receptor positive: 97.8%; human epidermal growth factor receptor 2 negative: 84.4%) with a median age of 63.8 (43.0-79.4) years at diagnosis. Intermediate and low recurrence scores were most common in male and female patients respectively; mean score was similar between groups (20.3 vs. 19.8). The proportion of male breast cancer patients treated with adjuvant chemotherapy and post-mastectomy radiation was lower compared to female patients (42.2% vs. 65.3%, p=0.013; 22.7% vs. 44.4%, p=0.030, respectively). Overall survival and distant disease-free survival between male and female patients were similar.

Conclusion: Male breast cancer patient outcomes were similar compared to well-matched female patients suggesting that breast cancer specific factors are more prognostic than gender.
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http://dx.doi.org/10.5152/ejbh.2020.5536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337913PMC
July 2020

A Genome-Wide Pooled shRNA Screen Identifies PPP2R2A as a Predictive Biomarker for the Response to ATR and CHK1 Inhibitors.

Cancer Res 2020 08 10;80(16):3305-3318. Epub 2020 Jun 10.

Department of Radiation Oncology, The Ohio State University James Comprehensive Cancer Center and College of Medicine, Ohio.

There is currently a lack of precise predictive biomarkers for patient selection in clinical trials of inhibitors targeting replication stress (RS) response proteins ATR and CHK1. The objective of this study was to identify novel predictive biomarkers for the response to these agents in treating non-small cell lung cancer (NSCLC). A genome-wide loss-of-function screen revealed that tumor suppressor PPP2R2A, a B regulatory subunit of protein phosphatase 2 (PP2A), determines sensitivity to CHK1 inhibition. A synthetic lethal interaction between PPP2R2A deficiency and ATR or CHK1 inhibition was observed in NSCLC and and was independent of p53 status. ATR and CHK1 inhibition resulted in significantly increased levels of RS and altered replication dynamics, particularly in PPP2R2A-deficient NSCLC cells. Mechanistically, PPP2R2A negatively regulated translation of oncogene c-Myc protein. c-Myc activity was required for PPP2R2A deficiency-induced alterations of replication initiation/RS and sensitivity to ATR/CHK1 inhibitors. We conclude that PPP2R2A deficiency elevates RS by upregulating c-Myc activity, rendering cells reliant on the ATR/CHK1 axis for survival. Our studies show a novel synthetic lethal interaction and identify PPP2R2A as a potential new predictive biomarker for patient stratification in the clinical use of ATR and CHK1 inhibitors. SIGNIFICANCE: This study reveals new approaches to specifically target PPP2R2A-deficient lung cancer cells and provides a novel biomarker that will significantly improve treatment outcome with ATR and CHK1 inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518641PMC
August 2020

Review of different platforms to perform rapid onsite evaluation via telecytology.

Authors:
Keluo Yao Zaibo Li

Cytopathology 2020 09 5;31(5):379-384. Epub 2020 Jul 5.

Deparment of Pathology, The Ohio State Unversity, Columbus, Ohio, USA.

There is increased utilisation of cytopathology to provide a rapid onsite evaluation (ROSE) of fine needle aspiration and touch preparations of small biopsies. A well-executed ROSE procedure can significantly impact the diagnostic quality and appropriate specimen triage of procured biopsy materials. To accommodate the demand for ROSE, telecytology has been increasingly implemented to facilitate ROSE occurring remotely. Telecytology can be categorised based on camera systems including eyepiece system, camera port system and robotic microscope/whole slide image scanner system. Image sharing methods include static images, broadcast only live video streaming, teleconferencing and whole slide image management system. In this review, we will discuss the advantages and disadvantages of each of these systems and deployment considerations.
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http://dx.doi.org/10.1111/cyt.12871DOI Listing
September 2020

Genetic alterations and their association with clinicopathologic characteristics in advanced breast carcinomas: focusing on clinically actionable genetic alterations.

Hum Pathol 2020 08 21;102:94-103. Epub 2020 May 21.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA. Electronic address:

Breast carcinomas (BCs) are genetically heterogeneous and associated with numerous mutations which can be used to predict outcomes and initiate targeted therapies. We investigated clinicopathologic characteristics associated with gene mutations detected using the FoundationOne CDx assay in a cohort of 223 clinically advanced BCs (66 locally recurrent and 157 metastatic) from our institution. One hundred fifty unique mutations were identified (total 1008) in the cohort, with the most prevalent (>10%) including TP53 (53.8%), PIK3CA (35%), MYC (22%), CCND1 (19.7%), FGF19 (19.7%), FGF4 (16.6%), FGF3 (16.1%), ZNF703 (14.8%), ESR1 (13.9%), FGFR1 (13.5%), PTEN (12.1%), and CDH1 (10.8%). ERBB2 genetic alteration was most common in human epidermal growth factor receptor 2 (HER2)-positive BCs, and GATA3 and ESR1 mutations were only identified in hormone receptor-positive BC. Mutations enriched in triple-negative BCs (TNBCs) included TP53, PTEN, RB1, and CDKN2A/B. CDH1 mutation was predominantly found in lobular carcinomas, and PIK3CA mutation was also enriched. Mutations enriched in metaplastic carcinomas with heterologous mesenchymal differentiation included TP53, PTEN, MCL1, CDKN2A/B, and NOTCH2. An increase in mutations of CCND1, FGF19, FGF4, FGF3, ESR1, and EMSY was identified in metastatic BCs compared with locally recurrent BCs. Overall, PIK3CA was the most frequent clinically actionable genetic alteration (35%), followed by MYC (22%), CCND1 (19.7%), and FGF3/FGF4/FGFR1 (16%). In conclusion, our study provides genetic insight into the biology of advanced BCs and summarizes their most frequent clinically actionable genetic alterations, generating useful genomic information for potential improvement of patient management.
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http://dx.doi.org/10.1016/j.humpath.2020.05.005DOI Listing
August 2020

Exploratory analysis of immune checkpoint receptor expression by circulating T cells and tumor specimens in patients receiving neo-adjuvant chemotherapy for operable breast cancer.

BMC Cancer 2020 May 19;20(1):445. Epub 2020 May 19.

The Ohio State University Comprehensive Cancer Center, The Ohio State University, 410 W 12th Avenue, Columbus, OH, 43210, USA.

Background: While combinations of immune checkpoint (ICP) inhibitors and neo-adjuvant chemotherapy (NAC) have begun testing in patients with breast cancer (BC), the effects of chemotherapy on ICP expression in circulating T cells and within the tumor microenvironment are still unclear. This information could help with the design of future clinical trials by permitting the selection of the most appropriate ICP inhibitors for incorporation into NAC.

Methods: Peripheral blood samples and/or tumor specimens before and after NAC were obtained from 24 women with operable BC. The expression of CTLA4, PD-1, Lag3, OX40, and Tim3 on circulating T lymphocytes before and at the end of NAC were measured using flow cytometry. Furthermore, using multi-color immunohistochemistry (IHC), the expression of immune checkpoint molecules by stromal tumor-infiltrating lymphocytes (TILs), CD8+ T cells, and tumor cells was determined before and after NAC. Differences in the percentage of CD4+ and CD8+ T cells expressing various checkpoint receptors were determined by a paired Student's t-test.

Results: This analysis showed decreased ICP expression by circulating CD4+ T cells after NAC, including significant decreases in CTLA4, Lag3, OX40, and PD-1 (all p values < 0.01). In comparison, circulating CD8+ T cells showed a significant increase in CTLA4, Lag3, and OX40 (all p values < 0.01). Within tumor samples, TILs, CD8+ T cells, and PD-L1/PD-1 expression decreased after NAC. Additionally, fewer tumor specimens were considered to be PD-L1/PD-1 positive post-NAC as compared to pre-NAC biopsy samples using a cutoff of 1% expression.

Conclusions: This work revealed that NAC treatment can substantially downregulate CD4+ and upregulate CD8+ T cell ICP expression as well as deplete the amount of TILs and CD8+ T cells found in breast tumor samples. These findings provide a starting point to study the biological significance of these changes in BC patients.

Trial Registration: NCT04022616.
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http://dx.doi.org/10.1186/s12885-020-06949-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236344PMC
May 2020

High tumor mutation burden is associated with DNA damage repair gene mutation in breast carcinomas.

Diagn Pathol 2020 May 11;15(1):50. Epub 2020 May 11.

Department of Pathology, The Ohio State University Wexner Medical Center, 410 W. 10th Ave, Columbus, 43210, OH, USA.

Background: Immunotherapy has demonstrated encouraging clinical benefits in patients with advanced breast carcinomas and Programmed death ligand 1 (PD-L1) expression has been proposed as an immunotherapy biomarker. Challenges with current PD-L1 testing exist and tumor mutation burden (TMB) is emerging as a biomarker to predict clinical response to immunotherapy in melanoma and non-small cell lung cancer patients. However, TMB has not been well characterized in breast carcinomas.

Methods: The study cohort included 62 advanced breast cancer patients (13 primary and 49 metastatic). Genetic alterations and TMB were determined by FoundationOne CDx next generation sequencing (NGS) and the association with clinicopathologic features was analyzed.

Results: High TMB was observed in a relatively low frequency (3/62, 4.8%). TMB levels were positively associated tumor infiltrating lymphocytes and significantly higher TMB was observed in breast carcinomas with DNA damage repair gene mutation(s). There was no significant association between TMB levels and other analyzed clinicopathologic characteristics.

Conclusions: Our data indicate the importance of DNA damage repair proteins in maintaining DNA integrity and immune reaction and breast carcinoma patients with DDR mutation may benefit from immunotherapy.
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http://dx.doi.org/10.1186/s13000-020-00971-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212599PMC
May 2020

HER2 intratumoral heterogeneity is independently associated with distal metastasis and overall survival in HER2-positive breast carcinomas.

Breast Cancer Res Treat 2020 Jun 25;181(3):519-527. Epub 2020 Apr 25.

Department of Pathology, Wexner Medical Center at The Ohio State University, 410 W. 10th Ave, Columbus, OH, 43210, USA.

Purpose: Human epidermal growth factor receptor 2 (HER2) intratumoral heterogeneity (ITH) occurs in a subset of breast cancers. Our recent study revealed it as an independent predictive factor for the response to anti-HER2 neoadjuvant therapy. In this study, we aimed to investigate its association with distal metastasis.

Methods: HER2 ITH was assessed using HER2 gene protein assay (GPA) on whole tissue sections of pretreatment biopsies from a cohort of 158 HER2-positive invasive breast carcinomas and correlated with patients' clinical follow-up outcomes along with other clinicopathologic characteristics.

Results: Fifty-seven cases (36%) showed HER2 ITH including 19 with genetic, 8 with both genetic and non-genetic, and 30 with non-genetic ITH. Multivariate analysis demonstrated larger tumor size, positive resected lymph node(s), negative PR, and the presence of HER2 ITH were independently associated with distal metastasis. Additionally, multivariate analysis demonstrated larger tumor size and the presence of HER2 ITH were the only independent factors associated with decreased overall survival (death).

Conclusion: The presence of HER2 ITH is an independent factor associated with poor overall survival and increased distal metastasis in HER2-positive breast cancer patients.
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http://dx.doi.org/10.1007/s10549-020-05650-1DOI Listing
June 2020

Stromal Platelet-Derived Growth Factor Receptor-β Signaling Promotes Breast Cancer Metastasis in the Brain.

Cancer Res 2021 Feb 23;81(3):606-618. Epub 2020 Apr 23.

The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Platelet-derived growth factor receptor-beta (PDGFRβ) is a receptor tyrosine kinase found in cells of mesenchymal origin such as fibroblasts and pericytes. Activation of this receptor is dependent on paracrine ligand induction, and its preferred ligand PDGFB is released by neighboring epithelial and endothelial cells. While expression of both PDGFRβ and PDGFB has been noted in patient breast tumors for decades, how PDGFB-to-PDGFRβ tumor-stroma signaling mediates breast cancer initiation, progression, and metastasis remains unclear. Here we demonstrate this paracrine signaling pathway that mediates both primary tumor growth and metastasis, specifically, metastasis to the brain. Elevated levels of PDGFB accelerated orthotopic tumor growth and intracranial growth of mammary tumor cells, while mesenchymal-specific expression of an activating mutant PDGFRβ (PDGFRβ) exerted proproliferative signals on adjacent mammary tumor cells. Stromal expression of PDGFRβ also promoted brain metastases of mammary tumor cells expressing high PDGFB when injected intravenously. In the brain, expression of PDGFRβ was observed within a subset of astrocytes, and aged mice expressing PDGFRβ exhibited reactive gliosis. Importantly, the PDGFR-specific inhibitor crenolanib significantly reduced intracranial growth of mammary tumor cells. In a tissue microarray comprised of 363 primary human breast tumors, high PDGFB protein expression was prognostic for brain metastases, but not metastases to other sites. Our results advocate the use of mice expressing PDGFRβ in their stromal cells as a preclinical model of breast cancer-associated brain metastases and support continued investigation into the clinical prognostic and therapeutic use of PDGFB-to-PDGFRβ signaling in women with breast cancer. SIGNIFICANCE: These studies reveal a previously unknown role for PDGFB-to-PDGFRβ paracrine signaling in the promotion of breast cancer brain metastases and support the prognostic and therapeutic clinical utility of this pathway for patients..
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http://dx.doi.org/10.1158/0008-5472.CAN-19-3731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581545PMC
February 2021

Cytopathology of Xp11 translocation renal cell carcinoma: a report of 5 cases.

J Am Soc Cytopathol 2020 Mar - Apr;9(2):95-102. Epub 2020 Jan 28.

Department of Pathology, The Ohio State University College of Medicine, Wexner Medical Center, Columbus, Ohio. Electronic address:

Introduction: Xp11.2 translocation-associated RCC (Xp11RCC) defined by molecular alterations involving TFE3 genetic rearrangements constitutes a large percentage of primary renal neoplasms in children, but less than 4% of adult cases. Fewer than 10 single case reports constitute the English cytopathology literature regarding this neoplasm. Our objective is to describe and illustrate the cytopathology of this uncommon renal neoplasm from a series of 5 cases using cytologic imprints, effusion specimens, and fine-needle aspiration (FNA) cytology.

Materials And Methods: Review was made of our cytopathology and surgical pathology databases. FNA biopsy smears and imprint smears were performed using a standard technique. Effusion samples were processed using liquid-based slides.

Results: Five cytologic specimens from 4 patients with histopathologically confirmed Xp11RCC were identified (mean age: 36 years) over a period of 7 years. All cases contained large cells with voluminous amounts of vacuolated cytoplasm arranged in non-descript clusters and as single forms. A "tigroid" pattern consisting of linear strips of detached cytoplasm was seen in both imprint smear cases and the single FNA case. Psammomatous calcifications, true papillary structures, and hyaline globules were absent in all cases. Four examples were diagnosed as Xp11RCC, but 3 represented metastatic disease, and 1 was diagnosed using both cytology and core needle tissue histopathology. The remaining case was diagnosed nonspecifically as a clear cell malignant neoplasm.

Conclusions: The cytopathologic features of Xp1RCC are relatively nonspecific, and overlap with other renal cell carcinoma subtypes. A definitive diagnosis is only possible with ancillary immunohistochemistry with or without additional TFE3 fluorescence in situ hybridization.
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http://dx.doi.org/10.1016/j.jasc.2019.10.005DOI Listing
January 2020

Assessment of outcomes and novel immune biomarkers in metaplastic breast cancer: a single institution retrospective study.

World J Surg Oncol 2020 Jan 14;18(1):11. Epub 2020 Jan 14.

Stefanie Spielman Comprehensive Breast Cancer, The Ohio State University, Columbus, OH, USA.

Background: Metaplastic breast cancer remains poorly characterized given its rarity and heterogeneity. The majority of metaplastic breast cancers demonstrate a phenotype of triple-negative breast cancer; however, differences in clinical outcomes between metaplastic breast cancer and triple-negative breast cancer in the era of third-generation chemotherapy remain unclear.

Methods: We compared the clinical outcomes between women with metaplastic breast cancer and women with triple-negative breast cancer diagnosed between 1994 and 2014. Metaplastic breast cancer patients were matched 1:3 to triple-negative breast cancer patients by stage and age at diagnosis. Distant disease-free survival (DDFS) and overall survival (OS) were estimated using Kaplan Meier methods and Cox proportional hazard regression models. Immune checkpoint markers were characterized by immunohistochemistry in a subset of samples.

Results: Forty-four metaplastic breast cancer patients (stage I 14%; stage II 73%; stage III 11%; stage IV 2%) with an average age of 55.4 (± 13.9) years at diagnosis. Median follow-up for the included metaplastic breast cancer and triple-negative breast cancer patients (n = 174) was 2.8 (0.1-19.0) years. The DDFS and OS between matched metaplastic breast cancer and triple-negative breast cancer patients were similar, even when adjusting for clinical covariates (DDFS: HR = 1.64, p = 0.22; OS: HR = 1.64, p = 0.26). Metaplastic breast cancer samples (n = 27) demonstrated greater amount of CD163 in the stroma (p = 0.05) and PD-L1 in the tumor (p = 0.01) than triple-negative breast cancer samples (n = 119), although more triple-negative breast cancer samples were positive for CD8 in the tumor than metaplastic breast cancer samples (p = 0.02).

Conclusions: Patients with metaplastic breast cancer had similar outcomes to those with triple-negative breast cancer based on DDFS and OS. The immune checkpoint marker profile of metaplastic breast cancers in this study may prove useful in future studies attempting to demonstrate an association between immune profile and survival.
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http://dx.doi.org/10.1186/s12957-019-1780-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961248PMC
January 2020

Clinicopathologic Factors Associated With Response to Neoadjuvant Anti-HER2-Directed Chemotherapy in HER2-Positive Breast Cancer.

Clin Breast Cancer 2020 02 18;20(1):19-24. Epub 2019 Sep 18.

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA. Electronic address:

Background: HER2-targeted neoadjuvant therapy has high efficacy in treating HER2-positive breast cancer. Response to neoadjuvant therapy helps clinicians make treatment decisions and make estimates about prognosis. This study examined clinicopathologic features to determine which may be most predictive of response to neoadjuvant therapy in HER2 breast cancer.

Patients And Methods: Patients with HER2 breast cancer (n = 173) who had an initial biopsy performed between 2010 and 2016 were identified at our institution. Tumor response was evaluated on excisional specimens using the MD Anderson residual cancer burden (RCB) classification. Tumors with pathologic complete response (defined as no residual invasive carcinoma in the breast and lymph nodes) and RCB-I were classified as having response and tumors with RCB-II and -III as having no response. Patient age, tumor size, nuclear grade (1/2 vs. 3), mitosis, Nottingham grade, HER2 immunohistochemistry (1/2+ vs. 3+), HER2/CEP17 (chromosome enumeration probe 17) ratio, HER2 copy number, estrogen receptor, progesterone receptor, Ki-67, and tumor-infiltrating lymphocytes (TIL) were evaluated and correlated with response. TILs were evaluated for an average and also for the hot spot/total tumor stromal ratio.

Results: Small tumor size, low estrogen receptor and progesterone receptor expression, HER2 immunohistochemistry 3+, high Ki-67, high HER2/CEP17 ratio, and high HER2 copy number were significantly associated with response (all P < .05). TIL hot spot was associated with RCB in univariate (P < .05) but not multivariate analyses.

Conclusion: Clinicopathologic features may help predict HER2 breast cancer response to neoadjuvant therapy. Larger studies would be useful to confirm these associations, which may have relevance to clinical practice.
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http://dx.doi.org/10.1016/j.clbc.2019.09.003DOI Listing
February 2020

The Differential Diagnosis of Reparative Changes and Malignancy: Performance in the College of American Pathologists Pap Education and Proficiency Testing Programs.

Arch Pathol Lab Med 2020 Jul;144(7):846-852

From the Department of Pathology, University of Maryland School of Medicine, Baltimore (Dr Staats); Statistics/Biostatistics (Ms Souers) and Surveys Department (Ms Goodrich), College of American Pathologists, Northfield, Illinois; Pathology Group of Louisiana, Baton Rouge (Dr Nunez); the Department of Pathology, Ohio State University Wexner Medical Center, Columbus (Dr Li); the Department of Pathology and Laboratory Medicine and Wisconsin State Laboratory of Hygiene, University of Wisconsin - Madison, Madison (Dr Kurtycz); the Department of Pathology, Huntsman Cancer Hospital, Salt Lake City, Utah (Dr Witt); the Department of Clinical Sciences, University of Central Florida College of Medicine, Orlando (Dr Davey); and the Department of Pathology, Cleveland Clinic, Cleveland, Ohio (Dr Booth).

Context.—: Repair is a challenging diagnosis and a significant source of false-positive (FP) interpretations in cervical cytology. No large-scale study of performance of repair in the liquid-based era has been performed.

Objective.—: To evaluate the performance of repair in the College of American Pathologists Pap Education and Proficiency Testing (PT) programs.

Design.—: The FP rate for slides classified as repair was evaluated by preparation type, participant type (cytotechnologist, pathologist, or laboratory), and program. The specific misdiagnosis category and individual slide performance were also evaluated. The rate of misclassification of slides as repair by participants for other diagnostic categories in the Pap Education program was assessed.

Results.—: The overall FP rate was 1700 of 12 715 (13.4%). There was no significant difference by program or preparation type. Within the Education program there was no difference by participant type, but pathologists' FP rate in the PT program (47 of 514, 9.1%) was significantly better than cytotechnologists in the PT program (51 of 380, 13.4%) and pathologists in the Education program (690 of 4900, 14.1%). High-grade squamous intraepithelial lesions/cancers (HSIL+) accounted for 1380 of 1602 FP interpretations (86%) in Education, but 43 of 98 (43.9%) in PT. Most slides had a low rate of misclassification, but a small number were poor performers. False-negative diagnosis of HSIL+ as repair was less common, ranging from 0.7% to 1.8%.

Conclusions.—: Despite initial indications that liquid-based cytology might reduce the rate of misclassification of repair, FP interpretations remain common and are no different by preparation type. Misclassification is most commonly as HSIL or carcinoma, potentially resulting in significant patient harm.
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http://dx.doi.org/10.5858/arpa.2019-0298-CPDOI Listing
July 2020

The reporting rates of atypical glandular cells and their HPV testing and histologic follow-up results: a comparison between ThinPrep and SurePath preparations from a single academic institution.

J Am Soc Cytopathol 2019 May - Jun;8(3):128-132. Epub 2018 Nov 29.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address:

Introduction: The interpretation of atypical glandular cells (AGCs) remains a major challenge in gynecologic cytopathology using liquid-based cytology (LBC) (ThinPrep and SurePath). The comparison of performance of detecting glandular abnormalities using these 2 methods is lacking. We investigated the reporting rates of AGCs, human papillomavirus (HPV) testing, and histologic follow-up results in ThinPrep (TP) and SurePath (SP) samples.

Materials And Methods: In our institution, both TP and SP were utilized during the period between January 2014 and June 2017. A retrospective search was conducted to identify patients with AGCs from 58,591 LBCs (27,041 TP and 31,550 SP). Roche (Pleasanton, CA) cobas HPV testing and histologic follow-up results were collected.

Results: The reporting rates of AGCs for TP (0.7%) or SP (0.2%) were within the College of American Pathologists benchmark ranges, but the reporting for TP was significantly greater than that for SP (P < 0.0001). The HPV-positive rates were 26.0% and 19.4% in TP-AGCs and SP-AGCs, respectively, with no statistical significance. A total of 137 (74.9%) TP-AGCs and 54 (74%) SP-AGCs had histologic follow-up. High-grade squamous intraepithelial lesions (HSIL)/squamous cell carcinoma were identified in 8.8% (12 of 137) of TP-AGCs and 13% (7 of 54) of SP-AGCs. Adenocarcinomas including endocervical and endometrial adenocarcinomas were identified in 9.5% (13 of 137) of TP-AGCs and 13% (7 of 54) of SP-AGCs. Together, 18.2% (25 of 137) of TP-AGCs and 25.9% (14 of 54) of SP-AGCs showed either HSIL or carcinoma in histologic follow-up, but with no statistical significance.

Conclusions: TP preparation detected considerably more AGCs than SP preparation. There was no statistical significant difference in HPV-positive rates or histologic follow-up outcomes between TP-detected AGCs and SP-detected AGCs.
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http://dx.doi.org/10.1016/j.jasc.2018.11.003DOI Listing
May 2020

The Immune Microenvironment in Hormone Receptor-Positive Breast Cancer Before and After Preoperative Chemotherapy.

Clin Cancer Res 2019 08 6;25(15):4644-4655. Epub 2019 May 6.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Hormone receptor-positive/HER2-negative (HR/HER2) breast cancer is associated with low levels of stromal tumor-infiltrating lymphocytes (sTIL) and PD-L1, and demonstrates poor responses to checkpoint inhibitor therapy. Evaluating the effect of standard chemotherapy on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches to treating HR/HER2 breast tumors.

Experimental Design: HR/HER2 breast tumors were analyzed before and after neoadjuvant chemotherapy. sTIL were assessed histologically; CD8 cells, CD68 cells, and PD-L1 staining were assessed immunohistochemically; whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed.

Results: Ninety-six patients were analyzed from two cohorts ( = 55, Dana-Farber cohort; = 41, MD Anderson cohort). sTIL, CD8, and PD-L1 on tumor cells were higher in tumors with basal PAM50 intrinsic subtype. Higher levels of tissue-based lymphocyte (sTIL, CD8, PD-L1) and macrophage (CD68) markers, as well as gene expression markers of lymphocyte or macrophage phenotypes (NanoString or CIBERSORT), correlated with favorable response to neoadjuvant chemotherapy, but not with improved distant metastasis-free survival in these cohorts or a large gene expression dataset ( = 302). In paired pre-/postchemotherapy samples, sTIL and CD8 cells were significantly decreased after treatment, whereas expression analyses (NanoString) demonstrated significant increase of multiple myeloid signatures. Single gene expression implicated increased expression of immunosuppressive (M2-like) macrophage-specific genes after chemotherapy.

Conclusions: The immune microenvironment of HR/HER2 tumors differs according to tumor biology. This cohort of paired pre-/postchemotherapy samples suggests a critical role for immunosuppressive macrophage expansion in residual disease. The role of macrophages in chemoresistance should be explored, and further evaluation of macrophage-targeting therapy is warranted.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677598PMC
August 2019

Programmed cell death ligand 1 expression in cytologic and surgical non-small cell lung carcinoma specimens from a single institution: Association with clinicopathologic features and molecular alterations.

Cancer Cytopathol 2019 07 26;127(7):447-457. Epub 2019 Apr 26.

Department of Pathology, Ohio State University Wexner Medical Center, Columbus, Ohio.

Background: Programmed cell death ligand 1 (PD-L1) expression by the 22C3 pharmDx companion assay has been validated in surgical specimens to support pembrolizumab treatment decisions for patients with non-small cell lung carcinoma (NSCLC). The aims of this study were 1) to assess the adequacy of cytologic specimens for PD-L1 evaluation and 2) to explore correlations of PD-L1 expression with clinicopathologic and molecular features.

Methods: The study cohort included 100 cytology specimens (fluid [n = 28] and fine-needle aspiration [n = 72]) and 165 surgical specimens (biopsy [n = 138] and resection [n = 27]). The PD-L1 immunohistochemistry 22C3 assay and staining assessment were performed according to the manufacturer's instructions. PD-L1 expression was correlated with patients' demographics, pathologic characteristics, and molecular alterations.

Results: One hundred forty-two specimens (53.6%) were positive for PD-L1 expression (≥1%). No statistically significant difference in PD-L1 expression was identified between cytologic (56.0%) and surgical specimens (52.1%). Seventy-four of 190 tested cases (38.9%) had genetic alterations. PD-L1 positivity was significantly more prevalent in cases with genetic alterations than in cases without genetic alterations. Furthermore, both PD-L1 positivity and high PD-L1 expression (≥50%) had statistically significant associations with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. PD-L1 expression had no significant association with histologic phenotypes or other clinicopathologic features.

Conclusions: The data indicate that cytologic specimens are comparable to surgical specimens for PD-L1 evaluation. The association of PD-L1 expression with KRAS mutations may have clinical relevance in selecting patients with NSCLC for immunotherapy.
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http://dx.doi.org/10.1002/cncy.22140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724201PMC
July 2019

Systemic cervical cytology training and quality control programs can improve the interpretation of Papanicolaou tests.

J Am Soc Cytopathol 2019 Jan - Feb;8(1):27-33. Epub 2018 Jun 15.

Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. Electronic address:

Introduction: There is no national cervical screening program or national standards for cervical cytology quality control in China. Since 2013, systematic training and quality control programs were implemented in the Papanicolaou testing process at Jinan KingMed Diagnostics. Pathologists were required to complete 1 year of cytology study in the KingMed Diagnostics Cytology School, including 6 months of a diagnostic course and 6 months of practical training in the clinical laboratory. In this study, we compared the Papanicolaou abnormal reporting rates before and after the implementation systematic training and quality control programs.

Materials And Methods: Systematic cytology training and quality control (QC) programs were implemented in 2013. Results from 997,162 cases of liquid-based cytology (LBC) and 100,066 cases of conventional Papanicolaou smears (CPS) rendered between 2008 and 2015 at Jinan KingMed Diagnostics were collected and analyzed.

Results: After implementation of training and programs, the abnormal reporting rates of atypical squamous cells of unknown significance (ASC-US), low-grade squamous intraepithelial lesions (LSIL), atypical squamous cells cannot exclude HSIL (ASC-H), atypical glandular cells (AGC), and high-grade squamous intraepithelial lesions (HSIL) in LBC were significantly increased. Similar trends were also observed in CPS reporting, except for ASC-H, squamous cell carcinoma, and AGC, probably due to the small percentages of these categories.

Conclusions: The study demonstrates the importance of the formal cytology training and QC programs to ensure standardized and effective cervical cancer screening in undeveloped countries, which account for the largest percentage of the world's annual incidence of cervical cancer and with a largely unscreened population.
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http://dx.doi.org/10.1016/j.jasc.2018.06.002DOI Listing
March 2020

Inhibition of miR-328-3p Impairs Cancer Stem Cell Function and Prevents Metastasis in Ovarian Cancer.

Cancer Res 2019 05 20;79(9):2314-2326. Epub 2019 Mar 20.

Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, Ohio.

Cancer stem cells (CSC) play a central role in cancer metastasis and development of drug resistance. miRNA are important in regulating CSC properties and are considered potential therapeutic targets. Here we report that miR-328-3p (miR-328) is significantly upregulated in ovarian CSC. High expression of miR-328 maintained CSC properties by directly targeting DNA damage binding protein 2, which has been shown previously to inhibit ovarian CSC. Reduced activity of ERK signaling in ovarian CSC, mainly due to a low level of reactive oxygen species, contributed to the enhanced expression of miR-328 and maintenance of CSC. Inhibition of miR-328 in mouse orthotopic ovarian xenografts impeded tumor growth and prevented tumor metastasis. In summary, our findings provide a novel mechanism underlying maintenance of the CSC population in ovarian cancer and suggest that targeted inhibition of miR-328 could be exploited for the eradication of CSC and aversion of tumor metastasis in ovarian cancer. SIGNIFICANCE: These findings present inhibition of miR-328 as a novel strategy for efficient elimination of CSC to prevent tumor metastasis and recurrence in patients with epithelial ovarian cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777340PMC
May 2019

Comprehensive Study of Telecytology Using Robotic Digital Microscope and Single Z-Stack Digital Scan for Fine-Needle Aspiration-Rapid On-Site Evaluation.

J Pathol Inform 2018 24;9:49. Epub 2018 Dec 24.

Department of Pathology, The Ohio State University, Columbus, Ohio, USA.

Background: The current technology for remote assessment of fine-needle aspiration-rapid on-site evaluation (FNA-ROSE) is limited. Recent advances may provide solutions. This study compared the performance of VisionTek digital microscope (VDM) (Sakura, Japan) and Hamamatsu NanoZoomer C9600-12 single Z-stack digital scan (SZDS) to conventional light microscopy (CLM) for FNA-ROSE.

Methods: We assembled sixty FNA cases from the thyroid ( = 16), lymph node ( = 16), pancreas ( = 9), head and neck ( = 9), salivary gland ( = 5), lung ( = 4), and rectum ( = 1) based on a single institution's routine workflow. One Diff-Quik-stained slide was selected for each case. Two board-certified cytopathologists independently evaluated the cases using VDM, SZDS, and CLM. A "washout" period of at least 14 days was placed between the reviews. The results were categorized into satisfactory versus unsatisfactory for adequacy assessment (AA) and unsatisfactory, benign, atypical, suspicious, and malignant for preliminary diagnosis (PD).

Results: For AA, the Cohen's kappa statistics (CKS) scores of intermodality agreement (IMA) were 0.74-0.94 (CLM vs. VDM) and 0.86-1 (CLM vs. SZDS). The discordant rates of IMA were 3.3% (4/120) for VDM versus CLM, and 1.7% (2/120) for SZDS versus CLM. For PD, the CKS scores of IMA ranged 0.7-0.93. The overall discordant rates of IMA were 15% (18/120) for CLM versus VDM and 10.8% (13/120) for CLM versus SZDS. The discordant rates of IMA with 2 or higher degrees were 5.8% (7/120) for CLM versus VDM and 1.7% (2/120) for CLM versus SZDS. The average time spent per slide was 270 s for VDM, significantly longer than that for CLM (113 s) or for SZDS (122 s).

Conclusions: Our data demonstrate that both VDM and SZDS are suitable to provide AA and reasonable PD evaluation. VDM, however, has a significantly longer turnaround time and worse diagnostic performance. The study demonstrates both the potentials and challenges of using VDM and SZDS for FNA-ROSE.
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http://dx.doi.org/10.4103/jpi.jpi_75_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319035PMC
December 2018

Clinicopathologic characteristics, tumor infiltrating lymphocytes and programed cell death ligand-1 expression in 162 endometrial carcinomas with deficient mismatch repair function.

Int J Gynecol Cancer 2019 01;29(1):113-118

Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, Ohio, USA

Objective: Endometrial carcinoma (EC) with deficient mismatch repair (dMMR) protein has been reported to have increased tumor infiltrating lymphocytes (TILs) and programed cell death ligand-1 (PD-L1) expression. TILs and PD-L1 expression are compared between two main types of dMMR ECs (epigenetic dMMR due to MLH1 promoter methylation vs mutated dMMR due to genetic mutation).

Methods: Immunohistochemistry for PD-L1 was performed in triplicate on tissue microarray sections. TILs were semi-quantitatively evaluated on whole-slide images of whole histologic sections. The clinicopathologic characteristics together with PD-L1 expression and TILs were analyzed between mutated and epigenetic dMMR ECs.

Results: Of the 162 dMMR ECs identified, 126 had epigenetic dMMR and 36 had mutated dMMR. Univariate analysis demonstrated mutated dMMR ECs showed younger age, less myometrium invasion of >50%, less lymphovascular invasion, and more TILs than epigenetic dMMR ECs. Multivariate analysis demonstrated significantly younger age and more TILs in mutated dMMR ECs than in epigenetic ECs. PD-L1 expression did not show any significant difference between these two groups. Seventeen (13.5%) patients with epigenetic dMMR EC had recurrence and 13 (10.3%) patients died of disease. In contrast, only one patient with mutated dMMR EC had recurrence (3%) and died of disease (3%).

Conclusion: ECs with mutated dMMR demonstrated significantly increased TILs than ECs with epigenetic dMMR, suggesting a stronger immune reaction and potential response to immunotherapy in these tumors.
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http://dx.doi.org/10.1136/ijgc-2018-000042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724202PMC
January 2019

PD-L1 and CD8 are associated with deficient mismatch repair status in triple-negative and HER2-positive breast cancers.

Hum Pathol 2019 04 8;86:108-114. Epub 2019 Jan 8.

Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH 43210. Electronic address:

Triple-negative and HER2-positive breast cancers (BCs) are more aggressive than hormone receptor-positive/HER2-negative BCs and show higher levels of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression. Recently, US Food and Drug Administration approved anti-PD-L1 immunotherapy for solid tumors with deficient mismatch repair (MMR). In this study, we aimed to examine the prevalence of deficient MMR and its association with checkpoint immune markers in BCs. Immunohistochemistries (IHCs) with anti-MMR proteins (MLH1, PMS2, MSH2 and MSH6) and multiplex IHCs with anti-PD-L1, anti-CD8 or anti-CD163 were performed on tissue microarrays (TMAs) with 101 triple-negative BCs (TNBC) and 197 HER2-positive BCs. Additional IHCs for MMR proteins were also performed on whole-tissue sections from selected cases. Thirteen cases (4.4%) showed complete loss of MMR protein on TMAs, including 7 TNBCs (6.9%) and 6 HER2-positive BCs. On whole-tissue sections, only one of 13 cases showed complete loss of MMR proteins, while the other 12 cases showed partial loss. PD-L1 expression was identified in 37% of cases and was significantly higher in TNBCs than in HER2-positive BCs (71% versus 19%). Furthermore, BCs with complete/partial loss of MMR demonstrated significantly more PD-L1 and CD8 expressions than BCs with preserved MMR proteins. Although complete loss of MMR proteins exists in an extremely low frequency, partial loss is not uncommon in BCs. The association of partial loss of MMR proteins with increased PD-L1 and CD8 expression suggests a potential use of MMR testing as a screening method for anti-PD-L1 immunotherapy in BCs.
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http://dx.doi.org/10.1016/j.humpath.2018.12.007DOI Listing
April 2019

Atypical Squamous Cells of Undetermined Significance Cervical Cytology Report Rate and Histologic Follow-up Findings From the Largest College of American Pathologists-Certified Laboratory in China.

Arch Pathol Lab Med 2019 06 28;143(6):748-752. Epub 2018 Dec 28.

From Guangzhou Kingmed Diagnostics, Guangzhou, Guangdong, China (Drs Zheng, You, Wei, and Mr Zeng); the Department of Pathology, Conemaugh Health System, Johnstown, Pennsylvania (Dr Yang); the Department of Pathology, Wexner Medical Center at Ohio State University, Columbus (Dr Li); the Department of Pathology, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Drs Zhang and Zhao); and Jinan Kingmed Diagnostics, Jinan, Shandong, China (Dr Xie).

Context.—: Reports for atypical squamous cells of undetermined significance (ASC-US) and histologic findings are rare in China.

Objective.—: To analyze the correlation findings of ASC-US cytology with high-risk human papillomavirus (hrHPV) test and histopathologic follow-ups.

Design.—: ASC-US cases with hrHPV test and histologic follow-ups between 2011 and 2015 were analyzed at a College of American Pathologists-certified laboratory.

Results.—: A total of 2 206 588 Papanicolaou (Pap) tests were performed, including 1 513 265 liquid-based cytology preparations (68.58%), and 693 323 conventional Pap tests (31.42%). The overall ASC-US reporting rate was 3.77% (83 199 of 2 206 588), with the highest in women aged 40 to 49 years. Of 18 574 women with ASC-US Pap and HPV testing, the hrHPV positivity rate was 34.98% (6498 of 18 574) with the highest in women younger than 30 years. A total of 6012 women with ASC-US Pap test findings had histologic follow-ups within 6 months; the overall cervical intraepithelial neoplasia 2 and above (CIN2+) detection rate was 7.87% (473 of 6012). One thousand nine hundred nine women with ASC-US Pap and HPV testing had histologic results. CIN2+ lesion was found in 13.98% (124 of 887) of women with ASC-US Pap/HPV-positive test results, significantly higher than 2.84% (29 of 1022) for women with ASC-US Pap/HPV-negative test results. Cervical squamous cell carcinoma was found in 3.95% (35 of 887) of women with ASC-US/HPV-positive test results.

Conclusions.—: This is one of the largest studies to investigate HPV and histologic follow-up findings in women with ASC-US in China. The ASC-US reporting rate, HPV positivity rate, and CIN2+ detection rate were all within the currently recognized benchmark ranges. These findings may contribute to establishing a baseline for better understanding of the status of cervical screening in China.
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http://dx.doi.org/10.5858/arpa.2018-0244-OADOI Listing
June 2019

Identification of HER2 Immunohistochemistry-Negative, FISH-Amplified Breast Cancers and Their Response to Anti-HER2 Neoadjuvant Chemotherapy.

Am J Clin Pathol 2019 01;151(2):176-184

Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH.

Objectives: Either immunohistochemistry (IHC) or in situ hybridization (ISH) can be used to determine human epidermal growth factor receptor 2 (HER2) status. Breast cancers (BCs) with HER2 IHC-negative (IHC-) and ISH-amplified (ISH+) results have been rarely reported but not well studied. We investigated the frequency of HER2 IHC-/ISH+ BCs and their response to anti-HER2 neoadjuvant chemotherapy (NAC).

Methods: Seventeen BCs with HER2 IHC-/ISH+ results were identified from 1,107 consecutive invasive BCs (1.5%, 17/1,107).

Results: Gene protein assay confirmed the original HER2 IHC and ISH results. Increased HER2 RNA level was detected in HER2 IHC-/ISH+ cases compared with HER2 IHC-/ISH- cases. Eight patients had anti-HER2 NAC; three had pathologic complete response, and five had residual tumors.

Conclusions: A small percentage of patients (1.5%) showed discordant HER2 IHC and ISH results (IHC-/ISH+) and would have lost the opportunity for potentially beneficial anti-HER2-targeted therapy if only HER2 IHC testing had been used.
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http://dx.doi.org/10.1093/ajcp/aqy136DOI Listing
January 2019