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Purpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

Perspective on This Article from Estrogen Stimulates the Expression of Mismatch Repair Gene hMLH1 in Colonic Epithelial Cells

Supplementary Methods

Supplementary Figures S1-S13

Purpose:Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features.Experimental Design:Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55).Results:Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%).Conclusions:An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.

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Cell morphology is a fundamental feature used to evaluate patient specimens in pathological analysis. However, traditional cytopathology analysis of patient effusion samples is limited by low tumor cell abundance coupled with high background of non-malignant cells, restricting the ability for downstream molecular and functional analyses to identify actionable therapeutic targets. We applied the Deepcell platform that combines microfluidic sorting, brightfield imaging, and real-time deep learning interpretations based on multi-dimensional morphology to enrich carcinoma cells from malignant effusions without cell staining or labels. Carcinoma cell enrichment was validated with whole genome sequencing and targeted mutation analysis, which showed higher sensitivity for detection of tumor fractions and critical somatic variant mutations that were initially at low-levels or undetectable in pre-sort patient samples. Combined, our study demonstrates the feasibility and added value of supplementing traditional morphology-based cytology with deep learning, multi-dimensional morphology analysis, and microfluidic sorting.

Breast cancer cells secrete abundant nanometer-sized vesicles. Small extracellular vesicle (or sEV) cargos are known to have similar biomolecular signatures to their secreting parental breast cance...

Introduction: Multiplex biomarker analysis of cytological body fluid specimens is often used to assist cytologists in distiguishing metastatic cancer cells from reactive mesothelial cells. However, evaluating biomarker expression visually may be challenging, especially when the cells of interest are scant. Deep-learning algorithms (DLAs) may be able to assist cytologists in analyzing multiple biomarker expression at the single cell level in the multiplex fluorescence imaging (MFI) setting. This preliminary study was performed to test the feasibility of using DLAs to identify immunofluorescence-stained metastatic adenocarcinoma cells in body fluid cytology samples. Methods: A DLA was developed to analyze MFI-stained cells in body fluid cytological samples. A total of 41 pleural fluid samples, comprising of 20 positives and 21 negatives, were retrospectively collected. Multiplex immunofluorescence labeling for MOC31, BerEP4, and calretinin, were performed on cell block sections, and results were analyzed by manual analysis (manual MFI) and DLA analysis (MFI-DLA) independently. Results: All cases with positive original cytological diagnoses showed positive results either by manual MFI or MFI-DLA, but 2 of the 14 (14.3%) original cytologically negative cases had rare cells with positive MOC31 and/or BerEP4 staining in addition to calretinin. Manual MFI analysis and MFI-DLA showed 100% concordance. Conclusion: MFI combined with DLA provides a potential tool to assist in cytological diagnosis of metastatic malignancy in body fluid samples. Larger studies are warranted to test the clinical validity of the approach.

Background Currently, several commercial molecular tests have been developed for reclassifying thyroid nodules with indeterminate fine needle aspiration cytology. These tests are quite expensive and not available in China. Previous studies demonstrated a very high prevalence of the BRAF V600E mutation in Asian people. A high incidence may result in a robust sensitivity. We conducted this study to determine the prevalence of BRAF V600E mutation and its ability to reclassify cytologically indeterminate thyroid nodules in the Chinese population. Methods Between January 2016 and October 2018, consecutive patients who underwent a fine needle aspiration procedure and agreed to provide materials for molecular analysis in our hospital were recruited in this study. All were followed up until they had a thyroidectomy and a final pathological diagnosis or until January 2019 (those did not have surgery). Results A total of 1960 patients were included in this study. Until January 2019, 1240 patients underwent surgery. Using histopathological diagnosis as a gold standard, the overall sensitivity and specificity of the BRAF V600E mutational analysis for the discrimination of benign nodules from cancer in thyroid fine needle aspiration samples were 83.3% (81.0–85.3%) and 96.0% (77.7–99.8%), respectively, with an area under the ROC curve of 0.90 (95% CI 0.85–0.95, P Conclusion The BRAF V600E mutation is highly prevalent in the Chinese population and can accurately complement cytopathology in the guidance of thyroid surgery. Mini-abstract: The BRAF V600E mutation has both high specificity and sensitivity to predict thyroid malignancy in the Chinese population. It can accurately complement cytopathology in the guidance of thyroid surgery.

Identifying patients who respond to immune checkpoint blockade (ICB) is a significant challenge in oncology. While PD-L1 expression by immunohistochemistry (IHC) is the current diagnostic gold standard for patient selection, it nevertheless does not capture all patients who may respond to ICB. Recent gene expression studies in high-grade serous ovarian carcinoma have defined an immunoreactive molecular subtype that has a measurable difference in patient survival compared with non-immunoreactive subtypes, but no studies have yet demonstrated its impact on predicting response to ICB. As a step toward establishing the predictive value of gene expression classifiers in ICB, we assessed the relationship between PD-L1 IHC and molecular subtypes of ovarian epithelial cancer. This was done by analyzing a total of 93 tissue specimens from patients with stage III and IV disease, and comparing PD-L1 IHC with gene expression by Agilent microarrays using TCGA-defined subtypes. We showed that ovarian tumors with elevated IHC PD-L1 expression are most strongly associated with immunoreactive subtype as compared with other molecular subtypes, reaching statistical significance against differentiated (Dunn’s test, 33.39, p = 0.0003) and mesenchymal (39.63, p

PURPOSE The purpose of this study was to evaluate the expression of cytokeratin (K) 13 on the corneal surface and to validate its application in the diagnosis of limbal stem cell deficiency (LSCD). METHODS This prospective comparative study included 26 corneal impression cytology (IC) specimens from patients diagnosed with LSCD. Twenty-three IC specimens from normal donors served as controls. K12 and K13 expression were detected on the IC specimens by immunohistochemistry study. The number of K12+ or K13+ cells in all areas of the IC was quantified using ImageJ software. RESULTS The epithelial cells harvested from IC specimens from control corneas were all K12+. In eyes with LSCD, K13+ and K12+/K13+ cells accounted for 93.8% and 2.6%, respectively, in the cornea. In eyes with sectoral LSCD, the median number of K13+ cells in the clinically affected area was higher than that in the unaffected area (810.0 vs. 115.0 cells/mm2; P < 0.001). No significant correlation was found between the LSCD severity and the number of K12+ cells (r = -0.284, P = 0.16) or K13+ cells (r = -0.011, P = 0.95). The presence of at least 16 K13+ cells/mm2 was suggestive of LSCD. CONCLUSIONS Identification of K13+ cells on IC specimens provides a simple and reliable method to detect conjunctival epithelial cells on the cornea. K13 is a marker for diagnosing LSCD and localizing the involved area in sectoral LSCD.

Several advances in recent decades in digital imaging, artificial intelligence, and multiplex modalities have improved our ability to automatically analyze and interpret imaging data. Imaging technologies such as optical coherence tomography, optical projection tomography, and quantitative phase microscopy allow analysis of tissues and cells in 3-dimensions and with subcellular granularity. Improvements in computer vision and machine learning have made algorithms more successful in automatically identifying important features to diagnose disease. Many new automated multiplex modalities such as antibody barcoding with cleavable DNA (ABCD), single cell analysis for tumor phenotyping (SCANT), fast analytical screening technique fine needle aspiration (FAST-FNA), and portable fluorescence-based image cytometry analyzer (CytoPAN) are under investigation. These have shown great promise in their ability to automatically analyze several biomarkers concurrently with high sensitivity, even in paucicellular samples, lending themselves well as tools in FNA. Not yet widely adopted for clinical use, many have successfully been applied to human samples. Once clinically validated, some of these technologies are poised to change the routine practice of cytopathology.

Long-term PM2.5 exposure might predispose populations to SARS-CoV-2 infection and intervention policies might interrupt SARS-CoV-2 transmission and reduce the risk of COVID-19. We conducted an ecologic study across the United States, using county-level COVID-19 incidence up to 12 September 2020, to represent the first two surges in the U.S., annual average of PM2.5 between 2000 and 2016 and state-level facemask mandates and stay home orders. We fit negative binomial models to assess COVID-19 incidence in association with PM2.5 and policies. Stratified analyses by facemask policy and stay home policy were also performed. Each 1-µg/m3 increase in annual average concentration of PM2.5 exposure was associated with 7.56% (95% CI: 3.76%, 11.49%) increase in COVID-19 risk. Facemask mandates and stay home policies were inversely associated with COVID-19 with adjusted RRs of 0.8466 (95% CI: 0.7598, 0.9432) and 0.9193 (95% CI: 0.8021, 1.0537), respectively. The associations between PM2.5 and COVID-19 were consistent among counties with or without preventive policies. Our study added evidence that long-term PM2.5 exposure increased the risk of COVID-19 during each surge and cumulatively as of 12 September 2020, in the United States. Although both state-level implementation of facemask mandates and stay home orders were effective in preventing the spread of COVID-19, no clear effect modification was observed regarding long-term exposure to PM2.5 on the risk of COVID-19.

After two decades of unchanged paradigms, the treatment strategies for advanced urothelial bladder cancer have been revolutionized by emerging programmed death ligand-1 (PD-L1)/programmed death-1 (PD1) inhibition therapy. Increased evidence is demonstrating the efficacy of PD-L1/PD1 inhibition therapy in both second-line and first-line settings. However, the percentage of patients who benefit from anti-PD-L1/anti-PD1 therapy is still low. Many questions have been raised in the development of biomarker-driven approaches for disease classification and patient selection. In this perspective, we discuss PD-L1/PD1 expression in urothelial bladder carcinoma, review approved anti-PD-L1/anti-PD1 agents for bladder cancer treatment and current ongoing studies investigating combination treatment strategies, and explore PD-L1 expression status for the evaluation of bladder cancer immunotherapy. Keywords: Immune checkpoint therapy, Urothelial carcinoma, Bladder cancer, Programmed death-ligand 1, Programmed death-1

We address the dilemma faced by oncologists in administering preventative measures to “at risk” patients diagnosed with atypical and nonatypical hyperplasias due to lack of any molecular means of risk stratification and identifying high-risk subjects. Our study purpose is to investigate a four marker risk signature, MMP-1, CEACAM6, HYAL1, and HEC1, using 440 hyperplastic tissues for identifying high-risk subjects who will benefit from preventative therapies. We assayed the markers by IHC and combined their expression levels to obtain a composite value from 0–10, which we called a “Cancer Risk Score.” We demonstrate that the four marker-based risk scores predict subsequent cancer development with an accuracy of 91% and 86% for atypical and nonatypical subjects, respectively. We have established a correlation between risk scores and cancer rates by stratifying the samples into low risk (score ≤ 0.5); intermediate risk (score ≤ 5.4), and high risk (score >5.4) groups using Kaplan–Meier survival analysis. We have evaluated cancer rates at 5, 10, and 15 years. Our results show that the average cancer rates in the first 5 years among low- and intermediate-risk groups were 2% and 15%, respectively. Among high-risk group, the average cancer rates at 5 years were 73% and 34% for atypical and nonatypical subjects, respectively. The molecular risk stratification described here assesses a patient's tumor biology–based risk level as low, intermediate, or high and for making informed treatment decisions. The outcomes of our study in conjunction with the available prophylactic measures could prevent approximately 20%–25% of sporadic breast cancers.

Carcinoma-associated fibroblasts (CAFs) function as a double-edged sword in tumor progression. However, factors affecting the transition between tumor promotion and inhibition remain to be investigated. Here, we found that the transition was determined by stiffness heterogeneity of the tumor stroma in which tumor cells and CAFs were grown. When tumor cells were grown on a rigid plastic substrate, supernatants from CAFs inhibited the cytotoxic effects of 5-fluorouracil. In contrast, when tumor cells were grown on a soft substrate (5.3 kPa), supernatants from CAFs grown on a soft substrate increased the cytotoxicity of 5-fluorouracil. The diverse effects of CAFs were mediated by mechanotransduction factors, including stroma stiffness-induced cytokine expression in CAFs and signal transduction associated with stress fiber formation of CAFs. Moreover, we found that the cytokine expression in CAFs was regulated by nuclear Yes-associated protein, which changed according to cell stiffness, as characterized by atomic force microscopy. Overall, these findings suggested that modulating the mechanotransduction of the stroma together with CAFs might be important for increasing the efficacy of chemotherapy.

Long-term PM2.5 exposure might predispose populations to SARS-CoV-2 infection and intervention policies might interrupt SARS-CoV-2 transmission and reduce the risk of COVID-19. We conducted an ecologic study across the United States, using county-level COVID-19 incidence up to 12 September 2020, to represent the first two surges in the U.S., annual average of PM2.5 between 2000 and 2016 and state-level facemask mandates and stay home orders. We fit negative binomial models to assess COVID-19 incidence in association with PM2.5 and policies. Stratified analyses by facemask policy and stay home policy were also performed. Each 1-µg/m3 increase in annual average concentration of PM2.5 exposure was associated with 7.56% (95% CI: 3.76%, 11.49%) increase in COVID-19 risk. Facemask mandates and stay home policies were inversely associated with COVID-19 with adjusted RRs of 0.8466 (95% CI: 0.7598, 0.9432) and 0.9193 (95% CI: 0.8021, 1.0537), respectively. The associations between PM2.5 and COVID-19 were consistent among counties with or without preventive policies. Our study added evidence that long-term PM2.5 exposure increased the risk of COVID-19 during each surge and cumulatively as of 12 September 2020, in the United States. Although both state-level implementation of facemask mandates and stay home orders were effective in preventing the spread of COVID-19, no clear effect modification was observed regarding long-term exposure to PM2.5 on the risk of COVID-19.

We report a case of atypical de Quervain's thyroiditis diagnosed as atypia of undetermined significance by cytology and suspicious for cancer by Afirma Genomic Sequencing Classifier. A 71-year-old male underwent thyroid ultrasound for goiter and was found to have two American Thyroid Association (ATA) 2015 high-suspicion nodules. The larger, 2.2-cm nodule was biopsied and the cytology showed atypical follicular cells and histiocytes. The Afirma Genomic Sequencing Classifier (detecting mRNA expression profile) result was ''suspicious'' (risk of malignancy ~50%) but Afirma Xpression Atlas (detecting specific mutations) did not find mutations in BRAF V600E, RET/PTC1, or RET/PTC3. The patient saw two endocrine surgeons and two endocrinologists who each recommended hemithyroidectomy. The patient chose to monitor the nodules. A new diagnostic ultrasound performed 3 months after the first one showed that the thyroid was significantly smaller and the previously seen nodules were no longer found. Re-examination of the cellular smears confirmed that the cytological findings were also compatible with de Quervain's thyroiditis. This case illustrates that atypical de Quervain's thyroiditis should be in the differential diagnosis of thyroid nodules for cytologists, radiologists, and clinicians. Furthermore, this case demonstrates that atypical de Quervain's thyroiditis can generate false positive results of molecular tests for indeterminate thyroid nodules.

Chronic gastrointestinal symptoms (CGS) negatively affect the quality of life in about 15–30% of the population without effective drugs. Recent studies suggest that dietary supplement may improve CGS, but inconsistent results exist. The goal of this study is to evaluate the effect of a polyherbal-based supplement ColonVita on the gastrointestinal quality of life index (GIQLI) in 100 old adults with CGS (63.1 ± 9.6 years) who were randomly assigned to daily ColonVita or placebo tablets (n = 50/group) for 12 weeks in a double-blind, randomized controlled trial design. No significant fibrdifferences were found between ColonVita and placebo in the baseline total GIQLI score (101.12 ± 16.87 vs. 101.80 ± 16.48) ( P > 0.05 ) or postintervention total GIQLI score (114.78 ± 9.62 vs. 111.74 ± 13.01) ( P > 0.05 ). However, ColonVita significantly improved 16 scores of the 19 core GI symptoms compared with 10 items improved by placebo. The ColonVita group significantly improved the remission rate of 5 core GI symptoms compared to placebo and significantly improved the total GIQLI scores (118.09 ± 7.88 vs. 109.50 ± 16.71) ( P < 0.05 ) and core GI symptom scores (64.61 ± 3.99 vs. 60.00 ± 8.65) ( P < 0.05 ) in people ≥60 years of age (n = 49) but not in those under 60 y (n = 51). ColonVita significantly improved the total GIQLI scores and core GI symptom scores in people without cardiovascular diseases (CVD) (n = 56) (116.74 ± 9.38 vs. 110.10 ± 14.28) ( P < 0.05 ) and (63.11 ± 4.53 vs. 59.93 ± 8.03) ( P = 0.07 ), respectively, but not in those with CVD (n = 44). Thus, ColonVita was beneficial for old adults with CGS, especially those ≥60 years of age and without CVD. Because a heterogenous pathogenesis of CGS-like irritable bowel syndrome (IBS) and inflammatory bowel disease (ISD) is differentially associated with CVD, different comorbidities may have influenced the outcomes of different trials that should be controlled in further studies.

Background Although there is some evidence of positive associations between both the glycemic index (GI) and glycemic load (GL) with cancer risk, the relationships with lung cancer risk remain largely unexplored. We evaluated the associations between GI and GL with lung cancer. Methods The analyses were performed using data from a population-based case-control study recruited between 1999 and 2004 in Los Angeles County. Dietary factors were collected from 593 incident lung cancer cases and 1026 controls using a modified food frequency questionnaire. GI and GL were estimated using a food composition table. Adjusted odds ratios (ORs) and 95 % confidence intervals (CI) were estimated using unconditional logistic regression adjusting for potential confounders. Results Dietary GI was positively associated with lung cancer (OR for upper vs. lower tertile = 1.62; 95 % CI: 1.17, 2.25). For histologic subtypes, positive associations were observed between GI and adenocarcinoma (OR for upper vs. lower tertile = 1.82; 95 % CI: 1.22, 2.70) and small cell carcinoma (OR for upper vs. lower tertile = 2.68; 95 % CI: 1.25, 5.74). No clear association between GL and lung cancer was observed. Conclusion These findings suggest that high dietary GI was associated with increased lung cancer risk, and the positive associations were observed for both lung adenocarcinoma and small cell lung carcinoma. Replication in an independent dataset is merited for a broader interpretation of our results.

Background: The surgical management of nodular thyroid disease has been influenced by the advent of molecular diagnostics and recent guidelines recommending a more conservative approach to low-risk...

Introduction: Urine cytology plays an important role in diagnosing urothelial carcinoma (UC). However, urine cytology interpretation is subjective and difficult. Morphogo (ALAB, Boston, MA, USA), equipped with automatic acquisition and scanning, optical focusing, and automatic classification with convolutional neural network has been developed for bone marrow aspirate smear analysis of hematopoietic diseases. The goal of this preliminary study was to determine the feasibility of developing a machine learning algorithm on Morphogo for identifying abnormal urothelial cells in urine cytology slides. Methods: Thirty-seven achieved abnormal urine cytology slides from cases with the diagnosis of atypical urothelial cells and above (suspicions or positive for UC) were obtained from 1 hospital. A pathologist (J.R.) reviewed the slides and manually selected and annotated representative cells to feed into Morphogo with following categories: benign (urothelial cells, squamous cells, degenerated cells, and inflammatory cells), atypical cells, and suspicious cells. Initial validation of the algorithm was performed on a subset of the original 37 cases. Urine samples from additional 12 unknown cases with various histological diagnoses (6 cases of high-grade urothelial carcinoma (HGUC), 1 case of low-grade urothelial carcinoma (LGUC), 1 case of prostate adenocarcinoma, 1 case of renal cell carcinoma, and 4 cases of non-neoplastic conditions) were collected from another hospital for initial blind testing. Results: A total of 1,910 benign and 1,978 abnormal (atypical and suspicious) cells from 37 slides were annotated for developing and training of the algorithm. This algorithm was validated on 27 slides that resulted in identification of at least 1 abnormal cell per slide, with a total of 200 abnormal cells, and an average of 7.4 cells per slide. Of the 12 unknown cases tested, the original cytology was positive for tumor cells in 2 HGUC samples. Morphogo was abnormal (atypical or suspicious) for 6 samples from patients with UC, including one with LGUC and one with prostate adenocarcinoma. Conclusion: Morphogo machine learning algorithm is capable of identifying abnormal urothelial cells. Further validation studies with a larger number of urine samples will be needed to determine if it can be used to assist the cytological diagnosis of UC.

Cancer cell mechanotype changes are newly recognized cancer phenotypic events, whereas metastatic cancer cells show decreased cell stiffness and increased deformability relative to normal cells. To further examine how cell mechanotype changes in early stages of cancer transformation and progression, anin vitromulti-step human urothelial cell carcinogenic model was used to measure cellular Young’s modulus, deformability, and transit time using single-cell atomic force microscopy, microfluidic-based deformability cytometry, and quantitative deformability cytometry, respectively. Measurable cell mechanotype changes of stiffness, deformability, and cell transit time occur early in the transformation process. As cells progress from normal, to preinvasive, to invasive cells, Young’s modulus of stiffness decreases and deformability increases gradually. These changes were confirmed in three-dimensional cultured microtumor masses and urine exfoliated cells directly from patients. Using gene screening and proteomics approaches, we found that the main molecular pathway implicated in cell mechanotype changes appears to be epithelial to mesenchymal transition.

Purpose of review Immune checkpoint blockade (ICB) is a promising area of cancer therapeutic research. Therapies targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) mechanism of tumor immune evasion have resulted in durable responses in many difficult-to-treat tumor types. While these inhibitors are being actively investigated in clinical trials for ovarian cancer, most patients fail to respond to initial treatment with immune therapy. This review focuses on biomarkers for predicting response to treatment, and discusses clinical trials using ICB for recurrent ovarian cancer. Recent findings While PD-L1 detection by immunohistochemistry (IHC) is approved as a companion or complementary diagnostic in some cancers, there are many limitations with its use as a predictive marker. Recent research has explored biomarkers beyond PD-L1 that assess for somatic mutations, immune cell infiltrate, and gene signatures. Summary With improved understanding of the tumor microenvironment and genomic classifications of ovarian tumors, new diagnostics and biomarkers that supplement conventional IHC may help predict response to therapy.

International telecytology can improve patient care by increasing access to regional and international expertise in cytopathology. The majority of international telecytology studies published to date have been based on static telepathology platforms. Overall concordance rates for these studies ranged from 71% to 93%. This is comparable to the concordance rates published for other studies comparing diagnoses made by digital still images to reference glass slides, which vary from 80% to 95%. Static telepathology systems are relatively cheap and easy to use, and have the potential to increase access to international experts in developing countries with limited resources. In contrast, resource-rich academic and private medical centers can use whole slide digital imaging (WSI) for telecytology consultation, though few studies have been published addressing this topic. International telepathology consultation services with digital whole slide image capabilities have been established at several academic medical centers including the University of Pittsburgh Medical Center (UPMC) and the University of California at Los Angeles (UCLA), through the UCLA Center for Telepathology and Digital Pathology. In a small series of 20 telecytology cases submitted to UCLA from 2014 to 2017 (10 gynecologic and 10 fine needle aspiration cases), a meaningful diagnosis was rendered for 100% of cases, with 100% concordance between the submitting institution, versus consultation diagnosis provided by UCLA. These limited results are promising, and in the future both WSI and static telecytology consultation may have a place serving clinical needs in different practice settings.

Context Molecular testing has reduced the need for diagnostic hemithyroidectomy for indeterminate thyroid nodules. No studies have directly compared molecular testing techniques. Objective Compare the diagnostic performance of Afirma Gene Expression Classifier (GEC) with that of ThyroSeq v2 next-generation sequencing assay. Design Parallel randomized trial, monthly block randomization of patients with Bethesda III/IV cytology to GEC or ThyroSeq v2. Setting University of California, Los Angeles. Participants Patients who underwent thyroid biopsy (April 2016 to June 2017). Intervention Testing with GEC or ThyroSeq v2. Main outcome measure Molecular test performance. Results Of 1372 thyroid nodules, 176 (13%) had indeterminate cytology and 149 of 157 eligible indeterminate nodules (95%) were included in the study. Of nodules tested with GEC, 49% were suspicious, 43% were benign, and 9% were insufficient. Of nodules tested with ThyroSeq v2, 19% were mutation positive, 77% were mutation negative, and 4% were insufficient. The specificities of GEC and ThyroSeq v2 were 66% and 91%, respectively (P = 0.002); the positive predictive values of GEC and ThyroSeq v2 were 39% and 57%, respectively. Diagnostic hemithyroidectomy was avoided in 28 patients tested with GEC (39%) and 49 patients tested with ThyroSeq v2 (62%). Surveillance ultrasonography was available for 46 nodules (45 remained stable). Conclusions ThyroSeq v2 had higher specificity than Afirma GEC and allowed more patients to avoid surgery. Long-term surveillance is necessary to assess the false-negative rate of these particular molecular tests. Further studies are required for comparison with other available molecular diagnostics and for newer tests as they are developed.

This abstract was withdrawn by the authors.