The current state of digital cytology and artificial intelligence (AI): global survey results from the American Society of Cytopathology Digital Cytology Task Force.

INTRODUCTION: The integration of whole slide imaging (WSI) and artificial intelligence (AI) with digital cytology has been growing gradually. Therefore, there is a need to evaluate the current state of digital cytology. This study aimed to determine the current landscape of digital cytology via a survey conducted as part of the American Society of Cytopathology (ASC) Digital Cytology White Paper Task Force. MATERIALS AND METHODS: A survey with 43 questions pertaining to the current practices and experiences of WSI and AI in both surgical pathology and cytology was created. The survey was sent to members of the ASC, the International Academy of Cytology (IAC), and the Papanicolaou Society of Cytopathology (PSC). Responses were recorded and analyzed. RESULTS: In total, 327 individuals participated in the survey, spanning a diverse array of practice settings, roles, and experiences around the globe. The majority of responses indicated there was routine scanning of surgical pathology slides (n = 134; 61%) with fewer respondents scanning cytology slides (n = 150; 46%). The primary challenge for surgical WSI is the need for faster scanning and cost minimization, whereas image quality is the top issue for cytology WSI. AI tools are not widely utilized, with only 16% of participants using AI for surgical pathology samples and 13% for cytology practice. CONCLUSIONS: Utilization of digital pathology is limited in cytology laboratories as compared to surgical pathology. However, as more laboratories are willing to implement digital cytology in the near future, the establishment of practical clinical guidelines is needed.

A retrospective analysis of molecular testing in cytologically indeterminate thyroid nodules with histologic correlation: Experience at a heterogenous multihospital system.

INTRODUCTION: Thyroid malignancy is one of the most common types of cancer in developed nations. Currently, fine-needle aspiration cytology (FNAC) is the most practical screening test for thyroid nodules. However, cytologically indeterminate samples comprise approximately 15%-30% of cases. These include cases classified as atypia of undetermined significance (AUS), follicular neoplasm (FN), and suspicious for malignancy (SFM). Indeterminate cases can be sent for molecular testing for more definitive classification to help guide management and prevent overtreatment of benign thyroid nodules. We conducted a retrospective review on molecular testing of indeterminate thyroid FNAC and reviewed subsequent histologic diagnoses in resection specimens to assess how molecular testing supported a diagnosis and its effect on clinical management of patients at our institution. METHODS: A retrospective chart review was performed on all thyroid FNAC specimens, corresponding molecular testing, and subsequent surgical resection specimens over a 6-year period. RESULTS: A total of 10,253 thyroid FNAC were performed in our hospital system during our study period, of which 10% (n = 1102/10,253) had indeterminate FNAC results. Molecular testing was performed in 16% (n = 178/1102) of indeterminate cytology cases. Genetic alterations were identified in 39% (n = 69/178) of the cases sent for molecular testing. The majority of cytologically indeterminate cases sent for molecular testing were follicular-patterned lesions and their corresponding resection specimens revealed mostly low grade follicular derived neoplasms (i.e., follicular adenoma, non-invasive follicular thyroid neoplasm with papillary-like nuclear features, and follicular variant of papillary thyroid carcinoma). Of the cases with identified genetic alterations, 75% (n = 52/69) were treated surgically. In cases with no genetic alterations identified, only 18% (n = 20/109) were treated surgically. DISCUSSION/CONCLUSION: Molecular testing on cytologically indeterminate thyroid nodules can help provide a more accurate risk of malignancy assessment in patients with lesions that are difficult to diagnosis based solely on FNAC morphology. The types of genetic alterations identified in the resected thyroid lesions were consistent with what has been previously described in the literature. Additionally, we found that in the patients with indeterminate thyroid FNAC with adjunct molecular testing, more than half did not undergo surgical resection. This finding emphasizes the value of adding molecular testing in patients, particularly when attempting to reduce unnecessary surgical intervention.

One procedure-one report: the Re-Imagine Cytopathology Task Force position paper on small tissue biopsy triage in anatomic pathology.

INTRODUCTION: Endoscopic biopsy procedures increasingly generate multiple tissue samples from multiple sites, and frequently retrieve concurrent cytologic specimens and small core needle biopsies. There is currently lack of consensus in subspecialized practices as to whether cytopathologists or surgical pathologists should review such samples, and whether the pathology findings should be reported together or separately. MATERIALS AND METHODS: In December 2021, the American Society of Cytopathology convened the Re-Imagine Cytopathology Task Force to examine various workflows that would facilitate unified pathology reporting of concurrently obtained biopsies and improve clinical care. RESULTS AND CONCLUSIONS: This position paper summarizes the key points and highlights the advantages, challenges, and resources available to support the implementation of such workflows that result in "one procedure-one report".

Rescreening of high-risk HPV positive Papanicolaou tests initially screened as negative is a low yield procedure in the era of HPV genotyping.

INTRODUCTION: Many laboratories rescreen Papanicolaou test slides initially interpreted as negative, but positive for human papillomavirus (HPV) high-risk types, as a quality control measure. We have evaluated the utility of this practice in the era of HPV genotyping as a laboratory improvement project. MATERIAL AND METHODS: Between August 2016 and October 2019, we identified 3618 rescreened Papanicolaou tests with follow-up biopsies. The biopsy results were put into 3 groups: 1) Negative; 2) LSIL: HPV changes or low-grade squamous intraepithelial lesion; and 3) HSIL: high-grade squamous intraepithelial lesion or carcinoma. HPV molecular testing results with subtyping for types 16 and 18 were available for 3117 of these cases. RESULTS: A total of 530 of 2812 Papanicolaou tests (18.8%) with positive HPV results were reinterpreted as cytologically abnormal after rescreening; 75 (14.2%) had a biopsy result of HSIL. The subset positive for HPV types 16/18 had 38 of 133 cytology positive cases diagnosed as HSIL on biopsy vs. 107 of 935 cytology negative cases diagnosed as HSIL on biopsy (28.6% vs. 11.4%, P < 0.0001). The subset positive for "other" (non-16/18) high-risk HPV types had 37 of 397 cytology positive follow-up HSIL vs. 84 of 1288 cytology negative follow-up HSIL (9.3% vs. 6.5%, P = 0.075). CONCLUSIONS: Rescreening has the highest yield in specimens positive for types 16/18. However, for this group colposcopy is recommended regardless of cytology findings, reducing the patient benefit. Routine rescreening of cytology negative/HPV positive Papanicolaou tests has reduced utility when HPV subtyping is performed and should be reconsidered.

Small core needle biopsies in cytology practice: a survey of members of the American Society of Cytopathology.

INTRODUCTION: The introduction of a new generation of core needle biopsies (CNBs) for endoscopic procedures has prompted reconsideration of the role of cytopathologists in the handling of small biopsies. The American Society of Cytopathology (ASC) has therefore conducted a survey with the intention of elucidating current practices regarding the handling of small CNBs. MATERIALS AND METHODS: The membership of the ASC was invited by email to participate in an online survey over a 2-month period. The survey consisted of 20 multiple choice questions with 2-8 possible responses per question. RESULTS: Of 2651 members contacted by e-mail, 282 (10.6%) responded to the survey questions, including 196 pathologists (69.5%) and 86 cytotechnologists (30.5%). Of these, 265 respondents were from the US/Canada (94.0%), with 156 from academic institutions (58.9%) and 109 from non-academic practices (41.1%); 17 were from other countries (6.0%). In 18.8% of all practices, cytopathologists sign out >90% of small CNBs from endoscopic and radiologically guided procedures; in 36.5% of practices >90% are signed out by surgical pathologists; the remainder have such cases divided more evenly between cytopathologists and surgical pathologists. Responses show that 78.0% of all respondents are interested in signing out more small biopsies in the future, and 80.5% desire increased small biopsy-related resources from the ASC. CONCLUSIONS: The survey responses indicate that practices currently vary widely across institutions. Most indicated an interest in greater incorporation of small biopsies into the practice of cytopathology.

Automated screening of Papanicolaou tests: A review of the literature.

Automated Papanicolaou test screening systems have now been available for over 25 years. Currently two automated screening systems are in widespread clinical use. These are the ThinPrep Imaging System and the FocalPoint GS Imaging System. In their current configurations, both facilitate faster screening by showing a limited number of fields of view (FOV) to cytotechnologists. The FOV are based on the use of proprietary algorithms applied to computerized images of the slide that determine the cells and cell groups with the highest likelihood of abnormality. If all of the FOV are deemed to be negative, the case can be signed out with no additional review; if one or more fields appear possibly abnormal, the entire slide must be manually screened. The United States Food and Drug Administration has ruled that for workload calculation purposes, looking at only the FOV review counts as one-half slide, potentially greatly increasing the number of slides that can be screened. However, follow-up studies of this technology have shown that screening accuracy declines when very large numbers of cases are reviewed per day. Recommendations designed to limit screening volumes to levels that do not jeopardize patient care have therefore been created. The development of fully automated screening that does not rely on human judgment remains an unrealized aspiration. This review covers the history of the development and clinical implementation of automated screening technology with descriptions of the various automated screening systems and their performance as reported in published literature.

The effects of the Bethesda System 2014 on endometrial cell reporting and follow-up endometrial biopsies in women 45 years of age and over.

INTRODUCTION: The Bethesda System (TBS) guidelines for reporting the presence of endometrial cells on Papanicolaou tests increased the reporting age from 40 (TBS 2001) to 45 (TBS 2014) years. Exfoliated endometrial cells (EMC) are usually a normal finding. Nevertheless, benign-appearing EMC occasionally correspond to endometrial hyperplasia or malignancy, especially in older, postmenopausal women. This study assesses the impact of this age cutoff change. MATERIALS AND METHODS: This retrospective review compares endometrial biopsies following TBS 2001 and TBS 2014. Papanicolaou tests with EMC reported in women older than age 40 or 45 years were correlated with follow-up endometrial biopsies performed between May 25, 2014, to May 26, 2015, and May 27, 2015, to May 26, 2016, respectively. RESULTS: The number of reported EMC declined from 770 to 492 (a 36.1% decrease). The follow-up endometrial biopsy rate for Papanicolaou tests reporting EMC using TBS 2001 was 13.6% (105 of 770) versus TBS 2014 at 13.8% (68 of 492; P = 0.92). For TBS 2001, 15% of women aged 45 and older had follow-up biopsies (65 of 434; P = 0.62). Most follow-up biopsies showed benign endometrium. In the TBS 2001 group, 1 biopsy showed malignancy and another showed complex hyperplasia with atypia. Both patients were older than 45 years. The TBS 2014 group contained 1 biopsy of malignancy and 1 with simple hyperplasia with focal atypia. CONCLUSIONS: The implementation of TBS 2014 reduced the frequency of reporting benign-appearing endometrial cells. The follow-up biopsy rate has remained essentially the same, but the total number of biopsies performed decreased, with a similar low yield of significant abnormalities.

Cervical biopsy rates before and after the introduction of human papillomavirus type reporting in co-tests with negative cytology.

INTRODUCTION: In 2013, our laboratory introduced Roche cobas high-risk human papillomavirus (HRHPV) testing, which includes limited HPV genotype reporting. The shift from Hybrid Capture II (HC2) HPV testing to Roche led to an observed increase in biopsies for patients with negative Papanicolaou tests with positive HRHPV. MATERIALS AND METHODS: We conducted a retrospective review of data from our facility to examine biopsies conducted on patients with negative Papanicolaou tests and positive HRHPV. We compared data from 2012 (HC2) to 2015 after implementation of Roche cobas platform. RESULTS: In 2012, 37 biopsies were performed on patients with negative Papanicolaou test and positive HRHPV, out of 82,721 Papanicolaou tests (0.045%). In 2015, the number of biopsies performed on patients with negative Papanicolaou test and positive HRHPV test was 281, out of 115,104 Papanicolaou tests (0.244%; P < 0.001). Of these, 141 had HPV type 16 or 18, and 140 had "other" HRHPV types. We observed an increased detection rate of high-grade squamous intraepithelial lesion (HSIL) or greater lesions (5.4% in 2012 to 8.9% in 2015), but it was not statistically significant (P = 0.398). Fifteen HSIL or greater lesions were found in women with types 16 or 18 (5.3%) and 10 were found in women with "other" HRHPV types (3.6%). CONCLUSION: The introduction of HRHPV testing with type reporting is associated with a marked increase in the number of women undergoing colposcopy and biopsy for HRHPV despite negative cytology. Half of these have a HRHPV type other than type 16 or 18, despite recommendations to repeat co-testing instead.

Effect of Lower Anogenital Squamous Terminology Recommendations on the Use of p16 Immunohistochemistry and the Proportion of High-Grade Diagnoses in Cervical Biopsy Specimens.

OBJECTIVES: The Lower Anogenital Squamous Terminology (LAST) group has recommended that cervical intraepithelial neoplasia (CIN) terminology be replaced by squamous intraepithelial lesion (SIL) terminology, with p16 immunohistochemistry used to separate lesions formerly diagnosed as CIN grade 2 into high-grade SILs (HSILs) and low-grade SILs. This study investigated the impact of these changes on the frequency of p16 testing and the diagnosis of high-grade lesions. METHODS: Pathology reports for all cervical biopsy specimens in the 1 year before and after the introduction of LAST recommendations (July 2011 to June 2013) were examined. RESULTS: Before and after the implementation of LAST, 365 (15.4%) of 2,376 cases were diagnosed as high grade (CIN 2/3) vs 486 (17.6%) of 2,761 cases diagnosed as HSILs (P = .0343), and p16 was performed 79 (3.3%) times vs 383 (13.9%) times (P < .0001). CONCLUSIONS: Immunohistochemistry for p16 increased dramatically as a result of LAST recommendations, and high-grade diagnoses increased.

Utility of flow cytometry analysis for pleural and peritoneal fluids.

INTRODUCTION: Pleural and peritoneal/ascites fluid samples with many lymphocytes are commonly received in the cytology laboratory. It is often difficult to distinguish reactive lymphocytes from hematopoietic malignancy based on morphology alone, however. Flow cytometry can be a useful adjunct in body fluids, although literature on this subject is limited. MATERIALS AND METHODS: This study is a single-institution 5-year retrospective review of 377 fluid samples from 341 patients with corresponding flow cytometry analysis. The cytologic findings were correlated with the flow cytometry results and clinical data, as available. RESULTS: Of 4158 pleural fluids received over 5 years, 325 (7.8%) had corresponding flow cytometry analysis. Of these 325 samples, 57 (17.5%) were positive for hematopoietic malignancy by flow cytometry. Of the positive cases, only 24 (8.7%) represented a new diagnosis of hematopoietic malignancy (ie, did not have a known history). Of 3020 peritoneal/ascites fluids received over 5 years, 52 (2%) had corresponding flow cytometry. Of these, 8 were positive for hematopoietic malignancy, and only 2 represented a presumed new diagnosis. CONCLUSIONS: Routine flow cytometry analysis for pleural and peritoneal/ascitic fluids is of limited utility, with only rare cases positive for hematopoietic malignancy without a known history. Of these cases, many had atypical cells that suggested a positive diagnosis. Conversely, in cases with a known history, about 75% were positive for hematopoietic malignancy. Our study suggests that the utility of flow cytometry for pleural and peritoneal/ascitic fluids is limited, and should be used sparingly in cases without atypical cytologic features, high clinical suspicion, or known history.

Human Lung Fibroblasts Inhibit Non-Small Cell Lung Cancer Metastasis in Ex Vivo 4D Model.

BACKGROUND: We determined the effect of human lung fibroblasts (LFs) in metastatic lesion formation in a four-dimensional (4D) lung cancer model. METHODS: Human cancer-associated fibroblasts (CAFs) were isolated from the primary tumor, and normal LFs were isolated from adjacent lung using fluorescence-activated cell sorting. The 4D metastatic lung cancer model was seeded with the human lung cancer cell lines (H460, A549, and H1299) alone or was seeded with CAFs or LFs. In addition, the 4D model seeded with human lung cancer cell lines was also treated with conditioned media of LFs or CAFs grown on the 4D model. We determined the number of metastatic tumor cells per high-power field on the model. RESULTS: There were significantly fewer metastatic lesions per high-power field in the 4D model seeded with the H460 cell line and LFs compared with H460 alone on day 15 (p = 0.008) or compared with H460 and CAFs (p = 0.002). This relationship was also seen with A549 and H1299 tumor cells. Moreover, the H460 cell line treated with conditioned media from the 4D model seeded with LFs had significantly fewer metastatic lesions than the 4D model seeded with CAFs. This was also seen with two other pairs of human fibroblasts obtained from patients. CONCLUSIONS: The secreted factor from LFs grown on the 4D model inhibits the formation of metastatic lesions. The 4D model may be used to determine the role of different components of the tumor's microenvironment in metastatic lesion formation, and this secreted factor may provide a novel therapy for treatment of cancer metastasis.

Validation of multiple whole slide imaging scanners based on the guideline from the College of American Pathologists Pathology and Laboratory Quality Center.

CONTEXT: Whole slide imaging (WSI) produces a virtual image that can be transmitted electronically. This technology has clinical applications in situations in which glass slides are not readily available. OBJECTIVE: To examine the results of a validation study performed using the draft version of the WSI clinical validation guideline recently released by the College of American Pathologists. DESIGN: Ten iScan Coreo Au scanners (Ventana Medical Systems, Tucson, Arizona) were validated, 6 with one set of 100 cases and 4 with a different set of 100 cases, for 1000 case examinations. The cases were selected consecutively from the following case types: internal consultations and malignancies and cases with frozen sections, special stains, and/or immunohistochemistry. Only key slides were scanned from each case. The slides were scanned at ×20 magnification. Pathologists reviewed the cases as both glass slides and WSI, with at least a 3-week washout period between viewings. RESULTS: Intraobserver agreement between glass slides and WSI was present for 786 (79%) of the 1000 cases. Major discrepancies occurred in 18 cases (1.8%). κ statistics compiled for the subset of cases (n = 504; 50%) with concern for neoplasia showed excellent agreement (κ = 0.8782). Individual scanners performed similarly to one another. Analysis of the results revealed an area of concern: small focal findings. CONCLUSIONS: The results were felt to validate the use of WSI for the intended applications in our multiinstitutional laboratory system, although scans at ×20 magnification may be insufficient for cases hinging on small focal findings, such as microorganisms and inflammatory processes.

Glandular Lesions of the Cervix in Clinical Practice: A Cytology, Histology, and Human Papillomavirus Correlation Study From 2 Institutions.

CONTEXT: The Papanicolaou (Pap) test has indisputably decreased cervical cancer mortality, as rates have declined by up to 80% in the United States since its implementation. However, the Pap test is considered less sensitive for detecting glandular lesions than for detecting those of squamous origin. Some studies have even suggested an increasing incidence of cervical adenocarcinoma, which may be a consequence of a relatively reduced ability to detect glandular lesions with cervical cancer screening techniques. OBJECTIVE: To evaluate the detection rate of glandular lesions with screening techniques currently used for cervical cancer screening and to provide insight as to which techniques are most efficacious in our study population. DESIGN: We retrospectively reviewed any available cytology, human papillomavirus (HPV), and histologic malignancy data in patients diagnosed with adenocarcinoma in situ and adenocarcinoma from 2 geographically and socioeconomically disparate hospital systems. Identified patients having had a negative/unsatisfactory Pap test within 5 years of adenocarcinoma in situ or adenocarcinoma tissue diagnosis were considered Pap test screening failures. Patients with negative HPV tests on cytology samples were considered HPV screening failures. RESULTS: One hundred thirty cases were identified (age range, 22-93 years); 39 (30%) had no Pap history in our files. Eight of 91 remaining cases (8.8%) were screening failures. The detected sensitivity for identifying adenocarcinoma in situ/adenocarcinoma in this study was 91.2% by cytology alone and 92.3% when incorporating HPV testing. The most common cytologic diagnosis was atypical glandular cells (25 cases), and those diagnosed with adenocarcinoma were 7.4 years older than those diagnosed with adenocarcinoma in situ (50.3 versus 42.9 years). Nine of 24 HPV-tested cases (37.5%) were called atypical squamous cell of undetermined significance on cytology. CONCLUSIONS: Our results highlight the importance of combined Pap and HPV cotesting. Although the number of cases identified is relatively small, our data suggest screening for squamous lesions facilitates the recognition of glandular lesions in the cervix. Additionally, increased use of combined Pap and HPV cotesting may decrease detection failure rates with regard to glandular lesions.

Ex vivo four-dimensional lung cancer model mimics metastasis.

BACKGROUND: We have developed a four-dimensional (4D) lung cancer model that forms perfusable tumor nodules. We determined if the model could be modified to mimic metastasis. METHODS: We modified the 4D lung cancer model by seeding H1299, A549, or H460 cells through the trachea only to the left lobes of the acellular lung matrix. The model was modified so that the tumor cells can reach the right lobes of the acellular lung matrix only through the pulmonary artery as circulating tumor cells (CTC). We determined the gene expressions of the primary tumor, CTCs, and metastatic lesions using the Human OneArray chip. RESULTS: All cell lines formed a primary tumor in the left lobe of the ex vivo 4D lung cancer model. The CTCs were identified in the media and increased over time. All cell lines formed metastatic lesions with H460 forming significantly more metastatic lesions than H1299 and A549 cells. The CTC gene signature predicted poor survival in lung cancer patients. Unique genes were significantly expressed in CTC compared with the primary tumor and metastatic lesion. CONCLUSIONS: The 4D lung cancer model can isolate tumor cells in 3 phases of tumor progression. This 4D lung cancer model may mimic the biology of lung cancer metastasis and may be used to determine its mechanism and potential therapy in the future.

The clinical impact of including pictures in Papanicolaou test reports.

INTRODUCTION: Although the inclusion of representative photomicrographic images in pathology reports remains uncommon, the frequency has increased in recent years. The impact of the inclusion of pictures has not previously been examined in peer-reviewed literature. MATERIALS AND METHODS: We compared the Papanicolaou (Pap) test interpretations produced by our laboratory before and after the introduction of a requirement to include pictures in reports with interpretations of low-grade squamous intraepithelial lesion (LSIL); atypical squamous cells, cannot rule out high-grade squamous intraepithelial lesion; high-grade squamous intraepithelial lesion; atypical glandular cells; or carcinoma. Atypical squamous cells of undetermined significance (ASC-US) did not require a picture, creating an incentive to interpret borderline cases as ASC-US instead of LSIL. We compared 1810 Pap tests from before the picture requirement to 1807 after. RESULTS: The number of cases upgraded by the pathologists from a cytotechnologist interpretation of negative or ASC-US to one of the positive interpretations requiring a picture decreased from 99 in the prepicture era to 80 in the picture era (P = 0.19). Conversely, the number of cases downgraded by the pathologists increased from 65 to 98 (P = 0.015). The ASC-US to LSIL (ASC-SIL) ratio for the laboratory went from 0.92 to 1.45. CONCLUSIONS: The introduction of a picture requirement in Pap test reports significantly affected the practice of pathologists in our laboratory. The ASC-SIL ratio of the laboratory shifted toward the national mean in association with this change.

Circulating tumor cells from 4D model have less integrin beta 4 expression.

BACKGROUND: Currently, there is no in vitro or ex vivo model that can isolate circulating tumor cells (CTCs). Recently, we developed a four-dimensional (4D) lung cancer model that allows for the isolation of CTCs. We postulated that these cells have different properties than parental (2D) cells. MATERIALS AND METHODS: We obtained CTCs by growing A549, H1299, 393P, and 344SQ cell lines on the 4D lung model. The CTCs were functionally characterized in vitro and gene expression of the cell adhesion molecules was compared with respective 2D cells. Integrin beta 4 (ITGB4) was further investigated by stably transfecting the A549 and H1299 cells. RESULTS: We found that all cell lines produced CTCs, and that CTCs from the 4D model were less adherent to the plastic and have a slower growth rate than respective 2D cells (P < 0.01). Most of the cell adhesion molecules were downregulated (P < 0.05) in CTCs, and ITGB4 was the common molecule, significantly more underexpressed in CTCs from all cell lines than their respective 2D cells. The modulation of ITGB4 led to a differential function of 2D cells. CONCLUSIONS: CTCs from the 4D model have different transcriptional, translational, and in vitro characteristics than the same cells grown on a petri dish, and these CTCs from the 4D model have the properties of CTCs that are responsible for metastasis.

Validation of a novel robotic telepathology platform for neuropathology intraoperative touch preparations.

BACKGROUND: Robotic telepathology (RT) allows a remote pathologist to control and view a glass slide over the internet. This technology has been demonstrated to be effective on several platforms, but we present the first report on the validation of RT using the iScan Coreo Au whole slide imaging scanner. METHODS: One intraoperative touch preparation slide from each of 100 cases were examined twice (200 total cases) using glass slides and RT, with a 3 week washout period between viewings, on two different scanners at two remote sites. This included 75 consecutive neuropathology cases and 25 consecutive general surgical pathology cases. Interpretations were compared using intraobserver variability. RESULTS: Of the 200 total cases, one failed on RT. There were 47 total interpretive variances. Most of these were the result of less specific interpretations or an inability to identify scant diagnostic material on RT. Nine interpretive variances had potentially significant clinical implications (4.5%). Using the final diagnosis as a basis for comparison to evaluate these nine cases, three RT interpretations and three glass slide interpretations were considered to be discrepant. In the other three cases, both modalities were discrepant. This distribution of discrepancies indicates that underlying case difficulty, not the RT technology, probably accounts for these major variances. For the subset of 68 neoplastic neuropathology cases, the unweighted kappa of agreement between glass slides and RT was 0.68 (good agreement). RT took 225 s on average versus only 71 s per glass slide. CONCLUSIONS: This validation demonstrates that RT using the iScan Coreo Au system is a reasonable method for supplying remote neuropathology expertise for the intraoperative interpretation of touch preparations, but is limited by the slowness of the robotics, crude focusing, and the challenge of determining where to examine the slide using small thumbnail images.

Circulating tumor cells from a 4-dimensional lung cancer model are resistant to cisplatin.

OBJECTIVE: To determine the effect of cisplatin on circulatory tumor cells (CTC) and tumor nodules in a four-dimensional (4D) lung cancer model. METHODS: CTCs from the 4D model seeded with H1299, A549, or H460 and respective cells that were grown under two-dimensional conditions in a Petri dish were treated with 50 µM cisplatin for 24 and 48 hours and cell viability was determined. The lung nodules in the 4D model were then treated with different continuous or intermittent doses of cisplatin and the nodule size, the number of CTCs, and the level of matrix metalloproteinase (MMP) were determined. RESULTS: Cisplatin led to a significant decrease in the viability of tumor cells grown under 2D conditions (P < .01) but not in CTCs from the 4D model after both 24 hours and 48 hours. Cisplatin led to regression of tumor nodules with both the continuous and intermittent treatments. Moreover, there was a significantly higher number of CTCs per tumor area (P < .05) and MMP-2 production per tumor area (P = .007) for all human lung cancer cell lines grown in the 4D model when treated with cisplatin. CONCLUSIONS: The 4D lung cancer model allows for the isolation of CTCs that are resistant to cisplatin treatment. The model may allow us to better understand the biology of cisplatin resistance.