2015

Introducing the SCIEX IVD-MS™ Kit for 25-OH-Vitamin D3/D2 in Serum/Plasma for routine Vitamin D analysis

Introduction

The following information outlines the instrument performance and expected results obtainable from the SCIEX IVD-MS™ Kit for 25-OH-Vitamin D₃/D₂ in Serum/Plasma when using an AB SCIEX API 3200MD™ or 3200MD QTRAP^® LC/MS/MS system. This reagent kit is intended for in vitro diagnostic use for the quantification of the main metabolites of vitamin D₃ and D₂, 25-Hydroxycholecalciferol and 25-Hydroxyergocalciferol, in patient serum and plasma samples by LC-MS/MS (liquid chromatography-tandem mass spectrometry).

Calibration is performed using a lyophilized multilevel plasma calibrator set of known concentration. Lyophilized plasma control samples at clinically relevant low and high concentrations serve to establish the target analyte range. The method uses a deuterated 25-OH- Vitamin D₃ as an internal standard to correct for sample and instrument variability. Samples are analyzed using an atmospheric pressure chemical ionization (APCI) source for maximum sensitivity.

Figure 1: Example Chromatogram for SCIEX calibrator level 2 as expected on an AB SCIEX 3200MD QTRAP® system with a Shimadzu LC system using the SCIEX IVD-MS™ Kit for 25-OH-Vitamin D3/D2 in Serum/Plasma. Please note the SCIEX IVD-MS™ Kit for 25-OH-Vitamin D3/D2 in Serum/Plasma is not available in all geographic locations. Please see www.sciex.com/IVD-MS-kits for details.

Separation is performed using a SCIEX IVD-MS™ 25-OH-Vitamin D₃/D₂ analytical and trap column in conjunction with the HPLC configuration defined in system requirements below for an overall LC run time of 5.0 minutes. This method was evaluated using SCIEX IVD-MS™ 25-OH-Vitamin D₃/D₂ multilevel calibrators. Control sample responses were obtained at clinically relevant low and high 25-OH-Vitamin D₃ and 25-OH-Vitamin D₂ concentrations. %CV values for the target analytes were obtained using 10 replicates at these low and high concentrations. The achieved lower limits of quantification (LLOQ) for each analyte are given in the Performance Criteria below.

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On-line Quality Control Measurements in Varying Conditions

Introduction

Even as advances in engineering technologies and manufacturing processes have lowered the cost to make and distribute products, the demand for continued improvement is as strong as ever. In an environment where small improvements in characterization of raw materials or subtle changes in process parameters can result in significant production savings, the ability to design faster, smarter and more robust instrumentation is paramount.

When the emergence of miniature spectrometers coincided with development of modular fiber optics, spectroscopy was no longer limited to the lab. Now you can bring the instrument to the sample, which allows industrial users to integrate the measurement into the process. Small-footprint modular systems can be rapidly configured for a variety of absorbance, reflectance and emission measurements, with a number of potential applications. The Flame spectrometer addresses some of the limitations associated with miniature spectroscopy systems in dynamic process environments.

Measurement Conditions

To evaluate the effectiveness of the Flame spectrometer at different temperatures, we measured transmission of several concentration levels of food dye mixtures on a simulated process line with simulated conditions encountered in a process environment. Then we isolated each Flame spectrometer in a different temperature environment – cool (using a chiller), ambient and hot (using a lab heater). Several sample mixtures were prepared for testing, using the Z-type flow cell to move each sample through the system. Water moving through the flow cell was measured as a reference (Figure 1).

Results

Although the Flame spectrometers measured the transmission of the mixtures flowing through the system at different temperature conditions, the resulting spectra – and sample composition information derived from the spectra – were nearly identical (Figures 2, 3). This result is significant for process line applications, where temperatures can vary from zone to zone within the stream. For quality control professionals, getting the correct answers under all sorts of conditions -- including temperature extremes -- is critical.

Conclusions

Process environments can be harsh, with extremes in temperature and humidity, and the harmful effects of dust and vibration. That’s why process-ready spectroscopic instrumentation such as Flame has been designed with few moving parts, has a high degree of thermal stability, and is easily adapted for different setups. The availability of such robust, repeatable, thermally stable instrumentation allows manufacturers to assess sample quality online at multiple points in processes, helping to improve yields, eliminate waste and reduce costs.

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Visualizing the Cancer Transcriptome

Summary

Cancer is a disease of aberrant gene expression, and delineating the critical gene expression events during cancer development and progression is vital for cancer research. Here we summarize the role of novel RNA in situ hybridization technology in expanding the tool set available to researchers, thereby overcoming the challenges of cancer research in four key areas:

1. Understanding tumor heterogeneity in gene expression
2. Studying non-coding transcripts
3. Developing biomarkers
4. Driving and refining the diagnostic strategies of the future

Cancer is becoming an increasingly critical medical challenge, with the number of new cases expected to rise by about 70% globally over the next two decades.1 Since this disease essentially arises on the genomic level, investigating the tumor’s genomic and transcriptomic landscape is invaluable for both basic and translational cancer research.

Cutting-edge research employs a range of approaches to unravel the complexities of cancer, looking at the disease from all levels – the genome, the transcriptome, and the proteome. Over recent years, cancer transcriptomic profiling programs have proven that, like protein, RNA is a rich source of biomarkers for diagnosis, prognosis and predicting therapeutic response (recently coined as theranosis).2,3 Indeed, the significance of RNA within the cell has become increasingly apparent, with many discoveries indicating structural and regulatory functions. Alongside our growing understanding of RNA, methods for the analysis of this molecule are also evolving. The evolution of Next Generation Sequencing (NGS) technology over the past 10 years has offered cancer researchers the ability to look at the cancer genome and transcriptome, while PCR has offered researchers the ability to determine gene expression levels averaged across heterogeneous cell populations. However, up until now, a lack of robust methods for in situ analysis of RNA transcripts has held back the potential of RNA studies in cancer research. With the latest developments in RNA in situ hybridization (RNA ISH), however, this situation is changing.

Why RNA?

Cellular physiology involves many components besides RNA, and it is common to study cancer at the level of DNA and protein. So why focus on RNA? The cancer genome: Gross changes (gene amplifications, deletions and gene rearrangements) in the genome can be detected in situ using fluorescence in situ hybridization (FISH), but looking at DNA only provides limited information. The cancer transcriptome: Not merely a messenger, RNA is a versatile and functionally significant molecule, reflecting the dynamic nature of a cancer cell. Novel RNA ISH techniques are quickly realizing this potential. The cancer proteome: Proteins are the final products of protein-coding genes in the genome, and their analysis can provide a wealth of insights. However, antibody-based detection is limited. Only 33% of 60,000 human genes code for proteins,4 and as antibodies have variable levels of sensitivity and specificity, high quality antibodies are not available for the majority of proteins.

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Specific Detection of Inflammation Markers with Tissue Context Using RNAscope® Technology

Introduction

Understanding molecular mechanisms is critical for identifying pathogenesis, evaluating disease progression and developing new therapeutic strategies for autoimmunity, infectious diseases, and cancer. RNAscope^® in situ hybridization (ISH) technology enables precise cell- and tissue-specific localization of RNA transcripts. With RNAscope^® ISH assays, you can detect specifically expressed immune markers in lymphoid and non-lymphoid tissues while maintaining the morphological context. For example, RNAscope^® chromogenic in situ hybridization (CISH) robustly identified the expression pattern of CD274 mRNA in formalin-fixed paraffin-embedded (FFPE) kidney cancer tissue (Figure 1).

FIGURE 1. CD274 mRNA expression in a FFPE human kidney tumor tissue using the RNAscope® 2.0 HD Reagent Kit -BROWN. Each brown spot represents a single CD274 mRNA.

FIGURE 2. IL6 mRNA expression in FFPE human lung cancer tissue using the RNAscope®2.0 HD Reagent Kit –RED. Each red spot represents a single IL6 mRNA.

Visualization of any RNA

In the past few decades, the field of immunology benefited greatly from emergent immunoassays, flow cytometry and immunohistochemistry. However, these assays are limited by the availability and specificity of antibodies. With RNAscope^® ISH technology, one can assess the expression of any genes in any species. RNAscope_® ISH is particularly powerful in detecting mRNA of low-expressing or secreted proteins (Figure 2), as well as targets to which specific antibodies are not available.

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Trends and outlook for clinical diagnostics testing

Summary

Clinical diagnostic tests have traditionally involved antibody-based recognition of proteins or disease markers, but these immunoassays are prone to both false negative and false positive results, and cannot detect numerous disease markers in one test. In recent years there has been growing interest in using more accurate, efficient and reliable technologies such as mass spectrometry. Despite the important scientific advantages of such technologies, many clinical diagnostics scientists have continued to use traditional immunoassays, due to perceived barriers such as the need for investment and expertise in mass spectrometry (MS) technologies. This report describes the results of a recent independent survey of clinical diagnostics scientists worldwide. The survey explored respondents’ current diagnostic assays, instrument and reagent usage; conference attendance; purchasing behaviours and future technology needs. Key findings from the survey showed that the majority of respondents still use immunoassay-based diagnostics and around one third use liquid chromatography with tandem mass spectrometry (LC-MS/MS). There was broad awareness of MS techniques, with a greater proportion intending to purchase MS platforms rather than immunoanalyzers over the next 12 months. However, the majority of respondents said they did not fully understand the concepts or have expert knowledge of MS technologies, despite using these technologies in their labs. Therefore there is an urgent need for improved understanding of MS in clinical labs, so that more scientists can adopt these technologies for more accurate and confident diagnostics.

Introduction

Clinical diagnostics tests are carried out in hospital laboratories, Physician Office Labs and CLIA Labs (or equivalent European labs) worldwide, through analysis of human blood and other tissue samples. These in vitro diagnostic (IVD) tests are typically carried out to detect wide-ranging diseases and conditions such as cystic fibrosis, metabolic disorders and vitamin D deficiency, and to monitor levels of drugs in patients, including therapeutic drugs and immunosuppressants, as well as drugs of abuse. For many years, clinical scientists have used immunoassays such as ELISAs (enzyme-linked immunosorbent assays) for diagnostics. More recently, however, there has been growing concern about the accuracy of immunoassays for diagnostics. In particular, immunoassays are susceptible to interference that can lead to both false negative and false positive results, which can have serious impacts on patient care as well as increasing costs and labor burdens for health authorities^1-3. Immunoassays can also show variation in results, between labs using the same assays as well as between different assays⁴. Furthermore, immunoassays are not always able to detect certain metabolites or can even over-estimate their levels, which can complicate diagnosis of conditions such as vitamin D deficiency that depend on accurate detection of both the vitamin D₂ and D₃ 25-OH metabolites⁵. These concerns have driven the development of alternative testing methods based on mass spectrometry techniques, which offer higher accuracy and robustness than immunoassays. Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is particularly powerful for high-resolution separation, identification and quantitation of proteins and peptides, even at very low levels of expression. LC-MS/MS methods are also very versatile and can be developed rapidly for the analyte of interest; moreover numerous proteins can be detected and quantified in a single run, saving considerably on precious samples, as well as time, labor and reagent costs. These benefits for diagnostics are clear, but clinical laboratories have been slow to adopt LC-MS/MS. Part of the reluctance to switch technologies may be attributed to a traditional perception that only mass spectrometry experts could run the instruments and analyse results. Accordingly, instrument providers have made a number of developments to improve the simplicity, ease-of-use and robustness of LC-MS/MS systems in recent years. These include the introduction of in vitro diagnostic (IVD) MS analyzers and reagents kits that have been CE marked to the European in vitro diagnostics Directive (98/79/EC), and registration of the MS analyzers as general medical devices in other selected countries around the world. These products are developed specifically to be safe and effective for routine clinical diagnostics laboratories, and designed to bring down costs by delivering accurate, rapid and reliable results.

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Thermo Scientific Excelsior Tissue Processors offer performance, safety and savings for Torbay Hospital.

Summary

Torbay Hospital is a leading screening centre for bowel cancer and a regional training centre for NHS consultants. In 2014, the histopathology department experienced a twelve percent increase in cases over the previous year. The efficiency of Thermo Fisher™ Excelsior™ tissue processors helped the hospital keep up with the increased demand and meet targeted turnaround times – all in a cost effective and reliable manner.

Profile

As part of the South Devon NHS Foundation Trust, Torbay Hospital serves a population of approximately 370,000 people, with a service area from South Dartmoor, England to the coast stretching from Dawlish to Dartmouth. In 2006, it became one of the first screening centres for bowel cancer and is now a regional training centre for NHS consultants for early detection. The histopathology department is a vital resource for the hospital and in 2014 experienced a twelve percent increase in the number of cases over the previous year. With such a high demand, and the associated pressures to meet targets for turnaround time, it is vital that tissue processing instrumentation is both cost effective and reliable.

Maximising productivity – minimising costs

Nigel Kenneison is the Histopathology Manager at South Devon, overseeing this busy, but highly efficient, department. For the last eleven years, they have relied upon Thermo Scientific’s Excelsior ES tissue processors. Since his appointment to the role in November 2003, Nigel has maximised productivity while greatly reducing costs.  Last year they dealt with over 21,000 new cases and, with a dedicated team of seventeen staff comprising different grades and full/part time roles, they processed over 48,000 blocks of tissue in the lab. When Nigel joined South Devon, they were utilising two older tissue processors. The department was spending a great deal of money on processing reagents, changing them three times per week – a costly and very time consuming process. When Nigel made the decision in 2004 to replace the processors he was keen to trial the available instruments in the market to decide which would be most suitable. He explains, “We trialled three instruments at the same time. We will always look at a piece of equipment before we purchase. Is it reliable and easy to use? Is it easy to change reagents? Does it do what it says on the box?”

Excelsior – proven against the competition

During the trial the Excelsior proved its worth and two instruments were purchased. “It was easier to use and cheaper compared to anybody else’s on the market at the time”, comments Nigel. “It was innovative because you didn’t have pipes sticking out and, with the auto rotation, reagent change is easy. Waste reagent is discarded and you only need to change two 5-litre containers and put two new one in. It is very easy to use.” Nigel also recognises the importance of the health and safety of his staff. The ease and speed of reagent changes with the Excelsior minimise chemical exposure. Additionally, downdraft fume control and filters for Formalin and solvent vapours maximise safety. The all-enclosed system and fire-resistant cabinet are also useful, especially in a portacabin where the histopathology department is based. Ease of use and reduction of reagent usage are just two of the key features of the Excelsior tissue processor. When you are running a busy laboratory it is vital that instrumentation is straightforward and requires minimal maintenance and downtime. As Nigel comments, “All tissue processors do the job of processing tissue, but the Excelsior’s ease of use and maintenance makes the day easier and more controllable.” All of the tissue processing at South Devon is done overnight and the workflow is very efficient. Furthermore, they always achieve their targets for turnaround times. Nigel again comments, “The national requirements guidelines target is 90% on-time turnaround – our laboratory averages 98%. In fact last month we reported 52% of samples within three calendar days. We have a good, smooth operation and very good staff.”

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Remote intra-operative diagnosis in neurosurgery

Excerpt from an article by Graham McHardy CSci FIBMS Department of Pathology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, UK. Full article originally published in Hospital Healthcare Europe 2015 The introduction of digital slide scanning for remote reporting has restored an important service for patient healthcare at a Scottish hospital

Telepathology is the process of digitising histological images for transmission electronically to remote centres, often for the purposes of diagnosis. Some telepathology systems employ robotic microscopes, which can be controlled remotely in order to select microscopic fields and to adjust magnification and focussing. This type of system may suffer from delays due to slowness and lags in the robotics.¹ The Aperio system from Leica Biosystems described in this report uses Whole Slide Imaging (WSI) to produce a complete digital representation of the tissue. The images produced by WSI are stored on a local server, which can be accessed by remote users who have been granted the required access level. The images are viewed at the remote site on a computer screen, with the remote user having complete control of selection of fields across the entire slide. In a comparison of WSI with conventional microscopic interpretations of frozen sections of ovary, Fallon et al concluded that WSI is accurate, reproducible and reliable for remote reporting.²

Frozen section is a well-established procedure for the intra-operative reporting of urgent biopsies. These cases are treated urgently with the aim of producing stained sections as quickly as possible so that a report may be relayed to the surgeon while the patient is still in theatre. In neuropathology, it is also common for fresh smears to be produced instead of, or as well as, frozen sections. In some centres, ‘touch’ preparations of fresh neurosurgical specimens have also been used.¹ Fresh neurosurgical tissue, including some types of tumour, is usually soft and amenable to the production of smears quickly and easily, providing, in most cases, relatively flat layers of cells. Some specimens however, are more fibrous, for example, Schwannomas, and might be less suitable for smear preparations.³ Despite this, it was also reported that the thickness of smears does not impose an impediment to diagnosis, as many thinner areas of the slide will be available for study.³ Promptly fixed and stained smears usually provide excellent cellular and nuclear detail that is probably superior to that of frozen sections, although the latter have the advantage of retaining the architectural detail of the tissue. Also, although frozen sections are usually suitable for a wide range of neurosurgical tissues, they are more time-consuming to prepare compared with smears. In our department, both frozen sections and smears are usually prepared to give a ‘best of both worlds’ protocol, but this may vary according to several factors including the clinical details, and the type and quantity of specimen received. Also for consideration is the availability of follow-on formalin-fixed tissue, which is used to prepare higher quality formalinfixed, paraffin-embedded sections at a later time.

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Aperio RNA ISH Algorithm Validation

Abstract

RNA ISH (Ribonucleic acid in situ hybridization) assays are an ever-expanding application due to the ability to evaluate molecular targets with the added benefit of retaining tissue morphology. The rate limiting step in RNA ISH assays is the time consuming and error prone method of manually counting signal when reviewing under a microscope. The Aperio RNA ISH algorithm offers a reproducible, fast, and quantitative method of evaluating tissue samples which have been stained to detect RNA ISH signal. This single algorithm can be used on numerous tissue types for both single and dual-plex assays.

Within this paper, we describe a validation study, which was performed in order to verify the correlation between the Aperio RNA ISH algorithm and the current gold standard method of manual interpretation. A total of 30 digital slides ranging in tissue source and assays types were scored manually by a scientist and the resulting data were correlated with scores obtained from the Aperio RNA ISH algorithm. In both modalities, the number of cells, count of signal within the cell, and signal in all tissue were recorded. The high level of correlation between the two methods (>R2 0.99) confirm that automated image analysis can be used as a fast and reproducible alternative to the traditional methods of manual interpretation.

Introduction

RNA ISH is a rapidly growing method for the analysis of molecular targets within tissue samples. It enables identification of individual copies of targets, whilst maintaining tissue morphology, a feature which is lost in other methods such as PCR¹. RNA ISH technology is being used in many areas of cancer research today^2-5. In addition, there is the potential benefit of being able to combine RNA ISH assays with traditional IHC assays, thereby enabling users to be able to visualize both RNA and protein status on a single slide6. Manual interpretation of RNA ISH signal is time-consuming and typically reverts to the semi-qualitative approach of ordinal scores (0, 1+, 2+, 3+), which often mask discrete cohorts that are readily identifiable when quantitative analysis is performed. Moreover, manual reads are subject to inter- and intra-observer variability, resulting in a lack of reproducibility and standardization in formalin fixed paraffin embedded tissue staining interpretation^7–10. The Aperio RNA ISH algorithm identifies and counts single or dual-plex chromogenic signals and will distinguish whether the expression is within the nuclei or cytoplasmic cellular compartments of FFPE tissue. It has been optimized for usage on brightfield digital slides from Aperio scanners or the Ariol System, at both 20x and 40x resolution. Individual signals or clusters of signals can be identified within the subcellular compartments, in uncategorized tissue (i.e. tissue not identified as a nuclei or cytoplasm) or across all tissue within the sample. The resulting data provides quantitative numerical counts of cells, signals and clusters. In addition, a semi-quantitative score is also generated by the algorithm, RNA ISH Score (0, 1+, 2+, 3+, 4+). Herein, we describe the validation study which was performed in order to ensure the Aperio RNA ISH algorithm correlates with the current gold standard of manual interpretation.

Methods & Materials

A total of 30 FFPE whole tissue sections were gathered, from human and animal sources (kidney, liver, prostate, breast, small intestine, head and neck, ovarian cell lines, colon, placenta, skin, and rat kidney). Tissue sections were stained with single-plex RNA ISH probes (Red, Brown or Green chromogens) or dual-plex (Red/Brown, Brown/Green chromogens) either manually or on the BOND RX IHC/ISH stainer.

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Significant cost savings and optimized workflow efficiencies with one vendor consolidation.

Introduction

Pathology laboratories in the United States are facing dramatic changes. Balancing the demands for personalized medicine with the quality and economic requirements implemented as part of the Affordable Care Act is a tough challenge even for the most efficient labs. Labs need new solutions to achieve the requirements of greater accountability, quality and efficiencies while lowering costs. Labs are also looking for solutions that will meet the high quality preparation, staining and image analysis of tissue specimens required for many of today’s biomarker tests related to personalized medicine. All of these changes must be addressed in the face of shifting from a fee-forservice structure to a value-based reimbursement model.

Pathology, Inc. is an independent laboratory in Southern California with subspecialties in anatomic and molecular pathology. It has experienced rapid growth over the past few years, but with industrywide cuts in reimbursement, the lab has sought solutions to help maximize its workflow, reduce labor and reagent costs, and still maintain the high quality its clients know and trust.

As part of the answer, Pathology, Inc. chose to consolidate the majority of its histology laboratory instruments and add digital Pathology, Inc – Torrance, California pathology using Leica Biosystems end-to-end solutions. By working with one vendor with whom it can order, install, validate and train, Pathology, Inc. has been able to realize increased workflow efficiencies and significant cost savings: »» Tissue processing with the PELORIS II has provided 50% labor and 70% reagent savings annually.
»» Utilization of the BOND-III immunoshistochemistry (IHC) stainers has provided combined labor and reagent savings of over $250,000 per year and reduced per slide cost by 50%.
»» The implementation of automated image analysis has reduced pathologist review time for Immunohistochemistry (IHC) slides by 66% (7-10 minutes vs. 30+ minutes). By consolidating histology instrumentation with one vendor, Pathology, Inc. was able to achieve efficiency and economic benefits through a single source solution. In addition, the lab has maximized workflow, reduced costs while maintaining quality, and ensured rapid turnaround time required for today’s patient results.

Case Study

Pathology, Inc. began providing full service, anatomic and molecular services in Southern California in 1979. Pathology, Inc. has a strong commitment to innovation and value-added services that can provide comprehensive diagnostic and prognostic information for treatment planning. The laboratory’s primary focus is Women’s Health, but it also offers pathology services in other subspecialties. With this breadth of offerings, its histology and IHC departments have seen rapid growth. Approximately 1,000 tissue blocks are processed and 300 IHC stains are performed per day. Like many labs, Pathology, Inc. has been faced with challenges to work more efficiently due to the changes in healthcare delivery and decreasing reimbursement. “Changes over the last year and impending changes next year are resulting in a significant reduction in reimbursement and driving profits down,” noted Dennis Sevilla, PhD, Senior Vice President,Laboratory Operations. “This downward trend will force independent labs like Pathology, Inc. to become more efficient and leaner as consolidation within the industry increases.” As a part of its strategy to meet these challenges and continue to provide high quality services as well as required turnaround times, the laboratory looked for flexible and cost-saving solutions in tissue processing and staining. In addition, the laboratory wanted to initiate digital pathology and image analysis. Hence, Leica Biosystems was the chosen solution provider.

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Leica Biosystems CEREBRO automated sample tracking

Summary

East Kent Hospitals University NHS Foundation Trust (EKHUNFT) is one of the country’s largest NHS Hospital Trusts, serving a population of 759,000 comprising five hospital sites: Buckland Hospital, Dover; Kent and Canterbury Hospital, Dover; Queen Elizabeth The Queen Mother Hospital, Canterbury; Royal Victoria Hospital, Margate; Folkestone and the William Harvey Hospital, Ashford.

The Cellular Pathology department provides a centralised service for the population of East Kent located at the William Harvey Hospital, Ashford. The laboratory provides a routine histopathology service and Tables 1 and 2 show average weekly slide production and annual workload, respectively. To maintain and keep up with this growing workload (6% per annum), we apply Lean principles and embrace modern technology wherever possible to provide a safe and efficient service, which includes digital voice recording, speech recognition and specimen tracking.

Histology remains traditionally a collection of predominantly manual processes easily divided into definable and auditable stages. Prior to CEREBRO of 2014 (Figures 1–4). The CEREBRO pilot had proven it was able to significantly improve patient safety and facilitate the management of the workflow with effective monitoring of each part of the process.

Fig. 1: CEREBRO terminal with barcode printer used for printing specimen accession numbers or slide labels Fig. 2: Leica IPC barcode cassette printer used at grossing to produce barcoded cassettes Fig. 3: Microtome station with CEREBRO terminal and slide label printer Fig. 4: CEREBRO universal send out station

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