A.L. acknowledges a &#34;Margarita Salas&#34; postdoctoral contract (number 21-076), and MAM-T a &#39;Maria Zambrano&#39; research contract (number MAZ/2021/03 UP2021-021). Both contracts have been funded by the European Union-Next generation EU.

This method was developed through collaborative efforts involving different clinical services (Urology, Pathology, and the La Fe Hospital Biobank). The study was conducted in compliance with institutional, national, and international guidelines for human welfare, and it received approval from the Ethics Committee for Biomedical Research at the Instituto de Investigaci&#243;n Sanitaria Hospital Universitario y Polit&#233;cnico La Fe (Valencia, Spain). All samples were stored at the La Fe Hospital Biobank (PT13/0010/0026). The overall procedure is detailed in Figure 1.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/65635/65635fig01.jpg" /> 
Figure 1: Overall procedure scheme. Schematic representation of the stepwise procedure described in the protocol section. <a href="https://www.jove.com/files/ftp_upload/65635/65635fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
1. Tumor targeting
<ol>
	<li>Before surgery, utilize multiparametric or biparametric Magnetic Resonance Imaging (mpMRI or bpMRI)17,18 to locate the tumor and map its position within the prostate gland. Combine the information obtained from MRI with findings from transrectal ultrasound or rectal examination if the latter yields discordant results.</li>
	<li>To enhance tumor localization, review the results of preoperative ultrasound-guided and MRI-guided transrectal prostate biopsies. 
	&#8203;NOTE: In the diagnostic procedure for prostate cancer, biopsies are taken directly from the prostate via transrectal access. These biopsies include systematic sampling from the prostate (involving cylinders distributed all around the gland) and cylinders directly targeted to suspicious findings on MRI. To target the retrieval of these samples, transrectal ultrasound is used, which is combined with MRI findings in a cognitive manner (&#34;cognitive fusion&#34;) or with &#34;real MRI-ultrasound fusion software&#34; when available.</li>
</ol>
2. Radical prostatectomy and prostate collection
<ol>
	<li>Perform a standardized robotic-assisted radical prostatectomy through a transperitoneal approach, following the steps outlined by Huynh et al.19.
	<ol>
		<li>Start with abdominal access, insufflation, and camera port placement (see Table of Materials). Place the remaining five ports under direct vision. Set pneumoperitoneum to 12 mm.</li>
		<li>Release the bladder by incising the peritoneum and dissect the perirectal space.</li>
		<li>Open the pelvic fascia on each side.</li>
		<li>Perform a complete dissection of the anterior and lateral aspects of the prostate and bladder.</li>
		<li>Carry out the opening of the bladder neck, identify and section the proximal urethra to gain access to the posterior aspects of the prostate and bladder.</li>
		<li>Dissect the seminal vesicles and rectum space19.</li>
		<li>Dissect the lateral aspects of the prostate, sparing the neurovascular bundles.</li>
		<li>Ensure hemostasis of vessels in the retropubic space.</li>
		<li>Dissect the apex and section the distal urethra.</li>
		<li>Complete the vesicourethral anastomosis.</li>
		<li>Extract the prostate and perform the closure of the incision19.</li>
	</ol>
	</li>
	<li>Collect the fresh prostate in a dry container. It is crucial not to fix or paraffin-embed the sample specimen.</li>
	<li>Transport the fresh surgical specimen, which includes the entire prostate, to the Biobank for sample processing.</li>
</ol>
3. Prostate processing and sample collection
<ol>
	<li>Select targeted prostate zones for sampling based on tumor location information retrieved from preoperative mpMRI, preoperative biopsy results, and direct prostatectomy specimen palpation. Record this information on a form that includes patient identification data, prostate areas finally sampled, and the number of samples collected. 
	NOTE: When MRI findings, preoperative biopsy results, and direct prostatectomy specimen palpation are concordant, target all the samples to that or those locations (between 4 and 6 cylinders). If there is any discordance, increase the number of cylinders and separately target all zones that are suspicious of being affected by any of those methods.</li>
	<li>Use a disposable automatic needle (surgeon) to retrieve cylindrical samples from the selected areas (step 1.1). Then, identify (pathologist) the outer zone of the cylinder, clamp the cylinder with tissue forceps, place it on a slide, and mark the outer zone with tissue ink. Repeat this process with all cylinders taken.</li>
	<li>Place the collected cylinders horizontally on a sample holder disk (see Table of Materials) filled with cryostat embedding medium and transfer them to the microtome cooling platen for cutting.</li>
	<li>Once placed on the platen, attach the sample holder disk to the specimen chuck, and cut it with careful movements of the wheel following the next steps:
	<ol>
		<li>Use the optimal cutting temperature compound (OCT compound, see Table of Materials) to embed the tissue sample before frozen sectioning on a microtome-cryostat.</li>
		<li>Afterward, cut the sample using a cryostat-microtome at -25 &#176;C. Collect thin cylinder-shaped sections of tissue (10 &#181;m) onto treated microscope slides. Ensure to collect only a few microns of tissue to ensure an adequate amount of intact tumor tissue for storage in the Biobank.</li>
		<li>Gather two or three thin sections per slide and manually stain them to control the final coloration. The technician&#39;s eye ensures optimal staining, and any necessary re-staining can be done. Follow these steps
		<ol>
			<li>Fix slides in 96% ethanol, hydrate in distilled water, and stain with Harris hematoxylin (see Table of Materials) for 1 min to stain the nuclei. Remove excess hematoxylin by rinsing the slides with distilled water.</li>
			<li>Treat slides with 30% ammonium hydroxide to turn the hematoxylin blue. Remove excess solution with rinses of distilled water.</li>
			<li>Stain slides with eosin (see Table of Materials) for 30 s.</li>
			<li>Next, dehydrate the slides with increasing titrations of alcohol, clear with xylene (100%), and mount them with DPX (a mixture of distyrene, a plasticizer, and xylene, used as a synthetic resin mounting media that replaces xylene-balsam, see Table of Materials). During these steps, dip the slides into and remove them from the jar of Coplin solution.</li>
			<li>Finally, place a coverslip on top of the stained tissue and use a medium with a suitable refractive index (see Table of Materials) for viewing under a microscope.</li>
		</ol>
		</li>
	</ol>
	</li>
</ol>
4. Sample characterization
<ol>
	<li>Analyze the sample under a light microscope (pathologist), discriminating the areas of carcinoma and determining the Gleason score of the tumor. Document all these data and mark the precise tumor zones on the slides.</li>
	<li>During this step, label the slide with the precise location of the tumor and its respective Gleason Score20. Also, mark the location of PIN (Prostatic Intraepithelial Neoplasm) based on morphological identification.</li>
</ol>
5. Sample micro-macro-dissection and storage
<ol>
	<li>Clearly mark different histological components with distinct markers on the slide (pathologist) and directly correlate them with frozen tissue on the disk.</li>
	<li>Then, using a surgical blade, macro-micro dissect the areas of the sample marked on the slide within the OCT disc, dividing them into tumoral, peri-tumoral, PIN, and normal prostatic tissue.</li>
	<li>As the embedding medium begins to defrost, handle the tissue with forceps and place it into correctly labeled cryotubes. 
	NOTE: Carefully store each dissected fragment within the corresponding tube, following the histological diagnosis of the cryo-slices.</li>
	<li>Store the labeled cryotubes with fully characterized histological samples in the Biobank at -80 &#176;C for subsequent use in research studies. 
	NOTE: The steps described in this section can be performed by a trained technician under the supervision of the pathologist. The surgical specimen should be transported to the Biobank as soon as possible to prevent tissue and nucleic acid degradation. According to the reference guides, efforts must be made to avoid prolonged ischemia time (&#62;30 min)21. The samples can be kept in the Biobank indefinitely as long as the sample quality principles are maintained.</li>
</ol>

Protocol for Prostatectomy Specimen Mapping and Dissection

<ol>
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I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+2019+Genitourinary+Pathology+Society+(GUPS)+white+paper+on+contemporary+grading+of+prostate+cancer.">The 2019 Genitourinary Pathology Society (GUPS) white paper on contemporary grading of prostate cancer.</a> Archives of Pathology &amp; Laboratory Medicine. 145 (4), 461-493 (2021).</li><li>Zhang, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intratumor+heterogeneity+and+clonal+evolution+revealed+in+castration-resistant+prostate+cancer+by+longitudinal+genomic+analysis.">Intratumor heterogeneity and clonal evolution revealed in castration-resistant prostate cancer by longitudinal genomic analysis.</a> Translational Oncology. 16, 101311 (2022).</li><li>Haffner, M. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Genomic+and+phenotypic+heterogeneity+in+prostate+cancer.">Genomic and phenotypic heterogeneity in prostate cancer.</a> Nature Reviews Urology. 18 (2), 79-92 (2021).</li><li>Woodcock, D. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prostate+cancer+evolution+from+multilineage+primary+to+single+lineage+metastases+with+implications+for+liquid+biopsy.">Prostate cancer evolution from multilineage primary to single lineage metastases with implications for liquid biopsy.</a> Nature Communications. 11 (1), 5070 (2020).</li><li>Heo, Y. J., Hwa, C., Lee, G. H., Park, J. M., An, J. 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E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Robot-assisted+radical+prostatectomy:+a+step-by-step+guide.">Robot-assisted radical prostatectomy: a step-by-step guide.</a> Journal of Endourology. 32 (S1), S28-S32 (2018).</li><li>van Leenders, G. J. L. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+2019+International+Society+of+Urological+Pathology+(ISUP)+consensus+conference+on+grading+of+prostatic+carcinoma.">The 2019 International Society of Urological Pathology (ISUP) consensus conference on grading of prostatic carcinoma.</a> The American Journal of Surgical Pathology. 44 (8), e87-e99 (2020).</li><li>Liu, A., Collins, C. C., Diemer, S. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Biobanking+metastases+and+biopsy+specimens+for+personalized+medicine.">Biobanking metastases and biopsy specimens for personalized medicine.</a> Journal of Biorepository Science for Applied Medicine. 3, 57-67 (2015).</li><li>Ellervik, C., Vaught, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preanalytical+variables+affecting+the+integrity+of+human+biospecimens+in+biobanking.">Preanalytical variables affecting the integrity of human biospecimens in biobanking.</a> Clinical Chemistry. 61 (7), 914-934 (2015).</li><li>Arellano, H. L., Castillo, C. O., Metrebi&#225;n, B. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diagnostic+agreement+of+the+Gleason+score+in+needle+biopsy+and+radical+prostatectomy+and+its+clinical+consequences.">Diagnostic agreement of the Gleason score in needle biopsy and radical prostatectomy and its clinical consequences.</a> Rev M&#233;d Chile. 132 (8), 971-978 (2004).</li><li>. Concordancia en los valores de gleason en biopsia prost&#225;tica transrectal y en prostatectomia radical en pacientes con c&#225;ncer de pr&#243;stata del Hospital Cirujano Mayor Santiago T&#225;vara entre enero 2010 - junio del 2018 Available from: <a target="_blank" href="https://repositorio.urp.edu.pe/handle/20.500.14138/1886">https://repositorio.urp.edu.pe/handle/20.500.14138/1886</a> (2019)</li><li>Chavolla-Canal, A. 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The authors declare no conflict of interest.

In any research study, obtaining quality samples is an essential requirement to reduce systematic biases and obtain reliable results22. Therefore, control of preanalytical variables such as the temperature at which samples are processed and stored, the time elapsed from sample collection to storage, the use of sterilized materials, or the effects that the addition of preservatives or other additives can have on samples must be considered in any protocol involving biological samples. Not only is th...

Prostate cancer (PC) is the 2nd most frequent cancer in men and the 5th leading cause of death worldwide1. Patient treatment and prognosis depend on the staging and grading (Gleason score) of the tumor, as evidenced by the higher 5-year survival rates of localized and low-grade tumors (Gleason grade 6) (99%) compared to high Gleason grades and metastatic tumors (31%)2.
PC local relapse and treatment failure have been linked to the characteristic high genetic intratumor heterogeneity of this tumor type3. Additionally, PC is considered to be a multifocal disease with several tumor foci exhibiting different morphological, histological, and molecular characteristics4, which may originate independently or derive from a common tumor cell ancestor5. Previous studies have shown that tumor evolution differs among patients based on specific genetic drivers that can promote metastasis or confine the cell lineage to the prostate5. Therefore, molecular characterization of the different tumor foci is crucial not only for providing a more accurate diagnosis and prognosis but also for tailoring effective and personalized treatment for the patient.
In this context, biomedical research and integrative multi-omics approaches are offering unprecedented opportunities to classify cancers into different subtypes, identify diagnostic and prognostic biomarkers, and discover markers related to treatment response. Furthermore, these approaches contribute to a better understanding of the biology of this disease6,7. Biological samples, whether tissues or biofluids, can be analyzed using various multi-omics platforms (genomics, transcriptomics, proteomics, metabolomics, etc.) to uncover the biological features underlying cancer pathophysiology, thereby addressing current limitations related to genetic and phenotypic heterogeneity6. However, it&#39;s important to consider that the quality of data derived from omics studies depends on the quality of the samples collected from tumors, their accurate characterization, and subsequent processing and storage8.
In this context, obtaining fresh PC tissue for research presents a methodological challenge due to the difficulty of successful tumor sampling9. Previous methods involved random sampling following radical prostatectomy, yielding poor results10. However, more recent approaches incorporate targeted protocols based on both magnetic resonance imaging (MRI) and biopsy data, resulting in improved efficacy in tumor sample collection11.
On the other hand, histopathological characterization of samples prior to their storage without significant tissue alteration also poses an interesting challenge. Consequently, in many cases, the histopathological determination of samples is performed after their analysis (e.g., HR 1H NMR metabolomic analysis)12. This practice entails unnecessary expenses, time consumption, and the loss of a significant number of samples that are eventually excluded from the analysis (for example, samples that, following histopathological analysis, turn out not to be tumor samples). In other cases, the histopathological characterization of samples is performed before their analysis. In fact, some previous studies have attempted to standardize methods for providing representative high-quality research samples from radical prostatectomy specimens for genomics and metabolomics13,14. Nevertheless, sampling efficiency is significantly higher when performed from already histologically confirmed sections (88%) that disrupt tissue, compared to when performed from unconfirmed sections (45%)1.
Here, a new methodology is presented to overcome these limitations, aiming to obtain fresh and well-characterized PC samples before storage in the Biobank. This method has been developed through collaborative efforts between different clinical services (Urology, Pathology, and the La Fe Hospital Biobank). It&#39;s important to highlight that Biobanks play an essential role in the collection, processing, preservation, and storage of biological samples while ensuring the high quality of samples and data, as well as compliance with ethical and legal requirements8,15,16.

<table><tbody><tr><td>Cadiere forceps</td><td>Intuitive</td><td>PN1052082-US 10/2021</td><td>Part number: 471049. 18 uses.</td></tr><tr><td>Conventional slides</td><td>Knittel Glass</td><td>2021</td><td>Ground/ Frosted end</td></tr><tr><td>Cryostat microtome</td><td>Thermo Fisher Scientific</td><td>---</td><td>Criostato CryoStar NX50</td></tr><tr><td>Cryotubes</td><td>Greiner Bio-One GmbH</td><td>Ref.: 122280.</td><td>CRYO S. PP, with screw cap, sterile.&amp;nbsp;</td></tr><tr><td>Da Vinci surgical system</td><td>Intuitive</td><td>PN1052082-US 10/2021</td><td>XI model</td></tr><tr><td>Dissection instruments</td><td>Bayer</td><td>---</td><td>Two tweezers and a surgical blade&amp;nbsp;</td></tr><tr><td>DPX Eukitt&amp;nbsp;</td><td>Medizin- und Labortechnik GmbH</td><td>6.00.01.0001.06.01.01</td><td></td></tr><tr><td>Eosin</td><td>Agilent</td><td>157252</td><td></td></tr><tr><td>Fenestrated bipolar forceps</td><td>Intuitive</td><td>PN1052082-US 10/2021</td><td>Part number: 471205. 14 lives.</td></tr><tr><td>Force bipolar</td><td>Intuitive</td><td>PN1052082-US 10/2021</td><td>Part number: 471405. 12 uses.</td></tr><tr><td>Freezers</td><td>Thermo Scientific</td><td></td><td>MODEL 907. -80 &amp;ordm;C</td></tr><tr><td>Hematoxylin</td><td>Agilent</td><td>157251</td><td></td></tr><tr><td>Inmunohistochemistry Slides</td><td>Agilent-Dako</td><td>K802021-2</td><td></td></tr><tr><td>Large needle driver</td><td>Intuitive</td><td>PN1052082-US 10/2021</td><td>Part number: 471006. 15 uses.</td></tr><tr><td>Maryland bipolar forceps</td><td>Intuitive</td><td>PN1052082-US 10/2021</td><td>Part number: 471172. 14 uses.</td></tr><tr><td>Microscope</td><td>Olympus</td><td>---</td><td>Olympus cx40</td></tr><tr><td>Microtome blades</td><td>PFM Medical</td><td>a35</td><td></td></tr><tr><td>Monopolar curved scissors</td><td>Intuitive</td><td>PN1052082-US 10/2021</td><td>Part number: 470179. 10 uses.</td></tr><tr><td>OCT compound</td><td>NEG-50</td><td>LOT.117340</td><td></td></tr><tr><td>PlusSpeed S Single-use Biopsy Device with beveled tip</td><td>Peter Pflugbeil GmbH&amp;nbsp;</td><td>PSS-1825-S</td><td></td></tr><tr><td>ProGasp forceps</td><td>Intuitive</td><td>PN1052082-US 10/2021</td><td>Part number: 471093. 18 uses.</td></tr><tr><td>Sample holder Disc</td><td>Davidson Cryo Chuck. BradleyProducts</td><td></td><td>30 mm&amp;nbsp;</td></tr><tr><td>Tissue ink</td><td>Pelikan</td><td>2021</td><td>Ink 4001 brilliant black (301168)</td></tr><tr><td>Xylol</td><td>Quimipur</td><td>Ref. 169</td><td></td></tr></tbody></table>

enhancing prostate tumor biobanking reliability with improved sampling technique and histological characterization

Acquiring fresh and well-characterized tumor tissue samples is critical for conducting high-quality &#34;omics&#34; studies. However, it can be particularly challenging in the context of prostate cancer (PC) due to the unique nature of this organ and the high heterogeneity associated with this tumor. On the other hand, histopathologically characterizing samples before their storage without causing significant tissue alterations is also an intriguing challenge. In this context, we present a new method for acquiring, mapping, characterizing, and micro-dissecting resected prostate tissue based on anatomopathological criteria.
Unlike previously published protocols, this method reduces the time required for histopathological analysis of the prostate specimen without compromising its structure, which is crucial for assessing surgical margins. Furthermore, it enables the delineation and micro-macro dissection of fresh prostate tissue samples, with a focus on histological tumor areas defined by pathological criteria such as Gleason score, precursor lesions (high-grade prostatic intraepithelial neoplasia - PIN), and inflammatory lesions (prostatitis). These samples are then stored in a Biobank for subsequent research analyses.

The results reveal that this technique has made it possible to obtain tumor material in 61% of the cases studied (25 out of 41 cases) (Table 1).
Table 1: Histopathological data of study samples. Summary of histopathological data for the samples used in the study. The diagnostic cylinder refers to the prostate biopsy sample obtained for diagnostic purposes, while the processed cylinder corresponds to the cylinder obtained from the prostatectomy specimen for res...

Read this Scientific Article Protocol about Author Spotlight: Advancing Prostate Cancer Research Through Improved Tissue Sampling and Biobanking at JoVE.com

Author Spotlight: Advancing Prostate Cancer Research Through Improved Tissue Sampling and Biobanking

This protocol describes a method for facilitating the collection of samples from radical prostatectomy specimens. The goal is to map, characterize, and micro-macro dissect tissue samples from the specimens based on anatomopathological criteria before storing them in a Biobank.

Enhancing Prostate Tumor Biobanking Reliability with Improved Sampling Technique and Histological Characterization

Acquiring fresh and well-characterized tumor tissue samples is critical for conducting high-quality &#34;omics&#34; studies. However, it can be ...

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Research

JoVE Journal

Cancer Research

604 Views.  Hospital Universitario y Politécnico La Fe. Ons onderzoek richt zich op het verbeteren van de methodologie om weefselmonsters van prostaatkanker van hoge kwaliteit te verkrijgen. Het richt zich op uitdagingen zoals genetische intratumorale heterogeniteit, multifocaliteit en nauwkeurige moleculaire karakterisering van tumorfoci in onderzoek naar prostaatkanker. Biobanking is een technologiegedreven praktijk die systematisch biologische monsters verzamelt, verwerkt en opslaat.Door deze technologieën te integreren, kan een uitgebr...

Video: Auteur in de schijnwerpers: Onderzoek naar prostaatkanker bevorderen door verbeterde weefselbemonstering en biobankieren

A Murine Orthotopic Bladder Tumor Model and Tumor Detection System

This protocol describes the generation of bladder tumors in female C57BL/6J mice using the murine bladder cancer cell line MB49, which has been modified to secrete human Prostate Specific Antigen (PSA), and the procedure for the confirmation of tumor implantation. In brief, mice are anesthetized using injectable drugs and are made to lay in the dorsal position. Urine is vacated from the bladder and 50 &#181;L of poly-L-lysine (PLL) is slowly instilled at a rate of 10 &#181;L/20 s using a 24 G IV catheter. It is left in the bladder for 20 min by stoppering the catheter. The catheter is removed and PLL is vacated by gentle pressure on the bladder. This is followed by instillation of the murine bladder cancer cell line (1 x 105 cells/50 &#181;L) at a rate of 10 &#181;L/20 s. The catheter is stoppered to prevent premature evacuation. After 1 h, the mice are revived with a reversal drug, and the bladder is vacated. The slow instillation rate is important, as it reduces vesico-ureteral reflux, which can cause tumors to occur in the upper urinary tract and in the kidneys. The cell line should be well re-suspended to reduce clumping of cells, as this can lead to uneven tumor sizes after implantation.
This technique induces tumors with high efficiency. Tumor growth is monitored by urinary PSA secretion. PSA marker monitoring is more reliable than ultrasound or fluorescence imaging for the detection of the presence of tumors in the bladder. Tumors in mice generally reach a maximum size that negatively impacts health by about 3 - 4 weeks if left untreated. By monitoring tumor growth, it is possible to differentiate mice that were cured from those that were not successfully implanted with tumors. With only end-point analysis, the latter may be mistakenly assumed to have been cured by therapy.

This protocol describes the generation of murine orthotopic bladder tumors in female C57BL/6J mice and the monitoring of tumor growth.

This protocol describes the generation of bladder tumors in female C57BL/6J mice using the murine bladder cancer cell line MB49, which has been modified ...

Protocol for HER2 FISH Using a Non-cross-linking, Formalin-free Tissue Fixative to Combine Advantages of Cryo-preservation and Formalin Fixation

Morphologic assessment of formalin-fixed, paraffin-embedded (FFPE) tissue samples has been the gold standard for cancer diagnostics for decades due to its excellent preservation of morphology. Personalized medicine increasingly provides individually adapted and targeted therapies for characterized individual diseases enabled by combined morphological and molecular analytical technologies and diagnostics. Performance of morphologic and molecular assays from the same FFPE specimen is challenging because of the negative impact of formalin due to chemical modification and cross-linking of nucleic acids and proteins. A non-cross-linking, formalin-free tissue fixative has been recently developed to fulfil both requirements, i.e., to preserve morphology like FFPE and biomolecules like cryo-preservation. Since FISH is often required in combination with histopathology and molecular diagnostics, we tested the applicability of FISH protocols on tissues treated with this new fixative. We found that formalin post-fixation of histological sections of non-cross-linking, formalin-free and paraffin-embedded (NCFPE) breast cancer tissue generated equivalent results to those with FFPE tissue in human epidermal growth factor receptor 2 (HER2) FISH analysis. This protocol describes how a FISH assay originally developed and validated for FFPE tissue can be used for NCFPE tissues by a simple post-fixation step of histological sections.

Fluorescence in-situ hybridization (FISH) is often required in combination with histopathology and molecular diagnostics for selection of therapy in personalized medicine. A novel non-cross-linking, formalin-free tissue fixative that allows high quality morphologic, molecular and FISH analyses from the same specimen by addition of a post-fixation step before FISH is presented.

Morphologic assessment of formalin-fixed, paraffin-embedded (FFPE) tissue samples has been the gold standard for cancer diagnostics for decades due to its ...

Target Cell Pre-enrichment and Whole Genome Amplification for Single Cell Downstream Characterization

Rare target cells can be isolated from a high background of non-target cells using antibodies specific for surface proteins of target cells. A recently developed method uses a medical wire functionalized with anti-epithelial cell adhesion molecule (EpCAM) antibodies for in vivo isolation of circulating tumor cells (CTCs)1. A patient-matched cohort in non-metastatic prostate cancer showed that the in vivo isolation technique resulted in a higher percentage of patients positive for CTCs as well as higher CTC counts as compared to the current gold standard in CTC enumeration. As cells cannot be recovered from current medical devices, a new functionalized wire (referred to as Device) was manufactured allowing capture and subsequent detachment of cells by enzymatic treatment. Cells are allowed to attach to the Device, visualized on a microscope and detached using enzymatic treatment. Recovered cells are cytocentrifuged onto membrane-coated slides and harvested individually by means of laser microdissection or micromanipulation. Single-cell samples are then subjected to single-cell whole genome amplification allowing multiple downstream analysis including screening and target-specific approaches. The procedure of isolation and recovery yields high quality DNA from single cells and does not impair subsequent whole genome amplification (WGA). A single cell&#39;s amplified DNA can be forwarded to screening and/or targeted analysis such as array comparative genome hybridization (array-CGH) or sequencing. The device allows ex vivo isolation from artificial rare cell samples (i.e. 500 target cells spiked into 5 mL of peripheral blood). Whereas detachment rates of cells are acceptable (50 - 90%), the recovery rate of detached cells onto slides spans a wide range dependent on the cell line used (&#60;10 - &#62;50%) and needs some further attention. This device is not cleared for the use in patients.

This protocol is to recover and prepare rare target cells from a mixture with non-target background cells for molecular genetic characterization at the single-cell level. DNA quality is equal to non-treated single cells and allows for single-cell application (both screening based and targeted analysis).

Rare target cells can be isolated from a high background of non-target cells using antibodies specific for surface proteins of target cells. A recently ...

Characterization of Tumor Cells Using a Medical Wire for Capturing Circulating Tumor Cells: A 3D Approach Based on Immunofluorescence and DNA FISH

Circulating tumor cells (CTCs) are associated with poor survival in metastatic cancer. Their identification, phenotyping, and genotyping could lead to a better understanding of tumor heterogeneity and thus facilitate the selection of patients for personalized treatment. However, this is hampered because of the rarity of CTCs. We present an innovative approach for sampling a high volume of the patient blood and obtaining information about presence, phenotype, and gene translocation of CTCs. The method combines immunofluorescence staining and DNA fluorescent-in-situ-hybridization (DNA FISH) and is based on a functionalized medical wire. This wire is an innovative device that permits the in vivo isolation of CTCs from a large volume of peripheral blood. The blood volume screened by a 30-min administration of the wire is approximately 1.5-3 L. To demonstrate the feasibility of this approach, epithelial cell adhesion molecule (EpCAM) expression and the chromosomal translocation of the ALK gene were determined in non-small-cell lung cancer (NSCLC) cell lines captured by the functionalized wire and stained with an immuno-DNA FISH approach. Our main challenge was to perform the assay on a 3D structure, the functionalized wire, and to determine immuno-phenotype and FISH signals on this support using a conventional fluorescence microscope. The results obtained indicate that catching CTCs and analyzing their phenotype and chromosomal rearrangement could potentially represent a new companion diagnostic approach and provide an innovative strategy for improving personalized cancer treatments.

We present a new approach to characterize tumor cells. We combined immunofluorescence with DNA fluorescent-in-situ-hybridization to evaluate cells captured by a functionalized medical wire capable of in vivo enriching CTCs directly from patient blood.

Circulating tumor cells (CTCs) are associated with poor survival in metastatic cancer. Their identification, phenotyping, and genotyping could lead to a ...

Isolation and Characterization of Tumor-initiating Cells from Sarcoma Patient-derived Xenografts

The existence and importance of tumor-initiating cells (TICs) have been supported by increasing evidence during the past decade. These TICs have been shown to be responsible for tumor initiation, metastasis, and drug resistance. Therefore, it is important to develop specific TIC-targeting therapy in addition to current chemotherapy strategies, which mostly focus on the bulk of non-TICs. In order to further understand the mechanism behind the malignancy of TICs, we describe a method to isolate and to characterize TICs in human sarcomas. Herein, we show a detailed protocol to generate patient-derived xenografts (PDXs) of human sarcomas and to isolate TICs by fluorescence-activated cell sorting (FACS) using human leukocyte antigen class I (HLA-1) as a negative marker. Also, we describe how to functionally characterize these TICs, including a sphere formation assay and a tumor formation assay, and to induce differentiation along mesenchymal pathways. The isolation and characterization of PDX TICs provide clues for the discovery of potential targeting therapy reagents. Moreover, increasing evidence suggests that this protocol may be further extended to isolate and characterize TICs from other types of human cancers.

We describe a detailed protocol for the isolation of tumor-initiating cells from human sarcoma patient-derived xenografts by fluorescence-activated cell sorting, using human leukocyte antigen-1 (HLA-1) as a negative marker, and for the further validation and characterization of these HLA-1-negative tumor-initiating cells.

The existence and importance of tumor-initiating cells (TICs) have been supported by increasing evidence during the past decade. These TICs have been ...

Creation and Maintenance of a Living Biobank - How We Do It

In light of the growing knowledge about the inter-individual properties and heterogeneity of cancers, the emerging field of personalized medicine requires a platform for preclinical research. Over recent years, we have established a biobank of colorectal and pancreatic cancers comprising of primary tumor tissue, normal tissue, sera, isolated peripheral blood lymphocytes (PBL), patient-derived xenografts (PDX), as well as primary and secondary cancer cell lines. Since original tumor tissue is limited and the establishment rate of primary cancer cell lines is still relatively low, PDX allow not only the preservation and extension of the biobank but also the generation of secondary cancer cell lines. Moreover, PDX-models have been proven to be the ideal in vivo model for preclinical drug testing. However, biobanking requires careful preparation, strict guidelines and a well attuned infrastructure. Colectomy, duodenopancreatectomy or resected metastases specimens are collected immediately after resection and transferred to the pathology department. Respecting priority of an unbiased histopathological report, at the discretion of the attending pathologist who carries out the dissections, small tumor pieces and non-tumor tissue are harvested. 
Necrotic parts are discarded and the remaining tumor tissue is cut into small, identical cubes and cryopreserved for later use. Additionally, a small portion of the tumor is minced and strained for primary cancer cell culture. Additionally, blood samples drawn from the patient pre- and postoperatively, are processed to obtain serum and PBLs. For PDX engraftment, the cryopreserved specimens are defrosted and implanted subcutaneously into the flanks of immunodeficient mice. The resulting PDX closely recapitulate the histology of the "donor" tumors and can be either used for subsequent xenografting or cryopreserved for later use. In the following work, we describe the individual steps of creation, maintenance and administration of a large biobank of colorectal and pancreatic cancer. Moreover, we highlight the crucial details and caveats associated with biobanking.

In the following work, we describe the consecutive steps necessary for the establishment of a large biobank of colorectal and pancreatic cancer.

In light of the growing knowledge about the inter-individual properties and heterogeneity of cancers, the emerging field of personalized medicine requires ...

Microarray-based Identification of Individual HERV Loci Expression: Application to Biomarker Discovery in Prostate Cancer

The prostate-specific antigen (PSA) is the main diagnostic biomarker for prostate cancer in clinical use, but it lacks specificity and sensitivity, particularly in low dosage values1&#8203;&#8203;. &#8216;How to use PSA&#39; remains a current issue, either for diagnosis as a gray zone corresponding to a concentration in serum of 2.5-10 ng/ml which does not allow a clear differentiation to be made between cancer and noncancer2 or for patient follow-up as analysis of post-operative PSA kinetic parameters can pose considerable challenges for their practical application3,4. Alternatively, noncoding RNAs (ncRNAs) are emerging as key molecules in human cancer, with the potential to serve as novel markers of disease, e.g. PCA3 in prostate cancer5,6 and to reveal uncharacterized aspects of tumor biology. Moreover, data from the ENCODE project published in 2012 showed that different RNA types cover about 62% of the genome. It also appears that the amount of transcriptional regulatory motifs is at least 4.5x higher than the one corresponding to protein-coding exons. Thus, long terminal repeats (LTRs) of human endogenous retroviruses (HERVs) constitute a wide range of putative/candidate transcriptional regulatory sequences, as it is their primary function in infectious retroviruses. HERVs, which are spread throughout the human genome, originate from ancestral and independent infections within the germ line, followed by copy-paste propagation processes and leading to multicopy families occupying 8% of the human genome (note that exons span 2% of our genome). Some HERV loci still express proteins that have been associated with several pathologies including cancer7-10. We have designed a high-density microarray, in Affymetrix format, aiming to optimally characterize individual HERV loci expression, in order to better understand whether they can be active, if they drive ncRNA transcription or modulate coding gene expression. This tool has been applied in the prostate cancer field (Figure 1).

Human endogenous retroviruses (HERV), which occupy 8% of the human genome, retain scarce coding capacities but a hundred thousand long terminal repeats (LTRs). A custom Affymetrix microarray was designed to identify individual HERV locus expression and was used on prostate cancer tissues as a proof of concept for future clinical studies.

The prostate-specific antigen (PSA) is the main diagnostic biomarker for prostate cancer in clinical use, but it lacks specificity and sensitivity, ...

Medicine

Biobank for Translational Medicine: Standard Operating Procedures for Optimal Sample Management

Biobanks are key research infrastructures aimed at the collection, storage, processing, and sharing of high-quality human biological samples and associated data for research, diagnosis, and personalized medicine. The Biobank for Translational and Digital Medicine Unit at the European Institute of Oncology (IEO) is a landmark in this field. Biobanks collaborate with clinical divisions, internal and external research groups, and industry, supporting patients' treatment and scientific progress, including innovative diagnostics, biomarker discovery, and clinical trial design. Given the central role of biobanks in modern research, biobanking standard operating procedures (SOPs) should be extremely precise. SOPs and controls by certified specialists ensure the highest quality of samples for the implementation of science-based, diagnostic, prognostic, and therapeutic personalized strategies. However, despite numerous efforts to standardize and harmonize biobanks, these protocols, which follow a strict set of rules, quality controls, and guidelines based on ethical and legal principles, are not easily accessible. This paper presents the biobank standard operating procedures of a large cancer center.

Biobanks are crucial resources for biomedical research and the Biobank for Translational and Digital Medicine Unit at the European Institute of Oncology is a model in this field. Here, we provide a detailed description of biobanks' standard operating procedures for the management of different types of human biological samples.

Biobanks are key research infrastructures aimed at the collection, storage, processing, and sharing of high-quality human biological samples and ...

Use of Magnetic Resonance Imaging and Biopsy Data to Guide Sampling Procedures for Prostate Cancer Biobanking

Previous methods for biobanking prostate tissue, following radical prostatectomy, generally involved random sampling. In order to increase efficiency, and enable a greater range of downstream applications, a more targeted method of sampling prostate tissue was developed. Here we use both magnetic resonance imaging (MRI) and biopsy data to target specific areas of the organ for sampling. The method involves use of a previously published prostate slicing device which removes a 5 mm transverse slice from a predetermined region of the prostate, followed by the removal of 6 mm punch biopsies from predetermined areas of this slice. These samples can be stored frozen or fixed for biobanking purposes, or used fresh immediately with 70% confidence of tumor content, as compared with 10% confidence from the random sampling approach. This enables the use of all standard downstream techniques such as genomics, proteomics or histological work, but also work that requires fresh tissue such as live tissue imaging or ex vivo culture.

This method involves utilization of clinical diagnostic data for prostate cancer patients in order to guide sampling procedures, when biobanking tissue following radical prostatectomy. This overcomes issues with previously published methods around efficiency and availability of fresh tissue for a wider range of downstream applications.

Previous methods for biobanking prostate tissue, following radical prostatectomy, generally involved random sampling. In order to increase efficiency, and ...

Sampling Prostate Cancer Tissue for Biobanking: An MRI-guided Targeted Technique to Remove Biopsy Punches from Fresh Tumor Tissue

After the specimen has been collected, sterilize the laminar flow hood and prostate-slicing apparatus with 70% ethanol, and weigh the prostate on a standard scale in grams. Then, paint the right side with blue ink and the left side of the specimen with black ink, covering the full capsule and seminal vesicles with ink to allow discrimination of the surgical margins.
To slice the prostate, place the tissue with the base and apex facing opposite walls of the apparatus with the posterior side down and the anterior side up. Place gold pins around the tissue specimen, pushing the prostate inward slightly, if necessary, to achieve a snug fit, and measure the prostate length from the base to the apex to compare this measurement to the prostate length as measured by MRI.
If the prostate has shrunk, adjust the anticipated slicing position by the appropriate percentage of the reduction. Next, measure from the base to the desired transverse slice and select the pin that sits closest to this measurement to slice around. Wearing chainmail gloves to prevent injury, place the blades of the slicing device on either side of the identified pin, and use the spacer to keep the blades 5 millimeters apart.
To acquire the slice, use long strokes to slowly but firmly move the blades downward, forward, and backward, confirming by feel that a full slice has been separated before disassembling the apparatus. Then, remove the walls and pins, and use gloves to carefully transfer the slice onto a sterile piece of corkboard.
After acquiring the specimen, visually inspect the transverse slice for comparison with the axial MRI image. In some cases, the tumor area may appear paler than the surrounding tissue. Palpate the transverse slice gently. The tumor may feel firmer than the surrounding tissue. Using the axial MRI image as a guide, select one or more areas for sampling, and use a 6-millimeter punch to push down on the tissue area of interest.
Twist the tissue punch on the spot and down against the cork to ensure a full separation, using a sharp scalpel to separate the biopsy sample from the specimen as necessary. When the sample has been acquired, remove the punch and use the plunger to eject the sample into the appropriate container for the subsequent downstream analysis.

Enhancing Prostate Tumor Biobanking Reliability with Improved Sampling Technique and Histological Characterization

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