Growth Factors and Receptors: A Practical Approach (Practical Approach Series)

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Growth factors : a practical approach. Ian A. McKay , Irene M. There has been a major expansion of interest in growth factors reflecting their very important role in the regulation of the proliferation and differentiation of specific cell types. Multiple case reports suggest that acanthosis nigricans improves with treatment of its underlying condition Table 2.

Whether the duration of therapy was sufficient to see a clinical change is uncertain.

Growth Factors and Receptors: A Practical Approach by Ian McKay, Kenneth D. Brown -

Retinoids have been successfully used to treat AN. Topical 0. Another patient had clearing of AN of the left axilla after tretinoin 0. In another case report, the combination of 0. Oral retinoids, such as isotretinoin and acitretin, also can be effective [ 92 , 93 , 94 ]. Improvement required large doses and extended courses, and relapse was described. An year-old man with generalized idiopathic AN experienced complete recovery after 45 days with acitretin 0. Use of systemic retinoids for AN may be inappropriate given their side effect profile and potential for toxicity.

Chemoprevention: an essential approach to controlling cancer

Other therapies found beneficial in case reports include calcipotriol, fish oil, and laser. Another obese woman improved with calcipotriol ointment twice daily, also for 3 months [ 96 ]. This occurred after 6 months of taking 10 to 20g per day of fish oil. Multiple anecdotal reports suggest that acanthosis nigricans is reversible. However, whether another therapy is superior remains unclear. Figure 1.

Figure 2. When possible, on-slide controls with defined HER2 expression levels should be included on each sample slide and if available, cell lines with defined HER2 expression levels can also be used as run-controls. Controls should be prepared using similar fixation- and paraffin-embedding methods to the test samples.

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  • HER2 testing in gastric cancer: a practical approach | Modern Pathology.

The controls provided or recommended in the validated kits for gastric cancer should be used wherever possible. For practical purposes tissue microarrays comprising tumor cores of different HER2 status may be valuable tools for quality control assessments. In particular, outside of high-throughput labs, tissue microarrays can provide a rapid overview of testing quality. Tissue microarrays need to be carefully constructed to avoid bias by tumor heterogeneity as otherwise they may not be appropriate for quality assurance purposes.

When interpreting HER2 staining, it is important to be aware of focal staining that is commonly reported in gastric cancer 7 , 28 , 29 and the finding that gastric tumor cells often show incomplete HER2 membrane reactivity that can be basolateral or lateral in distribution Figure 1b. Only cells showing specific membrane staining at the cell—to—cell contact sites not at the luminal or apical parts should be evaluated. This excludes single, noncohesive stained cells from scoring, as these cells often correspond to nonspecifically stained signet ring cells which typically show no HER2 gene amplification.

Samples with poorly preserved tissue including edge crushing or shrinkage artifacts , nonspecific staining eg, cytoplasmic or nucleic staining , or staining in the normal mucosa particularly intestinal metaplasia should be excluded or retested with fluorescence in situ hybridization or silver in situ hybridization Figures 3a—d. Accordingly, when the observer concentrates not only on the intensity of staining, but also focuses on the identification of a distinct structure ie, membranous staining , interobserver concordance is markedly increased.

Lateral- or U-shaped membranous staining is typically seen at cell—cell junctions Figure 1b. The scores for both assays should be indicated separately on the report. It is also appropriate to score an alternative sample of the tumor or a lymph node containing a metastasis in these cases. If such a sample is fluorescence in situ hybridization- or silver in situ hybridization-positive the tumor may be considered to be HER2-positive similar to scoring on biopsy samples; scores for both assays should be indicated separately on the report.

Within the trastuzumab for GAstric cancer study it was not possible to determine a relationship between treatment benefit and degree of HER2-related tumor heterogeneity, mainly due to the small sample sizes of the respective subgroups involved.

TGF Beta signaling pathway - tricks to remember cell signaling pathway

As with immunohistochemistry, a standard operating procedure should be developed for fluorescence in situ hybridization and silver in situ hybridization within each testing laboratory, including standardization of protocols and laboratory equipment. It is important to note that samples may need to be treated differently according to whether fluorescence in situ hybridization or silver in situ hybridization will be utilized.

In order to achieve a good in situ hybridization signal, it is important that sufficient well-preserved tumor tissue is collected and that samples are carefully prepared. Insufficient deparaffinization can lead to nuclear bubbles, and nuclear holes may be present as a result of overdigestion. It is strongly recommended that validated fluorescence in situ hybridization and silver in situ hybridization kits be used for testing in gastric cancer as per the manufacturer's instructions to ensure the production of accurate and reliable data.

Preanalytical tissue preparation should also be performed according to the manufacturer's instructions for the in situ hybridization testing kits. Use of other in situ hybridization methodologies in gastric cancer eg, PathVysion Abbott , which is commonly used in countries where other tests are not yet approved, or chromogenic in situ hybridization require validation of the assay against the validated tests. Silver in situ hybridization slides also have the advantage of being more suitable for long-term storage than fluorescence in situ hybridization slides, as there is no risk of bleaching.

Breast cancer and therapeutic deployment of growth factor receptors

Another key recommendation for HER2 testing is to align the use of immunohistochemistry and in situ hybridization particularly silver in situ hybridization in order to help identify heterogeneous areas of HER2 reactivity. Immunohistochemistry should be used as the initial test to identify HER2-positive regions, the location of which can then be used to guide the fluorescence in situ hybridization or silver in situ hybridization assessment Figures 2b and c. The requirement for a bright-field methodology to identify heterogeneity further supports the use of immunohistochemistry as the initial HER2 testing modality in gastric cancer. Fluorescence in situ hybridization and silver in situ hybridization results are expressed as the ratio between the number of copies of the HER2 gene and the number of copies of chromosome 17 within the nucleus counted in at least 20 cancer cells. When analyzing in situ hybridization samples, it is important to consider how the area for testing should be assessed.

Areas with overlapping nuclei or high nonspecific background staining dark field methods only or where there is a weak signal or the presence of artifacts eg, dust grains should not be included in the interpretation. In borderline amplification cases ratio of 1. If there is a cluster of, eg, only five HER2 -amplified tumor cells, the final in situ hybridization result should still be based on a total of 20 counted cells.

In addition to the HER2 :chromosome 17 ratio, the overall HER2 gene count is also an important consideration for scoring fluorescence in situ hybridization and silver in situ hybridization samples. If the ratio suggests borderline amplification ratio close to 2.

If there are four to six HER2 gene copies then a dual-probe test is advised and the ratio should be calculated by counting an additional 20 cells. It is also important to have a hematoxylin and eosin section of the tumor available as a guide to scoring the in situ hybridization slide. If a particularly low ratio is observed, it may be necessary to check for polysomy and re-check immunohistochemistry results Figure 2g. Caution must be applied when interpreting polysomy in gastric cancer as sometimes this may represent a coamplification of the centromere region of chromosome 17 rather than a true polysomy ie, increased copy number of the whole chromosome In order to achieve quality HER2 testing results that are consistent across testing laboratories, it is strongly recommended that testing be performed by centralized reference laboratories wherever possible.

In regions where centralized testing is not possible, testing should be conducted by experienced local pathology laboratories with previous experience of both immunohistochemical and in situ hybridization testing in breast cancer that have undergone comprehensive training specific to the analysis of gastric tumor samples. At the onset of diagnostic testing for HER2 in any centre, the initial 25—50 cases should always be analyzed in parallel using both immunohistochemistry and in situ hybridization.

Owing to the differences between breast cancer and gastric cancer HER2 testing and scoring, it is imperative that personnel should be specifically trained in HER2 testing methods and interpretation for gastric cancer, irrespective of previous experience in breast cancer. This should include training on preanalytical procedures through to the scoring and interpretation of gastric cancer samples, as applying the breast cancer scoring system to gastric cancer samples may result in a large number of inaccurate HER2 scoring results that could lead to some patients with HER2-positive gastric cancer not being identified.

It is anticipated that specific training and regular gastric cancer-related teaching activities will increase the number of accurate HER2 testing results and ensure patients have access to suitable treatments.

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All centers responsible for HER2 testing should be governed by a validated procedure, and subject to an internal quality assurance program. In addition to internal quality assurance programs, all technical and medical staff should undergo continual competency assessments and training. HER2 testing laboratories should actively participate in proficiency testing schemes though external quality assurance programs.

On the basis the data from the trastuzumab for GAstric cancer study, 1 trastuzumab was approved by the European Medicines Agency for patients with metastatic gastric cancer. It is clear that accurate patient identification, and thus clinical benefit, is dependent on quality HER2 testing.

The recommendations described here have been developed based on the trastuzumab for GAstric cancer study and the expert opinions of the authors who share a wealth of experience in HER2 testing. For an overview of the key recommendations for both immunohistochemistry and in situ hybridization, see Table 3. Briefly, the main recommendations are that all patients with gastric cancer should be tested for HER2 status at the time of initial diagnosis, with biopsies being the preferred specimen type due to specimen quality reasons, and that testing and scoring should be performed with adherence to the recommendations specifically devised for gastric cancer.

The subsequent treatment of patients with HER2-positive tumors will vary globally, dependent on local regulations and approvals, and as such the practical guidance provided here is intended to be broad and wide-reaching and should therefore be applicable across all regions following the European Medicines Agency approval. It is anticipated that as experience of HER2 testing in gastric cancer grows, these recommendations will continue to evolve.

Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer ToGA : a phase 3, open-label, randomised controlled trial.

Lancet ; — Current perspectives on HER2 testing: a review of national testing guidelines. Mod Pathol ; 16 — HER-2 amplification is highly homogenous in gastric cancer.