| 1. |
- Bertolotto, Corine, et al.
(author)
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A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
- 2011
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 480:7375, s. 94-98
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Journal article (peer-reviewed)abstract
- So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes(1); risk factors associated with RCC include smoking, obesity and hypertension(2). A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers(3). The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene(4); it also stimulates the transcription of hypoxia inducible factor(5) (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes(6). We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (Psi KXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.
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| 2. |
- Lazar, Vladimir, et al.
(author)
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Integrated molecular portrait of non-small cell lung cancers
- 2013
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In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 6:1, s. 53-
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Journal article (peer-reviewed)abstract
- Background: Non-small cell lung cancer (NSCLC), a leading cause of cancer deaths, represents a heterogeneous group of neoplasms, mostly comprising squamous cell carcinoma (SCC), adenocarcinoma (AC) and large-cell carcinoma (LCC). The objectives of this study were to utilize integrated genomic data including copy-number alteration, mRNA, microRNA expression and candidate-gene full sequencing data to characterize the molecular distinctions between AC and SCC. Methods: Comparative genomic hybridization followed by mutational analysis, gene expression and miRNA microarray profiling were performed on 123 paired tumor and non-tumor tissue samples from patients with NSCLC. Results: At DNA, mRNA and miRNA levels we could identify molecular markers that discriminated significantly between the various histopathological entities of NSCLC. We identified 34 genomic clusters using aCGH data; several genes exhibited a different profile of aberrations between AC and SCC, including PIK3CA, SOX2, THPO, TP63, PDGFB genes. Gene expression profiling analysis identified SPP1, CTHRC1and GREM1 as potential biomarkers for early diagnosis of the cancer, and SPINK1 and BMP7 to distinguish between AC and SCC in small biopsies or in blood samples. Using integrated genomics approach we found in recurrently altered regions a list of three potential driver genes, MRPS22, NDRG1 and RNF7, which were consistently over-expressed in amplified regions, had wide-spread correlation with an average of similar to 800 genes throughout the genome and highly associated with histological types. Using a network enrichment analysis, the targets of these potential drivers were seen to be involved in DNA replication, cell cycle, mismatch repair, p53 signalling pathway and other lung cancer related signalling pathways, and many immunological pathways. Furthermore, we also identified one potential driver miRNA hsa-miR-944. Conclusions: Integrated molecular characterization of AC and SCC helped identify clinically relevant markers and potential drivers, which are recurrent and stable changes at DNA level that have functional implications at RNA level and have strong association with histological subtypes.
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| 3. |
- Al-Abbadi, Mousa A., et al.
(author)
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A Proposal for the Performance, Classification, and Reporting of Lymph Node Fine-Needle Aspiration Cytopathology : The Sydney System
- 2020
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In: Acta Cytologica. - : S. Karger AG. - 0001-5547 .- 1938-2650. ; 64:4, s. 306-322
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Journal article (peer-reviewed)abstract
- BACKGROUND: The evaluation of lymph nodes (LN) by fine-needle aspiration cytology (FNAC) is routinely used in many institutions but it is not uniformly accepted mainly because of the lack of guidelines and a cytopathological diagnostic classification. A committee of cytopathologists has developed a system of performance, classification, and reporting for LN-FNAC. METHODS: The committee members prepared a document that has circulated among them five times; the final text has been approved by all the participants. It is based on a review of the international literature and on the expertise of the members. The system integrates clinical and imaging data with cytopathological features and ancillary techniques. The project has received the endorsement and patronage of the International Academy of Cytology and the European Federation of the Cytology Societies. RESULTS: Clinical, imaging, and serological data of lymphadenopathies, indications for LN-FNAC, technical procedures, and ancillary techniques are evaluated with specific recommendations. The reporting system includes two diagnostic levels. The first should provide basic diagnostic information and includes five categories: inadequate/insufficient, benign, atypical lymphoid cells of undetermined/uncertain significance, suspicious, and malignant. For each category, specific recommendations are provided. The second diagnostic level, when achievable, should produce the identification of specific benign or malignant entities and additional information by utilizing ancillary testing. CONCLUSION: The authors believe that the introduction of this system for performing and reporting LN-FNAC may improve the quality of the procedure, the report, and the communication between cytopathologists and the clinicians. This system may lead to a greater acceptance and utilization of LN-FNAC and to a better interdisciplinary understanding of the results of this procedure.
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| 4. |
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| 5. |
- Bibbo, Marluce, et al.
(author)
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How technology is reshaping the practice of nongynecologic cytology - Frontiers of cytology symposium
- 2007
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In: Acta Cytologica. - 0001-5547. ; 51:2, s. 123-152
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Journal article (other academic/artistic)abstract
- To pay tribute to the Founders of Acta Cytologica, this Golden Anniversary symposium on nongynecologic cytology revives the written symposium style of the 1950s. Participants from countries throughout the world were asked how new technologies are currently applied in their laboratories and whether future advances and challenges can be predicted. The specific questions and the participants' answers follow.
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| 6. |
- Caputo, Alessandro, et al.
(author)
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Digital Examination of LYmph node CYtopathology Using the Sydney system (DELYCYUS). An international, multi-institutional study
- 2023
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In: Cancer Cytopathology. - 1934-662X. ; 131:11, s. 679-692
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Journal article (peer-reviewed)abstract
- Background: After a series of standardized reporting systems in cytopathology, the Sydney system was recently introduced to address the need for reproducibility and standardization in lymph node cytopathology. Since then, the risk of malignancy for the categories of the Sydney system has been explored by several studies, but no studies have yet examined the interobserver reproducibility of the Sydney system. Methods: The authors assessed interobserver reproducibility of the Sydney system on 85 lymph node fine-needle aspiration cytology cases reviewed by 15 cytopathologists from 12 institutions in eight different countries, resulting in 1275 diagnoses. In total, 186 slides stained with Diff-Quik, Papanicolaou, and immunocytochemistry were scanned. A subset of the cases included clinical data and results from ultrasound examinations, flow cytometry immunophenotyping, and fluorescence in situ hybridization analysis. The study participants assessed the cases digitally using whole-slide images. Results: Overall, the authors observed an almost perfect agreement of cytopathologists with the ground truth (median weighted Cohen κ = 0.887; interquartile range, κ = 0.210) and moderate overall interobserver concordance (Fleiss κ = 0.476). There was substantial agreement for the inadequate and malignant categories (κ = 0.794 and κ = 0.729, respectively), moderate agreement for the benign category (κ = 0.490), and very slight agreement for the suspicious (κ = 0.104) and atypical (κ = 0.075) categories. Conclusions: The Sydney system for reporting lymph node cytopathology shows adequate interobserver concordance. Digital microscopy is an adequate means to assess lymph node cytopathology specimens.
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| 7. |
- Malapelle, Umberto, et al.
(author)
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Reference standards for gene fusion molecular assays on cytological samples : an international validation study
- 2023
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In: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 76:1, s. 47-52
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Journal article (peer-reviewed)abstract
- Aims Gene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated. Methods Cell lines harbouring EML4(13)–ALK(20) and SLC34A2(4)–ROS1(32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides. Results Four (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms. Conclusions Reference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches.
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| 8. |
- Mercan, Caner, et al.
(author)
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Deep learning for fully-automated nuclear pleomorphism scoring in breast cancer
- 2022
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In: npj Breast Cancer. - : Nature Portfolio. - 2374-4677. ; 8:1
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Journal article (peer-reviewed)abstract
- To guide the choice of treatment, every new breast cancer is assessed for aggressiveness (i.e., graded) by an experienced histopathologist. Typically, this tumor grade consists of three components, one of which is the nuclear pleomorphism score (the extent of abnormalities in the overall appearance of tumor nuclei). The degree of nuclear pleomorphism is subjectively classified from 1 to 3, where a score of 1 most closely resembles epithelial cells of normal breast epithelium and 3 shows the greatest abnormalities. Establishing numerical criteria for grading nuclear pleomorphism is challenging, and inter-observer agreement is poor. Therefore, we studied the use of deep learning to develop fully automated nuclear pleomorphism scoring in breast cancer. The reference standard used for training the algorithm consisted of the collective knowledge of an international panel of 10 pathologists on a curated set of regions of interest covering the entire spectrum of tumor morphology in breast cancer. To fully exploit the information provided by the pathologists, a first-of-its-kind deep regression model was trained to yield a continuous scoring rather than limiting the pleomorphism scoring to the standard three-tiered system. Our approach preserves the continuum of nuclear pleomorphism without necessitating a large data set with explicit annotations of tumor nuclei. Once translated to the traditional system, our approach achieves top pathologist-level performance in multiple experiments on regions of interest and whole-slide images, compared to a panel of 10 and 4 pathologists, respectively.
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| 9. |
- Vigliar, Elena, et al.
(author)
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COVID-19 pandemic impact on cytopathology practice in the post-lockdown period: An international, multicenter study
- 2022
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In: Cancer Cytopathology. - : WILEY. - 1934-662X .- 1934-6638. ; 130:5, s. 344-351
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Journal article (peer-reviewed)abstract
- Background In a previous worldwide survey, the authors showed a drastic reduction in the number of cytological specimens processed during the coronavirus disease 2019 "lockdown" period along with an increase in malignancy rates. To assess the continued impact of the pandemic on cytological practices around the world, they undertook a second follow-up worldwide survey collecting data from the post-lockdown period (2020). Methods Participants were asked to provide data regarding their cytopathology activity during the first 12 weeks of their respective national post-lockdown period (2020), which ranged from April 4 to October 31. Differences between the post-lockdown period and the corresponding 2019 period were evaluated, and the authors specifically focused on rates of malignant diagnoses. Results A total of 29 respondents from 17 countries worldwide joined the survey. Overall, a lower number of cytological specimens (n = 236,352) were processed in comparison with the same period in 2019 (n = 321,466) for a relative reduction of 26.5%. The overall malignancy rate showed a statistically significant increase (12,442 [5.26%] vs 12,882 [4.01%]; P < .001) during the same time period. Similar results were obtained if both malignancy and suspicious for malignancy rates were considered together (15,759 [6.58%] vs 16,011 [4.98%]; P < .001). Conclusions The data showed a persistent reduction in the cytological specimen volume during the post-lockdown period (2020). However, the relative increase in the cytological workload in the late part of the post-lockdown is a promising finding of a slow return to normality.
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| 10. |
- Vigliar, Elena, et al.
(author)
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Global impact of the COVID-19 pandemic on cytopathology practice: Results from an international survey of laboratories in 23 countries
- 2020
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In: Cancer Cytopathology. - : WILEY. - 1934-662X .- 1934-6638. ; 128:12, s. 885-894
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Journal article (peer-reviewed)abstract
- Background To the authors knowledge, the impact of the coronavirus disease 2019 (COVID-19) pandemic on cytopathology practices worldwide has not been investigated formally. In the current study, data from 41 respondents from 23 countries were reported. Methods Data regarding the activity of each cytopathology laboratory during 4 weeks of COVID-19 lockdown were collected and compared with those obtained during the corresponding period in 2019. The overall number and percentage of exfoliative and fine-needle aspiration cytology samples from each anatomic site were recorded. Differences in the malignancy and suspicious rates between the 2 periods were analyzed using a meta-analytical approach. Results Overall, the sample volume was lower compared with 2019 (104,319 samples vs 190,225 samples), with an average volume reduction of 45.3% (range, 0.1%-98.0%). The percentage of samples from the cervicovaginal tract, thyroid, and anorectal region was significantly reduced (P < .05). Conversely, the percentage of samples from the urinary tract, serous cavities, breast, lymph nodes, respiratory tract, salivary glands, central nervous system, gastrointestinal tract, pancreas, liver, and biliary tract increased (P < .05). An overall increase of 5.56% (95% CI, 3.77%-7.35%) in the malignancy rate in nongynecological samples during the COVID-19 pandemic was observed. When the suspicious category was included, the overall increase was 6.95% (95% CI, 4.63%-9.27%). Conclusions The COVID-19 pandemic resulted in a drastic reduction in the total number of cytology specimens regardless of anatomic site or specimen type. The rate of malignancy increased, reflecting the prioritization of patients with cancer who were considered to be at high risk. Prospective monitoring of the effect of delays in access to health services during the lockdown period is warranted.
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| 11. |
- Zeppa, Pio, et al.
(author)
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Announcement : The International System for Reporting Lymph Node Cytopathology
- 2020
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In: Acta Cytologica. - : S. Karger AG. - 0001-5547 .- 1938-2650. ; 64:4, s. 299-305
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Research review (peer-reviewed)abstract
- Fine needle aspiration biopsy cytopathology (FNAC) of lymph nodes is a very common, inexpensive, and rapid diagnostic procedure and can lead to the accurate and timely diagnosis of one of the wide range of pathological processes that involve lymph nodes. These diagnoses include specific reactive processes, specific infections such as tuberculosis, metastatic carcinomas and melanomas, and some lymphomas. The FNAC effectively triages the lymph node material, but the initial diagnosis often requires ancillary testing as a second diagnostic step to make a specific diagnosis, such as the particular infectious agent, the type of lymphoma or Hodgkin lymphoma, or the specific type of metastatic malignancy. An international group of cytopathologists have begun the process of developing a system for the standardized reporting of lymph node FNAC. The group is addressing the pre-analytical issues related to the FNAC, including the role of clinical information and the use of ultrasound, and developing a structure of reporting categories based on the cytopathological findings linked to management recommendations. The basis of the system is the integration of the FNAC with the clinical setting, imaging, and ancillary tests that utilize the FNAC material, to produce a final report that will enhance patient care.
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