Crossing the Andes: Challenges and opportunities for digital pathology in Latin America.

The most widely accepted and used type of digital pathology (DP) is whole-slide imaging (WSI). The USFDA granted two WSI system approvals for primary diagnosis, the first in 2017. In Latin America, DP has the potential to reshape healthcare by enhancing diagnostic capabilities through artificial intelligence (AI) and standardizing pathology reports.

Claudin 18.2 as a New Biomarker in Gastric Cancer-What Should We Know?

Gastric cancer (GC) remains a formidable global health challenge, ranking among the top-five causes of cancer-related deaths worldwide. The majority of patients face advanced stages at diagnosis, with a mere 6% five-year survival rate. First-line treatment for metastatic GC typically involves a fluoropyrimidine and platinum agent combination; yet, predictive molecular markers have proven elusive.

Complete Response to Immunotherapy in a Patient with -Associated Polyposis and Gastric Cancer: A Case Report.

MUTYH-associated polyposis syndrome is an uncommon, autosomal recessive colorectal polyposis syndrome caused by biallelic inactivation of . Most patients present with multiple colorectal polyps. However, other primary tumor sites have been described as less frequent.

Independent real-world application of a clinical-grade automated prostate cancer detection system.

Artificial intelligence (AI)-based systems applied to histopathology whole-slide images have the potential to improve patient care through mitigation of challenges posed by diagnostic variability, histopathology caseload, and shortage of pathologists. We sought to define the performance of an AI-based automated prostate cancer detection system, Paige Prostate, when applied to independent real-world data. The algorithm was employed to classify slides into two categories: benign (no further review needed) or suspicious (additional histologic and/or immunohistochemical analysis required).

Phenotypic drift in metastatic progression of breast cancer: A case report with histologically heterogeneous lesions that are clonally related.

Breast cancer metastasis to the stomach is rare; invasive lobular carcinoma has a predilection to spread to the gastrointestinal system and is morphologically similar to primary diffuse gastric carcinoma. This case highlights heterogeneous metastatic progression and that documentation of heterogeneity is important for informing future treatment strategies and prognostication.

Mixed ductal-lobular carcinomas: evidence for progression from ductal to lobular morphology.

Mixed ductal-lobular carcinomas (MDLs) show both ductal and lobular morphology, and constitute an archetypal example of intratumoural morphological heterogeneity. The mechanisms underlying the coexistence of these different morphological entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinicopathological analysis of a cohort of 82 MDLs, and found that: (1) MDLs more frequently coexist with ductal carcinoma in situ (DCIS) than with lobular carcinoma in situ (LCIS); (2) the E-cadherin-catenin complex was normal in the ductal component in 77.

The calcium pump plasma membrane Ca(2+)-ATPase 2 (PMCA2) regulates breast cancer cell proliferation and sensitivity to doxorubicin.

Regulation of Ca(2+) transport is vital in physiological processes, including lactation, proliferation and apoptosis. The plasmalemmal Ca(2+) pump isoform 2 (PMCA2) a calcium ion efflux pump, was the first protein identified to be crucial in the transport of Ca(2+) ions into milk during lactation in mice. In these studies we show that PMCA2 is also expressed in human epithelia undergoing lactational remodeling and also report strong PMCA2 staining on apical membranes of luminal epithelia in approximately 9% of human breast cancers we assessed.

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families.

An epithelial to mesenchymal transition programme does not usually drive the phenotype of invasive lobular carcinomas.

Epithelial to mesenchymal transition (EMT) is a cellular phenotype switching phenomenon which occurs during normal development and is proposed to promote tumour cell invasive capabilities during tumour progression. Invasive lobular carcinoma (ILC) is a histological special type of breast cancer with a peculiar aetiology - the tumour cells display an invasive growth pattern, with detached, single cells or single files of cells, and a canonical feature is the loss of E-cadherin expression. These characteristics are indicative of an EMT or at the very least that they represent some plasticity between phenotypes.

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing.

Heregulin-HER3-HER2 signaling promotes matrix metalloproteinase-dependent blood-brain-barrier transendothelial migration of human breast cancer cell lines.

HER2-positive breast tumors are associated with a high risk of brain relapse. HER3 is thought to be an indispensible signaling substrate for HER2 (encoded by ERBB2) and is induced in breast cancer-brain metastases, though the molecular mechanisms by which this oncogenic dimer promotes the development of brain metastases are still elusive. We studied the effects of the HER3-HER2 ligand, heregulin (neuregulin-1, broadly expressed in the brain), on luminal breast cancer cell lines in vitro.

Rad51 supports triple negative breast cancer metastasis.

In contrast to extensive studies on familial breast cancer, it is currently unclear whether defects in DNA double strand break (DSB) repair genes play a role in sporadic breast cancer development and progression. We performed analysis of immunohistochemistry in an independent cohort of 235 were sporadic breast tumours. This analysis suggested that RAD51 expression is increased during breast cancer progression and metastasis and an oncogenic role for RAD51 when deregulated.

Expression and function of the protein tyrosine phosphatase receptor J (PTPRJ) in normal mammary epithelial cells and breast tumors.

The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years.

Calcium channel TRPV6 as a potential therapeutic target in estrogen receptor-negative breast cancer.

Calcium signaling is a critical regulator of cell proliferation. Elevated expression of calcium channels and pumps is a characteristic of some cancers, including breast cancer. We show that the plasma membrane calcium channel TRPV6, which is highly selective for Ca(2+), is overexpressed in some breast cancer cell lines.

Gene expression profiling of tumour epithelial and stromal compartments during breast cancer progression.

The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in the evolution of breast cancer. There is some evidence to suggest that dynamic interactions between the neoplastic cells and the tumour microenvironment play an important role. Using the whole-genome cDNA-mediated annealing, selection, extension and ligation assay (WG-DASL, Illumina), we performed gene expression profiling on 87 formalin-fixed paraffin-embedded (FFPE) samples from 17 patients consisting of matched IDC, DCIS and three types of stroma: IDC-S (<3 mm from IDC), DCIS-S (<3 mm from DCIS) and breast cancer associated-normal stroma (BC-NS; >10 mm from IDC or DCIS).

Rare variants in the ATM gene and risk of breast cancer.

Introduction: The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved.

Tumor heterogeneity in a follicular carcinoma of thyroid: a study by comparative genomic hybridization.

We report a follicular carcinoma of thyroid that showed a range of histologic appearances, with microfollicular, macrofollicular/pseudopapillary, oncocytic, and poorly differentiated areas. We used comparative genomic hybridization to detect the major DNA copy number changes in each component, in order to study the inter-relationships among them. All showed gains in 11q and 17q, suggesting that these were early events in the development of the tumor, and these were the only changes in the follicular component.

Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary.

Clinical management of breast cancer families is complicated by identification of BRCA1 and BRCA2 sequence alterations of unknown significance. Molecular assays evaluating the effect of intronic variants on native splicing can help determine their clinical relevance. Twenty-six intronic BRCA1/2 variants ranging from the consensus dinucleotides in the splice acceptor or donor to 53 nucleotides into the intron were identified in multiple-case families.

Intra-operative four-stranded hamstring tendon graft diameter evaluation.

Purpose: To evaluate whether clinical factors enable prediction of the diameter of hamstring tendons harvested for anterior cruciate ligament (ACL) reconstruction.

Methods: Eighty patients were submitted for reconstruction of the ACL with hamstring tendons in a quadruple manner. During surgery the diameter of the graft was measured.

Molecular aspects of breast cancer metastasis to the brain.

Our knowledge of the biology underlying the development of brain metastases (BM) from breast cancer has improved over the last decade due to large clinical epidemiological studies, animal models of metastasis, and the use of high-resolution gene expression profiling technologies. However, there are still major gaps in our understanding of the mechanisms utilized by breast cancer cells to colonize the brain microenvironment, thus our arsenal of therapies remains relatively nonspecific, and the prognosis for breast cancer patients with BM remains poor. Additional insights into these mechanisms are necessary to facilitate the development of new preventive and curative therapeutic regimens to block this fatal disease.

Dissecting the transcriptional networks underlying breast cancer: NR4A1 reduces the migration of normal and breast cancer cell lines.

Introduction: Breast cancer currently accounts for more than one-quarter of all female cancers and, despite the great progress in treatment observed in the past few years, the need for identification of new gene targets that can be used for diagnosis, prognosis and therapy is evident. A previous study identified the transcription factor NR4A1 as a gene upregulated in primary breast cancer compared with normal tissue by microarray analysis and sequencing technologies. The purpose of the study was to identify the role of NR4A1 in normal mammary epithelial and breast cancer cell biology.

Gene expression profiling of formalin-fixed, paraffin-embedded familial breast tumours using the whole genome-DASL assay.

Tissue sample acquisition is a limiting step in many studies. There are many thousands of formalin-fixed, paraffin-embedded archival blocks collected around the world, but in contrast relatively few fresh frozen samples in tumour banks. Once samples are fixed in formalin, the RNA is degraded and traditional methods for gene expression profiling are not suitable.

The contribution of breast cancer pathology to statistical models to predict mutation risk in BRCA carriers.

BRCA1 and BRCA2 associated breast cancer comprises a small but important group of hereditary breast cancer. Testing for BRCA1 and BRCA2 has significant clinical and personal implications for the patients in terms of therapy and follow-up of individual family members. The sequencing of the genes is expensive and since the information derived may have a profound effect on the individual and family members, it is important that testing is done only when the risk of carrying a mutation is thought to be high.