Flower isoforms promote competitive growth in cancer.

In humans, the adaptive immune system uses the exchange of information between cells to detect and eliminate foreign or damaged cells; however, the removal of unwanted cells does not always require an adaptive immune system1,2. For example, cell selection in Drosophila uses a cell selection mechanism based on 'fitness fingerprints', which allow it to delay ageing3, prevent developmental malformations3,4 and replace old tissues during regeneration5. At the molecular level, these fitness fingerprints consist of combinations of Flower membrane proteins3,4,6. Proteins that indicate reduced fitness are called Flower-Lose, because they are expressed in cells marked to be eliminated6. However, the presence of Flower-Lose isoforms at a cell's membrane does not always lead to elimination, because if neighbouring cells have similar levels of Lose proteins, the cell will not be killed4,6,7. Humans could benefit from the capability to recognize unfit cells, because accumulation of damaged but viable cells during development and ageing causes organ dysfunction and disease8-17. However, in Drosophila this mechanism is hijacked by premalignant cells to gain a competitive growth advantage18. This would be undesirable for humans because it might make tumours more aggressive19-21. It is unknown whether a similar mechanism of cell-fitness comparison is present in humans. Here we show that two human Flower isoforms (hFWE1 and hFWE3) behave as Flower-Lose proteins, whereas the other two isoforms (hFWE2 and hFWE4) behave as Flower-Win proteins. The latter give cells a competitive advantage over cells expressing Lose isoforms, but Lose-expressing cells are not eliminated if their neighbours express similar levels of Lose isoforms; these proteins therefore act as fitness fingerprints. Moreover, human cancer cells show increased Win isoform expression and proliferate in the presence of Lose-expressing stroma, which confers a competitive growth advantage on the cancer cells. Inhibition of the expression of Flower proteins reduces tumour growth and metastasis, and induces sensitivity to chemotherapy. Our results show that ancient mechanisms of cell recognition and selection are active in humans and affect oncogenic growth.

HIF-transcribed p53 chaperones HIF-1α.

Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.

E-cadherin immunohistochemistry in breast pathology: uses and pitfalls.

E-cadherin immunohistochemistry is used commonly in surgical pathology practice to help distinguish lobular carcinoma in situ from ductal carcinoma in situ and invasive lobular carcinoma from invasive ductal carcinoma in histologically problematic or indeterminate cases. However, the interpretation of E-cadherin immunostains is not always straightforward. Failure to recognize the pitfalls and limitations of E-cadherin immunostains can lead to an erroneous diagnosis which may result in inappropriate patient management, particularly for patients with in-situ lesions. In this paper we review the uses and, particularly, the pitfalls in the interpretation of E-cadherin immunostains in distinguishing lobular from ductal lesions of the breast.

Targeted Axillary Dissection after Chemotherapy: Feasibility Study with Clip and Carbon Dye Tattoo - Neotarget Trial.

Background: Axillary staging in patients with complete response after neoadjuvant chemotherapy (NAC) is still controversial. Our objective was to test tattoo alone and subsequentially tattoo plus clip as markers in the targeted axillary dissection of ycN0 patients. Methods: Prospective cohort of cT1-T3, cN1 (proven histologically), M0 patients scheduled to receive NAC. Exclusion criteria were lobular histology, prior axillary surgery, and clinical N2/3. In cohort 1 this positive node (Neotarget node) was tattooed at diagnosis. If ycN0, a targeted axillary dissection was performed. After an interim analysis with negative results we changed the protocol in order to do a double marking procedure (Cohort 2): the positive node was clipped at diagnosis and after NAC a tattoo was done before surgery. Results: Thirteen patients in Cohort 1 and 18 patients in Cohort 2. Failure to identify the Neotarget node with multiple nodes retrieved in 9/13 (69%) of Cohort 1 patients. Also in 5/13 (38%) of Cohort 1 patients and 3/18 (17%) of Cohort 2 there was a failure to clearly identify tattooed nodes. In Cohort 2, clip identification by surgical specimen radiography allowed the identification of the tagged node in 17/18 (94,4%) of cases. The concordance between the clipped node and sentinel nodes was 16/18 (89%). Conclusions: The introduction of double marking by clipping the metastatic node and verifying their removal by surgical specimen radiography, using carbon ink as a tracer, allowed the identification of the metastatic node in 94% of cases, with a simple, reproducible, and easy-to-implement targeted axillary dissection procedure.

Artificial Intelligence Improves the Accuracy in Histologic Classification of Breast Lesions.

OBJECTIVES: This study evaluated the usefulness of artificial intelligence (AI) algorithms as tools in improving the accuracy of histologic classification of breast tissue. METHODS: Overall, 100 microscopic photographs (test A) and 152 regions of interest in whole-slide images (test B) of breast tissue were classified into 4 classes: normal, benign, carcinoma in situ (CIS), and invasive carcinoma. The accuracy of 4 pathologists and 3 pathology residents were evaluated without and with the assistance of algorithms. RESULTS: In test A, algorithm A had accuracy of 0.87, with the lowest accuracy in the benign class (0.72). The observers had average accuracy of 0.80, and most clinically relevant discordances occurred in distinguishing benign from CIS (7.1% of classifications). With the assistance of algorithm A, the observers significantly increased their average accuracy to 0.88. In test B, algorithm B had accuracy of 0.49, with the lowest accuracy in the CIS class (0.06). The observers had average accuracy of 0.86, and most clinically relevant discordances occurred in distinguishing benign from CIS (6.3% of classifications). With the assistance of algorithm B, the observers maintained their average accuracy. CONCLUSIONS: AI tools can increase the classification accuracy of pathologists in the setting of breast lesions.

Histopathologic challenges: The second OPINION issue.

Classification and definition criteria for rare cancer is still an open issue in clinical practice due to several factors, which include the limited available molecular data to better defining specific tumor groups or "families" of interest. An important issue related to the proper management of these entities is the correct diagnosis and subtyping of a given entity. The high complexity associated with the histopathologic diagnosis and eventual molecular analysis may suggest the use of a histopathologic second opinion from a specialized pathologist. Diagnostic inaccuracies and difference between primary diagnosis and second opinion are expected at the population level: however, the magnitude of this difference is remarkably high and calls for implementation of second opinion in routine practice outside reference centers.

Invasive carcinoma arising from sclerosing polycystic adenosis of the salivary gland.

Sclerosing polycystic adenosis is a rare salivary gland lesion. Recently, this entity has been regarded as a neoplastic lesion of low-grade malignant potential but, to date, no invasive carcinoma, metastases, or associated mortality have been reported. We report the first case of an invasive carcinoma component in a recurrent sclerosing polycystic adenosis lesion.

Small cell carcinoma of the bladder associated with schistosomiasis: a case report.

BACKGROUND: Smoking and occupational exposure to bladder cancer carcinogens are the major risk factors for bladder cancer development in industrialized countries, where urothelial carcinoma is the most common histologic type, accounting for >90% of cases. In Africa and the Middle East, with highly prevalent chronic infection by Schistosoma haematobium (S. haematobium), urinary bladder squamous cell carcinoma is the most prevalent histologic type of bladder cancer, followed by transitional cell carcinoma. Small cell carcinoma accounts for <1% of all primary bladder malignancies. It has the same demographic and clinical features as conventional urothelial carcinoma, and to our knowledge there is no data regarding its association with S. haematobium infection. CASE: We report on the clinicopathological characteristics of a 62-year-old, African man who presented with gross hematuria and advanced disease, resulting in a diagnosis of small cell carcinoma of the bladder associated with S. haematobium infection. He was treated with neoadjuvant chemotherapy followed by cystoprostatectomy, and remains alive after 19 months of follow-up. CONCLUSION: We cannot rule out the possibility that a parasitic infection played a major role in the pathogenesis of small cell bladder carcinoma in this particular case.