Recent Developments in the Treatment of Pancreatic Cancer.

Pancreatic duct adenocarcinoma is currently the sixth-leading cause of cancer death worldwide and the fourth in Europe, with a continuous increase in annual lethality in Portugal during the last two decades. Surgical en-bloc resection of the tumor with microscopic-negative margins and an adequate lymphadenectomy is the only possibility of long-term survival. As this type of cancer is a systemic disease, there is a high rate of recurrence even after curative resection, turning systemic therapy the core of its management, mostly based on chemotherapy. Neoadjuvant strategies for nonmetastatic disease showed significant improvement in overall survival compared with upfront surgery, namely in borderline resectable disease. Moreover, these strategies provided downstaging in several situations allowing R0 resections. Under these new oncologic strategies, several recent surgical issues were introduced, namely more aggressive vascular resections and even tumor resections in oligometastatic disease. This review revisits the state-of-the-art of surgical and oncological interventions in pancreatic duct adenocarcinoma and highlights recent advances in the field aiming to achieve higher survival rates.

An isothermal lab-on-phone test for easy molecular diagnosis of SARS-CoV-2 near patients and in less than 1 hour.

OBJECTIVES: The performance of a new point-of-care CE-IVD-marked isothermal lab-on-phone COVID-19 assay was assessed in comparison to a gold standard real-time reverse transcriptase-PCR method. METHODS: The study was conducted following a nonprobability sampling of ≥16-year-old volunteers from three different laboratories, using direct mouthwash (N = 24) or nasopharyngeal (N = 191) clinical samples. RESULTS: The assay demonstrated 95.19% sensitivity and 100% specificity for detection of SARS-CoV-2 in direct nasopharyngeal crude samples and 78.95% sensitivity and 100% specificity in direct mouthwash crude samples. It also successfully detected currently predominant SARS-CoV-2 variants of concern (Beta B.1.351, Delta B.1.617.2, and Omicron B.1.1.529) and demonstrated to be inert against potential cross-reactions of other common respiratory pathogens that cause infections that present similar symptoms to COVID-19. CONCLUSION: This lab-on-phone pocket-sized assay relies on an isothermal amplification of SARS-CoV-2's N and E genes, taking just 50 minutes from sample to result, with only 2 minutes of hands-on time. It presents good performance when using direct nasopharyngeal crude samples, enabling a low-cost, real-time, rapid, and accurate identification of SARS-CoV-2 infections at the point of care, which is important for both clinical management and population screening, as a tool to break the chain of transmission of COVID-19 pandemic, especially in low-resources environments.

Predictive and Therapeutic Implications of a Novel PLCγ1/SHP2-Driven Mechanism of Cetuximab Resistance in Metastatic Colorectal Cancer.

PURPOSE: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. EXPERIMENTAL DESIGN: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. RESULTS: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. CONCLUSIONS: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.

Treatment optimization of locally advanced and metastatic pancreatic cancer (Review).

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumor types, being the sixth leading cause of mortality worldwide and the fourth in Europe. Globally, it has a mortality/incidence ratio of 98%, and the 5­year survival rate in Europe is only 3%. Although risk factors, such as obesity, diabetes mellitus, smoking, alcohol consumption and genetic factors, have been identified, the causes of PDAC remain elusive. Additionally, the only curative treatment for PDAC is surgery with negative margins. However, upon diagnosis, ~30% of the patients already present with locally advanced disease. In these cases, a multidisciplinary approach is required to improve disease­related symptoms and prolong patient survival. In the present article, a comprehensive review of PDAC epidemiology, physiology and treatment is provided. Moreover, guidelines on patient treatment are suggested. Among the different available therapeutic options for the treatment of advanced PDAC, results are modest, most likely due to the complexity of the disease, and so the prognostic remains poor. Molecular approaches based on multi­omics research are promising and will contribute to groundbreaking personalized medicine. Thus, economic investment that promotes research of pancreatic cancer will be critical to the development of more efficient diagnostic and treatment strategies.

Beta-HCG secretion by a pulmonary pleomorphic carcinoma: A case report.

Ectopic secretion of beta-subunit of human chorionic gonadotropin (ß-HCG) in pulmonary pleomorphic carcinoma is remarkably rare. Such unusual ectopic hormone production by lung cancer may be initially misinterpreted as extragonadal choriocarcinoma or germ cell tumor. We report a 56-year-old postmenopausal female, smoker, who presented a 5-month history of progressive dyspnea, dry paroxysmal cough, and significant weight loss. She was referred by a local hospital with the preliminary diagnosis of gestational trophoblastic neoplasia due to a rapidly growing thoracic tumor with persistently elevated serum ß-HCG. Computed tomography of the chest showed a lung mass in the right upper lobe associated with homolateral pleural effusion. Positron emission tomography showed pathological 2-[18F]FDG uptake at the mass lesion. Biopsies were performed. Histological examination described pleomorphic carcinoma with positive immunostaining for ß-HCG. The serum levels of ß-HCG were also elevated indicating ectopic secretion. The patient had rapid clinical deterioration and deceased before chemotherapy initiation. Only a few cases of paraneoplastic ß-HCG secretion have been reported in the literature. Previous studies suggested that the ability to secrete ß-hCG in tumors may correlate to some extent to chemoresistance; thus, it might be useful as a prognosis marker.

Exploring sialyl-Tn expression in microfluidic-isolated circulating tumour cells: A novel biomarker and an analytical tool for precision oncology applications.

Circulating tumour cells (CTCs) originating from a primary tumour, lymph nodes and distant metastases hold great potential for liquid biopsies by providing a molecular fingerprint for disease dissemination and its temporal evolution through the course of disease management. CTC enumeration, classically defined on the basis of surface expression of Epithelial Cell Adhesion Molecule (EpCAM) and absence of the pan-leukocyte marker CD45, has been shown to correlate with clinical outcome. However, existing approaches introduce bias into the subsets of captured CTCs, which may exclude biologically and clinically relevant subpopulations. Here we explore the overexpression of the membrane protein O-glycan sialyl-Tn (STn) antigen in advanced bladder and colorectal tumours, but not in blood cells, to propose a novel CTC isolation technology. Using a size-based microfluidic device, we show that the majority (>90%) of CTCs isolated from the blood of patients with metastatic bladder and colorectal cancers express the STn antigen, supporting a link with metastasis. STn+ CTC counts were significantly higher than EpCAM-based detection in colorectal cancer, providing a more efficient cell-surface biomarker for CTC isolation. Exploring this concept, we constructed a glycan affinity-based microfluidic device for selective isolation of STn+ CTCs and propose an enzyme-based strategy for the recovery of viable cancer cells for downstream investigations. Finally, clinically relevant cancer biomarkers (transcripts and mutations) in bladder and colorectal tumours, were identified in cells isolated by microfluidics, confirming their malignant origin and highlighting the potential of this technology in the context of precision oncology.

Um caso de liquen mixedematoso e cancro da mama / A case of lichen myxedematosus breast carcinoma

No disponible