Pancreatic ductal adenocarcinoma is a highly lethal malignancy, which has now become the seventh most common cause of cancer death in the world, with the highest mortality rates in Europe and North America. In the past 30 years, there has been some progress in 5-year survival (rates increasing from 2.5 to 10%), but this is still extremely poor compared to all other common cancer types. Targeted therapies for advanced pancreatic cancer based on actionable mutations have been disappointing, with only 3–5% showing even a short clinical benefit. There is, however, a molecular diversity beyond mutations in genes responsible for producing classical canonical signaling pathways. Pancreatic cancer is almost unique in promoting an excess production of other components of the stroma, resulting in a complex tumor microenvironment that contributes to tumor development, progression, and response to treatment. Various transcriptional subtypes have also been described. Most notably, there is a strong alignment between the Classical/Pancreatic progenitor and Quasi-mesenchymal/Basal-like/Squamous subtype signatures of Moffit, Collinson, Bailey, Puleo, and Chan-Seng-Yue, which have potential clinical impact. Sequencing of epithelial cell populations enriched by laser capture microscopy combined with single-cell RNA sequencing has revealed the potential genomic evolution of pancreatic cancer as being a consequence of a gene expression continuum from mixed Basal-like and Classical cell populations within the same tumor, linked to allelic imbalances in mutant KRAS, with metastatic tumors being more copy number-unstable compared to primary tumors. The Basal-like subtype appears more chemoresistant with reduced survival compared to the Classical subtype. Chemotherapy and/or chemoradiation will also enrich the Basal-like subtype. Squamous/Basal-like programs facilitate immune infiltration compared with the Classical-like programs. The immune infiltrates associated with Basal and Classical type cells are distinct, potentially opening the door to differential strategies. Single-cell and spatial transcriptomics will now allow single cell profiling of tumor and resident immune cell populations that may further advance subtyping. Multiple clinical trials have been launched based on transcriptomic response signatures and molecular subtyping including COMPASS, Precision Promise, ESPAC6/7, PREDICT-PACA, and PASS1. We review several approaches to explore the clinical relevance of molecular profiling to provide optimal bench-to-beside translation with clinical impact.
This article presents a low-noise transimpedance amplifier (TIA) designed for miniature ultrasound probes. It provides continuously variable gain to compensate for the time-dependent attenuation of the received echo signal. This time-gain compensation (TGC) compresses the echo-signal dynamic range (DR) while avoiding imaging artifacts associated with discrete gain steps. Embedding the TGC function in the TIA reduces the output DR, saving power compared to prior solutions that apply TGC after the low-noise amplifier. The TIA employs a capacitive ladder feedback network and a current-steering circuit to obtain a linear-in-dB gain range of 37 dB. A variable-gain loop amplifier based on current-reuse stages maintains constant bandwidth in a power-efficient manner. The TIA has been integrated in a 64-channel ultrasound transceiver applicationspecific integrated circuit (ASIC) in a 180-nm BCDMOS process and occupies a die area of 0.12 mm 2. It achieves a gain error below ±1 dB and a 1.7 pA/ √ Hz noise floor and consumes 5.2 mW from a ±0.9 V supply. B-mode images of a tissue-mimicking phantom are presented that show the benefits of the TGC scheme. Index Terms-Continuous gain control, time-gaincompensation (TGC), transimpedance amplifier (TIA), ultrasound application-specific integrated circuit (ASIC), ultrasound imaging. I. INTRODUCTION U LTRASOUND imaging is a safe and cost-effective tool for the diagnosis of medical conditions and the guidance of treatment. Size reduction of imaging devices has enabled ultrasound imaging from the tip of an mm-size catheter, for instance, for intracardiac echocardiography (ICE), as illustrated in Fig. 1(a) [1], [2]. Applications of ICE probes include guidance and monitoring of catheter ablation for the treatment of atrial fibrillation, guidance of closure of atrial septal defects, and guidance of transcatheter valve implantation [3], [4].
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