Primary Upper Urinary Tract Small Cell Carcinoma: A Case Series and Literature Review

Background: Primary upper urinary tract small cell carcinoma (SCC) is exceedingly rare with \u3c 30 cases reported in the literature. Little is known about the incidence, diagnosis, treatment, and outcomes in these patients. We present a series of three patients with primary upper tract SCC. Case Presentation: Patient 1 is an 89-year-old Caucasian male who presented with hydroureteronephrosis and a mass in the proximal right ureter. Biopsy revealed SCC. Without further intervention, the patient died 2 months after his diagnosis. Patient 2 is a 67-year-old Caucasian female who underwent left laparoscopic nephroureterectomy for primary distal ureteral SCC, pT4N1M0. She developed lymphadenopathy and completed external beam radiation to the pelvis and four courses of cisplatin-based chemotherapy. She died from metastatic disease 7 months after diagnosis. Patient 3 is a 45-year-old female who underwent open right radical nephrectomy, retroperitoneal lymph node dissection, and hepatic metastasectomy for metastatic primary upper tract SCC, pT3N1M1. She underwent two subsequent retroperitoneal debulking procedures for recurrence followed by treatment with octreotide. She developed widespread metastasis and was treated with temozolomide and capecitabine before her death 80 months after diagnosis. Conclusion: This series contributes to the limited knowledge of the management and natural course of primary upper tract SCC. Patient 1 represents the first disease-specific mortality reported in a patient who received no therapy. Patient 3 represents the longest reported survival with metastatic disease, and the first treated with octreotide. The patient was managed with aggressive repeat surgical resection and exhibited 2 years of progression-free survival on octreotide. Emphasis should be placed on aggressive resection of all visible disease combined with the use of multimodal adjuvant chemoradiation for selected patients in this rare disease

Formula SAE

The Formula SAE senior design project was truly unique. This project had been a 5 year long process to design, build, and test a raceable car. The car was this team\u27s prototype. While the original plan for the team was to develop an energy recovery system (ERS), this scope was altered because of the state of the car the team was left with. Upon examination, the car needed a lot of work before it was even going to start. Therefore, without a running car, there was no way of appropriately testing an ERS. Furthermore, had we developed a prototype for the ERS, there would have been no way to truly implement the design. It would only have stood as a proof of concept. Ultimately, the work required to start the car and develop and ERS would be a task that required two teams. By making the change in scope, the team had been the closest to date to achieving a running car. Currently the car does not start. However, the team was able to get the engine to backfire in an attempt to get it to start. To get the full state, the issue has been identified as the engine control unit\u27s (ECU) inability to get an accurate camshaft sensor reading. With a hardware adjustment, the team was recently able to deliver a reading to the ECU. It outputs a correct square wave, but its periodicity has yet to be tested. The team has left to test the new hardware with the engine. In order to get to the point where the car is in position to start, many major subsystems required re-working. These systems include the wiring of the car, the fuel injection system, and the engine control unit (ECU). First, upon receiving the car, its wiring was incomplete, and very unorganized. This was no easy feat to correct. Furthermore, wiring of the car was particularly challenging because the team had to develop its own wiring schematic that combined the wiring schematics of the 2007 Phazer snowmobile engine and the schematic of the MegaSquirt II ECU. Additionally, the team had to include adjustments to the schematic that included the primary master switch (Required by FSAE rule IC.9.3) and cockpit main switch (Required by FSAE rule IC.9.4). Next, the fuel injection system was not correct. The fuel system that the original snowmobile used was an in-tank fuel system. However, the car requires an in-line fuel system. The differentiation between these two fuel systems was critical because they each require different types of fuel pumps. The state of this subsystem when the team received the car was incorrect. While the set up was correct (an in-line fuel system), the pump used in the system was an in-tank pump. Additionally there was no fuel filter. The team was able to acquire the appropriate pump and a fuel filter for an in-line pump system and completely changed and corrected the fuel injection system. Lastly, the ECU was the most challenging of the subsystems to correct. The ECU acts as the brain of the car. It interprets the sensor readings all throughout the car and responds with signals so that the car can time itself appropriately, start, and turn-off when it needs to. The first step towards completing the ECU was to install its two daughter boards. These were vital because they help to interpret the certain sensors that are specific to the Phazer engine (i.e. the VR sensor). Next, programming the ECU was critical. While there was a code provided specifically for the Phazer engine, it required tweaking. All of the program installation and critiquing was done through TunerStudio. This was the most challenging of the major subsystems because it was the topic that the team had no prior experience working with. However, the team did extensive amounts of research and had many conversations with experts to understand how to best program and implement the ECU. It is important to note that this report is written as the car currently sits. That being said, it does not start. However, there is still time for the team to get the car running. The final step towards doing this is to make sure the hardware adjustment carries over appropriately to the final trial start of the car. Once it does this, the engine will have no issue injecting the fuel, and igniting its sparks (both of which have been tested and work). With the current status of the car understood, it is important to note that all design constraints, and applicability codes and standards were met. While the team\u27s most pressing constraint was time and money, neither has put a hindrance on the team working on, and improving the condition of the car. The codes and standards that are most applicable to the team were those provided by the FSAE rule book. However, there were not many regulations that regard getting the car to start. As mentioned it was important to include the master switch and emergency shutoff switch in accordance with the code. However, not much else was required for the team to get the car to start. It will be important for future teams to dive deeper into these standards as they get closer to racing the car. Primarily for the safety of the driver, but also, by not following the rule book, the team will be disqualified. Additionally, it will be helpful for future teams to refer to the design manual produced by this year\u27s team. It will encompass what has been completed by the team and what is left to do to get the car competition ready. Overall, the team progressed greatly with the car and has high hopes for the future of the FSAE senior design project

Novel Pharmacologic Targeting of Tight Junctions and Focal Adhesions in Prostate Cancer Cells

Cancer cell resistance to anoikis driven by aberrant signaling sustained by the tumor microenvironment confers high invasive potential and therapeutic resistance. We recently generated a novel lead quinazoline-based Doxazosin® derivative, DZ-50, which impairs tumor growth and metastasis via anoikis. Genome-wide analysis in the human prostate cancer cell line DU-145 identified primary downregulated targets of DZ-50, including genes involved in focal adhesion integrity (fibronectin, integrin-α6 and talin), tight junction formation (claudin-11) as well as insulin growth factor binding protein 3 (IGFBP-3) and the angiogenesis modulator thrombospondin 1 (TSP-1). Confocal microscopy demonstrated structural disruption of both focal adhesions and tight junctions by the downregulation of these gene targets, resulting in decreased cell survival, migration and adhesion to extracellular matrix (ECM) components in two androgen-independent human prostate cancer cell lines, PC-3 and DU-145. Stabilization of cell-ECM interactions by overexpression of talin-1 and/or exposing cells to a fibronectin-rich environment mitigated the effect of DZ-50. Loss of expression of the intracellular focal adhesion signaling effectors talin-1 and integrin linked kinase (ILK) sensitized human prostate cancer to anoikis. Our findings suggest that DZ-50 exerts its antitumor effect by targeting the key functional intercellular interactions, focal adhesions and tight junctions, supporting the therapeutic significance of this agent for the treatment of advanced prostate cancer

Rapid Cryogenic Electrical Characterization of Materials and Devices Using Gifford-McMahon Cryocoolers

Thin-film heterostructures are necessary building blocks for superconducting and phononic quantum computing devices. Many new generations of quantum hardware demand extensive materials research to optimize performances at cryogenic temperatures (below 10 K). Here, we demonstrate compact cryogenic measurement systems capable of reaching sub-10K temperatures in less than three hours with the ability to measure AC/DC resistance and dielectric properties of thin-film materials. Our platform utilizes Gifford-McMahon (GM) cryocoolers as effective tools for providing high throughput cooling-warming cycles. We successfully used the GM-based measurement systems to measure 1) the superconducting transition temperature for Nb thin films (Tc ~7.8 K), and 2) the temperature dependence of the dielectric constant in SiO2 thin films down to 10 K. The fast electrical characterization feedback will be critical in developing robust materials and components for cryogenic computing devices

Evaluation of Glutaminase Expression in Prostate Adenocarcinoma and Correlation with Clinicopathologic Parameters

High Glutaminase (GLS1) expression may have prognostic implications in colorectal and breast cancers; however, high quality data for expression in prostate cancer (PCa) are lacking. The purpose of this study is to investigate the status of GLS1 expression in PCa and correlated expression levels with clinicopathologic parameters. This study was conducted in two phases: an exploratory cohort analyzing RNA-Seq data for GLS1 from The Cancer Genome Atlas (TCGA) data portal (246 PCa samples) and a GLS1 immunohistochemical protein expression cohort utilizing a tissue microarray (TMA) (154 PCa samples; 41 benign samples) for correlation with clinicopathologic parameters. In the TCGA cohort, GLS1 mRNA expression did not show a statistically significant difference in disease-free survival (DFS) but did show a small significant difference in overall survival (OS). In the TMA cohort, there was no correlation between GLS1 expression and stage, Gleason score, DFS and OS. GLS1 expression did not significantly correlate with the clinical outcomes measured; however, GLS1 expression was higher in PCa cells compared to benign epithelium. Future studies are warranted to evaluate expression levels in greater numbers of high-grade and advanced PCa samples to investigate whether there is a rational basis for GLS1 targeted therapy in a subset of patients with prostate cancer

IGG3 Subclass Antibodies Recognize Antigenically Drifted Influenza Viruses and SARS-CoV-2 Variants Through Efficient Bivalent Binding

The constant domains of antibodies are important for effector functions, but less is known about how they can affect binding and neutralization of viruses. Here, we evaluated a panel of human influenza virus monoclonal antibodies (mAbs) expressed as IgG1, IgG2, or IgG3. We found that many influenza virus-specific mAbs have altered binding and neutralization capacity depending on the IgG subclass encoded and that these differences result from unique bivalency capacities of the subclasses. Importantly, subclass differences in antibody binding and neutralization were greatest when the affinity for the target antigen was reduced through antigenic mismatch. We found that antibodies expressed as IgG3 bound and neutralized antigenically drifted influenza viruses more effectively. We obtained similar results using a panel of SARS-CoV-2-specific mAbs and the antigenically advanced B.1.351 and BA.1 strains of SARS-CoV-2. We found that a licensed therapeutic mAb retained neutralization breadth against SARS-CoV-2 variants when expressed as IgG3, but not IgG1. These data highlight that IgG subclasses are not only important for fine-tuning effector functionality but also for binding and neutralization of antigenically drifted viruses

Audit, Feedback, and Education to Improve Quality and Outcomes in Transurethral Resection and Single-Instillation Intravesical Chemotherapy for Nonmuscle Invasive Bladder Cancer Treatment: Protocol for a Multicenter International Observational Study With an Embedded Cluster Randomized Trial

BACKGROUND: Nonmuscle invasive bladder cancer (NMIBC) accounts for 75% of bladder cancers. It is common and costly. Cost and detriment to patient outcomes and quality of life are driven by high recurrence rates and the need for regular invasive surveillance and repeat treatments. There is evidence that the quality of the initial surgical procedure (transurethral resection of bladder tumor [TURBT]) and administration of postoperative bladder chemotherapy significantly reduce cancer recurrence rates and improve outcomes (cancer progression and mortality). There is surgeon-reported evidence that TURBT practice varies significantly across surgeons and sites. There is limited evidence from clinical trials of intravesical chemotherapy that NMIBC recurrence rate varies significantly between sites and that this cannot be accounted for by differences in patient, tumor, or adjuvant treatment factors, suggesting that how the surgery is performed may be a reason for the variation. OBJECTIVE: This study primarily aims to determine if feedback on and education about surgical quality indicators can improve performance and secondarily if this can reduce cancer recurrence rates. Planned secondary analyses aim to determine what surgeon, operative, perioperative, institutional, and patient factors are associated with better achievement of TURBT quality indicators and NMIBC recurrence rates. METHODS: This is an observational, international, multicenter study with an embedded cluster randomized trial of audit, feedback, and education. Sites will be included if they perform TURBT for NMIBC. The study has four phases: (1) site registration and usual practice survey; (2) retrospective audit; (3) randomization to audit, feedback, and education intervention or to no intervention; and (4) prospective audit. Local and national ethical and institutional approvals or exemptions will be obtained at each participating site. RESULTS: The study has 4 coprimary outcomes, which are 4 evidence-based TURBT quality indicators: a surgical performance factor (detrusor muscle resection); an adjuvant treatment factor (intravesical chemotherapy administration); and 2 documentation factors (resection completeness and tumor features). A key secondary outcome is the early cancer recurrence rate. The intervention is a web-based surgical performance feedback dashboard with educational and practical resources for TURBT quality improvement. It will include anonymous site and surgeon-level peer comparison, a performance summary, and targets. The coprimary outcomes will be analyzed at the site level while recurrence rate will be analyzed at the patient level. The study was funded in October 2020 and began data collection in April 2021. As of January 2023, there were 220 hospitals participating and over 15,000 patient records. Projected data collection end date is June 30, 2023. CONCLUSIONS: This study aims to use a distributed collaborative model to deliver a site-level web-based performance feedback intervention to improve the quality of endoscopic bladder cancer surgery. The study is funded and projects to complete data collection in June 2023. TRIAL REGISTRATION: ClinicalTrials.org NCT05154084; https://clinicaltrials.gov/ct2/show/NCT05154084. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42254