B7-H3 Expression in Breast Cancer and Brain Metastasis.

Brain metastasis is a significant challenge for some breast cancer patients, marked by its aggressive nature, limited treatment options, and poor clinical outcomes. Immunotherapies have emerged as a promising avenue for brain metastasis treatment. B7-H3 (CD276) is an immune checkpoint molecule involved in T cell suppression, which is associated with poor survival in cancer patients. Given the increasing number of clinical trials using B7-H3 targeting CAR T cell therapies, we examined B7-H3 expression across breast cancer subtypes and in breast cancer brain metastases to assess its potential as an interventional target. B7-H3 expression was investigated using immunohistochemistry on tissue microarrays of three clinical cohorts: (i) unselected primary breast cancers (n = 347); (ii) brain metastatic breast cancers (n = 61) and breast cancer brain metastases (n = 80, including a subset of 53 patient-matched breast and brain metastasis cases); and (iii) mixed brain metastases from a range of primary tumours (n = 137). In primary breast cancers, B7-H3 expression significantly correlated with higher tumour grades and aggressive breast cancer subtypes, as well as poorer 5-year survival outcomes. Subcellular localisation of B7-H3 impacted breast cancer-specific survival, with cytoplasmic staining also correlating with a poorer outcome. Its expression was frequently detected in brain metastases from breast cancers, with up to 90% expressing B7-H3. However, not all brain metastases showed high levels of expression, with those from colorectal and renal tumours showing a low frequency of B7-H3 expression (0/14 and 2/16, respectively). The prevalence of B7-H3 expression in breast cancers and breast cancer brain metastases indicates potential opportunities for B7-H3 targeted therapies in breast cancer management.

Intraoperative gaze guidance with mixed reality.

Efficient communication and collaboration are essential in the operating room for successful and safe surgery. While many technologies are improving various aspects of surgery, communication between attending surgeons, residents, and surgical teams is still limited to verbal interactions that are prone to misunderstandings. Novel modes of communication can increase speed and accuracy, and transform operating rooms. A mixed reality (MR) based gaze sharing application on Microsoft HoloLens 2 headset that can help expert surgeons indicate specific regions, communicate with decreased verbal effort, and guide novices throughout an operation is presented. The utility of the application is tested with a user study of endoscopic kidney stone localization completed by urology experts and novice surgeons. Improvement is observed in the NASA task load index surveys (up to 25.23%), in the success rate of the task (6.98% increase in localized stone percentage), and in gaze analyses (up to 31.99%). The proposed application shows promise in both operating room applications and surgical training tasks.

Automated Upper Tract Urothelial Carcinoma Tumor Segmentation During Ureteroscopy Using Computer Vision Techniques.

INTRODUCTION: Endoscopic tumor ablation of upper tract urothelial carcinoma (UTUC) allows for tumor control with the benefit of renal preservation but is impacted by intraoperative visibility. We sought to develop a computer vision model for real-time, automated segmentation of UTUC tumors to augment visualization during treatment. MATERIALS AND METHODS: We collected twenty videos of endoscopic treatment of UTUC from two institutions. Frames from each video (N=3387) were extracted and manually annotated to identify tumors and areas of ablated tumor. Three established computer vision models (U-Net, U-Net++ and UNext) were trained using these annotated frames and compared. Eighty percent of the data was used to train the models while 10% was used for both validation and testing. We evaluated the highest performing model for tumor and ablated tissue segmentation using a pixel-based analysis. The model and a video overlay depicting tumor segmentation were further evaluated intraoperatively. RESULTS: All twenty videos (mean 36 seconds ± 58s) demonstrated tumor identification and 12 depicted areas of ablated tumor. The U-Net model demonstrated the best performance for segmentation of both tumors (AUC-ROC of 0.96) and areas of ablated tumor (AUC-ROC of 0.90). Additionally, we implemented a working system to process real-time video feeds and overlay model predictions intraoperatively. The model was able to annotate new videos at 15 fps. CONCLUSIONS: Computer vision models demonstrate excellent real-time performance for automated upper tract urothelial tumor segmentation during ureteroscopy.

Factors Affecting Holmium Laser Efficiency: Comparison of Laryngeal Mask Airway and Endotracheal Intubation During Ureteroscopy for Renal Stones.

Introduction: Holmium laser lithotripsy is a standard energy source used for treatment of kidney stones during flexible ureteroscopy. Efficiency of laser surgery may be affected by patient and operator characteristics or perioperative management. Here, we sought to examine intraoperative data from patients undergoing high frequency dusting with high-powered holmium laser lithotripsy to evaluate surgical and demographic factors associated with lasing efficiency (LE). Methods: A total of 82 intraoperative reports were analyzed from an ongoing laser lithotripsy clinical trial evaluating the Lumenis Pulse™ 120H holmium laser with renal stones up to 20 mm in diameter with and without Moses 2.0 technology. For each case, the total pause time between lasing activations was corrected to remove lengthy pauses and divided by the total lasing time to calculate an efficiency percentage. This was then compared with patient demographics, anesthesia administration, stone burden, postoperative complications, and stone-free rates using both univariate and multivariate analyses. Results: Of the 82 included patients, 36 received endotracheal tube (ETT) intubation and 46 had a laryngeal mask airway (LMA). Patients with ETT had significantly higher LE (78.7%) compared to those with an LMA (73.3%) in our univariate analysis (p < 0.01) as well as in the multivariate model that adjusted for maximum stone size, number of stones, stone density, and patient body mass index (p < 0.05). There was also significantly higher mean LE in patients with no postoperative complications (76.3%) compared to those with any grade (I-V) Clavien-Dindo complication within 30 days after surgery (70.0%) (p < 0.05). Conclusions: Flexible ureteroscopy and laser lithotripsy cases with higher LE are associated with lower rates of postoperative complications. The data also support the use of ETT over LMA to improve overall LE; however, this remains one consideration among many for choosing anesthesia administration. Clinical Trial Registration number: NCT04505956.

Targeted Hyperbranched Nanoparticles for Delivery of Doxorubicin in Breast Cancer Brain Metastasis.

Breast cancer brain metastases (BM) are associated with a dismal prognosis and very limited treatment options. Standard chemotherapy is challenging in BM patients because the high dosage required for an effective outcome causes unacceptable systemic toxicities, a consequence of poor brain penetration, and a short physiological half-life. Nanomedicines have the potential to circumvent off-target toxicities and factors limiting the efficacy of conventional chemotherapy. The HER3 receptor is commonly expressed in breast cancer BM. Here, we investigate the use of hyperbranched polymers (HBP) functionalized with a HER3 bispecific-antibody fragment for cancer cell-specific targeting and pH-responsive release of doxorubicin (DOX) to selectively deliver and treat BM. We demonstrated that DOX-release from the HBP carrier was controlled, gradual, and greater in endosomal acidic conditions (pH 5.5) relative to physiologic pH (pH 7.4). We showed that the HER3-targeted HBP with DOX payload was HER3-specific and induced cytotoxicity in BT474 breast cancer cells (IC50: 17.6 µg/mL). Therapeutic testing in a BM mouse model showed that HER3-targeted HBP with DOX payload impacted tumor proliferation, reduced tumor size, and prolonged overall survival. HER3-targeted HBP level detected in ex vivo brain samples was 14-fold more than untargeted-HBP. The HBP treatments were well tolerated, with less cardiac and oocyte toxicity compared to free DOX. Taken together, our HER3-targeted HBP nanomedicine has the potential to deliver chemotherapy to BM while reducing chemotherapy-associated toxicities.

Cultural Humility in Undergraduate Nursing Students and Faculty.

ABSTRACT: There exists a critical knowledge deficit in undergraduate nursing students when caring for multiculturally diverse clients. A mixed-methods study was conducted with a sample of undergraduate nursing faculty and students. Foronda's Cultural Humility Scale was used, along with a survey about cultural experiences in undergraduate nursing education. The study found that to provide opportunities for psychologically safe conversations and simulated cultural encounters, concepts related to cultural humility should be considered when redesigning nursing curricula.

Predicting breast cancer-specific survival in metaplastic breast cancer patients using machine learning algorithms.

Metaplastic breast cancer (MpBC) is a rare and aggressive subtype of breast cancer, with data emerging on prognostic factors and survival prediction. This study aimed to develop machine learning models to predict breast cancer-specific survival (BCSS) in MpBC patients, utilizing a dataset of 160 patients with clinical, pathological, and biological variables. An in-depth variable selection process was carried out using gain ratio and correlation-based methods, resulting in 10 variables for model estimation. Five models (decision tree with bagging; logistic regression; multilayer perceptron; naïve Bayes; and, random forest algorithms) were evaluated using 10-fold cross-validation. Despite the constraints posed by the absence of therapeutic information, the random forest model exhibited the highest performance in predicting BCSS, with an ROC area of 0.808. This study emphasizes the potential of machine learning algorithms in predicting prognosis for complex and heterogeneous cancer subtypes using clinical datasets, and their potential to contribute to patient management. Further research that incorporates additional variables, such as treatment response, and more advanced machine learning techniques will likely enhance the predictive power of MpBC prognostic models.

The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants-a multi-site prospective cohort study.

BACKGROUND: Many families and individuals do not meet criteria for a known hereditary cancer syndrome but display unusual clusters of cancers. These families may carry pathogenic variants in cancer predisposition genes and be at higher risk for developing cancer. METHODS: This multi-centre prospective study recruited 195 cancer-affected participants suspected to have a hereditary cancer syndrome for whom previous clinical targeted genetic testing was either not informative or not available. To identify pathogenic disease-causing variants explaining participant presentation, germline whole-genome sequencing (WGS) and a comprehensive cancer virtual gene panel analysis were undertaken. RESULTS: Pathogenic variants consistent with the presenting cancer(s) were identified in 5.1% (10/195) of participants and pathogenic variants considered secondary findings with potential risk management implications were identified in another 9.7% (19/195) of participants. Health economic analysis estimated the marginal cost per case with an actionable variant was significantly lower for upfront WGS with virtual panel ($8744AUD) compared to standard testing followed by WGS ($24,894AUD). Financial analysis suggests that national adoption of diagnostic WGS testing would require a ninefold increase in government annual expenditure compared to conventional testing. CONCLUSIONS: These findings make a case for replacing conventional testing with WGS to deliver clinically important benefits for cancer patients and families. The uptake of such an approach will depend on the perspectives of different payers on affordability.

Better Together: Collaboration to Enhance the Nursing Workforce.

Nursing is a demanding profession that calls for nurses to devote time, energy, advocacy, and compassion to improving clients' lives while providing safe, efficient care. Nurses make personal sacrifices to meet their clients' needs, which do not come without costs to their well-being. An increased migration of novice nurses out of the profession and the need to increase the volume of the nursing workforce by an average of 8% annually to address the projected nursing shortage presents a compelling need for immediate action. Reimagining the concept of academic-service partnerships to provide exposure to opportunities that can equip and empower novice nurses as they emerge into professional practice cannot be underestimated. Implementing approaches to assess, support, and nurture the health and well-being of nurses and health care organizations is foundational to retention.

Obesity-associated changes in molecular biology of primary breast cancer.

Obesity is associated with an increased risk of developing breast cancer (BC) and worse prognosis in BC patients, yet its impact on BC biology remains understudied in humans. This study investigates how the biology of untreated primary BC differs according to patients' body mass index (BMI) using data from >2,000 patients. We identify several genomic alterations that are differentially prevalent in overweight or obese patients compared to lean patients. We report evidence supporting an ageing accelerating effect of obesity at the genetic level. We show that BMI-associated differences in bulk transcriptomic profile are subtle, while single cell profiling allows detection of more pronounced changes in different cell compartments. These analyses further reveal an elevated and unresolved inflammation of the BC tumor microenvironment associated with obesity, with distinct characteristics contingent on the estrogen receptor status. Collectively, our analyses imply that obesity is associated with an inflammaging-like phenotype. We conclude that patient adiposity may play a significant role in the heterogeneity of BC and should be considered for BC treatment tailoring.

Eye gaze metrics for skill assessment and feedback in kidney stone surgery.

PURPOSE: Surgical skill assessment is essential for safe operations. In endoscopic kidney stone surgery, surgeons must perform a highly skill-dependent mental mapping from the pre-operative scan to the intraoperative endoscope image. Poor mental mapping can lead to incomplete exploration of the kidney and high reoperation rates. Yet there are few objective ways to evaluate competency. We propose to use unobtrusive eye-gaze measurements in the task space to evaluate skill and provide feedback. METHODS: We capture the surgeons' eye gaze on the surgical monitor with the Microsoft Hololens 2. To enable stable and accurate gaze detection, we develop a calibration algorithm to refine the eye tracking of the Hololens. In addition, we use a QR code to locate the eye gaze on the surgical monitor. We then run a user study with three expert and three novice surgeons. Each surgeon is tasked to locate three needles representing kidney stones in three different kidney phantoms. RESULTS: We find that experts have more focused gaze patterns. They complete the task faster, have smaller total gaze area, and the gaze fewer times outside the area of interest. While fixation to non-fixation ratio did not show significant difference in our findings, tracking the ratio over time shows different patterns between novices and experts. CONCLUSION: We show that a non-negligible difference holds between novice and expert surgeons' gaze metrics in kidney stone identification in phantoms. Expert surgeons demonstrate more targeted gaze throughout a trial, indicating their higher level of proficiency. To improve the skill acquisition process for novice surgeons, we suggest providing sub-task specific feedback. This approach presents an objective and non-invasive method to assess surgical competence.

BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

AIM: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. METHODS AND RESULTS: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non-carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1-3) compared with non-carriers (median n = 9, range = 1-7) (P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3-8) than non-carriers (median n = 5, range = 3-5) (P < 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non-carriers with prostate cancer (P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes (P < 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. CONCLUSION: Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole-body imaging resources are scant.

Persistent malperfusion after central aortic repair in acute type I aortic dissections.

OBJECTIVE: Acute dissection involving the ascending aorta and extending beyond the innominate artery (DeBakey type I) may be associated with acute ischemic complications owing to branch artery malperfusion. The purpose of this study was to document the prevalence of noncardiac ischemic complications associated with type I aortic dissections that persisted after initial ascending aortic and hemiarch repair, necessitating vascular surgery intervention. METHODS: Consecutive patients presenting with acute type I aortic dissections between 2007 and 2022 were studied. Patients who underwent initial ascending aortic and hemiarch repair were included in the analysis. Study end points included the need for additional interventions after ascending aortic repair and death. RESULTS: There were 120 patients (70% men; mean age, 58 ± 13 years) who underwent emergent repair for acute type I aortic dissections during the study period. Forty-one patients (34%) presented with acute ischemic complications. These included 22 (18%) with leg ischemia, 9 (8%) with acute strokes, 5 (4%) with mesenteric ischemia, and 5 (4%) with arm ischemia. After proximal aortic repair, 12 patients (10%) had persistent ischemia. Nine patients (8%) required additional interventions for persistent leg ischemia (n = 7), intestinal gangrene (n = 1), or cerebral edema (craniotomy, n = 1). Three other patients with acute stroke had permanent neurologic deficits. All other ischemic complications resolved after the proximal aortic repair despite mean operative times exceeding 6 hours. Comparing patients with persistent ischemia with those whose symptoms resolved after central aortic repair, there were no differences in demographics, distal extent of dissection, mean operative time for aortic repair, or need for venous-arterial extracorporeal bypass support. Overall, 6 of the 120 patients (5%) suffered perioperative deaths. Hospital deaths occurred in 3 of the 12 patients (25%) with persistent ischemia vs none of 29 patients who had resolution of the ischemia after aortic repair (P = .02). Over a mean follow-up of 51 ± 39 months, no patient required an additional intervention for persistent branch artery occlusion. CONCLUSIONS: One-third of patients with acute type I aortic dissections had associated noncardiac ischemia, prompting a vascular surgery consultation. Limb and mesenteric ischemia most often resolved after the proximal aortic repair and did not require further intervention. No vascular interventions were performed in patients with stroke. Although the presence of acute ischemia at presentation did not increase hospital or 5-year mortality rates, persistent ischemia after central aortic repair seems to be a marker for increased hospital mortality after type I dissections.

Risk factors for lower extremity vascular complications in adult patients on veno-arterial extracorporeal membrane oxygenation.

OBJECTIVE: Utilization of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has increased significantly over the last decade. Prior studies have reported worse mortality for patients with vascular complications on VA-ECMO; however, these were limited by small sample size. The purpose of this study is to investigate predictive risk factors for vascular complications in VA-ECMO patients and their potential impact on mortality. METHODS: Patients who underwent peripheral VA-ECMO from January 2011 to December 2021 were identified. Primary outcomes were lower extremity vascular complications and in-hospital mortality. Multivariate stepwise logistic regression models were used to identify predictors of vascular complications and in-hospital mortality. RESULTS: A total of 605 VA-ECMO patients (25% female) were identified. The mean age was 56.3 ± 13 years, and 56 (10.4%) were black. In-hospital mortality was 63.8% (n = 386), and VA-ECMO ipsilateral vascular complications occurred in 72 patients (11.9%). Vascular surgical interventions (thromboembolectomy, fasciotomies, amputation, and surgical management of cannula bleeding) were required in 30 patients (41.7%). Same-side arterial and venous cannulas, cannula size, and absence of distal perfusion cannula did not increase risk of vascular complication. Multivariate analysis identified age (odds ratio, 0.948; 95% confidence interval, 0.909-0.988; P = .0116) and pre-existing peripheral arterial disease (odds ratio, 3.489; 95% confidence inteval, 1.146-10.624; P = .0278) as independent predictors of need for vascular surgery interventions. The mortality rate of patients who developed vascular complications was not significantly different compared with the mortality rate of those who did not develop vascular complications (61% vs 64%; P = .92). CONCLUSIONS: This study represents one of the largest series to date of lower extremity vascular outcomes in patients undergoing VA-ECMO. Our results confirm the high mortality rate associated with VA-ECMO; however, vascular complications did not represent a risk factor for mortality as previously reported. Same-sided VA-ECMO cannulas, cannula size, and the presence or absence of distal perfusion cannula did not predict vascular complications. Increasing age and presence of peripheral arterial disease are independent predictors of need for vascular surgery intervention in patients on VA-ECMO.

The Role of Routine Ureteral Stenting Following Uncomplicated Ureteroscopic Treatment for Upper Ureteral and Renal Stones: A Randomized Control Trial.

Purpose: Ureteral stenting following uncomplicated ureteroscopy (URS) is common practice. Several studies have proven the safety of omitting routine stent placement following distal ureteral stone treatment. However, there is a paucity of data regarding the utility of stent placement for proximal URS. We designed a prospective, randomized controlled trial to evaluate the role of ureteral stent placement following URS for proximal ureteral and renal stones. Methods: Seventy-two patients with proximal ureteral or renal stones measuring as much as 1.5 cm were prospectively randomized into stented (37) or unstented (35) groups. The surgeon was blinded to the treatment group until after stone treatment. Patients tracked postoperative pain medications and completed validated pain questionnaires on postoperative days 0, 3, 7, and 28. Stents were removed on postoperative day 7. Postoperative follow-up imaging was obtained at 4 weeks. Results: No statistical differences were observed between the two groups in terms of demographics or stone characteristics. The operative time was longer in the stented group (p < 0.03). Patients in the stented group had more irritative urinary symptoms (p < 0.0001) and pain (p < 0.0001), missed more days of work (p < 0.01), and used more narcotics (p < 0.0005) during the first week, but no differences were observed at 30 days. Emergency room visits and overall complication rates were similar between the two groups. Three nonstented patients required stent placement. Two stented patients required early stent removal. Urinary tract infections developed in three stented patients, but not in unstented patients. Postoperative imaging did not reveal any hydronephrosis in either group, and the total stone-free rate was 94%. Conclusions: For most patients undergoing uncomplicated ureteroscopic treatment for proximal ureteral and kidney stones, it may be safe to omit ureteral stents to potentially decrease urinary symptoms and pain while improving short-term quality of life. Further studies with larger patient cohorts may be warranted to confirm our results.

NDRG1 in Cancer: A Suppressor, Promoter, or Both?

N-myc downregulated gene-1 (NDRG1) has been variably reported as a metastasis suppressor, a biomarker of poor outcome, and a facilitator of disease progression in a range of different cancers. NDRG1 is poorly understood in cancer due to its context-dependent and pleiotropic functions. Within breast cancer, NDRG1 is reported to be either a facilitator of, or an inhibitor of tumour progression and metastasis. The wide array of roles played by NDRG1 are dependent on post-translational modifications and subcellular localization, as well as the cellular context, for example, cancer type. We present an update on NDRG1, and its association with hallmarks of cancer such as hypoxia, its interaction with oncogenic proteins such as p53 as well its role in oncogenic and metastasis pathways in breast and other cancers. We further comment on its functional implications as a metastasis suppressor and promoter, its clinical relevance, and discuss its therapeutic targetability in different cancers.

Foundations of Nursing: Comparing Face-to-Face Versus Blended Learning.

ABSTRACT: Research focusing on blended learning for foundations of nursing courses is limited. The purpose of this study was to compare course performance outcomes when teaching foundations using blended learning compared to face-to-face instruction and to evaluate learner satisfaction and perceptions of effectiveness regarding blended learning. No significant differences were found in exam or final course grades between the two modalities. Most participants perceived blended learning as effective in meeting the course objectives and rated the course as either excellent, very good, or good. Blended learning was a useful strategy for teaching foundations of nursing.

Modeling Brain Metastasis by Internal Carotid Artery Injection of Cancer Cells.

Brain metastasis is a cause of severe morbidity and mortality in cancer patients. Critical aspects of metastatic diseases, such as the complex neural microenvironment and stromal cell interaction, cannot be entirely replicated with in vitro assays; thus, animal models are critical for investigating and understanding the effects of therapeutic intervention. However, most brain tumor xenografting methods do not produce brain metastases consistently in terms of the time frame and tumor burden. Brain metastasis models generated by intracardiac injection of cancer cells can result in unintended extracranial tumor burden and lead to non-brain metastatic morbidity and mortality. Although intracranial injection of cancer cells can limit extracranial tumor formation, it has several caveats, such as the injected cells frequently form a singular tumor mass at the injection site, high leptomeningeal involvement, and damage to brain vasculature during needle penetration. This protocol describes a mouse model of brain metastasis generated by internal carotid artery injection. This method produces intracranial tumors consistently without the involvement of other organs, enabling the evaluation of therapeutic agents for brain metastasis.