Cardiac Loading using Passive Left Atrial Pressurization and Passive Afterload for Graft Assessment.

Ex vivo machine perfusion or normothermic machine perfusion is a preservation method that has gained great importance in the transplantation field. Despite the immense opportunity for assessment due to the beating state of the heart, current clinical practice depends on limited metabolic trends for graft evaluation. Hemodynamic measurements obtained from left ventricular loading have garnered significant attention within the field due to their potential as objective assessment parameters. In effect, this protocol provides an easy and effective manner of incorporating loading capabilities to established Langendorff perfusion systems through the simple addition of an extra reservoir. Furthermore, it demonstrates the feasibility of employing passive left atrial pressurization for loading, an approach that, to our knowledge, has not been previously demonstrated. This approach is complemented by a passive Windkessel base afterload, which acts as a compliance chamber to maximize myocardial perfusion during diastole. Lastly, it highlights the capability of capturing functional metrics during cardiac loading, including left ventricular pulse pressure, contractility, and relaxation, to uncover deficiencies in cardiac graft function after extended periods of preservation times (˃6 h).

Assessing the accuracy of a multisection robotic bronchoscope prototype in localization and targeting of small pulmonary lesions.

Objectives: Robotic bronchoscopy (RB) has emerged as a novel technique to address issues with the biopsy of small peripheral lung lesions. The objective of this study was to quantitatively assess the accuracy of a novel multisection robotic bronchoscope compared with current standards of care. Methods: This is a prospective, single-blind, comparative study where the accuracy of a multisection RB was compared against the accuracy of standard electromagnetic navigational bronchoscopy (EM-NB) during lesion localization and targeting. Five blinded subjects of varying bronchoscopy experience were recruited to use both RB and EM-NB in a swine lung model. Accuracy of localization and targeting success was measured as the distance from the center of pulmonary targets at each anatomic location. Subjects used both RB and EM-NB to navigate to 4 pulmonary targets assigned using 1:1 block randomization. Differences in accuracy and time between navigation systems were assessed using Wilcoxon rank-sum test. Results: Of the 40 total attempts per modality, successful targeting was achieved on 90% and 85% of attempts utilizing RB and EM-NB, respectively. Furthermore, RB demonstrated significantly lower median distance to the real-time EM target (1.1 mm; interquartile range [IQR], 0.6-2.0 mm) compared with EM-NB (2.6 mm; IQR, 1.6-3.8) (P < .001). Median target displacement resulting from lung and bronchus deformation during bronchoscopy was found to be significantly lower using RB (0.8 mm; IQR, 0.5-1.2 mm) compared with EM-NB (2.6 mm; IQR, 1.4-6.4 mm) (P < .001). Conclusions: The results of this study demonstrate that the multi-section RB prototype allows for improved localization and targeting of small peripheral lung nodules compared with current nonrobot bronchoscopy modalities.

Synthesis of Amphiphilic Amino Poly-Amido-Saccharide and Poly(lactic) Acid Block Copolymers and Fabrication of Paclitaxel-Loaded Mucoadhesive Nanoparticles.

Drug delivery to the esophagus through systemic administration remains challenging, as minimal drug reaches the desired target. Local delivery offers the potential for improved efficacy while minimizing off-target toxicities but necessitates bioadhesive properties for mucosal delivery. Herein, we describe the synthesis of two new mucoadhesive amphiphilic copolymers prepared by sequential ring-opening copolymerization or postpolymerization click conjugation. Both strategies yield block copolymers containing a hydrophilic amine-functionalized poly-amido-saccharide and either a hydrophobic alkyl derivatized poly-amido-saccharide or poly(lactic acid), respectively. The latter resulting copolymers readily self-assemble into spherical, ≈200 nm diameter, positively charged mucoadhesive nanoparticles. The NPs entrap ultrahigh levels of paclitaxel via encapsulation of free paclitaxel and paclitaxel conjugated to a biodegradable, biocompatible poly(1,2-glycerol carbonate). Paclitaxel-loaded NPs rapidly enter cells, release paclitaxel, are cytotoxic to esophageal OE33 and OE19 tumor cells in vitro, and, importantly, demonstrate improved mucoadhesion compared to conventional poly(ethylene glycol)-poly(lactic acid) nanoparticles to ex vivo esophageal tissue.

Decreased Lung Metastasis in Triple Negative Breast Cancer Following Locally Delivered Supratherapeutic Paclitaxel-Loaded Polyglycerol Carbonate Nanoparticle Therapy.

Breast cancer is among the most prevalent malignancies, accounting for 685,000 deaths worldwide in 2020, largely due to its high metastatic potential. Depending on the stage and tumor characteristics, treatment involves surgery, chemotherapy, targeted biologics, and/or radiation therapy. However, current treatments are insufficient for treating or preventing metastatic disease. Herein, we describe supratherapeutic paclitaxel-loaded nanoparticles (81 wt % paclitaxel) to treat the primary tumor and reduce the risk of subsequent metastatic lesions in the lungs. Primary tumor volume and lung metastasis are reduced by day 30, compared to the paclitaxel clinical standard treatment. The ultrahigh levels of paclitaxel afford an immunotherapeutic effect, increasing natural killer cell activation and decreasing NETosis in the lung, which limits the formation of metastatic lesions.

Effect of bisphosphonates and statins on the in vitro radiosensitivity of breast cancer cell lines.

BACKGROUND: Early-stage breast cancer is usually treated with breast-conserving surgery followed by adjuvant radiation therapy. Acute skin toxicity is a common radiation-induced side effect experienced by many patients. Recently, a combination of bisphosphonates (zoledronic acid) and statins (pravastatin), or ZOPRA, was shown to radio-protect normal tissues by enhancing DNA double-strand breaks (DSB) repair mechanism. However, there are no studies assessing the effect of ZOPRA on cancerous cells. The purpose of this study is to characterize the in vitro effect of the zoledronic acid (ZO), pravastatin (PRA), and ZOPRA treatment on the molecular and cellular radiosensitivity of breast cancer cell lines. MATERIALS: Two breast cancer cell lines, MDA MB 231 and MCF-7, were tested. Cells were treated with different concentrations of pravastatin (PRA), zoledronate (ZO), as well as their ZOPRA combination, before irradiation. Anti-γH2AX and anti-pATM immunofluorescence were performed to study DNA DSB repair kinetics. MTT assay was performed to assess cell proliferation and viability, and flow cytometry was performed to analyze the effect of the drugs on the cell cycle distribution. The clonogenic assay was used to assess cell survival. RESULTS: ZO, PRA, and ZOPRA treatments were shown to increase the residual number of γH2AX foci for both cell lines. ZOPRA treatment was also shown to reduce the activity of the ATM kinase in MCF-7. ZOPRA induced a significant decrease in cell survival for both cell lines. CONCLUSIONS: Our findings show that pretreatment with ZOPRA can decrease the radioresistance of breast cancer cells at the molecular and cellular levels. The fact that ZOPRA was previously shown to radioprotect normal tissues, makes it a good candidate to become a therapeutic window-widening drug.

Paraganglioma arising from the liver and abutting the heart.

A paraganglioma is a rare extra-adrenal neuroendocrine tumour with a variable clinical presentation. A paraganglioma can arise anywhere along the sympathetic and parasympathetic chains, but it can occasionally emerge from unusual locations such as the liver and the thoracic cavity. We report a rare case of a woman in her 30s who presented to our emergency department with symptoms of chest discomfort, episodic hypertension, tachycardia and diaphoresis. A diagnostic approach including a chest X-ray, an MRI and a positron emission tomography-CT scan showed a large exophytic liver mass protruding into the thoracic cavity. For further characterisation of the mass, a biopsy of the lesion was performed, demonstrating that the tumour is of neuroendocrine origin. This was supported by a urine metanephrine test showing high levels of catecholamine breakdown products. Treatment consisted of a unique multidisciplinary approach involving hepatobiliary and cardiothoracic surgery allowing a safe and complete extermination of the hepatic tumour and its cardiac extension.

The implications and management of complex biliary injuries at a tertiary hepatobiliary specialty center.

Injuries of the biliary tract and complex injuries involving vascular and parenchymal tissue can be detrimental despite the improved use of laparoscopy. Complex biliary injuries are variable depending on the type of injury as well as patient and surgeon factors. We present four cases of complex biliary injuries at our tertiary referral center with hepatobiliary expertise: biliary stenosis with obstruction, double duct system anatomy, combined right hepatic arterial transection and biliary duct injury, and a complete pedicle injury. Early identification and specialized repair of complex biliary injuries is essential to minimize patient morbidity. Notably, consulting a specialist intraoperatively in case of difficult dissection and visualization or a suspected injury and considering bail-out strategies such as a subtotal cholecystectomy or conversion are safe approaches to minimize complex biliary injuries. Earlier recognition and repair of complex biliary injuries improves outcomes when immediate intraoperative repair can be performed rather than delayed postoperatively.

Metastatic melanoma to the small bowel causing intussusception: A case report.

INTRODUCTION AND IMPORTANCE: Melanoma is a malignant skin neoplasm with a high metastatic potential. Several reports have shown that metastatic melanoma has a predilection to metastasize to the GI tract; however, diagnosing metastatic melanoma as a cause of intussusception has been reported in only few cases with variable presentations. CASE PRESENTATION: We present the case of a 48-year-old woman with a long history of metastatic melanoma who presented with recurrent enteric intussusception due to a melanoma lesion acting as a pathologic lead point despite immunotherapy treatment. We contribute the management plan, diagnostic modalities, and surgical approach of this rare form of adult intussusception in guidance of future management plans. CLINICAL DISCUSSION: The variability in presentation of adult intussusception makes diagnosis difficult and the lack of consensus on management and surgical strategies poses challenging hurdles. A diagnostic laparoscopy followed by reduction and resection of the intussuscepted lesion in a small surgical field is an effective and beneficial palliative procedure with favorable outcomes. Our patient developed intussusception despite receiving a trial of dual immunotherapy after chemotherapy. CONCLUSION: It may be insufficient to control disease even with dual immunotherapy after chemotherapy. Further studies are needed to determine the optimal surgical and oncological management in treating gastrointestinal metastasis of malignant melanoma.

Hypoalbuminemia is Associated with Mortality in Patients Undergoing Lower Extremity Amputation.

BACKGROUND: Poor nutritional status is common among patients undergoing lower extremity amputation (LEA). In this study, the association between preoperative hypoalbuminemia, a marker for malnutrition, and postoperative mortality in patients undergoing LEA was explored. METHODS: Data on patients undergoing LEA between 2005 and 2017 were retrospectively analyzed from the prospectively collected American College of Surgeons National Surgical Quality Improvement Program database. Patients were divided into clinically relevant categories based on their serum albumin level (<2.5, 2.5-3.39, ≥3.4 g/dl) and were further stratified according to amputation level. Operative death was compared across groups and multivariable logistic regression was performed to estimate risk-adjusted odds ratio (AOR). RESULTS: In 35,383 patients, the rate of 30-day postoperative mortality was 7.6% (n = 2693). Mortality rate was highest in patients with very low albumin levels (11%) as compared to low (6.8%) and normal levels (3.9%). On multivariable analysis, lower albumin levels emerged as a risk-adjusted independent predictor of mortality. After risk-adjustment, patients with very low albumin levels (AOR [95% CI]: 2.25 [1.969-2.56], P < 0.001) and low albumin levels (AOR [95% CI]: 1.42 [1.239-1.616], P < 0.001) had higher odds of mortality when compared to patients with normal albumin levels. On sensitivity analysis, a similar trend was seen in patients undergoing above knee amputation but not in patients undergoing minor amputations. CONCLUSIONS: In patients undergoing major LEA, hypoalbuminemia is associated with an increased risk of postoperative mortality in a dose response manner, specifically in above knee amputations. Monitoring and optimizing patients' nutritional status before surgery, when possible, may be warranted and should be further explored.

The potential use of tideglusib as an adjuvant radio-therapeutic treatment for glioblastoma multiforme cancer stem-like cells.

BACKGROUND: Glioblastoma multiforme (GBM), a stage IV astrocytoma, is the most common brain malignancy among adults. Conventional treatments of surgical resection followed by radio and/or chemotherapy fail to completely eradicate the tumor. Resistance to the currently available therapies is mainly attributed to a subpopulation of cancer stem cells (CSCs) present within the tumor bulk that self-renew leading to tumor relapse with time. Therefore, identification of characteristic markers specific to these cells is crucial for the development of targeted therapies. Glycogen synthase kinase 3 (GSK-3), a serine-threonine kinase, is deregulated in a wide range of diseases, including cancer. In GBM, GSK-3ß is overexpressed and its suppression in vitro has been shown to induce apoptosis of cancer cells. METHODS: In our study, we assessed the effect of GSK-3ß inhibition with Tideglusib (TDG), an irreversible non-ATP competitive inhibitor, using two human GBM cell lines, U-251 MG and U-118 MG. In addition, we combined TDG with radiotherapy to assess whether this inhibition enhances the effect of standard treatment. RESULTS: Our results showed that TDG significantly reduced cell proliferation, cell viability, and migration of both GBM cell lines in a dose- and time-dependent manner in vitro. Treatment with TDG alone and in combination with radiation significantly decreased the colony formation of U-251 MG cells and the sphere formation of both cell lines, by targeting and reducing their glioblastoma cancer stem-like cells (GSCs) population. Finally, cells treated with TDG showed an increased level of unrepaired radio-induced DNA damage and, thus, became sensitized toward radiation. CONCLUSIONS: In conclusion, TDG has proven its effectiveness in targeting the cancerous properties of GBM in vitro and may, hence, serve as a potential adjuvant radio-therapeutic agent to better target this deadly tumor.