Near Complete Response to Platinum-based Systemic Chemotherapy in High-risk Upper Tract Urothelial Carcinoma With an ERBB2 Gene Mutation: A Case Report.

In bladder urothelial carcinoma, ERBB2 mutations have been associated with favorable response to platinum-based neoadjuvant chemotherapy. However, this association has not been reported in upper tract urothelial carcinoma (UTUC). We describe an excellent response to cisplatin-based chemotherapy in metastatic UTUC with an ERBB2 mutation. Our patient is a 54-year-old female with metastatic UTUC who received systemic cisplatin and gemcitabine. Postchemotherapy imaging demonstrated decreased size of pyelocaliceal mass and decreased retroperitoneal adenopathy compared to initial imaging. Surgical pathology from consolidative resection showed 3 mm residual renal tumor and no viable lymph node disease. Genomic testing demonstrated an ERBB2 gain of function mutation.

Feasibility, Acceptability, and Outcomes of a Mobile Health Tool for Radical Cystectomy Recovery.

PURPOSE: Postoperative education and symptom tracking are essential following cystectomy to reduce readmission rates and information overload. To address these issues, an internet-based tool was developed to provide education, alerts, and symptom tracking. We aimed to evaluate the tool's feasibility, acceptability, and impact on complication and readmission rates. MATERIALS AND METHODS: Thirty-three eligible patients over 18 years old scheduled for cystectomy were enrolled. Patients were asked to use the mobile health (mHealth) tool daily for the first 2 weeks, then less frequently up to 90 days after discharge. Descriptive statistics were used to summarize study variables. Feasibility was defined as at least 50% of patients using the tool once a week, and acceptability as patient satisfaction of > 75%. RESULTS: Use of the mHealth tool was feasible, with 90% of patients using it 1 week after discharge, but engagement declined over time to 50%, with technological difficulties being the main reason for nonengagement. Patient and provider acceptability was high, with satisfaction > 90%. Within 90 days, 36% experienced complications after discharge and 30% were readmitted. Engagement with the mHealth application varied but was not statistically associated with readmission (P = .21). CONCLUSIONS: The study showed that the electronic mobile health intervention for patients undergoing cystectomy was feasible, acceptable, and provided valuable educational content and symptom management. Future larger studies are needed to determine the tool's effectiveness in improving patient outcomes and its potential implementation into routine clinical care.

Molecular characterization of plasmacytoid urothelial carcinoma and the impact on treatment implications.

Bladder cancer researchers and clinicians have increasingly viewed tumor biology through the lens of genomic and molecular alterations, drastically improving our knowledge of the underlying disease biology. This understanding has led to significant advances in treatment options that allow implementation of a personalized approach to cancer treatment. Large-scale genomic studies initially focused on the most common forms of bladder cancer. However, as genomic and molecular technologies become more widespread and are applied to less common variant histologies, we are gaining additional insight into the unique molecular and genomic characteristics driving the biology of variant histologies of bladder cancer. In this review, we summarize the current state of knowledge of molecular alterations underlying the distinct tumor biology of plasmacytoid urothelial carcinoma and how these alterations may impact treatment options.

Bilateral Thoracoscopic Sympathectomy After Sternotomy for Left Ventricular Assist Device Insertion.

Our case is a 73-year-old male patient with persistent ventricular tachycardia leading to recent syncopal episodes despite ventricular tachycardia ablation and multiple stellate ganglion blocks, frequent hospital admissions, and acute on chronic congestive heart failure requiring an intraaortic balloon pump. The decision was made to proceed with left ventricular assist device placement and bilateral sympathectomies simultaneously. After performing the sternotomy and widely opening bilateral pleural spaces, the lower third of the stellate ganglia to the level of T4 was removed using a combination of the thoracoscope with the sternotomy incision. The use of thoracoscopy greatly assisted with visualization during the sympathectomy.

Programmable Multivalent DNA-Origami Tension Probes for Reporting Cellular Traction Forces.

Mechanical forces are central to most, if not all, biological processes, including cell development, immune recognition, and metastasis. Because the cellular machinery mediating mechano-sensing and force generation is dependent on the nanoscale organization and geometry of protein assemblies, a current need in the field is the development of force-sensing probes that can be customized at the nanometer-length scale. In this work, we describe a DNA origami tension sensor that maps the piconewton (pN) forces generated by living cells. As a proof-of-concept, we engineered a novel library of six-helix-bundle DNA-origami tension probes (DOTPs) with a tailorable number of tension-reporting hairpins (each with their own tunable tension response threshold) and a tunable number of cell-receptor ligands. We used single-molecule force spectroscopy to determine the probes' tension response thresholds and used computational modeling to show that hairpin unfolding is semi-cooperative and orientation-dependent. Finally, we use our DOTP library to map the forces applied by human blood platelets during initial adhesion and activation. We find that the total tension signal exhibited by platelets on DOTP-functionalized surfaces increases with the number of ligands per DOTP, likely due to increased total ligand density, and decreases exponentially with the DOTP's force-response threshold. This work opens the door to applications for understanding and regulating biophysical processes involving cooperativity and multivalency.

Visualization of the Cellular Uptake and Trafficking of DNA Origami Nanostructures in Cancer Cells.

DNA origami is a promising molecular delivery system for a variety of therapeutic applications including cancer therapy, given its capability to fabricate homogeneous nanostructures whose physicochemical properties (size, shape, surface chemistry) can be precisely tailored. However, the correlation between DNA-origami design and internalization efficiency in different cancer cell lines remains elusive. We investigated the cellular uptake of four DNA-origami nanostructures (DONs) with programmed sizes and shapes in multiple human cancer cell lines. The cellular uptake efficiency of DONs was influenced by size, shape, and cell line. Scavenger receptors were responsible for the internalization of DONs into cancer cells. We observed distinct stages of the internalization process of a gold nanoparticle (AuNP)-tagged rod-shape DON, using high-resolution transmission electron microscopy. This study provides detailed understanding of cellular uptake and intracellular trafficking of DONs in cancer cells, and offers new insights for future optimization of DON-based drug delivery systems for cancer treatment.

Outcomes of Endurant stent graft in narrow aortic bifurcation.

OBJECTIVE: The purpose of this study was to compare the outcomes obtained with Endurant stent graft in the early and midterm period in the treatment of patients with narrow aortic bifurcation vs patients with standard aortic bifurcation. METHODS: Data were prospectively collected from 817 patients with abdominal aortic aneurysm treated between November 2007 and August 2014 with the Endurant stent graft at our center. There were 87 patients (10.6%) with a narrow aortic bifurcation (≤20 mm; NA group). The remaining 730 patients (89.4%) had a standard aortic bifurcation (SA group). Early and estimated 3-year outcomes were evaluated in these patients in terms of survival, freedom from any device-related reinterventions, and freedom from graft thrombosis. Univariate and multivariate analyses in the NA group were performed to detect possible predictors for poor outcomes. RESULTS: The two groups were similar in terms of demographics, preoperative diagnostic assessment, and intraoperative data. In 211 of 817 patients (25.8%), an adjunctive iliac limb stenting by balloon-expanding stents was performed. Overall, 41 patients in the NA group (47.1%) underwent iliac limb stenting, whereas an iliac stent was implanted in just 170 patients (23.3%) in the SA group (P < .001). The mean follow-up was 16.3 months (range, 1-73 months). The estimated 3-year survival rate was similar between the two groups (87.2% in the NA group vs 80.8% in the SA group; P = .84). Furthermore, the estimated freedom from any device-related reinterventions was 92.9% in the NA group and 85.5% in the SA group (P = .1). Finally, the estimated 3-year freedom from graft thrombosis was 96.9% in the NA group and 94.8% in the SA group (P = .79). In the NA group at univariate and multivariate analyses, none of the examined preoperative or intraoperative factors were independent predictors of poor outcomes. CONCLUSIONS: Use of bifurcated Endurant stent graft, combined in almost half of the patients with narrow aortic bifurcation with additional aortoiliac stent placement, is feasible and safe. Early and midterm outcomes are similar to those obtained in non-narrow aortic bifurcation.

Performance of the Endurant stent graft in patients with abdominal aortic aneurysms independent of their morphologic suitability for endovascular aneurysm repair based on instructions for use.

OBJECTIVE: The aim of this study was to prospectively evaluate the early and late 7-year experience with the Endurant bifurcated stent graft system (Medtronic, Santa Rosa, Calif) in patients with abdominal aortic aneurysms. METHODS: Between November 14, 2007, and December 2013, 712 consecutive high-risk patients with abdominal aortic aneurysms underwent elective or urgent placement of an Endurant bifurcated endograft in our institution. The included patients were consecutive (all comers) and treated independently from their morphologic eligibility for use of the Endurant device based on the instructions for use. The primary study outcome was freedom from all-cause reintervention. RESULTS: The median follow-up was 19.2 months (interquartile range, 6.3-35.9 months). Overall, 517 patients (72.6%) were treated on the basis of instructions for use conditions. On the other hand, 195 patients (27.4%) had morphologic data not consistent with the recommendations for the use of the Endurant system. The 30-day mortality was 1.4% (10 of 712). Nine patients (1.2%) were lost to follow-up because of relocation abroad. The overall mortality rate was 14.74% (101 of 703). Overall survival rate was 92.3% at 1 year, 86.4% at 2 years, and 65% at 5 years. Overall freedom from reintervention rate was 93.3%, 86.4%, and 65% at 1 year, 2 years, and 5 years, respectively. Five patients (0.7%) underwent a surgical conversion and explantation of the Endurant device. The reasons were endograft infection (n = 1), endoleak type Ia (n = 1), endoleak type II (n = 1), endograft and limb thrombotic occlusion (n = 1), and endotension (n = 1). The overall iliac limb occlusion rate was 2.1% (15 of 712). CONCLUSIONS: The performance of the Endurant stent graft during a period of 7 years under real-life conditions was good, with low incidence of reinterventions and endoleaks.

Midterm results of endovascular aneurysm repair using the Endurant stent-graft according to the instructions for use vs. off-label conditions.

PURPOSE: To compare the midterm results in patients treated with the Endurant stent-graft according to device-specific instructions for use (IFU) vs. those treated in an off-label (OL) situation. METHODS: Between November 2007 and March 2010, 177 patients (161 men; mean age 73.7 years) with abdominal aortic aneurysm were treated with the Endurant stent-graft at 2 European centers. Patients operated on according to the IFU (121, 68.4%) were compared with those who underwent endovascular aneurysm repair in OL circumstances (56, 31.6%) to evaluate estimated 5-year survival, freedom from any device-related reinterventions, freedom from graft thrombosis, and freedom from type I endoleak. Univariate and multivariate analyses were performed to identify independent predictors of poor outcomes in the OL group. RESULTS: Mean follow-up was 31.2 months (range 1-65). At 5 years, there were no differences in terms of survival (67.9% IFU vs. 54.1% OL, p=0.3), freedom from any device-related reintervention (91.2% IFU vs. 92.4% OL, p=0.8), or freedom from graft thrombosis (97.5% IFU vs. 92.7% OL, p=0.3). Estimated 5-year freedom from type I endoleak was significantly better in the IFU group than in OL (100% vs. 96.2%, respectively; p=0.03). In the OL group, multivariate analysis showed that female sex and coronary artery disease were independent predictors of poor survival. CONCLUSION: Off-label use of the Endurant stent-graft was associated with a greater but acceptable risk of type I endoleak. Otherwise, there was no difference between the IFU and off-label groups as regards survival, graft thrombosis, or reintervention.

Use of iliac branch devices for endovascular repair of aneurysmal distal seal zones after EVAR.

PURPOSE: To assess the feasibility and midterm outcomes of iliac branch devices (IBD) for the treatment of aneurysmal distal seal zones after endovascular aneurysm repair (EVAR). METHODS: Between January 2005 and January 2014, 188 patients with aortic aneurysms involving the iliac bifurcation underwent IBD implantation; of these, 18 consecutive patients (17 men; mean age 70±10 years) were treated for aneurysmal degeneration of 22 distal seal zones (mean 36±6-mm diameter) after EVAR. The main outcome measure was technical success. Further outcomes were primary and assisted primary patency of the internal iliac branch, types Ib/III endoleaks, reintervention, and all-cause mortality. RESULTS: The technical success rate was 100%. The primary patency rate was 100% over a median follow-up of 15 months (interquartile range 4-25). None of the patients developed type Ib or III endoleak. During surveillance, two device-related reinterventions were performed (thrombectomy of an occluded external iliac artery and angioplasty with stenting of a stenotic common iliac artery). One patient died due to metastatic prostate cancer. CONCLUSION: Iliac side branch endografting showed excellent feasibility and encouraging midterm outcomes for the challenging endovascular repair of aneurysmal distal seal zones post EVAR.

Durability of the Endurant stent graft in patients undergoing endovascular abdominal aortic aneurysm repair.

OBJECTIVE: Several studies have confirmed the excellent early performance of the Endurant (Medtronic Endovascular, Santa Rosa, Calif) endoprosthesis to treat abdominal aortic aneurysms (AAAs). However, data about the long-term durability of the device are still lacking. We conducted this prospective two-center single-arm study to assess the late outcomes of the endograft in patients undergoing AAA repair. METHODS: An intention-to-treat analysis was performed for all comers with AAAs who were implanted with an Endurant endograft between November 2007 and December 2010. Clinical and radiologic data were prospectively collected and analyzed. The primary end point was any AAA-related reintervention. Secondary end points were overall mortality, aneurysm shrinkage, all types of endoleak, and device-related complications. RESULTS: During the study period, 273 patients underwent implantation of the Endurant stent graft. The median follow-up time for the primary end point was 42 months (interquartile range, 30.7-50.7). AAA-related reinterventions were required in 26 patients (10%), resulting in a reintervention-free probability of 93%, 90%, and 87% at 3, 4, and 5 years, respectively. The leading cause for reintervention was iliac limb occlusion (n = 10). Only one AAA-related death (0.3%) was reported within an overall mortality of 29% (n = 78). The median aneurysm shrinkage was 9 mm (interquartile range, 3-15). Five type I (2%) and one type III (0.4%) endoleaks were identified. No proximal and two distal limb migrations (1%) were observed. CONCLUSIONS: Our study confirms late durability of the Endurant endoprosthesis for AAA repair, with very encouraging freedom from reintervention rates and overall outcomes.

The adult stem cell marker Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosis via Notch-1 and p21WAF1/CIP1.

The RNA-binding protein Musashi-1 has been proposed to maintain stem cell function during development and regenerative processes as a modulator of the Notch-1 signaling pathway. Musashi-1 expression is upregulated in endometrial carcinoma, however, its pathogenetic role in this tumor entity is unknown. Here we investigate the functional impact and mode of action of Musashi-1 on endometrial carcinoma cell behaviour in vitro. Aldehyde dehydrogenase-1 activity and side population (SP) measurement by Hoechst dye exclusion revealed that the Ishikawa endometrial carcinoma cell line contains a pool of putative cancer stem cells. Musashi-1 expression is 20.8-fold upregulated in SP+ compared to SP- and equally distributed between ALDH+ and ALDH- cell pools. siRNA-mediated knockdown of Musashi-1 mRNA expression lead to an altered expression of the signaling receptor Notch-1 and its downstream targets, the transcription factor Hes-1 and the cell cycle regulators p21(WAF1/CIP1) and cyclin B1, as determined by Western blotting and quantitative real-time PCR. Flow cytometric and ELISA analyses revealed that Musashi-1-mediated modulation of these factors exerted an antiproliferative effect on the cell cycle, and increased apoptosis in endometrial carcinoma cells. We conclude that Ishikawa cells contain a subpopulation of cells with stem cell-like properties. Musashi-1 modulates endometrial carcinoma cell cycle progression and apoptosis via the stemness-related factors Notch-1, Hes-1 and p21(WAF1/CIP1) , thus emerging as a novel future target for endometrial carcinoma therapy.