A 10-Item Checklist Improves Reporting of Critical Procedural Elements during Transurethral Resection of Bladder Tumor.

PURPOSE: Previous studies have demonstrated significant variation in recurrence rates after transurethral resection of bladder tumor, likely due to differences in surgical quality. We sought to create a framework to define, measure and improve the quality of transurethral resection of bladder tumor using a surgical checklist. MATERIALS AND METHODS: We formed a multi-institutional group of urologists with expertise with bladder cancer and identified 10 critical items that should be performed during every high quality transurethral bladder tumor resection. We prospectively implemented a 10-item checklist into practice and reviewed the operative reports of such resections performed before and after implementation. Results at all institutions were combined in a meta-analysis to estimate the overall change in the mean number of items documented. RESULTS: The operative notes for 325 transurethral bladder tumor resections during checklist use were compared to those for 428 performed before checklist implementation. Checklist use increased the mean number of items reported from 4.8 to 8.0 per resection, resulting in a mean increase of 3.3 items (95% CI 1.9-4.7) on meta-analysis. With the checklist the percentage of reports that included all 10 items increased from 0.5% to 27% (p <0.0001). Surgeons who reported more checklist items tended to have a slightly higher proportion of biopsies containing muscle, although not at conventional significance (p = 0.062). CONCLUSIONS: The use of a 10-item checklist during transurethral resection of bladder tumor improved the reporting of critical procedural elements. Although there was no clear impact on the inclusion of muscle in the specimen, checklist use may enhance surgeon attention to important aspects of the procedure and be a lever for quality improvement.

A comparison of preliminary oncologic outcome and postoperative complications between patients undergoing either open or robotic radical cystectomy.

PURPOSE: To compare complications and outcomes in patients undergoing either open radical cystectomy (ORC) or robotic-assisted radical cystectomy (RRC). MATERIALS AND METHODS: We retrospectively identified patients that underwent ORC or RRC between 2003- 2013. We statistically compared preliminary oncologic outcomes of patients for each surgical modality. RESULTS: 92 (43.2%) and 121 (56.8%) patients underwent ORC and RRC, respectively. While operative time was shorter for ORC patients (403 vs. 508 min; p<0.001), surgical blood loss and transfusion rates were significantly lower in RRC patients (p<0.001 and 0.006). Length of stay was not different between groups (p=0.221). There was no difference in the proportion of lymph node-positive patients between groups. However, RRC patients had a greater number of lymph nodes removed during surgery (18 vs. 11.5; p<0.001). There was no significant difference in the incidence of pre-existing comorbidities or in the Clavien distribution of complications between groups. ORC and RRC patients were followed for a median of 1.38 (0.55-2.7) and 1.40 (0.58-2.59) years, respectively (p=0.850). During this period, a lower proportion (22.3%) of RRC patients experienced disease recurrence vs. ORC patients (34.8%). However, there was no significant difference in time to recurrence between groups. While ORC was associated with a higher all-cause mortality rate (p=0.049), there was no significant difference in disease-free survival time between groups. CONCLUSIONS: ORC and RRC patients experience postoperative complications of similar rates and severity. However, RRC may offer indirect benefits via reduced surgical blood loss and need for transfusion.

Penoscrotal lymphedema associated with metastatic renal cell carcinoma.

A 64-year-old male presented with lower back pain, radiating in a sciatic-type distribution, swelling in his lower abdomen and right leg, and edema of the scrotum and penile shaft. A sonogram and CT imaging indicated an enhancing mass in the right kidney and a spinal metastasis. The right lower extremity and penoscrotal lymphedema was caused by lymphatic obstruction due to a sacral metastasis of renal cell carcinoma. He was treated with cytoreductive nephrectomy, radiation and a systemic tyrosine kinase inhibitor. Pelvic imaging is suggested to determine whether malignant lymphatic obstruction is present when presented with idiopathic penoscrotal edema.

Multiple intra-renal artery aneurysms causing renal obstruction managed with radical nephrectomy.

A 46-year-old male with a history of hypertension presented with symptoms of persistent abdominal fullness and a non-pulsatile abdominal mass. Subsequent computed tomographic angiography studies revealed the presence multiple large renal aneurysms from the segmental branches of the renal artery and an enlarged hydronephrotic kidney with minimal parenchyma. The renal deterioration appeared to be as a result of an obstruction caused by the large intra-renal aneurysms at the level of the renal calyces. Since the right kidney had no function, an open radical nephrectomy was subsequently performed without complications at 3 months follow up.

Weighted Gleason scores do not outperform standard clinical Gleason scores.

INTRODUCTION: Predicting patient survival rates following radical prostatectomy remains an area of clinical interest. We compared the ability of standard clinical Gleason scores and alternative 'weighted' Gleason scores to predict pathology, margin status and recurrence in prostate cancer. MATERIALS AND METHODS: Patients who underwent robotic radical prostatectomy performed by a single surgeon between Jan 2007 - Dec 2008 were included. Tumor at the inked margin in pathologic samples was considered a positive margin. Recurrence was defined as PSA ≥ 0.2 or the institution of salvage therapy. Standard pathologic Gleason scores were recorded. The proportion of tumor in each core was used to calculate 'weighted' and 'rounded weighted ' Gleason scores. The ability of each Gleason score to predict pathology, margin status and recurrence were statistically compared. RESULTS: Of 433 cases, 281 with uniform Gleason 6 cores were excluded. One hundred and fifty-two cases had Gleason scores ≥ 7, of which complete data were unavailable for three patients. In the final cohort of 149 cases, 72 (48.3%) patients had uniformly scored biopsies, while 77 (51.7%) had biopsies with non-uniform Gleason scores. The positive margin rate and recurrence free rates were 30.2% and 77.2%, respectively. Analyses of the entire patient cohort, and patients with non-uniform cores, found no significant difference between the predictive capacities of each scoring system. The alternative algorithms were not shown to be better predictors of pathologic Gleason score, margin status or recurrence. CONCLUSIONS: Using the highest standard Gleason score of all cores to define a preoperative Gleason score remains an appropriate clinical practice.

Surgical complications associated with robotic urologic procedures in elderly patients.

INTRODUCTION: Urologic malignancies are often diagnosed at an older age, and are increasingly managed utilizing robotic-assisted surgical techniques. As such, we assessed and compared peri-postoperative complication rates following robotic urologic surgery in elderly and younger patients. MATERIALS AND METHODS: A retrospective analysis of IRB-approved databases and electronic medical records identified patients who underwent robotic-assisted urologic surgery between December 2003-September 2013. Patients were grouped according to surgical procedure (partial nephrectomy, radical cystectomy, radical prostatectomy) and age at surgery (≤ 74 or ≥ 75 years old). Associations between age, comorbidities, Charlson comorbidity index (CCI), and patient outcomes were evaluated within each surgery type. RESULTS: 97.5% and 2.5% of patients were ≤ 74 or ≥ 75 years old, respectively. Cystectomies, partial nephrectomies and prostatectomies accounted for 3.5%, 9.5% and 87.1% of surgeries, respectively. Within cystectomy, nephrectomy and prostatectomy groups, 24.4%, 12.5% and 0.6% patients were ≥ 75 years old. Within each surgical type, elderly patients had significantly elevated CCI scores. Length of stay was significantly prolonged in elderly patients undergoing partial nephrectomy or prostatectomy. In elderly cystectomy, partial nephrectomy and prostatectomy patients, 36.7%, 14.3% and 5.9% suffered ≥ 1 Clavien grade 3-5 complication, respectively. Major complications were not significantly different between age groups. A qualitatively similar pattern was observed regarding Clavien grade 1-2 complications. CONCLUSIONS: The risks of robotic-assisted urologic surgery in elderly patients are not significantly elevated compared to younger patients.

Clinical and radiographic characteristics governing the selection of therapy of small renal masses.

INTRODUCTION: Renal masses are commonly managed by partial nephrectomy (PN) or active surveillance (AS). We assessed the impact of patient demographics and clinical indices in determining treatment decisions of renal masses between these two options. MATERIALS AND METHODS: We retrospectively reviewed our renal mass database to retrieve demographic and clinical records of patients who underwent immediate PN or entered a >= 12 month period of AS during February 1999 to May 2014. Age, gender, body mass index (BMI), Charlson Comorbidity Index (CCI) score, follow up time, tumor size, tumor location, renal invasion, creatinine, and estimated glomerular filtration rate (eGFR) were assessed as predictors of the selected treatment option. RESULTS: Seven hundred thirty-five patients with 744 renal masses underwent immediate PN, while 123 patients with 140 renal masses entered active surveillance. PN patients were predominantly male, younger, had elevated BMI, lower CCI scores, elevated eGFR and had larger tumors that invaded further into the renal collecting system. Renal masses in men were more likely to be treated by PN, while patients categorized as overweight or obese were 2-3 fold more likely to have their renal mass being manage by PN (versus patients with BMI in the normal range). Higher CCI scores were associated with a renal mass being more likely to be treated by AS, while increased renal mass size was associated with decisions to treat with PN. Compared to cortical location, renal masses abutting the renal collecting system were more likely to be treated by PN. CONCLUSIONS: Gender, BMI, CCI, tumor size, and tumor invasion into the renal system are useful predictors of renal mass treatment.

Active surveillance of renal masses: an analysis of growth kinetics and clinical outcomes stratified by radiological characteristics at diagnosis.

AIMS: To determine the growth rate of renal masses (RMs) under active surveillance (AS), and to describe the clinical outcome of AS patients. MATERIALS AND METHODS: We conducted a retrospective review of an AS database to obtain demographics, radiological and pathologic characteristics and RM size of patients. RMs were followed at 6-12 month intervals for ≥1 year with computed tomography (CT), magnetic resonance imaging (MRI), or renal ultrasound. Kaplan-Meier analysis determined the annual likelihood of intervention. RMs were divided into 3 radiographic subcategories (solid, cystic, and angiomyolipoma). A linear regression model determined RM growth rates. RESULTS: 131 RMs in 114 patients were included. Median age, Charlson Comorbidity Index score and mean follow-up were 69.1 years, 4.0 and 4.2±2.6 years, respectively. Maximal tumor diameter (MTD) at diagnosis was 2.1 ± 1.3 cm. 49 RMs exhibited negative or zero net growth. Mean MTD growth rate for all RMs was 0.72±3.2 (95% CI: 0.16-1.28) mm/year. When stratified by MTD at diagnosis, mean RM growth rates were 0.84, 0.84, 0.44, 0.74 and 0.71 mm/year for RMs ≤1 cm, 1-≤2cm, 2-≤ 3cm, 3-≤ 4cm and ≥4cm, respectively (p≤0.01). The 5 and 10-year freedom from intervention rates were 93.1% and 88.5%, respectively. There was a single case of suspected metastases, but no deaths related to kidney cancer. CONCLUSIONS: RMs under AS grew slowly, and had a low incidence of requiring surgical intervention and progression. Solid enhancing masses grew slowly, and were more likely to trigger intervention. AS should be considered for selected patients with small RMs.

Validation of a functional human AD model with four AD therapeutics utilizing patterned iPSC-derived cortical neurons integrated with microelectrode arrays.

Preclinical methods are needed for screening potential Alzheimer's disease (AD) therapeutics that recapitulate phenotypes found in the Mild Cognitive Impairment (MCI) stage or even before this stage of the disease. This would require a phenotypic system that reproduces cognitive deficits without significant neuronal cell death to mimic the clinical manifestations of AD during these stages. A potential functional parameter to be monitored is long-term potentiation (LTP), which is a correlate of learning and memory, that would be one of the first functions effected by AD onset. Mature human iPSC-derived cortical neurons and primary astrocytes were co-cultured on microelectrode arrays (MEA) where surface chemistry was utilized to create circuit patterns connecting two adjacent electrodes to model LTP function. LTP maintenance was significantly reduced in the presence of Amyloid-Beta 42 (Aß42) oligomers compared to the controls, however, co-treatment with AD therapeutics (Donepezil, Memantine, Rolipram and Saracatinib) corrected Aß42 induced LTP impairment. The results presented here illustrate the significance of the system as a validated platform that can be utilized to model and study MCI AD pathology, and potentially for the pre-MCI phase before the occurrence of significant cell death. It also has the potential to become an ideal platform for high content therapeutic screening for other neurodegenerative diseases.

Ultramassive transfusion and adjunctive therapies in a case of blood bank depletion.

Background: We present the case of a patient who presents with a high velocity thoracoabdominal gunshot wound requiring ultramassive transfusion who exhausted the county blood bank requiring adjunctive therapies to balanced blood product transfusion while additional blood products could be obtained. Summary: Thoracoabdominal gunshot wounds carry a high mortality of 14-37 % because of the risk to produce cardiopulmonary, solid organ as well as major vascular injuries (Mandal and Oparah (1989) [1]). Ultramassive transfusion (>20 units of blood product transfusion) also carries high morbidity and mortality and management has generally centered on balanced transfusion (Matthay et al. (2021) [2]). Conclusion: Balanced blood product transfusion reduces mortality for patients requiring ultramassive transfusion but when this is not possible utilization of adjuncts to blood products may temporize resuscitation until additional blood products can be obtained.

Development of a functional human induced pluripotent stem cell-derived nociceptor MEA system as a pain model for analgesic drug testing.

The control of severe or chronic pain has relied heavily on opioids and opioid abuse and addiction have recently become a major global health crisis. Therefore, it is imperative to develop new pain therapeutics which have comparable efficacy for pain suppression but lack of the harmful effects of opioids. Due to the nature of pain, any in vivo experiment is undesired even in animals. Recent developments in stem cell technology has enabled the differentiation of nociceptors from human induced pluripotent stem cells. This study sought to establish an in vitro functional induced pluripotent stem cells-derived nociceptor culture system integrated with microelectrode arrays for nociceptive drug testing. Nociceptors were differentiated from induced pluripotent stem cells utilizing a modified protocol and a medium was designed to ensure prolonged and stable nociceptor culture. These neurons expressed nociceptor markers as characterized by immunocytochemistry and responded to the exogenous toxin capsaicin and the endogenous neural modulator ATP, as demonstrated with patch clamp electrophysiology. These cells were also integrated with microelectrode arrays for analgesic drug testing to demonstrate their utilization in the preclinical drug screening process. The neural activity was induced by ATP to mimic clinically relevant pathological pain and then the analgesics Lidocaine and the opioid DAMGO were tested individually and both induced immediate silencing of the nociceptive activity. This human-based functional nociceptive system provides a valuable platform for investigating pathological pain and for evaluating effective analgesics in the search of opioid substitutes.

A functional hiPSC-cortical neuron differentiation and maturation model and its application to neurological disorders.

The maturation and functional characteristics of human induced pluripotent stem cell (hiPSC)-cortical neurons has not been fully documented. This study developed a phenotypic model of hiPSC-derived cortical neurons, characterized their maturation process, and investigated its application for disease modeling with the integration of multi-electrode array (MEA) technology. Immunocytochemistry analysis indicated early-stage neurons (day 21) were simultaneously positive for both excitatory (vesicular glutamate transporter 1 [VGlut1]) and inhibitory (GABA) markers, while late-stage cultures (day 40) expressed solely VGlut1, indicating a purely excitatory phenotype without containing glial cells. This maturation process was further validated utilizing patch clamp and MEA analysis. Particularly, induced long-term potentiation (LTP) successfully persisted for 1 h in day 40 cultures, but only achieved LTP in the presence of the GABAA receptor antagonist picrotoxin in day 21 cultures. This system was also applied to epilepsy modeling utilizing bicuculline and its correction utilizing the anti-epileptic drug valproic acid.

Classical Complement Pathway Inhibition in a "Human-On-A-Chip" Model of Autoimmune Demyelinating Neuropathies.

Chronic autoimmune demyelinating neuropathies are a group of rare neuromuscular disorders with complex, poorly characterized etiology. Here we describe a phenotypic, human-on-a-chip (HoaC) electrical conduction model of two rare autoimmune demyelinating neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), and explore the efficacy of TNT005, a monoclonal antibody inhibitor of the classical complement pathway. Patient sera was shown to contain anti-GM1 IgM and IgG antibodies capable of binding to human primary Schwann cells and induced pluripotent stem cell derived motoneurons. Patient autoantibody binding was sufficient to activate the classical complement pathway resulting in detection of C3b and C5b-9 deposits. A HoaC model, using a microelectrode array with directed axonal outgrowth over the electrodes treated with patient sera, exhibited reductions in motoneuron action potential frequency and conduction velocity. TNT005 rescued the serum-induced complement deposition and functional deficits while treatment with an isotype control antibody had no rescue effect. These data indicate that complement activation by CIDP and MMN patient serum is sufficient to mimic neurophysiological features of each disease and that complement inhibition with TNT005 was sufficient to rescue these pathological effects and provide efficacy data included in an investigational new drug application, demonstrating the model's translational potential.

Using Preoperative Pelvic Floor Assessment to Predict Early Return of Continence after Robotic Radical Prostatectomy.

OBJECTIVE: To evaluate whether pre-operative pelvic floor physical therapy (PFPT) parameters may predict early return of urinary continence after RP. While long-term urinary continence is eventually achieved in most patients who undergo radical prostatectomy (RP), predicting when patients will become continent is challenging. Prior studies aiming to predict return of post-operative continence have not evaluated patient-specific pelvic floor strength parameters. METHODS: We reviewed a prospectively maintained database of patients undergoing RP who underwent pre-operative PFPT consultation and completed 3-month patient-reported quality of life evaluation. Trained therapists documented pelvic strength parameters. Urinary continence was defined as using 0 or 1 pad per day. We evaluated the association of PFPT parameters with urinary continence at 3 months, adjusting for other factors that could affect continence. RESULTS: 144 men met inclusion criteria. The majority of patients underwent nerve-sparing procedures and had intermediate- or high-risk prostate cancer. At 3 months, 90 of 144 (62.5%) were continent, while 54 of 144 (37.5%) were not. On multivariable analysis, prostate volume (OR 0.98, 95% CI 0.96-1.00) and pelvic floor endurance (OR 2.71, 95% CI 1.23-6.17) were significantly associated with being continent at 3 months. 56 of 76 (74%) men with good pelvic floor endurance were continent at 3 months, while only 34 of 68 (50%) men with poor endurance were continent (P = .006). CONCLUSION: Pre-operative assessment of pelvic floor endurance is an objective measure that may allow more accurate prediction of early continence after radical prostatectomy. Improved patient counseling could positively impact patient satisfaction and quality of life and reduce decision regret.

Is It Safe to Perform Lung Surgery During the Coronavirus Pandemic?

BACKGROUND:  Coronavirus disease (COVID-19) patients are rapidly growing in our community. Patients with compromised lungs and older age are supposedly at high risk of poor outcomes with COVID-19. We aimed to evaluate the COVID-19 impact on lung surgery during this pandemic at our hospital. METHODOLOGY: This is a retrospective study of all lung surgery patients at our hospital in Boca Raton over three months (February to April 2020). All patients who remained for at least one-day inpatient post-lung surgery were assessed to see if they had an increased incidence of coronavirus infection during the hospital stay or at the follow-up office visit. RESULTS: A total of 44 patients underwent thoracic surgery. It was found that there was no incidence of coronavirus infection in these patients. CONCLUSION: With adequate precautions, older patients can undergo lung surgery during this pandemic. There was no incidence of COVID-19 found among the patients during the hospital stay or at the first follow-up in the office. Also, the postoperative course was not adversely affected.

A Human-Based Functional NMJ System for Personalized ALS Modeling and Drug Testing.

Loss of the neuromuscular junction (NMJ) is an early and critical hallmark in all forms of ALS. The study design was to develop a functional NMJ disease model by integrating motoneurons (MNs) differentiated from multiple ALS-patients' induced pluripotent stem cells (iPSCs) and primary human muscle into a chambered system. NMJ functionality was tested by recording myotube contractions while stimulating MNs by field electrodes and a set of clinically relevant parameters were defined to characterize the NMJ function. Three ALS lines were analyzed, 2 with SOD1 mutations and 1 with a FUS mutation. The ALS-MNs reproduced pathological phenotypes, including increased axonal varicosities, reduced axonal branching and elongation and increased excitability. These MNs formed functional NMJs with wild type muscle, but with significant deficits in NMJ quantity, fidelity and fatigue index. Furthermore, treatment with the Deana protocol was found to correct the NMJ deficits in all the ALS mutant lines tested. Quantitative analysis also revealed the variations inherent in each mutant lines. This functional NMJ system provides a platform for the study of both fALS and sALS and has the capability of being adapted into subtype-specific or patient-specific models for ALS etiological investigation and patient stratification for drug testing.

A human induced pluripotent stem cell-derived cortical neuron human-on-a chip system to study Aß42 and tau-induced pathophysiological effects on long-term potentiation.

INTRODUCTION: The quest to identify an effective therapeutic strategy for neurodegenerative diseases, such as mild congitive impairment (MCI) and Alzheimer's disease (AD), suffers from the lack of good human-based models. Animals represent the most common models used in basic research and drug discovery studies. However, safe and effective compounds identified in animal studies often translate poorly to humans, yielding unsuccessful clinical trials. METHODS: A functional in vitro assay based on long-term potentiation (LTP) was used to demonstrate that exposure to amyloid beta (Aß42) and tau oligomers, or brain extracts from AD transgenic mice led to prominent changes in human induced pluripotent stem cells (hiPSC)-derived cortical neurons, notably, without cell death. RESULTS: Impaired information processing was demonstrated by treatment of neuron-MEA (microelectrode array) systems with the oligomers and brain extracts by reducing the effects of LTP induction. These data confirm the neurotoxicity of molecules linked to AD pathology and indicate the utility of this human-based system to model aspects of AD in vitro and study LTP deficits without loss of viability; a phenotype that more closely models the preclinical or early stage of AD. DISCUSSION: In this study, by combining multiple relevant and important molecular and technical aspects of neuroscience research, we generated a new, fully human in vitro system to model and study AD at the preclinical stage. This system can serve as a novel drug discovery platform to identify compounds that rescue or alleviate the initial neuronal deficits caused by Aß42 and/or tau oligomers, a main focus of clinical trials.

Piezoelectric BioMEMS Cantilever for Measurement of Muscle Contraction and for Actuation of Mechanosensitive Cells.

A piezoelectric biomedical microelectromechanical system (bioMEMS) cantilever device was designed and fabricated to act as either a sensing element for muscle tissue contraction or as an actuator to apply mechanical force to cells. The sensing ability of the piezoelectric cantilevers was shown by monitoring the electrical signal generated from the piezoelectric aluminum nitride in response to the contraction of iPSC-derived cardiomyocytes cultured on the piezoelectric cantilevers. Actuation was demonstrated by applying electrical pulses to the piezoelectric cantilever and observing bending via an optical detection method. This piezoelectric cantilever device was designed to be incorporated into body-on-a-chip systems.

Stem cell derived phenotypic human neuromuscular junction model for dose response evaluation of therapeutics.

There are currently no functional neuromuscular junction (hNMJ) systems composed of human cells that could be used for drug evaluations or toxicity testing in vitro. These systems are needed to evaluate NMJs for diseases such as amyotrophic lateral sclerosis, spinal muscular atrophy or other neurodegenerative diseases or injury states. There are certainly no model systems, animal or human, that allows for isolated treatment of motoneurons or muscle capable of generating dose response curves to evaluate pharmacological activity of these highly specialized functional units. A system was developed in which human myotubes and motoneurons derived from stem cells were cultured in a serum-free medium in a BioMEMS construct. The system is composed of two chambers linked by microtunnels to enable axonal outgrowth to the muscle chamber that allows separate stimulation of each component and physiological NMJ function and MN stimulated tetanus. The muscle's contractions, induced by motoneuron activation or direct electrical stimulation, were monitored by image subtraction video recording for both frequency and amplitude. Bungarotoxin, BOTOX® and curare dose response curves were generated to demonstrate pharmacological relevance of the phenotypic screening device. This quantifiable functional hNMJ system establishes a platform for generating patient-specific NMJ models by including patient-derived iPSCs.