Oncologic control and predictors of urologic reconstruction after Mohs micrographic surgery for low-risk penile malignancy.

PURPOSE: Mohs micrographic surgery (MMS) is a low-risk penile cancer management option. However, contemporary patients' short-term oncologic control and preoperative characteristics predicting reconstruction needs are undefined. This study assesses MMS's oncologic efficacy for low-risk penile cancer and identifies baseline predictors of post-resection reconstruction referral. METHODS: We retrospectively reviewed 73 adult males with 78 penile cutaneous malignancies treated with MMS from 2005 to 2019. Patients underwent MMS with or without surgical reconstruction. Demographic information, MMS operative details, lesion pathology, and short-term outcomes were recorded. Descriptive statistics for all variables were calculated, and logistic regression identified predictive factors for urologic referral for complex reconstruction. RESULTS: Seventy-three men with 78 lesions, all staged ≤ cT1a prior to MMS, were identified. Twenty-one men were found to have invasive SCC. Median follow-up was 2.0 years (IQR 0.8-5.2 years). MMS was able to clear the disease in 90.4% of cases. One patient had disease related death following progression. Dermatology closed primarily in 68% of patients. Twenty percent of patients had a complication, most commonly poor wound healing. On univariate and multivariate linear regression analysis, lesion size > 3 cm and involvement of the glans independently predicted the need for referral to a reconstructive surgeon. CONCLUSIONS: MMS for penile cancer appears to provide sound oncologic control in the properly selected patient. Involvement of a reconstructive surgeon may be needed for glandular and large lesions, necessitating early referral to a comprehensive multidisciplinary care team.

Diminished Short-Term Efficacy of Reduced-Dose Induction BCG in the Treatment of Non-Muscle Invasive Bladder Cancer.

The ongoing Bacillus Calmette-Guérin (BCG) shortage has created challenges for the treatment of non-muscle invasive bladder cancer (NMIBCa). Our objective was to evaluate the efficacy of reduced-dose induction BCG (RD-iBCG) compared to full-dose induction BCG (FD-iBCG) regarding recurrence rates. We hypothesized that patients receiving RD-iBCG may recur at a higher rate compared to those who received FD-iBCG therapy. A retrospective review of all patients with NMIBCa treated with intravesical therapy at our institution between 2015-2020 was conducted. Inclusion criteria consisted of having a diagnosis of AUA intermediate or high-risk NMIBCa with an indication for a six-week induction course of FD or RD-BCG with at least 1 year of documented follow up. The data were censored at one year. Propensity score matching for age, sex, tumor pathology, and initial vs. recurrent disease was performed. The primary endpoint was bladder cancer recurrence, reported as recurrence-free survival. A total of 254 patients were reviewed for this study. Our final cohort was 139 patients after exclusion. Thirty-nine percent of patients had HGT1 disease. 38.6% of patients receiving RD-BCG developed a recurrence of bladder cancer within a one-year follow-up as compared to 33.7% of patients receiving FD therapy. After propensity matching, this value remained statistically significant (p = 0.03). In conclusion, RD-iBCG for NMIBCa is associated with a significantly greater risk of recurrence than full-dose induction therapy, suggesting that RD-iBCG may not be equivalent or non-inferior to full-dose administration in the short term.

Automated Society of Fetal Urology (SFU) grading of hydronephrosis on ultrasound imaging using a convolutional neural network.

INTRODUCTION: Grading of hydronephrosis severity on postnatal renal ultrasound guides management decisions in antenatal hydronephrosis (ANH). Multiple systems exist to help standardize hydronephrosis grading, yet poor inter-observer reliability persists. Machine learning methods may provide tools to improve the efficiency and accuracy of hydronephrosis grading. OBJECTIVE: To develop an automated convolutional neural network (CNN) model to classify hydronephrosis on renal ultrasound imaging according to the Society of Fetal Urology (SFU) system as potential clinical adjunct. STUDY DESIGN: A cross-sectional, single-institution cohort of postnatal renal ultrasounds with radiologist SFU grading from pediatric patients with and without hydronephrosis of stable severity was obtained. Imaging labels were used to automatedly select sagittal and transverse grey-scale renal images from all available studies from each patient. A VGG16 pre-trained ImageNet CNN model analyzed these preprocessed images. Three-fold stratified cross-validation was used to build and evaluate the model that was used to classify renal ultrasounds on a per patient basis into five classes based on the SFU system (normal, SFU I, SFU II, SFU III, or SFU IV). These predictions were compared to radiologist grading. Confusion matrices evaluated model performance. Gradient class activation mapping demonstrated imaging features driving model predictions. RESULTS: We identified 710 patients with 4659 postnatal renal ultrasound series. Per radiologist grading, 183 were normal, 157 were SFU I, 132 were SFU II, 100 were SFU III, and 138 were SFU IV. The machine learning model predicted hydronephrosis grade with 82.0% (95% CI: 75-83%) overall accuracy and classified 97.6% (95% CI: 95-98%) of the patients correctly or within one grade of the radiologist grade. The model classified 92.3% (95% CI: 86-95%) normal, 73.2% (95% CI: 69-76%) SFU I, 73.5% (95% CI: 67-75%) SFU II, 79.0% (95% CI: 73-82%) SFU III, and 88.4% (95% CI: 85-92%) SFU IV patients accurately. Gradient class activation mapping demonstrated that the ultrasound appearance of the renal collecting system drove the model's predictions. DISCUSSION: The CNN-based model classified hydronephrosis on renal ultrasounds automatically and accurately based on the expected imaging features in the SFU system. Compared to prior studies, the model functioned more automatically with greater accuracy. Limitations include the retrospective, relatively small cohort, and averaging across multiple imaging studies per patient. CONCLUSIONS: An automated CNN-based system classified hydronephrosis on renal ultrasounds according to the SFU system with promising accuracy based on appropriate imaging features. These findings suggest a possible adjunctive role for machine learning systems in the grading of ANH.

Prognostic significance of sarcomatoid features in metastatic renal cell carcinoma treated with cytoreductive nephrectomy and targeted therapy.

INTRODUCTION: The presence of sarcomatoid features in localized renal cell carcinoma (RCC) is associated with worse outcomes. We sought to use a national database to evaluate the outcomes and prognosis of metastatic RCC (mRCC) with sarcomatoid features treated with cytoreductive nephrectomy (CN) and targeted therapy (TT). METHODS: The National Cancer Database (2010-2013) was used to identify patients with mRCC at diagnosis. Only patients who underwent CN followed by TT were included. Kaplan-Meier curves, log-rank test, and multivariate Cox regression analysis were used to compare overall survival (OS) between mRCC with and without sarcomatoid features. Subgroup analysis in patients with clear cell RCC (ccRCC) was performed. RESULTS: A total of 1,427 patients with mRCC treated with CN followed by TT were included of which 364 (26%) had mRCC with sarcomatoid features. mRCC with sarcomatoid features were more likely to have Fuhrman grade 4 cancer. mRCC with sarcomatoid features had worse OS than mRCC without sarcomatoid features (24.6 vs 12.0 months, P < 0.001). For the clear cell cohort, mRCC with sarcomatoid features had worse OS than mRCC without sarcomatoid features (26.2 vs 14.0 months, P < 0.001). Multivariate Cox regression showed sarcomatoid features was significantly associated with worse OS in the overall cohort (hazard ratio [HR] =1.63, 95% confidence interval [CI] =1.38-1.91, P < 0.001) and the ccRCC subcohort (HR=1.53, 95% CI=1.23-1.90, P < 0.001). DISCUSSION/CONCLUSION: mRCC with sarcomatoid features treated with CN and TT has a very poor and drastically different prognosis compared with mRCC without sarcomatoid features. With the expansion of systemic RCC therapies, investigation is needed to optimize treatment in this high-risk cohort.

Spontaneous rupture of a bladder diverticulum with delayed open surgical repair.

Spontaneous rupture of a bladder diverticulum is a rare entity typically associated with tissue weakness, bladder outlet obstruction, increased intra-abdominal pressure, or inflammation. Diagnosis is most often achieved via cystogram with a reported role for pelvic ultrasound. Extraperitoneal ruptures are typically treated with catheterization and antibiosis while intraperitoneal ruptures are most frequently treated with immediate surgical intervention. In this case, an adult female presented with an intraperitoneal rupture with no clear inciting event with diagnosis confirmed by pelvic transvaginal ultrasound following a non-diagnostic cystogram. The patient was treated successfully with delayed open surgical repair.

Variability in biopsy quality informs translational research applications in hepatocellular carcinoma.

In the era of precision medicine, biopsies are playing an increasingly central role in cancer research and treatment paradigms; however, patient outcomes and analyses of biopsy quality, as well as impact on downstream clinical and research applications, remain underreported. Herein, we report biopsy safety and quality outcomes for percutaneous core biopsies of hepatocellular carcinoma (HCC) performed as part of a prospective clinical trial. Patients with a clinical diagnosis of HCC were enrolled in a prospective cohort study for the genetic, proteomic, and metabolomic profiling of HCC at two academic medical centers from April 2016 to July 2020. Under image guidance, 18G core biopsies were obtained using coaxial technique at the time of locoregional therapy. The primary outcome was biopsy quality, defined as tumor fraction in the core biopsy. 56 HCC lesions from 50 patients underwent 60 biopsy events with a median of 8 core biopsies per procedure (interquartile range, IQR, 7-10). Malignancy was identified in 45/56 (80.4%, 4 without pathology) biopsy events, including HCC (40/56, 71.4%) and cholangiocarcinoma (CCA) or combined HCC-CCA (5/56, 8.9%). Biopsy quality was highly variable with a median of 40% tumor in each biopsy core (IQR 10-75). Only 43/56 (76.8%) and 23/56 (41.1%) samples met quality thresholds for genomic or metabolomic/proteomic profiling, respectively, requiring expansion of the clinical trial. Overall and major complication rates were 5/60 (8.3%) and 3/60 (5.0%), respectively. Despite uniform biopsy protocol, biopsy quality varied widely with up to 59% of samples to be inadequate for intended purpose. This finding has important consequences for clinical trial design and highlights the need for quality control prior to applications in which the presence of benign cell types may substantially alter findings.

Allosteric control of hemoglobin S fiber formation by oxygen and its relation to the pathophysiology of sickle cell disease.

The pathology of sickle cell disease is caused by polymerization of the abnormal hemoglobin S upon deoxygenation in the tissues to form fibers in red cells, causing them to deform and occlude the circulation. Drugs that allosterically shift the quaternary equilibrium from the polymerizing T quaternary structure to the nonpolymerizing R quaternary structure are now being developed. Here we update our understanding on the allosteric control of fiber formation at equilibrium by showing how the simplest extension of the classic quaternary two-state allosteric model of Monod, Wyman, and Changeux to include tertiary conformational changes provides a better quantitative description. We also show that if fiber formation is at equilibrium in vivo, the vast majority of cells in most tissues would contain fibers, indicating that it is unlikely that the disease would be survivable once the nonpolymerizing fetal hemoglobin has been replaced by adult hemoglobin S at about 1 y after birth. Calculations of sickling times, based on a recently discovered universal relation between the delay time prior to fiber formation and supersaturation, show that in vivo fiber formation is very far from equilibrium. Our analysis indicates that patients survive because the delay period allows the majority of cells to escape the small vessels of the tissues before fibers form. The enormous sensitivity of the duration of the delay period to intracellular hemoglobin composition also explains why sickle trait, the heterozygous condition, and the compound heterozygous condition of hemoglobin S with pancellular hereditary persistence of fetal hemoglobin are both relatively benign conditions.

Interactions of an Anti-Sickling Drug with Hemoglobin in Red Blood Cells from a Patient with Sickle Cell Anemia.

The pathophysiology associated with sickle cell disease (SCD) includes hemolytic anemia, vaso-occlusive events, and ultimately end organ damage set off by the polymerization of deoxygenated hemoglobin S (HbS) into long fibers and sickling of red blood cells (RBCs). One approach toward mitigating HbS polymerization is to pharmacologically stabilize the oxygenated (R) conformation of HbS and thereby reduce sickling frequency and SCD pathology. GBT440 is an α-subunit-specific modifying agent that has recently been reported to increase HbS oxygen binding affinity and consequently delay in vitro polymerization. In addition, animal model studies have demonstrated the potential for GBT440 to be a suitable therapeutic for daily oral dosing in humans. Here, we report an optimized method for detecting GBT440 intermediates in human patient hemolysate using a combination of HPLC and mass spectrometry analysis. First, oxygen dissociation curves (ODCs) analyzed from patient blood showed that oxygen affinity increased in a dose dependent manner. Second, HPLC and integrated mass spectrometric analysis collectively confirmed that GBT440 labeling was specific to the α N-terminus thereby ruling out other potential ligand binding sites. Finally, the results from this optimized analytical approach allowed us to detect a stable α-specific GBT440 adduct in the patient's hemolysate in a dose dependent manner. The results and methods presented in this report could therefore potentially help therapeutic monitoring of GBT440 induced oxygen affinity and reveal critical insight into the biophysical properties of GBT440 Hb complexes.

Potential therapeutic action of nitrite in sickle cell disease.

Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions, increasing rigidity, fragility, calcium influx-mediated dehydration, and adhesivity of red blood cells. Increased red cell fragility results in hemolysis, which reduces nitric oxide (NO) bioavailability, and induces platelet activation and inflammation leading to adhesion of circulating blood cells. Nitric Oxide inhibits adhesion and platelet activation. Nitrite has emerged as an attractive therapeutic agent that targets delivery of NO activity to areas of hypoxia through bioactivation by deoxygenated red blood cell hemoglobin. In this study, we demonstrate anti-platelet activity of nitrite at doses achievable through dietary interventions with comparison to similar doses with other NO donating agents. Unlike other NO donating agents, nitrite activity is shown to be potentiated in the presence of red blood cells in hypoxic conditions. We also show that nitrite reduces calcium associated loss of phospholipid asymmetry that is associated with increased red cell adhesion, and that red cell deformability is also improved. We show that nitrite inhibits red cell adhesion in a microfluidic flow-channel assay after endothelial cell activation. In further investigations, we show that leukocyte and platelet adhesion is blunted in nitrite-fed wild type mice compared to control after either lipopolysaccharide- or hemolysis-induced inflammation. Moreover, we demonstrate that nitrite treatment results in a reduction in adhesion of circulating blood cells and reduced red blood cell hemolysis in humanized transgenic sickle cell mice subjected to local hypoxia. These data suggest that nitrite is an effective anti-platelet and anti-adhesion agent that is activated by red blood cells, with enhanced potency under physiological hypoxia and in venous blood that may be useful therapeutically.

Role of Crystallization in the Morphology of Polymer:Non-fullerene Acceptor Bulk Heterojunctions.

Many high efficiency organic photovoltaics use fullerene-based acceptors despite their high production cost, weak optical absorption in the visible range, and limited synthetic variability of electronic and optical properties. To circumvent this deficiency, non-fullerene small-molecule acceptors have been developed that have good synthetic flexibility, allowing for precise tuning of optoelectronic properties, leading to enhanced absorption of the solar spectrum and increased open-circuit voltages (VOC). We examined the detailed morphology of bulk heterojunctions of poly(3-hexylthiophene) and the small-molecule acceptor HPI-BT to reveal structural changes that lead to improvements in the fill factor of solar cells upon thermal annealing. The kinetics of the phase transformation process of HPI-BT during thermal annealing were investigated through in situ grazing incidence wide-angle X-ray scattering studies, atomic force microscopy, and transmission electron microscopy. The HPI-BT acceptor crystallizes during film formation to form micron-sized domains embedded within the film center and a donor rich capping layer at the cathode interface reducing efficient charge extraction. Thermal annealing changes the surface composition and improves charge extraction. This study reveals the need for complementary methods to investigate the morphology of BHJs.

Correlation of morphology with photocurrent generation in a polymer blend photovoltaic device.

Morphological effects on photovoltaic (PV) properties are studied through scanning photocurrent (PC) and photoluminescence (PL) microscopy of a solution processed, polymer blend PV device composed of PFB [poly(9,9'-dioctylfluorene-co-bis-N,N-(4-butylphenyl)-bis-N,N-phenyl-1,4-phenylenediamine] and F8BT [poly(9,9'-dioctylfluorene-co-benzothiadiazole]. As PFB and F8BT have unique absorbance bands, it is possible to selectively excite only F8BT (488 nm) or both PFB and F8BT (408 nm). Local voltage-dependent photocurrent (LVPC) measurements from particular regions of interest in the PV show that the diode characteristics between different morphologies are essentially the same, except in regard to the magnitude of PC generated. A local PL spectrum is measured simultaneously with PC generation at each pixel in the image maps. Through integration of the local PL spectrum over particular wavelength ranges, PL image maps are created of PFB-PL (435 to 475 nm), F8BT-PL (530 to 570 nm), exciplex-PL (620 to 685 nm) and total-PL (entire spectrum). These data allow direct correlation of PC generation with local chemical composition variations within the PV device. PL image maps show morphological variations on the order of 0.5 to 1 µm of alternating PFB-rich and F8BT-rich phases. While illuminating only F8BT (488 nm light), the PFB-rich phases produce the most PC, however, while illuminating both polymers but mostly PFB (408 nm light), the F8BT-rich phases produce the most PC. These results show that in the morphology where the light absorbing material is less concentrated, the PC generation is increased. Additionally, the exciplex-PL is found to not be a significant radiative loss mechanism of charge carriers for PC generation.

Copper indium gallium selenide (CIGS) photovoltaic devices made using multistep selenization of nanocrystal films.

The power conversion efficiency of photovoltaic devices made with ink-deposited Cu(InxGa1-x)Se2 (CIGS) nanocrystal layers can be enhanced by sintering the nanocrystals with a high temperature selenization process. This process, however, can be challenging to control. Here, we report that ink deposition followed by annealing under inert gas and then selenization can provide better control over CIGS nanocrystal sintering and yield generally improved device efficiency. Annealing under argon at 525 °C removes organic ligands and diffuses sodium from the underlying soda lime glass into the Mo back contact to improve the rate and quality of nanocrystal sintering during selenization at 500 °C. Shorter selenization time alleviates excessive MoSe2 formation at the Mo back contact that leads to film delamination, which in turn enables multiple cycles of nanocrystal deposition and selenization to create thicker, more uniform absorber films. Devices with power conversion efficiency greater than 7% are fabricated using the multiple step nanocrystal deposition and sintering process.

Influence of composition on the performance of sintered Cu(In,Ga)Se2 nanocrystal thin-film photovoltaic devices.

Thin-film photovoltaic devices (PVs) were prepared by selenization using oleylamine-capped Cu(In,Ga)Se2 (CIGS) nanocrystals sintered at a high temperature (>500 °C) under Se vapor. The device performance varied significantly with [Ga]/[In+Ga] content in the nanocrystals. The highest power conversion efficiency (PCE) observed in the devices studied was 5.1 % under air mass 1.5 global (AM 1.5 G) illumination, obtained with [Ga]/[In+Ga]=0.32. The variation in PCE with composition is partly a result of bandgap tuning and optimization, but the main influence of nanocrystal composition appeared to be on the quality of the sintered films. The [Cu]/[In+Ga] content was found to be strongly influenced by the [Ga]/[In+Ga] concentration, which appears to be correlated with the morphology of the sintered film. For this reason, only small changes in the [Ga]/[In+Ga] content resulted in significant variations in device efficiency.

The effects of aggregation on electronic and optical properties of oligothiophene particles.

Solution processing of oligothiophene molecules is shown to produce a range of particles with distinct morphologies. Once isolated on a substrate, the optical and electronic properties of individual particles were studied. From polarized scanning confocal microscopy experiments, distinct particles that are identifiable by shape were shown to have similar emission spectra except in regard to the 0-0 vibronic band intensity. This suppression of the 0-0 vibronic band correlates to the amount of energetic disorder present in a weakly coupled H-aggregate. The studied particles ranged from moderate to almost complete suppression of the 0-0 vibronic band when compared to the emission spectrum of the isolated molecule in solution. All particles were found to have a high degree of geometric order (molecular alignment) as observed from the fluorescence dichroism (FD) values of around 0.7-0.8 for all the studied morphologies. The structural and electronic properties of the particles were investigated with Kelvin probe force microscopy (KPFM) to measure the local contact potential (LCP) difference, a quantity that is closely related to the differences in intermolecular charge distribution between the oligothiophene particles. The LCP was found to vary by as much as 70 mV between different oligothiophene particles and a trend was observed that correlated the LCP changes with the amount of energetic disorder present, as signified by the suppression of the 0-0 vibronic peak in the emission spectra. Combined polarized scanning confocal microscopy studies, along with KPFM measurements, help to provide fundamental insights into the role of morphology, molecular packing, and intermolecular charge distributions in oligiothiophene particles.