Development and Validation of a Multivariable Nomogram Predictive of Post-Nephroureterectomy Renal Function.

BACKGROUND AND OBJECTIVE: The timing of perioperative nephrotoxic chemotherapy for upper tract urothelial carcinoma (UTUC) remains controversial and strongly depends on predicted platinum eligibility after radical nephroureterectomy (RNU). The study objective was to develop and validate a multivariable nomogram to predict estimated glomerular filtration rate (eGFR) following RNU. METHODS: This was a multi-institutional retrospective study of patients with UTUC treated with RNU from 2000 to 2020 at seven high-volume referral centers. Use of adjuvant chemotherapy was risk-stratified. Patients were retrospectively randomly allocated 2:1 to discovery and validation cohorts. Discovery data were used to identify independent factors associated with GFR at 1-3 mo after RNU on linear regression, and backward selection was applied for model construction. Accuracy was defined as the percentage of predicted eGFR results within 30% of the corresponding observed eGFR. KEY FINDINGS AND LIMITATIONS: We included 1100 patients, of whom 733 were in the discovery and 367 were in the validation cohort. Multivariable predictors of postoperative eGFR decline included advanced age (odds ratio [OR] -0.18, 95% confidence interval [CI] -0.28 to -0.08), diabetes (OR -2.38, 95% CI -4.64 to -0.11), and hypertension (OR -2.24, 95% CI -4.16 to -0.32). Factors associated with favorable postoperative eGFR included larger tumor size (OR 10.57, 95% CI 7.4-13.74 for tumors >5 cm vs ≤2 cm) and preoperative eGFR (OR 0.44, 95% CI 0.39-0.49). A composite nomogram predicted postoperative eGFR with good accuracy in both the discovery (80.5%) and validation (78.6%) cohorts. Limitations include exclusion of patients who received neoadjuvant chemotherapy. CONCLUSIONS: A nomogram that incorporates ubiquitous preoperative clinical variables can predict post-RNU eGFR and was validated with an independent cohort. PATIENT SUMMARY: We developed a tool that uses patient data to predict eligibility for chemotherapy after surgery to remove the kidney and ureter in patients with cancer in the upper urinary tract.

Virtual Shape-Editing of Patient-Specific Vascular Models Using Regularized Kelvinlets.

OBJECTIVE: Cardiovascular diseases, and the interventions performed to treat them, can lead to changes in the shape of patient vasculatures and their hemodynamics. Computational modeling and simulations of patient-specific vascular networks are increasingly used to quantify these hemodynamic changes, but they require modifying the shapes of the models. Existing methods to modify these shapes include editing 2D lumen contours prescribed along vessel centerlines and deforming meshes with geometry-based approaches. However, these methods can require extensive by-hand prescription of the desired shapes and often do not work robustly across a range of vascular anatomies. To overcome these limitations, we develop techniques to modify vascular models using physics-based principles that can automatically generate smooth deformations and readily apply them across different vascular anatomies. METHODS: We adapt Regularized Kelvinlets, analytical solutions to linear elastostatics, to perform elastic shape-editing of vascular models. The Kelvinlets are packaged into three methods that allow us to artificially create aneurysms, stenoses, and tortuosity. RESULTS: Our methods are able to generate such geometric changes across a wide range of vascular anatomies. We demonstrate their capabilities by creating sets of aneurysms, stenoses, and tortuosities with varying shapes and sizes on multiple patient-specific models. CONCLUSION: Our Kelvinlet-based deformers allow us to edit the shape of vascular models, regardless of their anatomical locations, and parametrically vary the size of the geometric changes. SIGNIFICANCE: These methods will enable researchers to more easily perform virtual-surgery-like deformations, computationally explore the impact of vascular shape on patient hemodynamics, and generate synthetic geometries for data-driven research.

Dosimetric predictors for genitourinary toxicity in MR-guided stereotactic body radiation therapy (SBRT): Substructure with fraction-wise analysis.

BACKGROUND: MR-guided radiation therapy (MRgRT) systems provide superior soft tissue contrast than x-ray based systems and can acquire real-time cine for treatment gating. These features allow treatment planning margins to be reduced, allowing for improved critical structure sparing and reduced treatment toxicity. Despite this improvement, genitourinary (GU) toxicity continues to affect many patients. PURPOSE: (1) To identify dosimetric predictors, potentially in combination with clinical parameters, of GU toxicity following SBRT by leveraging MRgRT to accurately monitor daily dose, beyond predicted dose calculated during planning. (2) Improve awareness of toxicity-sensitive bladder substructures, specifically the trigone and urethra. METHODS: Sixty-nine prostate cancer patients (NCT04384770 clinical trial) were treated on a ViewRay MRIdian MRgRT system, with 40 Gy prescribed to 95% of the PTV in over five fractions. Overall, 17 (24.6%) prostate patients reported acute grade 2 GU toxicity. The CTV, PTV, bladder, bladder wall, trigone, urethra, rectum, and rectal wall were contoured on the planning and daily treatment MRIs. Planning and daily treatment DVHs (0.1 Gy increments), organ doses (min, max, mean), and organ volumes were recorded. Daily dose was estimated by transferring the planning dose distributions to the daily MRI based on the daily setup alignment. Patients were partitioned into a training (55) and testing set (14). Dose features were pre-filtered using a t-test followed by maximum relevance minimum redundancy (MRMR) algorithm. Logistic regression was investigated with regularization to select dosimetric predictors. Specifically, two approaches: time-group least absolute shrinkage and selection (LASSO), and interactive grouped greedy algorithm (IGA) were investigated. Shared features across the planning and five treatment fractions were grouped to encourage consistency and stability. The conventional flat non-temporally grouped LASSO was also evaluated to provide a solid benchmark. After feature selection, a final logistic regression model was trained. Dosimetric regression models were compared to a clinical regression model with only clinical parameters (age, baseline IPSS, prostate gland size, ADT usage, etc.) and a hybrid model, combining the best performing dosimetric features with the clinical parameters, was evaluated. Final model performance was evaluated on the testing set using accuracy, sensitivity, and specificity determined by the optimal threshold of the training set. RESULTS: IGA had the best testing performance with an accuracy/sensitivity/specificity of 0.79/0.67/0.82, selecting 12 groups covering the bladder (V19.8 Gy, V20.5 Gy), bladder wall (19.7 Gy), trigone (15.9, 18.2, 43.3 Gy), urethra (V41.4 Gy, V41.7 Gy), CTV (V41.9 Gy), rectum (V8.5 Gy), and rectal wall (1.2, 44.1 Gy) dose features. Absolute bladder V19.8 Gy and V20.5 Gy were the most important features, followed by relative trigone 15.9  and 18.2 Gy. Inclusion of clinical parameters in the hybrid model with IGA did not significantly change regression performance. CONCLUSION: Overall, IGA feature selection resulted in the best GU toxicity prediction performance. This exploratory study demonstrated the feasibility of identification and analysis of dosimetric toxicity predictors with awareness to sensitive substructures and daily dose to potentially provide consistent and stable dosimetric metrics to guide treatment planning. Further patient accruement is warranted to further assess dosimetric predictor and perform validation.

27-year trends in incidence rates for testis cancer across a large statewide registry.

PURPOSE: To review 27-years of testicular cancer (TC) incidence data (1990-2017) within the state of Pennsylvania to better define incidence, geographic distribution, and trends over time. METHODS: The Pennsylvania Cancer Registry was reviewed for statewide and component county age-adjusted TC incidence rates and stage distribution. We reported annual percent changes (APCs) in age-adjusted rates. Maps plotting county-level incidence rates across the state in five-year time intervals were created. RESULTS: In Pennsylvania, 9,933 TC cases were recorded between 1990-2017. Over two-thirds of patients were < 40 years of age and 95% were White. Approximately 89% presented as local and regional disease. Age-adjusted annual rates of total TC increased from 4.80 to 7.20 patients per 100,000 with an APC of 0.94 (95% Confidence Interval (CI) = (0.59, 1.29), P < 0.01) over the study interval. Annual rates of local disease increased from 3.20 to 5.00 patients per 100,000 with an APC of 1.07 (95% CI = (0.67, 1.46), P < 0.01). Annual rates of distant disease were stable and ranged from 0.50 to 0.80 patients per 100,000 with an APC of 0.69 (95% CI = (-0.02, 1.40), P = 0.06). Geospatial investigation noted increased incidence in urban centers. CONCLUSIONS: Although TC is rare, incidence is rising. Rates of TC in Pennsylvania almost doubled over the past two decades. Fortunately, this rising trend is primarily attributed to increases in local and regional disease. Counties with higher incidence rates cluster in urban centers which may reflect exposure risk, access to care, or reporting bias.

A genetically encoded protein tag for control and quantitative imaging of CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has been successful for hematological malignancies. Still, a lack of efficacy and potential toxicities have slowed its application for other indications. Furthermore, CAR T cells undergo dynamic expansion and contraction in vivo that cannot be easily predicted or controlled. Therefore, the safety and utility of such therapies could be enhanced by engineered mechanisms that engender reversible control and quantitative monitoring. Here, we use a genetic tag based on the enzyme Escherichia coli dihydrofolate reductase (eDHFR), and derivatives of trimethoprim (TMP) to modulate and monitor CAR expression and T cell activity. We fused eDHFR to the CAR C terminus, allowing regulation with TMP-based proteolysis-targeting chimeric small molecules (PROTACs). Fusion of eDHFR to the CAR does not interfere with cell signaling or its cytotoxic function, and the addition of TMP-based PROTACs results in a reversible and dose-dependent inhibition of CAR activity via the proteosome. We show the regulation of CAR expression in vivo and demonstrate imaging of the cells with TMP radiotracers. In vitro immunogenicity assays using primary human immune cells and overlapping peptide fragments of eDHFR showed no memory immune repertoire for eDHFR. Overall, this translationally-orientied approach allows for temporal monitoring and image-guided control of cell-based therapies.

Urothelium-Specific Expression of Mutationally Activated Pik3ca Initiates Early Lesions of Noninvasive Bladder Cancer.

Although approximately 70% of bladder cancers are noninvasive and have high recurrence rates, early-stage disease is understudied. The lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. Although mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, a Upk2-Cre/Pik3caH1047R mouse model expressing one or two R26-Pik3caH1047R alleles in a urothelium-specific manner was generated. Pik3caH1047R functionality was confirmed by quantifying Akt phosphorylation, and mice were characterized by assessing urothelial thickness, nuclear atypia, and expression of luminal and basal markers at 6 and 12 months of age. While at 6 months, Pik3caH1047R mice developed increased urothelial thickness and nuclear atypia, progressive disease was not observed at 12 months. Immunohistochemistry showed urothelium maintained luminal differentiation characterized by high forkhead box A1 (Foxa1) and peroxisome proliferator-activated receptor γ expression. Surprisingly, Pik3caH1047R mice subjected to low-dose carcinogen exposure [N-butyl-N-(4-hydroxybutyl)nitrosamine] exhibited no significant differences after exposure relative to mice without exposure. Furthermore, single-sample gene set enrichment analysis of invasive human tumors showed those with mutant PIK3CA did not exhibit significantly increased phosphatidylinositol 3-kinase/AKT pathway activity compared with wild-type PIK3CA tumors. Overall, these data suggest that Pik3caH1047R can elicit early tumorigenic changes in the urothelium, but progression to invasion may require additional genetic alterations.

Sequence-based diagnostics and precision medicine in bacterial and viral infections: from bench to bedside.

PURPOSE OF REVIEW: Nucleic acid sequence-based organism identification plays an important role in the diagnosis and management of transplant and cancer-associated infectious diseases. Here, we provide a high-level overview of advanced sequencing technologies, discuss test performance, and highlight unmet research needs with a focus on immunocompromised hosts. RECENT FINDINGS: Next-generation sequencing (NGS) technologies are powerful tools with a growing role in managing immunocompromised patients with suspected infection. Targeted NGS (tNGS) can identify pathogens directly from patient specimens, especially for mixed samples, and has been used to detect resistance mutations in transplant-related viruses (e.g. CMV). Whole-genome sequencing (WGS) is increasingly used for outbreak investigations and infection control. Metagenomic NGS (mNGS) is useful for hypothesis-free testing and can simultaneously assess pathogens and host response to infection. SUMMARY: NGS testing increases diagnostic yield relative to standard culture and Sanger sequencing but may be limited by high cost, turnaround times, and detection of unexpected organisms or commensals of uncertain significance. Close collaboration with the clinical microbiology laboratory and infectious diseases is recommended when NGS testing is considered. Additional research is required to understand which immunocompromised patients are most likely to benefit from NGS testing, and when testing should ideally be performed.

Trait profiles in difficult-to-treat asthma: Clinical impact and response to systematic assessment.

BACKGROUND: Multidisciplinary systematic assessment improves outcomes in difficult-to-treat asthma, but without clear response predictors. Using a treatable-traits framework, we stratified patients by trait profile, examining clinical impact and treatment responsiveness to systematic assessment. METHODS: We performed latent class analysis using 12 traits on difficult-to-treat asthma patients undergoing systematic assessment at our institution. We examined Asthma Control Questionnaire (ACQ-6) and Asthma Quality of Life Questionnaire (AQLQ) scores, FEV1 , exacerbation frequency, and maintenance oral corticosteroid (mOCS) dose, at baseline and following systematic assessment. RESULTS: Among 241 patients, two airway-centric profiles were characterized by early-onset with allergic rhinitis (n = 46) and adult onset with eosinophilia/chronic rhinosinusitis (n = 60), respectively, with minimal comorbid or psychosocial traits; three non-airway-centric profiles exhibited either comorbid (obesity, vocal cord dysfunction, dysfunctional breathing) dominance (n = 51), psychosocial (anxiety, depression, smoking, unemployment) dominance (n = 72), or multi-domain impairment (n = 12). Compared to airway-centric profiles, non-airway-centric profiles had worse baseline ACQ-6 (2.7 vs. 2.2, p < .001) and AQLQ (3.8 vs. 4.5, p < .001) scores. Following systematic assessment, the cohort showed overall improvements across all outcomes. However, airway-centric profiles had more FEV1 improvement (5.6% vs. 2.2% predicted, p < .05) while non-airway-centric profiles trended to greater exacerbation reduction (1.7 vs. 1.0, p = .07); mOCS dose reduction was similar (3.1 mg vs. 3.5 mg, p = .782). CONCLUSION: Distinct trait profiles in difficult-to-treat asthma are associated with different clinical outcomes and treatment responsiveness to systematic assessment. These findings yield clinical and mechanistic insights into difficult-to-treat asthma, offer a conceptual framework to address disease heterogeneity, and highlight areas responsive to targeted intervention.

Cronkhite-Canada syndrome: treatment responses and improved overall survival.

BACKGROUND: Cronkhite-Canada syndrome (CCS) is considered a relentlessly progressive disease with high mortality rates. Although disease understanding and treatment options have greatly improved, the prognosis from these advancements has not been well documented. This study aimed to evaluate treatment outcomes and overall survival of CCS. METHODS: Seventeen patients who were diagnosed and treated over a 20-year period at Mayo Clinic (Rochester, Minnesota) were included. Data were abstracted, which included clinical and endoscopic manifestations, treatment course, and survival outcomes. RESULTS: The median (interquartile range) duration of follow-up was 8.3 (3.7-15.8) years. All patients received an initial prednisone dose equivalence of 30-80 mg daily, and five patients required steroids at the time of the last follow-up. Twelve patients trialed thiopurine therapy, and ten patients continued with a thiopurine until the last follow-up. Fifteen patients achieved clinical complete remission, and eleven patients achieved endoscopic complete remission after pharmacotherapy initiation. Seven patients required gastrointestinal surgeries during their disease course. The 5-year overall survival was 93.3% (95% confidence interval (CI): 81.5-100%), and the 3-year relapse-free survival was 82.4% (95% CI: 66.1-100%). CONCLUSION: The prognosis and overall survival of patients with CCS have markedly improved with advancement in disease understanding and therapies. Pharmacotherapy, including corticosteroids and immunomodulators, is effective in inducing and maintaining remission, and gastrointestinal surgery is commonly needed as an adjunct for managing CCS disease complications.

Synchronous melanosis of upper and lower urinary tract.

Urothelial melanosis is an exceptionally rare diagnosis, with less than 25 cases being reported in the literature. Melanosis of the urothelium is characterized by abnormal melanin deposition within tissues, producing a black, velvety appearance to the urothelial mucosa. We present a 67-year-old male undergoing cystoscopy during a routine percutaneous nephrolithotomy (PCNL), who was found to have diffuse bladder melanosis extending up the ureter and into the renal pelvis. To our knowledge, this is the first reported case of synchronous melanosis of upper and lower urinary tract.

Magnetic Resonance Imaging-Guided vs Computed Tomography-Guided Stereotactic Body Radiotherapy for Prostate Cancer: The MIRAGE Randomized Clinical Trial.

Importance: Magnetic resonance imaging (MRI) guidance offers multiple theoretical advantages in the context of stereotactic body radiotherapy (SBRT) for prostate cancer. However, to our knowledge, these advantages have yet to be demonstrated in a randomized clinical trial. Objective: To determine whether aggressive margin reduction with MRI guidance significantly reduces acute grade 2 or greater genitourinary (GU) toxic effects after prostate SBRT compared with computed tomography (CT) guidance. Design, Setting, and Participants: This phase 3 randomized clinical trial (MRI-Guided Stereotactic Body Radiotherapy for Prostate Cancer [MIRAGE]) enrolled men aged 18 years or older who were receiving SBRT for clinically localized prostate adenocarcinoma at a single center between May 5, 2020, and October 1, 2021. Data were analyzed from January 15, 2021, through May 15, 2022. All patients had 3 months or more of follow-up. Interventions: Patients were randomized 1:1 to SBRT with CT guidance (control arm) or MRI guidance. Planning margins of 4 mm (CT arm) and 2 mm (MRI arm) were used to deliver 40 Gy in 5 fractions. Main Outcomes and Measures: The primary end point was the incidence of acute (≤90 days after SBRT) grade 2 or greater GU toxic effects (using Common Terminology Criteria for Adverse Events, version 4.03 [CTCAE v4.03]). Secondary outcomes included CTCAE v4.03-based gastrointestinal toxic effects and International Prostate Symptom Score (IPSS)-based and Expanded Prostate Cancer Index Composite-26 (EPIC-26)-based outcomes. Results: Between May 2020 and October 2021, 156 patients were randomized: 77 to CT (median age, 71 years [IQR, 67-77 years]) and 79 to MRI (median age, 71 years [IQR, 68-75 years]). A prespecified interim futility analysis conducted after 100 patients reached 90 or more days after SBRT was performed October 1, 2021, with the sample size reestimated to 154 patients. Thus, the trial was closed to accrual early. The incidence of acute grade 2 or greater GU toxic effects was significantly lower with MRI vs CT guidance (24.4% [95% CI, 15.4%-35.4%] vs 43.4% [95% CI, 32.1%-55.3%]; P = .01), as was the incidence of acute grade 2 or greater gastrointestinal toxic effects (0.0% [95% CI, 0.0%-4.6%] vs 10.5% [95% CI, 4.7%-19.7%]; P = .003). Magnetic resonance imaging guidance was associated with a significantly smaller percentage of patients with a 15-point or greater increase in IPSS at 1 month (6.8% [5 of 72] vs 19.4% [14 of 74]; P = .01) and a significantly reduced percentage of patients with a clinically significant (≥12-point) decrease in EPIC-26 bowel scores (25.0% [17 of 68] vs 50.0% [34 of 68]; P = .001) at 1 month. Conclusions and Relevance: In this randomized clinical trial, compared with CT-guidance, MRI-guided SBRT significantly reduced both moderate acute physician-scored toxic effects and decrements in patient-reported quality of life. Longer-term follow-up will confirm whether these notable benefits persist. Trial Registration: ClinicalTrials.gov Identifier: NCT04384770.

Fully automated segmentation of prostatic urethra for MR-guided radiation therapy.

PURPOSE: Accurate delineation of the urethra is a prerequisite for urethral dose reduction in prostate radiotherapy. However, even in magnetic resonance-guided radiation therapy (MRgRT), consistent delineation of the urethra is challenging, particularly in online adaptive radiotherapy. This paper presented a fully automatic MRgRT-based prostatic urethra segmentation framework. METHODS: Twenty-eight prostate cancer patients were included in this study. In-house 3D half fourier single-shot turbo spin-echo (HASTE) and turbo spin echo (TSE) sequences were used to image the Foley-free urethra on a 0.35 T MRgRT system. The segmentation pipeline uses 3D nnU-Net as the base and innovatively combines ground truth and its corresponding radial distance (RD) map during training supervision. Additionally, we evaluate the benefit of incorporating a convolutional long short term memory (LSTM-Conv) layer and spatial recurrent convolution layer (RCL) into nnU-Net. A novel slice-by-slice simple exponential smoothing (SEPS) method specifically for tubular structures was used to post-process the segmentation results. RESULTS: The experimental results show that nnU-Net trained using a combination of Dice, cross-entropy and RD achieved a Dice score of 77.1 ± 2.3% in the testing dataset. With SEPS, Hausdorff distance (HD) and 95% HD were reduced to 2.95 ± 0.17 mm and 1.84 ± 0.11 mm, respectively. LSTM-Conv and RCL layers only minimally improved the segmentation precision. CONCLUSION: We present the first Foley-free MRgRT-based automated urethra segmentation study. Our method is built on a data-driven neural network with novel cost functions and a post-processing step designed for tubular structures. The performance is consistent with the need for online and offline urethra dose reduction in prostate radiotherapy.

Urethral Interfractional Geometric and Dosimetric Variations of Prostate Cancer Patients: A Study Using an Onboard MRI.

Purpose: For a cohort of prostate cancer patients treated on an MR-guided radiotherapy (MRgRT) system, we retrospectively analyzed urethral interfractional geometric and dosimetric variations based on onboard MRIs acquired at different timepoints and evaluated onboard prostatic urethra visualization for urethra-focused online adaptive RT. Methods: Twenty-six prostate cancer patients were prospectively scanned on a 0.35-T MRgRT system using an optimized T2-weighted HASTE sequence at simulation and final fraction. Two radiation oncologists (RO1 and RO2) contoured the urethras on all HASTE images. The simulation and final fraction HASTE images were rigidly registered, and urethral interobserver and interfractional geometric variation was evaluated using the 95th percentile Hausdorff distance (HD95), mean distance to agreement (MDA), center-of-mass shift (COMS), and DICE coefficient. For dosimetric analysis, simulation and final fraction HASTE images were registered to the 3D bSSFP planning MRI and 3D bSSFP final setup MRI, respectively. Both ROs' urethra contours were transferred from HASTE images for initial treatment plan optimization and final fraction dose estimation separately. Stereotactic body radiotherapy (SBRT) plans, 40 Gy in 5 fractions, were optimized to meet clinical constraints, including urethral V42Gy ≤0.03 cc, on the planning MRI. The initial plan was then forward calculated on the final setup MRI to estimate urethral dose on the final fraction and evaluate urethral dosimetric impact due to anatomy change. Results: The average interobserver HD95, MDA, COMS, and DICE were 2.85 ± 1.34 mm, 1.02 ± 0.36 mm, 3.16 ± 1.61 mm, and 0.58 ± 0.15, respectively. The average interfractional HD95, MDA, COMS, and DICE were 3.26 ± 1.54 mm, 1.29 ± 0.54 mm, 3.34 ± 2.01 mm, and 0.49 ± 0.18, respectively. All patient simulation MRgRT plans met all clinical constraints. For RO1 and RO2, 23/26 (88%) and 21/26 (81%) patients' final fraction estimated urethral dose did not meet the planned constraint. The average urethral V42Gy change was 0.48 ± 0.58 cc. Conclusion: Urethral interfractional motion and anatomic change can result in daily treatment violating urethral constraints. Onboard MRI with good visualization of the prostatic urethra can be a valuable tool to help better protect the urethra through patient setup or online adaptive RT.

Incidence and Distribution of New Renal Cell Carcinoma Cases: 27-Year Trends from a Statewide Cancer Registry.

Nationwide databases have implicated an increased incidence of renal cell carcinoma (RCC). The Pennsylvania (PA) Cancer Registry was queried to better define incidence, geographic distribution, and statewide trends of new RCC cases over a 27-year period. JoinPoint Trend Analysis Software modeled average annual percent changes (APCs) in age-adjusted rates (AAR). Maps plotting county-level incidence rates and stage distribution of disease across the state in 5-year time intervals were created using R 4.0.2 software. Overall, 59,628 cases of RCC were recorded in PA from 1990 to 2017. Eighty six percent of patients were >50 years of age, 61% were males, and 89% were Caucasian. Stage distribution using the SEER staging system included 64% local, 17% regional, and 16% distant. Over the study interval, AAR of all RCC cases increased from 9.9 to 18.0 patients per 100,000 population with an APC of 2.3% (p < 0.01). AAR of local disease increased from 5.4 to 12.7 patients per 100,000 population with an APC of 3.2% (p < 0.01). AAR of regional disease also increased from 1.9 to 2.9 patients per 100,000 population with an APC of 1.0% (p = 0.01). Younger patients (<50 years) had a greater rate of increase than older counterparts (APC 3.8% vs. 2.0%, p < 0.05). Geospatial investigation of new RCC cases noted certain geographic concentrations of greater disease incidence. The incidence of RCC in PA has increased over the past 27 years in PA. One-third of the cases are regional or metastatic at presentation and rates of increase were most notable in younger patients.

Erodible thermogelling hydrogels for localized mitochondrial transplantation to the spinal cord.

We developed a thermal-gelling, erodible hydrogel system for localized delivery of viable mitochondria in vivo, as well as labeled transplanted mitochondria with specific dyes and/or genetically modified mitochondria tagged with red fluorescence protein (RFP). We also employed cell lines to optimize a hydrogel composed of methylcellulose and hyaluronic acid designed to preserve bioenergetics while facilitating mitochondrial release. We further investigated how transplantation of allogeneic or xenogeneic mitochondria into respective cell lines affects host cellular metabolism, as measured by MTS assay. We found that 70% of mitochondria are released from the hydrogel within 20 min at 37 °C, that the respiratory capacity of hydrogel-released mitochondria over 60 min was greater than those without gel, and that MTR-labeling of mitochondria is not indelible. RFP-tagged transgenic mitochondria isolated from modified SH-SY5Y human neuroblastoma cells showed effective uptake into both naïve SH-SY5Y cells and rat PC-12 cells, notably when released from hydrogel. The hydrogel both protected the mitochondria at physiological conditions in vitro while solidifying and diffusing within 60 min locally in situ. To assess metabolic effects, both cell lines were transplanted with different concentrations of SH-SY5Y or PC-12 cell line-derived mitochondria and all resulted in significant increases in metabolism at 6- and 24-hour after transplantation. Alternatively, transplanted mitochondria at highest concentration from rat brain and spinal cord tissues reduced metabolic activities after 24-hour. Along with hydrogel refinements, we are further investigating whether such metabolic changes are due to alterations in cell proliferation or the number of exogenous mitochondria incorporated into individual host cells.

Dosimetric Effects of Air Cavities for MRI-Guided Online Adaptive Radiation Therapy (MRgART) of Prostate Bed after Radical Prostatectomy.

PURPOSE: To evaluate dosimetric impact of air cavities and their corresponding electron density correction for 0.35 tesla (T) Magnetic Resonance-guided Online Adaptive Radiation Therapy (MRgART) of prostate bed patients. METHODS: Three 0.35 T MRgRT plans (anterior-posterior (AP) beam, AP-PA beams, and clinical intensity modulated radiation therapy (IMRT)) were generated on a prostate bed patient's (Patient A) planning computed tomography (CT) with artificial rectal air cavities of various sizes (0-3 cm, 0.5 cm increments). Furthermore, two 0.35 T MRgART plans ('Deformed' and 'Override') were generated on a prostate bed patient's (Patient B) daily magnetic resonance image (MRI) with artificial rectal air cavities of various sizes (0-3 cm, 0.5 cm increments) and on five prostate bed patient's (Patient 1-5) daily MRIs (2 MRIs: Fraction A and B) with real air cavities. For each MRgART plan, daily MRI electron density map was obtained by deformable registration with simulation CT. In the 'Deformed' plan, a clinical IMRT plan is calculated on the daily MRI with electron density map obtained from deformable registration only. In the 'Override' plan, daily MRI and simulation CT air cavities are manually corrected and bulk assigned air and water density on the registered electron density map, respectively. Afterwards, the clinical IMRT plan is calculated. RESULTS: For the MRgRT plans, AP and AP-PA plans' rectum/rectal wall max dose increased with increasing air cavity size, where the 3 cm air cavity resulted in a 20%/17% and 13%/13% increase, relative to no air cavity, respectively. Clinical IMRT plan was robust to air cavity size, where dose change remained less than 1%. For the MRgART plans, daily MRI electron density maps, obtained from deformable registration with simulation CT, was unable to accurately produce electron densities reflecting the air cavities. However, for the artificial daily MRI air cavities, dosimetric change between 'Deformed' and 'Override' plan was small (<4%). Similarly, for the real daily MRI air cavities, clinical constraint changes between 'Deformed' and 'Override' plan was negligible and did not lead to change in clinical decision for adaptive planning except for two fractions. In these fractions, the 'Override' plan indicated that the bladder max dose and rectum V35.7 exceeded the constraint, while the 'Deformed' plan showed acceptable dose, although the absolute difference was only 0.3 Gy and 0.03 cc, respectively. CONCLUSION: Clinical 0.35 T IMRT prostate bed plans are dosimetrically robust to air cavities. MRgART air cavity electron density correction shows clinically insignificant change and is not warranted on low-field systems.

2-Step PLT16-AST44 method: Simplified liver fibrosis detection system in patients with non-alcoholic fatty liver disease.

AIM: Accurate detection of the hepatic fibrosis stage is essential to estimate the outcome of patients with non-alcoholic fatty liver disease (NAFLD). Many formulas, biomarkers, and imaging tests are being developed to predict advanced liver fibrosis without performing a liver biopsy. However, these tests do not have high efficiency in detecting early-stage hepatic fibrosis. Therefore, we aimed to detect the presence of hepatic fibrosis (≥F1) merely by using only standard clinical markers. METHODS: A total of 436 patients with NAFLD who underwent liver biopsy were retrospectively enrolled as the discovery cohort (316 patients) and the validation cohort (120 patients). Liver biopsy and laboratory data were matched to extract simple parameters for identifying ≥F1. RESULTS: We developed a novel simplified ≥F1 detecting system, designated as 2-Step PLT16-AST44 method, where (1) PLT of 16 × 104 /µl or less, or (2) PLT greater than 16 × 104 /µl and AST greater than 44 U/L is determined as having ≥F1 fibrosis. The 2-Step PLT16-AST44 method had a sensitivity of 68%, a specificity of 90%, a positive predictive value (PPV) of 97%, a negative predictive value (NPV) of 40%, and an accuracy of 72% to detect ≥F1 fibrosis in the discovery cohort. Validation studies further supported these results. Despite its simplicity, the 2-Step PLT16-AST44 method's power to detect ≥F1 fibrosis in total NAFLD patients was comparable to hyaluronic acid, type 4 collagen 7S, FIB-4, and APRI. CONCLUSIONS: We propose the 2-Step PLT16-AST44 method as a simple and beneficial early-stage hepatic fibrosis detection system.

The Cost of Guideline Adherence: A Multicenter Analysis of the Financial Implications of Adopting the US Multi-Society Task Force Polypectomy Guidelines.

GOAL: The goal of this study was to determine the financial impact of adopting the US Multi-Society Task Force (USMSTF) polypectomy guidelines on physician reimbursement and disposable equipment costs for gastroenterologists in the academic medical center and community practice settings. BACKGROUND: In 2020, USMSTF guidelines on polypectomy were introduced with a strong recommendation for cold snare rather than cold forceps technique for removing diminutive and small polyps. Polypectomy with snare technique reimburses physicians at a higher rate compared with cold forceps and also requires different disposable equipment. The financial implications of adopting these guidelines is unknown. MATERIALS AND METHODS: Patients that underwent screening colonoscopy where polypectomy was performed at an academic medical center (Loma Linda University Medical Center) and community practice medical center (Ascension Providence Hospital) between July 2018 and July 2019 were identified. The polypectomy technique performed during each procedure was determined (forceps alone, snare alone, forceps plus snare) along with the number and size of polyps as well as disposable equipment. Actual and projected provider reimbursement and disposable equipment costs were determined based on applying the new polypectomy guidelines. RESULTS: A total of 1167 patients underwent colonoscopy with polypectomy. Adhering to new guidelines would increase estimated physician reimbursement by 5.6% and 12.5% at academic and community practice sites, respectively. The mean increase in physician reimbursement per procedure was significantly higher at community practice compared with the academic setting ($29.50 vs. $14.13, P <0.00001). The mean increase in disposable equipment cost per procedure was significantly higher at the community practice setting ($6.11 vs. $1.97, P <0.00001). CONCLUSION: Adopting new polypectomy guidelines will increase physician reimbursement and equipment costs when colonoscopy with polypectomy is performed.

Impacts of lung cancer multidisciplinary meeting presentation: Drivers and outcomes from a population registry retrospective cohort study.

INTRODUCTION: Multidisciplinary Meetings (MDM) are recommended in routine lung cancer care, however its broader impacts demand further evaluation. We assessed the drivers and impacts of MDM presentation in the Victorian Lung Cancer Registry (VLCR). METHODS: We examined the effect of MDM presentation on receipt of treatment and survival in VLCR patients diagnosed between 2011 and 2020. We compared patient characteristics, drivers of MDM discussion and survival between the two groups. RESULTS: Of 9,628 patients, 5,900 (61.3%) were discussed at MDM, 3,728 (38.7%) were not. In the non-MDM group, a lower proportion received surgery (22.1% vs. 31.2%), radiotherapy (34.2% vs. 44.4%) and chemotherapy (44.7% vs. 49.0%). Patients were less likely to be discussed if ≥80 years (OR 0.73, p < 0.001), of ECOG performance status (PS) 4 (OR 0.23, p < 0.001), clinical stage IV (OR 0.34, p < 0.001) or referred from regional (OR 0.52, p < 0.001) or private hospital (OR 0.18, p < 0.001). MDM-presented patients had better median survival (1.70 vs 0.75 years, p < 0.001) and lower adjusted mortality risk (HR 0.75; 0.71-0.80, p < 0.001), a protective effect consistent across all hospital types. Undocumented PS, histopathology and clinical stage were associated with lower likelihood of MDM discussion and worse mortality. CONCLUSIONS: In the VLCR, being male, ≥80 years, of poorer PS, advanced clinical stage and poor clinical characterisation significantly disadvantaged patients in relation to MDM discussion. MDM-discussed patients were more likely to undergo treatment and had a 25% lower risk of mortality. This study supports the use of MDMs in lung cancer and identifies areas of inequity to be addressed.