Definitive local therapy for T4 prostate cancer associated with improved local control and survival.

OBJECTIVES: To evaluate patients with clinical (c)T4 prostate cancer (PCa), which represent both a heterogenous and understudied population, who often present with locally advanced disease and obstructive symptoms causing significant morbidity and mortality. We analysed whether receiving definitive local therapy influenced symptomatic and oncological outcomes. METHODS: Retrospective analysis of 154 patients with cT4 PCa treated at a single institution in 1996-2020. Systemic therapy with or without local treatment (surgery, radiotherapy [RT], or both). Uni- and multivariate analyses of associations between clinicopathological features (including obstructive symptoms) and receipt of local therapy on overall survival (OS) and disease control were done with Cox regression. RESULTS: The median follow-up time was 5.9 years. Most patients had adenocarcinoma (88%), Gleason score 9-10 (77%), and median baseline prostate-specific antigen (PSA) of 20 ng/mL; most (54%) had metastatic cT4N0-1M1 disease; 24% regionally advanced cT4N1M0, and 22% localised cT4N0M0. Local therapies were RT (n = 44), surgery (n = 28), or both (n = nine). Local therapy was associated with improved OS (hazard ratio [HR] 0.3, P < 0.001), longer freedom from local recurrence (HR 0.39, P = 0.002), less local progression (HR 0.41, P = 0.02), fewer obstructive symptoms with progression (HR 0.31, P = 0.01), and less death from local disease (HR 0.25, P = 0.002). On multivariate, local therapy was associated with improved survival (HR 0.58, P = 0.02), and metastatic disease (HR 2.93, P < 0.001) or high-risk pathology (HR 2.05, P = 0.03) was associated with worse survival. CONCLUSION: Definitive local therapy for cT4 PCa was associated with improved symptomatic outcomes and survival even among men with metastatic disease. Pending prospective evaluation, these findings support definitive treatment with local therapy for cT4 disease in select cases.

Outcomes in Endoscopic and Operative Transgastric Pancreatic Debridement.

OBJECTIVES: Select patients with anatomically favorable walled off pancreatic necrosis may be treated by endoscopic (Endo-TGD) or operative (OR-TGD) transgastric debridement (TGD). We compared our experience with these 2 approaches. SUMMARY BACKGROUND DATA: Select necrotizing pancreatitis (NP) patients are suitable for TGD which may be accomplished endoscopically or surgically. Limited experience exists contrasting these techniques exists. METHODS: Patients undergoing Endo-TGD and OR-TGD at a single, high-volume pancreatic center between 2008 and 2019 were identified from a prospective database. Patient characteristics, procedural details, and outcomes of these 2 groups were compared. RESULTS: Among 498 NP patients undergoing necrosis intervention, 160 (32%) had TGD: 59 Endo-TGD and 101 OR-TGD. The groups were statistically similar in age, comorbidity, pancreatitis etiology, necrosis anatomy, pancreatitis severity, and timing of TGD from pancreatitis insult. OR-TGD required 1.1 ±â€Š0.5 and Endo-TGD 3.0 ±â€Š2.0 debridements/patient. Fewer hospital readmissions and repeat necrosis interventions, and shorter total inpatient length of stay were observed in OR-TGD patients. New-onset organ failure [Endo-TGD (13%); OR-TGD (13%); P = 1.0] was similar between groups. Hospital length of stay after TGD was significantly longer in patients undergoing Endo-TGD (13.8 ±â€Š20.8 days) compared to OR-TGD (9.4 ±â€Š6.1 days; P = 0.047). Mortality was 7% in Endo-TGD and 1% in OR-TGD (P = 0.04). CONCLUSIONS: Operative and endoscopic transgastric debridement achieve necrosis resolution with different temporal and procedural profiles. Clear multidisciplinary communication is essential to determine appropriate approach to individual necrotizing pancreatitis patients.

Contemporary prostate cancer treatment choices in multidisciplinary clinics referenced to national trends.

BACKGROUND: The purpose of this study was to assess treatment choices among men with prostate cancer who presented at The University of Texas MD Anderson Cancer Center multidisciplinary (MultiD) clinic compared with nationwide trends. METHODS: In total, 4451 men with prostate cancer who presented at the MultiD clinic from 2004 to 2016 were analyzed. To assess nationwide trends, the authors analyzed 392,710 men with prostate cancer who were diagnosed between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. The primary endpoint was treatment choice as a function of pretreatment demographics. RESULTS: Univariate analyses revealed similar treatment trends in the MultiD and SEER cohorts. The use of procedural forms of definitive therapy decreased with age, including brachytherapy and prostatectomy (all P < .05). Later year of diagnosis/clinic visit was associated with decreased use of definitive treatments, whereas higher risk grouping was associated with increased use (all P < .001). Patients with low-risk disease treated at the MultiD clinic were more likely to receive nondefinitive therapy than patients in SEER, whereas the opposite trend was observed for patients with high-risk disease, with a substantial portion of high-risk patients in SEER not receiving definitive therapy. In the MultiD clinic, African American men with intermediate-risk and high-risk disease were more likely to receive definitive therapy than white men, but for SEER the opposite was true. CONCLUSIONS: Presentation at a MultiD clinic facilitates the appropriate disposition of patients with low-risk disease to nondefinitive strategies of patients with high-risk disease to definitive treatment, and it may obviate the influence of race.

Routine Venous Thromboembolism Prophylaxis May Be Inadequate in the Hypercoagulable State of Severe Coronavirus Disease 2019.

OBJECTIVES: The aim of this study was to determine the frequency of venous thromboembolism in critically ill coronavirus disease 2019 patients and associate a degree of inflammatory marker elevation to venous thromboembolism development. DESIGN: An observational study that identified patients with severe coronavirus disease 2019 between March 12, 2020, and March 31, 2020. Data reported are those available through May 6, 2020. SETTING: A multicenter study including three Indianapolis area academic hospitals. PATIENTS: Two-hundred forty consecutive patients with confirmed severe acute respiratory syndrome coronavirus 2 infection were admitted to one of three hospitals. One-hundred nine critically ill coronavirus disease 2019 patients admitted to the ICU were included in the analysis. INTERVENTIONS: All patients received routine subcutaneous chemical venous thromboembolism prophylaxis. MEASUREMENTS AND MAIN RESULTS: The primary outcome of this study was to determine the frequency of venous thromboembolism and the degree of inflammatory and coagulation marker elevation associated with venous thromboembolism development. Descriptive statistics outlined the frequency of venous thromboembolism at any time during severe coronavirus disease 2019. Clinical course and laboratory metrics were compared between patients that developed venous thromboembolism and patients that did not develop venous thromboembolism. Hypercoagulable thromboelastography was defined as two or more hypercoagulable parameters. MAIN RESULTS: One-hundred nine patients developed severe coronavirus disease 2019 requiring ICU care. The mean (± SD) age was 61 ± 16 years and 57% were male. Seventy-five patients (69%) were discharged home, 7 patients (6%) remain in the hospital, and 27 patients (25%) died. Venous thromboembolism was diagnosed in 31 patients (28%) 8 ± 7 days after hospital admission, including two patients diagnosed with venous thromboembolism at presentation to the hospital. Elevated admission D-dimer and peak D-dimer were associated with venous thromboembolism development (p < 0.05). D-dimer greater than 2,600 ng/mL predicted venous thromboembolism with an area under the receiver operating characteristic curve of 0.760 (95% CI, 0.661-0.858; p < 0.0001), sensitivity of 89.7%, and specificity of 59.5%. Twelve patients (11%) had thromboelastography performed and 58% of these patients had a hypercoagulable study. The calculated coagulation index was hypercoagulable in 50% of patients with thromboelastography. CONCLUSIONS: These data show that coronavirus disease 2019 results in a hypercoagulable state. Routine chemical venous thromboembolism prophylaxis may be inadequate in preventing venous thromboembolism in severe coronavirus disease 2019.

Machine Learning Analysis of Digital Clock Drawing Test Performance for Differential Classification of Mild Cognitive Impairment Subtypes Versus Alzheimer's Disease.

OBJECTIVE: To determine how well machine learning algorithms can classify mild cognitive impairment (MCI) subtypes and Alzheimer's disease (AD) using features obtained from the digital Clock Drawing Test (dCDT). METHODS: dCDT protocols were administered to 163 patients diagnosed with AD(n = 59), amnestic MCI (aMCI; n = 26), combined mixed/dysexecutive MCI (mixed/dys MCI; n = 43), and patients without MCI (non-MCI; n = 35) using standard clock drawing command and copy procedures, that is, draw the face of the clock, put in all of the numbers, and set the hands for "10 after 11." A digital pen and custom software recorded patient's drawings. Three hundred and fifty features were evaluated for maximum information/minimum redundancy. The best subset of features was used to train classification models to determine diagnostic accuracy. RESULTS: Neural network employing information theoretic feature selection approaches achieved the best 2-group classification results with 10-fold cross validation accuracies at or above 83%, that is, AD versus non-MCI = 91.42%; AD versus aMCI = 91.49%; AD versus mixed/dys MCI = 84.05%; aMCI versus mixed/dys MCI = 84.11%; aMCI versus non-MCI = 83.44%; and mixed/dys MCI versus non-MCI = 85.42%. A follow-up two-group non-MCI versus all MCI patients analysis yielded comparable results (83.69%). Two-group classification analyses were achieved with 25-125 dCDT features depending on group classification. Three- and four-group analyses yielded lower but still promising levels of classification accuracy. CONCLUSION: Early identification of emergent neurodegenerative illness is criterial for better disease management. Applying machine learning to standard neuropsychological tests promises to be an effective first line screening method for classification of non-MCI and MCI subtypes.

ABCB5 is a limbal stem cell gene required for corneal development and repair.

Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs), and LSC deficiency is a major cause of blindness worldwide. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts, a gene allowing for prospective LSC enrichment has not been identified so far. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5) marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs in mice and p63α-positive LSCs in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.

Inhibition of fascin in cancer and stromal cells blocks ovarian cancer metastasis.

OBJECTIVE: Ovarian cancer (OvCa) metastasis requires the coordinated motility of both cancer and stromal cells. Cellular movement is a dynamic process that involves the synchronized assembly of f-actin bundles into cytoskeletal protrusions by fascin. Fascin directly binds f-actin and is an integral component of filopodia, lamellapodia and stress fibers. Here, we examine the expression pattern and function of fascin in the cancer and stromal cells of OvCa tumors. METHODS: Fascin expression was evaluated in human cells and tissues using immunohistochemistry and immunofluorescence. The functional role of fascin in cancer and stromal cells was assessed with in vitro functional assays, an ex vivo colonization assay and in vivo metastasis assays using siRNA/shRNA and an inhibitor. The effect of fascin inhibition on Cdc42 and Rac1 activity was evaluated using GTPase activity assays and immunofluorescence. RESULTS: Fascin expression was found to be higher in the stromal cell, when compared to the cancer cell, compartment of ovarian tumors. The low expression of fascin in the cancer cells of the primary tumor indicated a favorable prognosis for non-serous OvCa patients. In vitro, both knockdown and pharmacologic inhibition of fascin decreased the migration of cancer and stromal cells. The inhibition of fascin impaired Cdc42 and Rac1 activity in cancer cells, and cytoskeletal reorganization in the cancer and stromal cells. Inhibition of fascin ex vivo blocked OvCa cell colonization of human omental tissue and in vivo prevented and reduced OvCa metastases in mice. Likewise, knockdown of fascin specifically in the OvCa cells using a fascin-specific lentiviral-shRNA also blocked metastasis in vivo. CONCLUSION: This study reveals the therapeutic potential of pharmacologically inhibiting fascin in both cancer and stromal cells of the OvCa tumor microenvironment.

Prostate Cancer Energetics and Biosynthesis.

Cancers must alter their metabolism to satisfy the increased demand for energy and to produce building blocks that are required to create a rapidly growing tumor. Further, for cancer cells to thrive, they must also adapt to an often changing tumor microenvironment, which can present new metabolic challenges (ex. hypoxia) that are unfavorable for most other cells. As such, altered metabolism is now considered an emerging hallmark of cancer. Like many other malignancies, the metabolism of prostate cancer is considerably different compared to matched benign tissue. However, prostate cancers exhibit distinct metabolic characteristics that set them apart from many other tumor types. In this chapter, we will describe the known alterations in prostate cancer metabolism that occur during initial tumorigenesis and throughout disease progression. In addition, we will highlight upstream regulators that control these metabolic changes. Finally, we will discuss how this new knowledge is being leveraged to improve patient care through the development of novel biomarkers and metabolically targeted therapies.

Quality of life after brachytherapy or bilateral nerve-sparing robot-assisted radical prostatectomy for prostate cancer: a prospective cohort.

OBJECTIVE: To provide comparative data on quality of life (QoL) after prostate cancer treatment to help patients make an informed decision regarding their choice of treatment. METHODS: Patients with pathologically proven, non-metastatic, T1-T3bN0 prostate cancer were included in this prospective non-randomized study if they were to receive treatment with curative intent. Sample size was at least 181 patients per cohort/treatment type. QoL was recorded at baseline and at each follow-up using the Expanded Prostate Cancer Index Composite (EPIC) instrument. The minimal clinically important difference was defined as half of the standard deviation of the baseline score for each domain. A mixed effects model was used to compare the different treatments. Data are presented on the brachytherapy and the bilateral nerve-sparing robot-assisted radical prostatectomy (RARP) cohorts. Hormonotherapy was not allowed. RESULTS: Between November 2007 and January 2013, 181 patients who received brachytherapy and 210 patients who underwent RARP were included. Of the patients who underwent RARP, 178 had bilateral nerve-sparing and were included in the present analysis. Response rate to EPIC questionnaires were higher in the brachytherapy than in the RARP arm: 82% vs 57% at 2 years after treatment and 55% vs 45% at 4 years after treatment. In the mixed effects model, patients in the RARP arm had better QoL with regard to urinary irritation/obstruction or bother and bowel function, and lower QoL regarding sexual function and urinary incontinence. Results were confirmed in a propensity score-matched model. Patient satisfaction was significantly higher in the brachytherapy group at 1, 2 and 3 years after treatment. CONCLUSION: This prospective non-randomized study shows long-term differences in QoL domains after bilateral nerve-sparing RARP and brachytherapy. Differences in patient satisfaction should be further explored. These results could be used to counsel patients in the decision-making process.

Mitochondrial Activity in Human White Adipocytes Is Regulated by the Ubiquitin Carrier Protein 9/microRNA-30a Axis.

The acquisition of beige adipocyte features by white fat cells corresponds to protection against obesity-induced metabolic diseases in humans and animal models of type 2 diabetes. In adipose tissue, expression of the E2 small ubiquitin-like modifier ligase ubiquitin carrier protein 9 (Ubc9) is positively correlated with markers of insulin resistance and corresponds with impaired browning of human white adipocytes. However, the molecular regulation of Ubc9 expression in adipocytes and other cells remains unclear. In this study, we demonstrate that the mRNA and protein expression of Ubc9 are regulated by the microRNA miRNA-30a (miR-30a) in human subcutaneous adipocytes. Ubc9 and miR-30a exhibit inverse expression in adipose tissue, with miR-30a robustly elevated in brown fat. Depletion of Ubc9 by siRNA or enforced expression of a miR-30a mimic augments mitochondrial volume and respiration in human white adipocytes, reflecting features of brown fat cells. Furthermore, Ubc9 depletion induces a brown fat gene program in human subcutaneous adipocytes. Induction of the beige-selective gene program corresponds to stabilization of the PR domain-containing 16 (PRDM16) protein, an obligate transcriptional regulator of the brown/beige fat metabolic program in white adipocytes that interacts with Ubc9. Taken together, our data demonstrate a previously unappreciated molecular axis that controls browning of human white adipocytes.

New diagnostic methods for laser plasma- and microwave-enhanced combustion.

The study of pulsed laser- and microwave-induced plasma interactions with atmospheric and higher pressure combusting gases requires rapid diagnostic methods that are capable of determining the mechanisms by which these interactions are taking place. New rapid diagnostics are presented here extending the capabilities of Rayleigh and Thomson scattering and resonance-enhanced multi-photon ionization (REMPI) detection and introducing femtosecond laser-induced velocity and temperature profile imaging. Spectrally filtered Rayleigh scattering provides a method for the planar imaging of temperature fields for constant pressure interactions and line imaging of velocity, temperature and density profiles. Depolarization of Rayleigh scattering provides a measure of the dissociation fraction, and multi-wavelength line imaging enables the separation of Thomson scattering from Rayleigh scattering. Radar REMPI takes advantage of high-frequency microwave scattering from the region of laser-selected species ionization to extend REMPI to atmospheric pressures and implement it as a stand-off detection method for atomic and molecular species in combusting environments. Femtosecond laser electronic excitation tagging (FLEET) generates highly excited molecular species and dissociation through the focal zone of the laser. The prompt fluorescence from excited molecular species yields temperature profiles, and the delayed fluorescence from recombining atomic fragments yields velocity profiles.

Analysis of interactions between the epigenome and structural mutability of the genome using Genboree Workbench tools.

BACKGROUND: Interactions between the epigenome and structural genomic variation are potentially bi-directional. In one direction, structural variants may cause epigenomic changes in cis. In the other direction, specific local epigenomic states such as DNA hypomethylation associate with local genomic instability. METHODS: To study these interactions, we have developed several tools and exposed them to the scientific community using the Software-as-a-Service model via the Genboree Workbench. One key tool is Breakout, an algorithm for fast and accurate detection of structural variants from mate pair sequencing data. RESULTS: By applying Breakout and other Genboree Workbench tools we map breakpoints in breast and prostate cancer cell lines and tumors, discriminate between polymorphic breakpoints of germline origin and those of somatic origin, and analyze both types of breakpoints in the context of the Human Epigenome Atlas, ENCODE databases, and other sources of epigenomic profiles. We confirm previous findings that genomic instability in human germline associates with hypomethylation of DNA, binding sites of Suz12, a key member of the PRC2 Polycomb complex, and with PRC2-associated histone marks H3K27me3 and H3K9me3. Breakpoints in germline and in breast cancer associate with distal regulatory of active gene transcription. Breast cancer cell lines and tumors show distinct patterns of structural mutability depending on their ER, PR, or HER2 status. CONCLUSIONS: The patterns of association that we detected suggest that cell-type specific epigenomes may determine cell-type specific patterns of selective structural mutability of the genome.

Melanoma depth in patients with an established dermatologist.

BACKGROUND: The impact of having an established dermatologist on melanoma depth at diagnosis is incompletely understood. OBJECTIVE: We sought to determine whether having had a previous dermatologic examination (an established dermatologist), the recency of the last examination, and the wait time for the dermatology appointment are associated with melanoma invasiveness and depth. METHODS: This was a retrospective cross-sectional study of 388 patients with primary melanoma at an academic dermatology department. RESULTS: Patients with an established dermatologist were more likely than patients without an established dermatologist to be given a diagnosis of melanoma in situ (103/162 [63.6%] vs 69/155 [44.5%], P = .001) and to have thinner invasive melanoma (0.48 [0.30-0.71] mm vs 0.61 [0.40-1.10] mm, respectively, P = .003). These trends were observed for patients with self-detected, but not dermatologist-detected, melanoma. Patient-detected melanomas made up 184/361 (51.0%) of all melanomas, 83/199 (41.7%) of in situ melanomas, and 101/162 (62.4%) invasive melanomas. Self-detected melanomas were in situ in 36 of 61 (59.0%) patients with an established dermatologist versus 40 of 108 (37.0%) patients without an established dermatologist, P = .006. Neither time from last dermatologic examination nor wait time for an appointment was associated with melanoma invasiveness or depth. LIMITATIONS: Data are retrospective and from 1 large academic health care system. CONCLUSION: Education obtained at the dermatology appointment may improve early self-detection of melanoma, and having an established dermatologist may facilitate earlier evaluation of concerning lesions.

The Potential Clinical Benefits of Direct Surgical Transgastric Pancreatic Necrosectomy for Patients With Infected Necrotizing Pancreatitis.

OBJECTIVE: Surgical transgastric pancreatic necrosectomy (STGN) has the potential to overcome the shortcomings (ie, repeat interventions, prolonged hospitalization) of the step-up approach for infected necrotizing pancreatitis. We aimed to determine the outcomes of STGN for infected necrotizing pancreatitis. MATERIALS AND METHODS: This observational cohort study included adult patients who underwent STGN for infected necrosis at two centers from 2008 to 2022. Patients with a procedure for pancreatic necrosis before STGN were excluded. Primary outcomes included mortality, length of hospital and intensive care unit (ICU) stay, new-onset organ failure, repeat interventions, pancreatic fistulas, readmissions, and time to episode closure. RESULTS: Forty-three patients underwent STGN at a median of 48 days (interquartile range [IQR] 32-70) after disease onset. Mortality rate was 7% (n = 3). After STGN, the median length of hospital was 8 days (IQR 6-17), 23 patients (53.5%) required ICU admission (2 days [IQR 1-7]), and new-onset organ failure occurred in 8 patients (18.6%). Three patients (7%) required a reintervention, 1 (2.3%) developed a pancreatic fistula, and 11 (25.6%) were readmitted. The median time to episode closure was 11 days (IQR 6-22). CONCLUSIONS: STGN allows for treatment of retrogastric infected necrosis in one procedure and with rapid episode resolution. With these advantages and few pancreatic fistulas, direct STGN challenges the step-up approach.

Stratification of Fusobacterium nucleatum by local health status in the oral cavity defines its subspecies disease association.

The ubiquitous inflammophilic oral pathobiont Fusobacterium nucleatum (Fn) is widely recognized for its strong association with inflammatory dysbiotic diseases and cancer. Fn is subdivided into four subspecies, which are historically considered functionally interchangeable in the oral cavity. To test this assumption, we analyzed patient-matched dental plaque and odontogenic abscess clinical specimens and examined whether an inflammatory environment selects for/against particular Fn subspecies. Dental plaque harbored a greater diversity of fusobacteria, with Fn. polymorphum dominating, whereas odontogenic abscesses were exceptionally biased for the largely uncharacterized organism Fn. animalis. Comparative genomic analyses revealed significant genotypic distinctions among Fn subspecies that correlate with their preferred ecological niches and support a taxonomic reassignment of each as a distinct Fusobacterium species. Despite originating as a low-abundance organism in dental plaque, Fn. animalis typically outcompetes other oral fusobacteria within the inflammatory abscess environment, which may explain its prevalence in other oral and extraoral diseases.

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials.

PURPOSE: A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. METHODS AND MATERIALS: This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. RESULTS: Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P = .02), worse biochemical recurrence (subdistribution HR, 2.39; P = .003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P = .005), and worse overall survival (HR, 4.51; P = .05). CONCLUSIONS: Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

Long-term outcomes for men with high-risk prostate cancer treated definitively with external beam radiotherapy with or without androgen deprivation.

BACKGROUND: Men with high-risk prostate cancer are often thought to have very poor outcomes in terms of disease control and survival even after definitive treatment. However, results after external beam radiotherapy have improved significantly through dose escalation and the use of androgen deprivation therapy (ADT). This report describes long-term findings after low-dose (< 75.6 Gy) or high-dose (≥ 75.6 Gy) external beam radiation, with or without ADT. METHODS: This analysis included 741 men with high-risk prostate cancer (clinical classification ≥ T3, Gleason score ≥ 8, or prostate-specific antigen level ≥ 20 ng/mL) treated with external beam radiotherapy at a single tertiary institution from 1987 through 2004. The radiation dose ranged from 60 to 79.3 Gy (median, 70 Gy); 295 men had received ADT for ≥ 2 years, and the median follow-up time was 8.3 years. RESULTS: The 5- and 10-year actuarial overall survival rates were significantly better for men treated with the higher radiation dose (no ADT plus ≥ 75.6 Gy, 87.3% and 72.0%, respectively; and ADT plus ≥ 75.6 Gy, 92.3% and 72%, respectively) (P = .0035). The corresponding 5- and 10-year biochemical failure-free survival rates were significantly better for patients treated with both ADT and higher radiation dose (82% and 77%, P < .0001). At 5 years, men who had not received ADT and had received radiation dose < 75.6 Gy had higher clinical local failure rates than those given ADT and radiation dose ≥ 75.6 Gy (24.2% versus 0%, P < .0001). The 10-year symptomatic local failure rate was only 2% for all patients. CONCLUSIONS: Contrary to lingering historical perceptions, treatment of high-risk prostate cancer with modern, high-dose, external beam radiotherapy and ADT can produce better biochemical, clinical, and survival outcomes over those from previous eras. Specifically, symptomatic local failure is uncommon, and few men die of prostate cancer even 10 or more years after treatment.

Androgen receptor agonism promotes an osteogenic gene program in preadipocytes.

Androgens regulate body composition by interacting with the androgen receptor (AR) to control gene expression in a tissue-specific manner. To identify novel regulatory roles for AR in preadipocytes, we created a 3T3-L1 cell line stably expressing human AR. We found AR expression is required for androgen-mediated inhibition of 3T3-L1 adipogenesis. This inhibition is characterized by decreased lipid accumulation, reduced expression of adipogenic genes, and induction of genes associated with osteoblast differentiation. Collectively, our results suggest androgens promote an osteogenic gene program at the expense of adipocyte differentiation.

Transgastric pancreatic necrosectomy: Tricks of the trade.

Necrotizing pancreatitis (NP) affects 20 % of the 300,000 patients diagnosed with acute pancreatitis every year. Mechanical intervention to debride necrotic and/or infected pancreatic and peripancreatic tissue is frequently required. Minimally invasive approaches to treat pancreatic necrosis have gained popularity over the last two decades, including transgastric pancreatic necrosectomy. The purpose of this report is to review the indications, surgical technique, advantages, and limitations of surgical transgastric necrosectomy.

The prevalence of Fusobacterium nucleatum subspecies in the oral cavity stratifies by local health status.

The ubiquitous inflammophilic pathobiont Fusobacterium nucleatum is widely recognized for its strong association with a variety of human dysbiotic diseases such as periodontitis and oral/extraoral abscesses, as well as multiple types of cancer. F. nucleatum is currently subdivided into four subspecies: F. nucleatum subspecies nucleatum (Fn. nucleatum), animalis (Fn. animalis), polymorphum (Fn. polymorphum), and vincentii/fusiforme (Fn. vincentii). Although these subspecies have been historically considered as functionally interchangeable in the oral cavity, direct clinical evidence is largely lacking for this assertion. Consequently, we assembled a collection of oral clinical specimens to determine whether F. nucleatum subspecies prevalence in the oral cavity stratifies by local oral health status. Patient-matched clinical specimens of both disease-free dental plaque and odontogenic abscess were analyzed with newly developed culture-dependent and culture-independent approaches using 44 and 60 oral biofilm/tooth abscess paired specimens, respectively. Most oral cavities were found to simultaneously harbor multiple F. nucleatum subspecies, with a greater diversity present within dental plaque compared to abscesses. In dental plaque, Fn. polymorphum is clearly the dominant organism, but this changes dramatically within odontogenic abscesses where Fn. animalis is heavily favored over all other fusobacteria. Surprisingly, the most commonly studied F. nucleatum subspecies, Fn. nucleatum, is only a minor constituent in the oral cavity. To gain further insights into the genetic basis for these phenotypes, we subsequently performed pangenome, phylogenetic, and functional enrichment analyses of oral fusobacterial genomes using the Anvi'o platform, which revealed significant genotypic distinctions among F. nucleatum subspecies. Accordingly, our results strongly support a taxonomic reassignment of each F. nucleatum subspecies into distinct Fusobacterium species. Of these, Fn. animalis should be considered as the most clinically relevant at sites of active inflammation, despite being among the least characterized oral fusobacteria.