Radiation necrosis or tumor progression? A review of the radiographic modalities used in the diagnosis of cerebral radiation necrosis.

PURPOSE: Cerebral radiation necrosis is a complication of radiation therapy that can be seen months to years following radiation treatment. Differentiating radiation necrosis from tumor progression on standard magnetic resonance imaging (MRI) is often difficult and advanced imaging techniques may be needed to make an accurate diagnosis. The purpose of this article is to review the imaging modalities used in differentiating radiation necrosis from tumor progression following radiation therapy for brain metastases. METHODS: We performed a review of the literature addressing the radiographic modalities used in the diagnosis of radiation necrosis. RESULTS: Differentiating radiation necrosis from tumor progression remains a diagnostic challenge and advanced imaging modalities are often required to make a definitive diagnosis. If diagnostic uncertainty remains following conventional imaging, a multi-modality diagnostic approach with perfusion MRI, magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single photon emission spectroscopy (SPECT), and radiomics may be used to improve diagnosis. CONCLUSION: Several imaging modalities exist to aid in the diagnosis of radiation necrosis. Future studies developing advanced imaging techniques are needed.

Use of human tissue stem cell-derived organoid cultures to model enterohepatic circulation.

The use of human tissue stem cell-derived organoids has advanced our knowledge of human physiological and pathophysiological processes that are unable to be studied using other model systems. Increased understanding of human epithelial tissues including intestine, stomach, liver, pancreas, lung, and brain have been achieved using organoids. However, it is not yet clear whether these cultures recapitulate in vivo organ-to-organ signaling or communication. In this work, we demonstrate that mature stem cell-derived intestinal and liver organoid cultures each express functional molecules that modulate bile acid uptake and recycling. These organoid cultures can be physically coupled in a Transwell system and display increased secretion of fibroblast growth factor 19 (FGF19) (intestine) and downregulation of P450 enzyme cholesterol 7 α-hydroxylase (CYP7A) (liver) in response to apical exposure of the intestine to bile acids. This work establishes that organoid cultures can be used to study and therapeutically modulate interorgan interactions and advance the development of personalized approaches to medical care.NEW & NOTEWORTHY Interorgan signaling is a critical feature of human biology and physiology, yet has remained difficult to study due to the lack of in vitro models. Here, we demonstrate that physical coupling of ex vivo human intestine and liver epithelial organoid cultures recapitulates in vivo interorgan bile acid signaling. These results suggest that coupling of multiple organoid systems provides new models to investigate interorgan communication and advances our knowledge of human physiological and pathophysiological processes.

Postoperative Management of Salivary Gland Tumors.

OPINION STATEMENT: Salivary gland tumors represent a heterogeneous group of neoplasms characterized by varied histologies and disease outcomes. Initial treatment for the primary and gross nodal disease is usually surgery. Management of the clinically node-negative neck depends upon the risk of lymph nodal involvement. This is usually determined by the AJCC "T" stage and histology. Both surgery and radiation may be utilized to address the lymph nodes at risk. This is especially important for minor salivary gland tumors. Radiation plays an important role in the adjuvant management of salivary gland tumors by reducing the risk of locoregional recurrence. Certain histologies like adenoid cystic carcinoma have a predilection for neurotropic spread to the skull base. Radiation is particularly important in controlling disease at the skull base. The role of concurrent chemotherapy in the adjuvant treatment of salivary gland tumors is not established and remains an area of active research. Certain histologies like salivary duct carcinoma exhibit readily identifiable molecular targets amenable to targeted therapy. Finally, advanced testing of these tumors using next-generation sequencing can also potentially identify molecular targets amenable to therapy. While useful in the management of metastatic disease, the role of these therapies in the adjuvant setting remains unknown.

Current Landscape and Future Directions on Bladder Sparing Approaches to Muscle-Invasive Bladder Cancer.

OPINION STATEMENT: Although radical cystectomy is considered the gold standard approach for patients with muscle-invasive bladder cancer, tri-modal therapy (TMT) is a well-tolerated and efficacious alternative to radical cystectomy that is underutilized in inoperable patients and rarely offered to cystectomy candidates in the USA. Retrospective data suggest similar outcomes between radical cystectomy and TMT after adjusting for patient selection and other confounding factors. Nearly 70-80% of patients can keep their native bladder with favorable post-treatment quality of life metrics. Current trials are investigating novel combination strategies including immune checkpoint inhibition along with chemoradiation or radiation. Emerging techniques for improved patient selection and risk stratification include incorporating MP-MRI, and novel biomarkers such as inflammatory, stromal, and DNA damage response gene signatures may guide patient selection and expand the landscape of bladder preservation options available to patients in the future.

Treatment Options in Oligometastatic Disease in Prostate Cancer: Thinking Outside the Box.

OPINION STATEMENT: Due to its relatively indolent disease course, the sensitivity of PSA testing, and the emergence of novel PET imaging, metastatic prostate cancer is particularly likely to present with a limited volume of disease. Patients with up to five metastatic lesions should be considered for an oligometastatic treatment approach. Systemic therapy remains the cornerstone of treatment for these patients. The optimal type and duration are unknown; however, the addition of a second agent to ADT appears to be beneficial. Multiple recent studies have found significant benefits to the integration of systemic therapy and local metastasis-directed therapies (MDT), including radiation and surgery, to the prostate and metastatic sites. MDT may also be used in select patients wishing to delay the initiation of systemic therapy. For patients with isolated regional nodal recurrences, whole pelvic radiotherapy or extensive lymphadenectomy is preferred, in combination with ADT.

Locoregional and distant recurrence for HPV-associated oropharyngeal cancer using AJCC 8 staging.

INTRODUCTION: The objective of this study is to evaluate locoregional and distant failure for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) using American Joint Committee on Cancer eighth edition (AJCC 8) staging. MATERIALS AND METHODS: Retrospective cohort study of 457 patients with HPV + OPSCC, treated with platinum-based chemoradiation from 2002 to 2018, followed for a median of 4.3 years. Time to locoregional failure (TTLRF) and distant failure (TTDF) were estimated by Kaplan-Meier method. Log-rank, recursive partitioning analysis (RPA), and multivariable Cox proportional hazards were used to evaluate associated factors and stratify risk. RESULTS: Rates of five-year locoregional control (LRC) and distant control (DC) were 92% (95% CI, 90-95%) and 89% (95% CI, 85-92%), respectively. Smoking, T4, N3, and stage III were associated with significantly worse TTLRF. RPA identified three distinct locoregional failure groups: cT1-3 and <19 pack-years vs. cT1-3 with ≥19 pack-years vs. cT4 (five-year LRC: 97% vs. 90% vs. 82%, P < .0001). The only factor associated with significantly worse TTDF was smoking status, while stage was not correlated. RPA identified two prognostic groups: former or never smokers vs. current smokers (five-year DC: 92% vs. 77%, P = .0003). DISCUSSION: In the largest evaluation of HPV + OPSCC after platinum-based chemoradiation using AJCC 8, risk for locoregional recurrence was stratified by smoking, T category, N category, and overall stage. Risk of distant recurrence was only stratified by smoking status and not related to stage. This has implications for surveillance and clinical trial design.

Rethinking the 10-pack-year rule for favorable human papillomavirus-associated oropharynx carcinoma: A multi-institution analysis.

BACKGROUND: De-intensified treatment strategies for early human papillomavirus-positive (HPV+) oropharynx cancer (OPC) rely on selecting patients with an excellent prognosis. The criterion for enrollment in current de-intensification trials is ≤10 pack-years. More nuance to the pack-year criteria may expand enrollment, improve patient outcomes, and prevent overtreatment. It was hypothesized that patients with more than 10 pack-years may experience favorable outcomes if smoking cessation has been achieved. METHODS: From an institutional review board-approved database, patients with HPV+ oropharyngeal squamous carcinoma treated definitively with radiation with or without chemotherapy were retrospectively identified. Patients with a history of smoking who were eligible for national de-intensification trials were included (cT1-2N1-2b or T3N0-2b [American Joint Committee on Cancer, seventh edition]). Cox regression with penalized smoothing splines was used to evaluate nonlinear effects of cessation. Recursive partitioning analysis (RPA) was used to objectively search for relationships between the 2 colinear variables (pack-years and time since cessation). RESULTS: Among 330 patients meeting the inclusion criteria, 130 (40%) were never smokers, 139 (42%) were former smokers, and 61 (18%) were current smokers. With standard therapy, all former smokers achieved a progression-free survival (PFS) rate higher than 91%, regardless of pack-year exposure. Nonlinear Cox regression demonstrated that more recent cessation was associated with significantly worse PFS even among those with ≤20 pack-years. RPA demonstrated that only current smokers experienced a 2-year PFS rate lower than 91%; former smokers, regardless of pack-years, experienced a 2-year PFS rate higher than 91%. CONCLUSIONS: The 10-pack-year rule may not apply to all early HPV+ OPCs, particularly for former smokers. Future randomized de-intensification trials should consider a broader and more nuanced approach until the predictive role of smoking status is established.

Bladder-sparing treatment of nonmetastatic muscle-invasive bladder cancer.

Bladder-sparing therapies for the treatment of nonmetastatic muscle-invasive bladder cancers are included in both American and European guidelines. Numerous treatment approaches have been described, including partial cystectomy, radiation monotherapy, and radical transurethral resection. However, the most oncologically favorable and well-studied regimen employs a multimodal approach that consists of maximal transurethral resection of the bladder tumor followed by concurrent radiosensitizing chemotherapy and radiotherapy. This sequence, referred to as trimodal therapy (TMT), has been evaluated with robust retrospective comparative studies and prospective series, although a randomized trial comparing TMT with radical cystectomy has not been performed. Despite promising reports of 5-year overall survival rates of 50% to 70% in well-selected patients, relatively few patients qualify as ideal candidates for TMT. Specifically, contemporary series exclude patients who have clinical stage T3 disease, multifocal tumors, coexisting carcinoma in situ, or hydronephrosis. Herein, we review all forms of bladder-preserving therapies with an emphasis on TMT, highlighting the rationale of each component, survival outcomes, and future directions.

COPII Vesicle Transport Is Required for Rotavirus NSP4 Interaction with the Autophagy Protein LC3 II and Trafficking to Viroplasms.

Many viruses that replicate in the cytoplasm dramatically remodel and stimulate the accumulation of host cell membranes for efficient replication by poorly understood mechanisms. For rotavirus, a critical step in virion assembly requires the accumulation of membranes adjacent to virus replication centers called viroplasms. Early electron microscopy studies describe viroplasm-associated membranes as "swollen" endoplasmic reticulum (ER). We previously demonstrated that rotavirus infection initiates cellular autophagy and that membranes containing the autophagy marker protein LC3 and the rotavirus ER-synthesized transmembrane glycoprotein NSP4 traffic to viroplasms, suggesting that NSP4 must exit the ER. This study aimed to address the mechanism of NSP4 exit from the ER and determine whether the viroplasm-associated membranes are ER derived. We report that (i) NSP4 exits the ER in COPII vesicles, resulting in disrupted COPII vesicle transport and ER exit sites; (ii) COPII vesicles are hijacked by LC3 II, which interacts with NSP4; and (iii) NSP4/LC3 II-containing membranes accumulate adjacent to viroplasms. In addition, the ER transmembrane proteins SERCA and calnexin were not detected in viroplasm-associated membranes, providing evidence that the rotavirus maturation process of "budding" occurs through autophagy-hijacked COPII vesicle membranes. These findings reveal a new mechanism for rotavirus maturation dependent on intracellular host protein transport and autophagy for the accumulation of membranes required for virus replication.IMPORTANCE In a morphogenic step that is exceedingly rare for nonenveloped viruses, immature rotavirus particles assemble in replication centers called viroplasms, and bud through cytoplasmic cellular membranes to acquire the outer capsid proteins for infectious particle assembly. Historically, the intracellular membranes used for particle budding were thought to be endoplasmic reticulum (ER) because the rotavirus nonstructural protein NSP4, which interacts with the immature particles to trigger budding, is synthesized as an ER transmembrane protein. This present study shows that NSP4 exits the ER in COPII vesicles and that the NSP4-containing COPII vesicles are hijacked by the cellular autophagy machinery, which mediates the trafficking of NSP4 to viroplasms. Changing the paradigm for rotavirus maturation, we propose that the cellular membranes required for immature rotavirus particle budding are not an extension of the ER but are COPII-derived autophagy isolation membranes.

Human Norovirus Cultivation in Nontransformed Stem Cell-Derived Human Intestinal Enteroid Cultures: Success and Challenges.

Noroviruses, in the genus Norovirus, are a significant cause of viral gastroenteritis in humans and animals. For almost 50 years, the lack of a cultivation system for human noroviruses (HuNoVs) was a major barrier to understanding virus biology and the development of effective antiviral strategies. This review presents a historical perspective of the development of a cultivation system for HuNoVs in human intestinal epithelial cell cultures. Successful cultivation was based on the discovery of genetically-encoded host factors required for infection, knowledge of the site of infection in humans, and advances in the cultivation of human intestinal epithelial cells achieved by developmental and stem cell biologists. The human stem cell-derived enteroid cultivation system recapitulates the multicellular, physiologically active human intestinal epithelium, and allows studies of virus-specific replication requirements, evaluation of human host-pathogen interactions, and supports the pre-clinical assessment of methods to prevent and treat HuNoV infections.

Patient-reported sexual quality of life after different types of radical prostatectomy and radiotherapy: Analysis of a population-based prospective cohort.

BACKGROUND: Although patients with prostate cancer face many treatment options, to the authors' knowledge the comparative effects of different surgical and radiotherapy (RT) options on sexual function are unclear. METHODS: In the current study, a population-based cohort of 835 men with newly diagnosed prostate cancer from 2011 through 2013 was recruited throughout North Carolina in collaboration with the Rapid Case Ascertainment system of the North Carolina Central Cancer Registry. All men were enrolled prior to treatment and followed prospectively using the validated Prostate Cancer Symptom Indices (PCSI) instrument. This analysis compares the sexual dysfunction scores of the PCSI among patients who received external-beam RT (EBRT), EBRT with androgen deprivation therapy (ADT), brachytherapy, nerve-sparing radical prostatectomy (RP), and non-nerve-sparing RP. Propensity scores were used to balance patient characteristics across groups, and multiple imputation was used for missing data. RESULTS: EBRT and brachytherapy resulted in similar PCSI scores through 24 months. Compared with those receiving EBRT, patients treated with EBRT with ADT and RP with or without nerve sparing were found to have worse PCSI scores at all posttreatment time points. Preservation of useful sexual function at 24 months was associated with treatment type, baseline score, and age. Predicted preservation rates were 14.1% to 70.7% for EBRT, 8.4% to 52.3% for EBRT with ADT, 4.7% to 45.3% for nerve-sparing RP, and 4.8% to 34.5% for non-nerve-sparing RP. CONCLUSIONS: The findings of the current study indicate that RT alone results in the best preservation of sexual function, and brachytherapy provides similar outcomes. RT with ADT and nerve-sparing RP yielded similar outcomes, whereas patients treated with non-nerve-sparing RP experienced the worst sexual function. These results help patients to make decisions among the specific types of surgery and RT they face based on each individual's diagnosis.

Risk Factors for Progression Among Low-Grade Gliomas After Gross Total Resection and Initial Observation in the Molecular Era.

PURPOSE: To identify risk factors for progression-free survival (PFS) in the molecular era among patients with low-grade glioma (LGG) who undergo gross total resection (GTR) followed by initial observation. METHODS AND MATERIALS: We reviewed patients with World Health Organization grade 2 LGG treated at a single institution. We included only those who underwent magnetic resonance imaging (MRI)-confirmed GTR followed by initial observation. Molecular classification was obtained at either the time of diagnosis or pathology review. Cox proportional hazards regression, the Kaplan-Meier method, and the log-rank test were used. P values <.05 were considered statistically significant. RESULTS: We included 144 patients who underwent MRI-confirmed GTR between 1994 and 2014 followed by initial observation. Median age was 29 years (interquartile range [IQR], 18-41), median tumor size was 2.7 cm (IQR, 1.8-4.0), and median follow-up was 81 months (IQR, 36-132). Molecular classification was 13% IDH-mutant 1p19q-codeleted; 21% IDH-mutant 1p19q-intact; 39% IDH1-R132H-wildtype; and 28% undetermined. For the entire cohort, 5- and 10-year PFS and overall survival were 71% and 53%, and 98% and 90%, respectively. On multivariate analysis, factors associated with worse PFS included increasing age at diagnosis (hazard ratio [HR], 1.05; 95% CI, 1.00-1.09; P = .03), increasing preoperative tumor size (HR, 1.07; 95% CI, 1.04-1.10; P < .0001), and IDH-mutant 1p19q-intact classification (HR, 3.18; 95% CI, 1.15-8.74, P = .025). Median PFS for patients with IDH-mutant 1p19q-codeleted, IDH-mutant 1p19q-intact, and IDH1-R132H-wildtype tumors were 113 months, 56 months, and not reached, respectively. Molecular classification was significantly associated with PFS (P < .0001) but not overall survival (P = .20). CONCLUSIONS: Among patients with LGG who undergo MRI-confirmed GTR and initial observation in the molecular era, increasing age, increasing tumor size, and IDH-mutant 1p19q-intact classification are associated with worse PFS. Because tumor progression is associated with adverse health-related quality of life, these factors may aid clinicians and patients in the shared decision-making process regarding goals of surgery and timing of postoperative therapy. Further study is required to elucidate why IDH-mutant 1p19q-intact LGGs are at higher risk for early progression.

Patient-reported Quality of Life Following Stereotactic Body Radiotherapy and Conventionally Fractionated External Beam Radiotherapy Compared with Active Surveillance Among Men with Localized Prostate Cancer.

BACKGROUND: Evidence supporting the efficacy of stereotactic body radiotherapy (SBRT) for localized prostate cancer is accumulating, but comparative studies of patient-reported quality of life (QOL) following SBRT versus conventionally fractionated external beam radiotherapy (EBRT) or active surveillance (AS) are limited. OBJECTIVE: To compare QOL of patients pursuing SBRT and EBRT versus AS. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort of 680 men with newly diagnosed localized prostate cancer was prospectively enrolled from 2011 to 2013. INTERVENTION: SBRT, EBRT without androgen deprivation therapy, or AS. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: QOL was prospectively assessed before treatment (baseline), and at 3, 12, and 24mo after treatment using the validated Prostate Cancer Symptom Indices, which contain four domains: sexual dysfunction, urinary obstruction/irritation, urinary incontinence, and bowel problems. Propensity weighting via logistic regression models was used to balance baseline characteristics, and the mean QOL scores of EBRT and SBRT patients were compared against AS patients as the control group. RESULTS AND LIMITATIONS: Compared with AS patients, EBRT patients had worse urinary obstructive/irritative symptoms and sexual dysfunction at 3mo, and worse bowel symptoms at 3 and 24mo. SBRT patients had similar scores as AS patients in all domains and across all time points; however, due to small sample size, worse sexual function and urinary incontinence in SBRT patients cannot be ruled out. Further research is needed to assess long-term outcomes. CONCLUSIONS: In a nonrandomized cohort of men with localized prostate cancer, SBRT appeared to result in favorable QOL results through 2yr of follow-up, but worse sexual function and urinary incontinence compared with AS cannot be ruled out completely. Larger studies with longer follow-up are needed to confirm these findings. PATIENT SUMMARY: Stereotactic body radiotherapy (SBRT) and active surveillance appear to have similar quality of life outcomes through 2yr, although worse sexual function and urinary incontinence from SBRT cannot be ruled out completely.

Prostate Cancer Patient Characteristics Associated With a Strong Preference to Preserve Sexual Function and Receipt of Active Surveillance.

Background: Men with early-stage prostate cancer have multiple options that have similar oncologic efficacy but vary in terms of their impact on quality of life. In low-risk cancer, active surveillance is the option that best preserves patients' sexual function, but it is unknown if patient preference affects treatment selection. Our objectives were to identify patient characteristics associated with a strong preference to preserve sexual function and to determine whether patient preference and baseline sexual function level are associated with receipt of active surveillance in low-risk cancer. Methods: In this population-based cohort of men with localized prostate cancer, baseline patient-reported sexual function was assessed using a validated instrument. Patients were also asked whether preservation of sexual function was very, somewhat, or not important. Prostate cancer disease characteristics and treatments received were abstracted from medical records. A modified Poisson regression model with robust standard errors was used to compute adjusted risk ratio (aRR) estimates. All statistical tests were two-sided. Results: Among 1194 men, 52.6% indicated a strong preference for preserving sexual function. Older men were less likely to have a strong preference (aRR = 0.98 per year, 95% confidence interval [CI] = 0.97 to 0.99), while men with normal sexual function were more likely (vs poor function, aRR = 1.59, 95% CI = 1.39 to 1.82). Among 568 men with low-risk cancer, there was no clear association between baseline sexual function or strong preference to preserve function with receipt of active surveillance. However, strong preference may differnetially impact those with intermediate baseline function vs poor function (Pinteraction = .02). Conclusions: Treatment choice may not always align with patients' preferences. These findings demonstrate opportunities to improve delivery of patient-centered care in early prostate cancer.

Gastrointestinal microphysiological systems.

Gastrointestinal diseases are a significant health care and economic burden. Prevention and treatment of these diseases have been limited by the available human biologic models. Microphysiological systems comprise organ-specific human cultures that recapitulate many structural, biological, and functional properties of the organ in smaller scale including aspects of flow, shear stress and chemical gradients. The development of intestinal microphysiological system platforms represents a critical component in improving our understanding, prevention, and treatment of gastrointestinal diseases. This minireview discusses: shortcomings of classical cell culture models of the gastrointestinal tract; human intestinal enteroids as a new model and their advantages compared to cell lines; why intestinal microphysiological systems are needed; potential functional uses of intestinal microphysiological systems in areas of drug development and modeling acute and chronic diseases; and current challenges in the development of intestinal microphysiological systems. Impact statement The development of a gastrointestinal MPS has the potential to facilitate the understanding of GI physiology. An ultimate goal is the integration of the intestinal MPS with other organ MPS. The development and characterization of nontransformed human intestinal cultures for use in MPS have progressed significantly since the inception of the MPS program in 2012, and these cultures are a key component of advancing MPS. Continued efforts are needed to optimize MPS to comprehensively and accurately recapitulate the complexity of the intestinal epithelium within intestinal tissue. These systems will need to include peristalsis, flow, and oxygen gradients, with incorporation of vascular, immune, and nerve cells. Regional cellular organization of crypt and villus areas will also be necessary to better model complete intestinal structure.

Association Between Choice of Radical Prostatectomy, External Beam Radiotherapy, Brachytherapy, or Active Surveillance and Patient-Reported Quality of Life Among Men With Localized Prostate Cancer.

Importance: Patients diagnosed with localized prostate cancer have to decide among treatment strategies that may differ in their likelihood of adverse effects. Objective: To compare quality of life (QOL) after radical prostatectomy, external beam radiotherapy, and brachytherapy vs active surveillance. Design, Setting, and Participants: Population-based prospective cohort of 1141 men (57% participation among eligible men) with newly diagnosed prostate cancer were enrolled from January 2011 through June 2013 in collaboration with the North Carolina Central Cancer Registry. Median time from diagnosis to enrollment was 5 weeks, and all men were enrolled with written informed consent prior to treatment. Final follow-up date for current analysis was September 9, 2015. Exposures: Treatment with radical prostatectomy, external beam radiotherapy, brachytherapy, or active surveillance. Main Outcomes and Measures: Quality of life using the validated instrument Prostate Cancer Symptom Indices was assessed at baseline (pretreatment) and 3, 12, and 24 months after treatment. The instrument contains 4 domains-sexual dysfunction, urinary obstruction and irritation, urinary incontinence, and bowel problems-each scored from 0 (no dysfunction) to 100 (maximum dysfunction). Propensity-weighted mean domain scores were compared between each treatment group vs active surveillance at each time point. Results: Of 1141 enrolled men, 314 pursued active surveillance (27.5%), 469 radical prostatectomy (41.1%), 249 external beam radiotherapy (21.8%), and 109 brachytherapy (9.6%). After propensity weighting, median age was 66 to 67 years across groups, and 77% to 80% of participants were white. Across groups, propensity-weighted mean baseline scores were 41.8 to 46.4 for sexual dysfunction, 20.8 to 22.8 for urinary obstruction and irritation, 9.7 to 10.5 for urinary incontinence, and 5.7 to 6.1 for bowel problems. Compared with active surveillance, mean sexual dysfunction scores worsened by 3 months for patients who received radical prostatectomy (36.2 [95% CI, 30.4-42.0]), external beam radiotherapy (13.9 [95% CI, 6.7-21.2]), and brachytherapy (17.1 [95% CI, 7.8-26.6]). Compared with active surveillance at 3 months, worsened urinary incontinence was associated with radical prostatectomy (33.6 [95% CI, 27.8-39.2]); acute worsening of urinary obstruction and irritation with external beam radiotherapy (11.7 [95% CI, 8.7-14.8]) and brachytherapy (20.5 [95% CI, 15.1-25.9]); and worsened bowel symptoms with external beam radiotherapy (4.9 [95% CI, 2.4-7.4]). By 24 months, mean scores between treatment groups vs active surveillance were not significantly different in most domains. Conclusions and Relevance: In this cohort of men with localized prostate cancer, each treatment strategy was associated with distinct patterns of adverse effects over 2 years. These findings can be used to promote treatment decisions that incorporate individual preferences.

Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle.

Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.

Management of Node-Positive and Oligometastatic Prostate Cancer.

Historically, stage IV prostate cancer was considered incurable. Although node-positive and oligometastatic prostate cancers are both classified as stage IV, these likely represent distinct clinical groups, and some patients may be curable with aggressive multimodality treatments. There is a lack of randomized evidence, but retrospective studies suggest that radical prostatectomy or radiotherapy may improve survival in these patients. This is an area of great current research interest and prospective randomized trials are needed to help define the optimal treatments for these patients.