Estimated Prostate Volume by Semiautomatic Segmentation of MRI Is More Accurately Correlated with Radical Prostatectomy Specimen Weight than the Volume Calculated by Ellipsoid Formula.

INTRODUCTION: Accurate in vivo prostate volume (PV) estimation is important for obtaining prostate-specific antigen density (PSAD) and further predicting clinically significant prostate cancer (csPCa). We aimed to evaluate the accuracy of multiparametric magnetic resonance imaging (mpMRI)-estimated PV compared to both volume and weight of radical prostatectomy (RP). METHODS: We identified 310 PCa patients who underwent RP following combined targeted and systematic biopsy in our institution from September 2019 to February 2021. The MRI PV was determined using a semiautomated segmentation algorithm. RP PV was calculated using the prolate ellipsoid formula (length × width × height × π/6). Formula (prostate weight = [actual weight-3.8 g]/1.05 g/mL) was applied, and the resulting volume was used in further analysis. RESULTS: The median PV from MRI, RP, and RP weight were 39 mL, 38 mL, and 44 mL, respectively. Spearman's rank correlation coefficients (ρ) were 0.841 (MRI PV vs. RP weight), 0.758 (RP PV vs. RP weight), and 0.707 (MRI PV vs. RP PV) (all p < 0.001). Decreased correlation between the MRI PV and RP PV was observed in the larger (more than 55 mL) prostate. The PSAD derived from MRI PV showed most efficient to detect csPCa in RP specimen (57.9% vs. 57.6% vs. 45.4%). CONCLUSION: MRI PV is correlated better with RP weight than calculated RP PV, especially in larger prostate. The high csPCa detection rate in final pathology suggested that PSAD derived from MRI PV can be confidently used in clinical practice.

A framework for standardised tissue sampling and processing during resection of diffuse intracranial glioma: joint recommendations from four RANO groups.

Surgical resection represents the standard of care for people with newly diagnosed diffuse gliomas, and the neuropathological and molecular profile of the resected tissue guides clinical management and forms the basis for research. The Response Assessment in Neuro-Oncology (RANO) consortium is an international, multidisciplinary effort that aims to standardise research practice in neuro-oncology. These recommendations represent a multidisciplinary consensus from the four RANO groups: RANO resect, RANO recurrent glioblastoma, RANO radiotherapy, and RANO/PET for a standardised workflow to achieve a representative tumour evaluation in a disease characterised by intratumoural heterogeneity, including recommendations on which tumour regions should be surgically sampled, how to define those regions on the basis of preoperative imaging, and the optimal sample volume. Practical recommendations for tissue sampling are given for people with low-grade and high-grade gliomas, as well as for people with newly diagnosed and recurrent disease. Sampling of liquid biopsies is also addressed. A standardised workflow for subsequent handling of the resected tissue is proposed to avoid information loss due to decreasing tissue quality or insufficient clinical information. The recommendations offer a framework for prospective biobanking studies.

Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial.

BACKGROUND: High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma. METHODS: In this dose-finding, first-in-human trial, treatment-naive adults aged 18-75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992. FINDINGS: Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1). INTERPRETATION: The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial. FUNDING: Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Early vs Delayed Transurethral Surgery in Acute Urinary Retention: Does Timing Make a Difference?

PURPOSE: Our goal was to compare outcomes of early vs delayed transurethral surgery for benign prostatic hyperplasia after an episode of acute urinary retention compared to men without preoperative acute retention. MATERIALS AND METHODS: We conducted a retrospective cohort analysis using data from the New York Statewide Planning and Research Cooperative System from 2002-2016. We identified men ≥40 years old who underwent primary ambulatory transurethral resection or photoselective vaporization of the prostate, assessing surgical failure as time to reoperation or recatheterization. We categorized presurgical acute urinary retention by number of episodes: none (reference), 1, or ≥2 precatheterizations, and time from first retention episode to surgery: none (reference), 0-6 months, and >6 months. We used Fine-Gray competing-risk models to predict surgical failure at 10 years, with presurgical acute retention as the primary predictor, adjusted for age, race, insurance, Charlson Comorbidity Index score, preoperative urinary infection, and procedure type, with death as the competing risk. RESULTS: Among 17,474 patients undergoing transurethral surgery, 10% had preoperative acute retention with a median time to surgery of 2.4 months (IQR: 1-18). Among men with preoperative retention, 37% had ≥6 months of delay to surgery. The 10-year cumulative treatment failure rate was 17.2% among catheter naïve men vs 34.0% with ≥2 precatheterizations and 32.9% with ≥6 months delay to surgery. Delays from catheterization to surgery were associated with higher rates of treatment failure (<6 months SHR 1.49, P < .001; ≥6 months SHR 2.11, P < .001) vs catheter naïve men. CONCLUSIONS: Preoperative acute urinary retention and delay to surgery once catheterized are associated with poorer long-term postoperative outcomes after surgery for benign prostatic hyperplasia.

Transperineal Multiparametric Magnetic Resonance Imaging-Ultrasound Fusion Targeted Prostate Biopsy Combined with Standard Template Improves Prostate Cancer Detection.

PURPOSE: Transperineal (TP) prostate biopsy provides an effective approach to prostate cancer (PCa) detection. Although transrectal targeted biopsy has been well described, the specific advantage of the standard TP template or TP targeted biopsy using multiparametric (mp) magnetic resonance imaging (MRI)-ultrasound (US) fusion remains less understood and without consensus. MATERIALS AND METHODS: We identified all men who underwent a transperineal standard 20-core template in addition to a targeted biopsy with mpMRI-US fusion-guided software from September 2019 to February 2021. We assessed and compared clinical, MRI and biopsy characteristics between standard TP template and fusion targeted biopsies. RESULTS: A total of 301 men underwent TP fusion biopsy during the study period. Target lesions on MRI were sampled with 3 targeted cores per patient (IQR 3-4). The overall cancer detection rate was 74.1% and 63.5% by standard template and targeted biopsy, respectively, of which 52.5% and 59.7% were clinically significant (cs) PCa. Combined csPCa detection rate was 62.2%. Of 176 cases with a cancer diagnosis by both biopsy methods, 18.8% were upgraded with targeted biopsies while 18.2% were upgraded with template biopsies. CONCLUSIONS: In men with suspicious lesions on mpMRI, TP MRI fusion-guided biopsies combined with standard template provide a higher overall cancer detection rate and higher detection rate of csPCa than the standard template or targeted biopsy alone. In the setting of a suspicious mpMRI prostate lesion, targeted plus standard template should be included as part of the TP biopsy procedure.

Ear-piercing complications in children and adolescents.

QUESTION: Ear piercing is one of the most common forms of body modification seen in children and adolescents presenting to my office. Parents of my younger pediatric patients inquire about potential post-piercing complications and risk factors associated with earlobe infections. What guidance should I give them? Also, are there any specific post-piercing complications to consider for older pediatric patients seeking second piercings in the upper cartilage area? ANSWER: Piercing the earlobe or auricular cartilage continues to be a popular procedure among children and adolescents. Despite its widespread practice, improper aseptic piercing technique, insufficient training, and trauma to the soft tissue during high-pressure piercing (eg, use of spring-loaded ear-piercing instruments) can increase one's susceptibility to infections, bleeding, and microfractures. Other post-piercing complications include embedded earrings, keloids, hypertrophic scarring, and cutaneous hypersensitivity. Early recognition and treatment of infections and perichondritis secondary to transcartilaginous piercings can prevent the progression of severe ear deformities requiring reconstructive surgical interventions.

A Claims Based Assessment of Reoperation and Acute Urinary Retention after Ambulatory Transurethral Surgery for Benign Prostatic Hyperplasia.

PURPOSE: We evaluated real-world use of common transurethral prostate procedures in the ambulatory surgical setting and compare subsequent rates of tr!eatment failure. MATERIALS AND METHODS: Using the New York Statewide Planning and Research Cooperative System database we identified men 40 years old or older undergoing ambulatory surgeries categorized as transurethral resection of the prostate, photoselective vaporization of the prostate, endoscopic enucleation or other (transurethral incision, microwave/radiofrequency ablation) from 2010 to 2016. Multivariate Cox proportional hazards regression was used to predict treatment failure, defined as reoperation or postoperative acute urinary retention greater than 30 days after procedure. RESULTS: We identified 15,982 men, median age 69 years (IQR 63-76), 61% of whom underwent photoselective vaporization of the prostate, 36% transurethral resection of the prostate, 1.5% endoscopic enucleation and 1.5% other transurethral prostate procedures from 2010 to 2016. At 7 years cumulative failure rates were 15.3% (transurethral resection of the prostate), 13.9% (photoselective vaporization of the prostate), 6.7% (endoscopic enucleation) and 17.8% (other procedures). Compared to transurethral resection of the prostate, photoselective vaporization of the prostate was not associated with increased hazards of treatment failure HR 1.07 (95% CI 0.93-1.22). Compared to transurethral resection of the prostate, endoscopic enucleation was associated with a nonsignificant trend toward lower treatment failure (HR 0.67, 95% CI 0.36-1.22), while other surgical modalities were associated with significantly higher treatment failure (HR 1.68. 95% CI 1.12-2.52). Among men treated from 2011 to 2012, endoscopic enucleations were associated with significantly lower failure than transurethral resection of the prostate (HR: 0.24, 95% CI 0.06-0.97). CONCLUSIONS: Supporting the generalizability of previous randomized trial findings, in real-world practice we found no differences in treatment failure up to 7 years after photoselective vaporization of the prostate or transurethral resection of the prostate. By comparison, endoscopic enucleation, although underused, may be associated with lower rates of treatment failure than transurethral resection of the prostate.

Post-COVID-19 multisystem inflammatory syndrome in children.

QUESTION: The effect of acute coronavirus disease 2019 (COVID-19) on morbidity and mortality in children has been relatively small. If a child presents to my office with persistent fever and systemic hyperinflammation but no known exposure to COVID-19, how likely are they to have multisystem inflammatory syndrome in children (MIS-C)? What is currently known about MIS-C and what is the prognosis for children affected by it? ANSWER: Amid the COVID-19 pandemic, the emergence of a novel condition presents yet another challenge to clinicians, public health professionals, and the pediatric population. Multisystem inflammatory syndrome in children is a rare but potentially severe condition seen in children with evidence of COVID-19 approximately 2 to 6 weeks before symptom onset. Common signs and symptoms include persistent fever, systemic hyperinflammation, gastrointestinal symptoms (eg, abdominal pain, vomiting, diarrhea), mucocutaneous changes (eg, rash, conjunctivitis), headache, or cardiac dysfunction. As many children present as asymptomatic or with mild symptoms of COVID-19, the development of MIS-C can seem sudden and surprising to families and providers. Although children with MIS-C usually require hospitalization, the outcomes are largely favourable with prompt recognition and intense therapy.

Le syndrome inflammatoire multisystémique post-COVID-19 chez les enfants.

QUESTION: Les répercussions de la maladie au coronavirus 2019 (COVID-19) sur la morbidité et la mortalité chez les enfants se sont révélées relativement faibles. Si un enfant se présente à ma clinique avec une fièvre persistante et une hyperinflammation systémique sans aucune exposition connue à la COVID-19, quelle est la probabilité qu'il soit atteint du syndrome inflammatoire multisystémique de l'enfant (MIS-C)? Que sait-on actuellement du MIS-C et quel est le pronostic pour les enfants qui en souffrent? RÉPONSE: En plein cœur de la pandémie de la COVID-19, l'émergence d'un nouveau problème présente encore une fois un défi additionnel aux cliniciens, aux professionnels de la santé publique et à la population pédiatrique. Le syndrome inflammatoire multisystémique chez les enfants est rare, mais potentiellement grave, et il a été observé chez des enfants dont la maladie à la COVID-19 a été confirmée environ 2 à 6 semaines avant l'apparition des symptômes. Au nombre des signes et des symptômes courants figurent une fièvre persistante, une hyperinflammation systémique, des malaises gastro-intestinaux (p. ex. douleurs abdominales, vomissements, diarrhée), des changements mucocutanés (p. ex. éruptions cutanées, conjonctivite), une céphalée ou une dysfonction cardiaque. Étant donné que de nombreux enfants sont asymptomatiques ou ne présentent que des symptômes légers de la COVID-19, le développement du MIS-C peut sembler soudain et surprenant aux familles et aux médecins. Même si les enfants atteints du MIS-C nécessitent habituellement une hospitalisation, les issues sont largement favorables grâce à une reconnaissance rapide du syndrome et à une thérapie intense.

Outcomes in Patients Treated with Laser Interstitial Thermal Therapy for Primary Brain Cancer and Brain Metastases.

Laser interstitial thermal therapy (LITT) is an emerging modality to treat benign and malignant brain lesions. LITT is a minimally invasive method to ablate tissue using laser-induced tissue heating and serves as both a diagnostic and therapeutic modality for progressive brain lesions. We completed a single-center retrospective analysis of all patients with progressive brain lesions treated with LITT since its introduction at our center in August of 2015. Twelve patients have been treated for a total of 13 procedures, of which 10 patients had brain metastases and 2 patients had primary malignant gliomas. Biopsies were obtained immediately prior to laser-induced tissue heating in 10 procedures (76.9%), of which seven biopsies showed treatment-related changes without viable tumor. After laser ablation, two of three patients previously on steroids were successfully weaned on first attempt. The results of this analysis indicate that LITT is a well-tolerated procedure enabling some patients to discontinue steroids that may be effective for diagnosing and treating radiation necrosis and tumor progression.

Dose-intensified chemoradiation is associated with altered patterns of failure and favorable survival in patients with newly diagnosed glioblastoma.

BACKGROUND AND PURPOSE: We evaluated whether dose-intensified chemoradiation alters patterns of failure and is associated with favorable survival in the temozolomide era. MATERIALS AND METHODS: Between 2003 and 2015, 82 patients with newly diagnosed glioblastoma were treated with 66-81 Gy in 30 fractions using conventional magnetic resonance imaging. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan-Meier methods. Factors associated with improved PFS, OS, and time to progression were assessed using multivariate Cox model and linear regression. RESULTS: Median follow-up was 23 months (95% CI 4-124 months). Sixty-one percent of patients underwent subtotal resection or biopsy, and 38% (10/26) of patients with available data had MGMT promoter methylation. Median PFS was 8.4 months (95% CI 7.3-11.0) and OS was 18.7 months (95% CI 13.1-25.3). Only 30 patients (44%) experienced central recurrence, 6 (9%) in-field, 16 (23.5%) marginal and 16 (23.5%) distant. On multivariate analysis, younger age (HR 0.95, 95% CI 0.93-0.97, p = 0.0001), higher performance status (HR 0.39, 95% CI 0.16-0.95, p = 0.04), gross total resection (GTR) versus biopsy (HR 0.37, 95% CI 0.16-0.85, p = 0.02) and MGMT methylation (HR 0.25, 95% CI 0.09-0.71, p = 0.009) were associated with improved OS. Only distant versus central recurrence (p = 0.03) and GTR (p = 0.02) were associated with longer time to progression. Late grade 3 neurologic toxicity was rare (6%) in patients experiencing long-term survival. CONCLUSION: Dose-escalated chemoRT resulted in lower rates of central recurrence and prolonged time to progression compared to historical controls, although a significant number of central recurrences were still observed. Advanced imaging and correlative molecular studies may enable targeted treatment advances that reduce rates of in- and out-of-field progression.

NRG brain tumor specialists consensus guidelines for glioblastoma contouring.

INTRODUCTION: NRG protocols for glioblastoma allow for clinical target volume (CTV) reductions at natural barriers; however, literature examining CTV contouring and the relevant white matter pathways is lacking. This study proposes consensus CTV guidelines, with a focus on areas of controversy while highlighting common errors in glioblastoma target delineation. METHODS: Ten academic radiation oncologists specializing in brain tumor treatment contoured CTVs on four glioblastoma cases. CTV expansions were based on NRG trial guidelines. Contour consensus was assessed and summarized by kappa statistics. A meeting was held to discuss the mathematically averaged contours and form consensus contours and recommendations. RESULTS: Contours of the cavity plus enhancement (mean kappa 0.69) and T2-FLAIR signal (mean kappa 0.74) showed moderate to substantial agreement. Experts were asked to trim off anatomic barriers while respecting pathways of spread to develop their CTVs. Submitted CTV_4600 (mean kappa 0.80) and CTV_6000 (mean kappa 0.81) contours showed substantial to near perfect agreement. Simultaneous truth and performance level estimation (STAPLE) contours were then reviewed and modified by group consensus. Anatomic trimming reduced the amount of total brain tissue planned for radiation targeting by a 13.6% (range 8.7-17.9%) mean proportional reduction. Areas for close scrutiny of target delineation were described, with accompanying recommendations. CONCLUSIONS: Consensus contouring guidelines were established based on expert contours. Careful delineation of anatomic pathways and barriers to spread can spare radiation to uninvolved tissue without compromising target coverage. Further study is necessary to accurately define optimal target volumes beyond isometric expansion techniques for individual patients.

The Association of Serum Testosterone Levels and Urinary Incontinence in Women.

PURPOSE: Pelvic floor integrity is an important predictor of stress urinary incontinence. Androgen receptors have been found in the pelvic floor musculature and fascia, and testosterone administration has been shown to increase levator ani hypertrophy and improve stress incontinence in a rodent model. We examined the relationship between serum total testosterone levels and self-reported urinary incontinence in women. MATERIALS AND METHODS: We included women older than 20 years in the 2012 NHANES (National Health and Nutrition Examination Survey) cycle who underwent serum total testosterone measurement and answered self-reported urinary incontinence questions. A weighted, multivariate logistic regression model was used to determine the association between incontinence and serum testosterone levels after adjusting for age, body mass index, diabetes, race, parity, menopause and time of venipuncture. RESULTS: A total of 2,321 women were included in analysis, of whom 37.5% had stress incontinence, 29.8% had urge incontinence and 16.4% had mixed incontinence. Women in the lowest quartile of serum testosterone were more likely to complain of stress and mixed incontinence (OR 1.45, 95% CI 1.03-2.12 and OR 1.68, 95% CI 1.23-2.22, respectively). No association was noted between serum testosterone levels and urge incontinence. CONCLUSIONS: Low serum testosterone is associated with an increased likelihood of stress and mixed incontinence in women. Given the role of pelvic musculature in maintaining urethral support and the anabolic effect of androgens on skeletal muscle, a physiological mechanism for this relationship can be proposed and further evaluated in prospective and translational studies.

Standard dose and dose-escalated radiation therapy are associated with favorable survival in select elderly patients with newly diagnosed glioblastoma.

We hypothesized elderly patients with good Karnofsky Performance Status (KPS) treated with standard dose or dose-escalated radiation therapy (SDRT/DERT) and concurrent temozolomide (TMZ) would have favorable overall survival (OS) compared to historical elderly patients treated with hypofractionated RT (HFRT). From 2004 to 2015, 66 patients age ≥ 60 with newly diagnosed, pathologically proven glioblastoma were treated with SDRT/DERT over 30 fractions with concurrent/adjuvant TMZ at a single institution. Kaplan-Meier methods and the log-rank test were used to assess OS and progression-free survival (PFS). Multivariate analysis (MVA) was performed using Cox Proportional-Hazards. Median follow-up was 12.6 months. Doses ranged from 60 to 81 Gy (median 66). Median KPS was 90 (range 60-100) and median age was 67 years (range 60-81), with 29 patients ≥ 70 years old. 32% underwent gross total resection (GTR). MGMT status was known in 28%, 42% of whom were methylated. Median PFS was 8.3 months (95% CI 6.9-11.0) and OS was 12.7 months (95% CI 9.7-14.1). Patients age ≥ 70 with KPS ≥ 90 had a median OS of 12.4 months. Median OS was 27.1 months for MGMT methylated patients. On MVA controlling for age, dose, KPS, MGMT, GTR, and adjuvant TMZ, younger age (HR 0.9, 95% CI 0.8-0.9, p < 0.01), MGMT methylation (HR:0.2, 95% CI 0.1-0.7, p = 0.01), and GTR (HR:0.5, 95% CI 0.3-0.9, p = 0.01) were associated with improved OS. Our findings do not support routine use of a standard 6-week course of radiation therapy in elderly patients with glioblastoma. However, a select group of elderly patients with excellent performance status and MGMT methylation or GTR may experience favorable survival with a standard 6-week course of treatment.

Early initiation of chemoradiation following index craniotomy is associated with decreased survival in high-grade glioma.

The Stupp protocol of post-resection external beam radiation therapy and concomitant temozolomide is the standard of care for patients with newly-diagnosed glioblastoma, with expanded use in anaplastic astrocytoma. However, the optimal interval between surgery and these adjuvant therapies, and its impact on survival, is unknown. To investigate this, de-identified claims from a large, private health insurance database were queried to identify adult patients who underwent index craniotomy for resection of a supratentorial neoplasm during the period 2005-2014 and began postoperative radiation and temozolomide within 13 weeks of surgery. A total of 2535 patients were assigned to groups based on interval from surgery to first radiation treatment of up to 4 weeks, 4-6 weeks, or 6-13 weeks. Of these, 1098 patients began radiation treatment within 4 weeks of craniotomy, 1019 between 4 and 6 weeks, and 418 between 6 and 13 weeks. There was significant regional variation in treatment schedule in the United States. Survival was calculated based on time from first craniotomy to death. Kaplan-Meier plot and multivariate Cox proportional hazard regression demonstrated a statistically significant association between earliest postoperative radiation and decreased survival (hazard ratio 1.31), along with older age and male sex. Earlier initiation of postoperative radiation for high-grade glioma is not associated with increased survival. Rather, beginning radiation treatment within 4 weeks of craniotomy was associated with significantly worse survival compared to initiation of treatment 4-13 weeks after craniotomy. This is the largest population-based study to date regarding timing of Stupp protocol initiation.

Anatomic and functional imaging in the diagnosis of spine metastases and response assessment after spine radiosurgery.

Spine stereotactic radiosurgery (SSRS) has recently emerged as an increasingly effective treatment for spinal metastases. Studies performed over the past decade have examined the role of imaging in the diagnosis of metastases, as well as treatment response following SSRS. In this paper, the authors describe and review the utility of several imaging modalities in the diagnosis of spinal metastases and monitoring of their response to SSRS. Specifically, we review the role of CT, MRI, and positron emission tomography (PET) in their ability to differentiate between osteoblastic and osteolytic lesions, delineation of initial bony pathology, detection of treatment-related changes in bone density and vertebral compression fracture after SSRS, and tumor response to therapy. Validated consensus guidelines defining the imaging approach to SSRS are needed to standardize the diagnosis and treatment response assessment after SSRS. Future directions of spinal imaging, including advances in targeted tumor-specific molecular imaging markers demonstrate early promise for advancing the role of imaging in SSRS.

Voiding Dysfunction in Multiple Sclerosis.

Voiding dysfunction is a common and debilitating consequence of multiple sclerosis (MS). The prevalence and severity of voiding dysfunction increases with the increasing severity of MS, but even the mildest forms of the disease are associated with urinary symptoms in 30% of patients. Every component of the central nervous system is involved in regulating voiding; as a result, MS can lead to a wide variety of urinary symptoms and urologic complications. The effect of MS on voiding can be classified according to the resulting function of the bladder and the urethral sphincter during storage and emptying of urine. Therapy is targeted to the specific bladder and sphincter abnormalities that occur. The primary goals of therapy are prevention of injury to the upper urinary tract (kidneys), reduction in urinary tract infections, and maintenance of urinary continence. These goals can be achieved by interventions ranging from behavioral modification to major reconstructive surgery.

Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study.

BACKGROUND: Epigenetic alterations have been strongly associated with tumour formation and resistance to chemotherapeutic drugs, and epigenetic modifications are an attractive target in cancer research. RRx-001 is activated by hypoxia and induces the generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation. The aim of this phase 1 study was to assess the safety, tolerability, and pharmacokinetics of RRx-001. METHODS: In this open-label, dose-escalation, phase 1 study, we recruited adult patients (aged >18 years) with histologically or cytologically confirmed diagnosis of advanced, malignant, incurable solid tumours from University of California at San Diego, CA, USA, and Sarah Cannon Research Institute, Nashville, TN, USA. Key eligibility criteria included evaluable disease, Eastern Cooperative Group performance status of 2 or less, an estimated life expectancy of at least 12 weeks, adequate laboratory parameters, discontinuation of all previous antineoplastic therapies at least 6 weeks before intervention, and no residual side-effects from previous therapies. Patients were assigned to receive intravenous infusions of RRx-001 at increasing doses (10 mg/m(2), 16·7 mg/m(2), 24·6 mg/m(2), 33 mg/m(2), 55 mg/m(2), and 83 mg/m(2)) either once or twice-weekly for at least 4 weeks, with at least three patients per dose cohort and allowing a 2-week observation period before dose escalation. Samples for safety and pharmacokinetics analysis, including standard chemistry and haematological panels, were taken on each treatment day. The primary objective was to assess safety, tolerability, and dose-limiting toxic effects of RRx-001, to determine single-dose pharmacokinetics, and to identify a recommended dose for phase 2 trials. All analyses were done per protocol. Accrual is complete and follow-up is still on-going. This trial is registered with ClinicalTrials.gov, number NCT01359982. FINDINGS: Between Oct 10, 2011, and March 18, 2013, we enrolled 25 patients and treated six patients in the 10 mg/m(2) cohort, three patients in the 16·7 mg/m(2) cohort, three patients in the 24·6 mg/m(2) cohort, four patients in the 33 mg/m(2) cohort, three patients in the 55 mg/m(2), and six patients in the 83 mg/m(2) cohort. Pain at the injection site, mostly grade 1 and grade 2, was the most common adverse event related to treatment, experienced by 21 (84%) patients. Other common drug-related adverse events included arm swelling or oedema (eight [32%] patients), and vein hardening (seven [28%] patients). No dose-limiting toxicities were observed. Time constraints related to management of infusion pain from RRx-001 resulted in a maximally feasible dose of 83 mg/m(2). Of the 21 evaluable patients, one (5%) patient had a partial response, 14 (67%) patients had stable disease, and six (29%) patients had progressive disease; all responses were across a variety of tumour types. Four patients who had received RRx-001 were subsequently rechallenged with a treatment that they had become refractory to; all four responded to the rechallenge. INTERPRETATION: RRx-001 is a well-tolerated novel compound without clinically significant toxic effects at the tested doses. Preliminary evidence of activity is promising and, on the basis of all findings, a dose of 16·7 mg/m(2) was recommended as the targeted dose for phase 2 trials. FUNDING: EpicentRx (formerly RadioRx).