Impact of time of day on outcomes after stereotactic radiosurgery for non-small cell lung cancer brain metastases.

BACKGROUND: This study tested the hypothesis that time of day of treatment with stereotactic radiosurgery (SRS) has an effect on local control (LC) and overall survival (OS) in a large cohort of patients with non-small cell lung cancer (NSCLC) brain metastases. METHODS: At Washington University in St. Louis, 437 patients with NSCLC were treated with SRS for NSCLC brain metastases. Receiver operating characteristics analysis was used to identify an optimal cut-point for OS relative to time of day. Kaplan-Meier log-rank statistics, and Cox regression univariate and multivariate analysis were employed to isolate any independent effect of treatment time on OS and LC. Matched-pair analysis was performed to isolate any independent effect of time on OS and LC of day while controlling for confounding variables. RESULTS: Receiver operating characteristics analysis identified a cut-point of 11:41 AM as providing the highest predictive value for OS. On univariate analysis, late SRS was associated with decreased OS, as was age, Karnofsky performance status, risk-stratification schemes, extracranial disease status, and overall burden of brain metastases. On univariate analysis for LC, late SRS was associated with decreased LC, as was burden of brain metastases. On multivariate analysis, only Graded Prognostic Assessment remained predictive of OS, and total number of targets and total tumor volume remained predictive of LC. Matched-pair analysis demonstrated no significant effect of time of day on LC or OS. CONCLUSIONS: Although earlier treatment appears to be associated with improved LC and OS, treatment time fails to remain significant when accounting for confounding variables.

Extreme Risk Protection Orders: Legislative Intent and Clinician Guidance.

In this second column of a 2-part series exploring extreme risk protections orders, we utilize recent events in Colorado, including legislative efforts to expand the list of eligible petitioners to include clinicians, as an opportunity to explore questions and challenges faced by mental health and medical professionals serving in this capacity. Clinicians are in need of more clear guidance, given an emerging role that comes without clear evidence or practice standards to inform individualized clinical decision-making, and which potentially pits public safety interests against patient care needs, especially those pertaining to therapeutic relationships. In the interim, clinicians will best serve their patients by continuing to practice in a fashion that is analogous to decision-making around other interventions with serious implications for patient autonomy such as involuntary hospitalization. Ongoing collaboration with legislators is needed to arrive at laws that are informed by the limitations inherent in clinical risk assessment and that can be translated into clinical practices that simultaneously support patient needs and community safety.

Oligodendrogliomas in children.

Oligodendrogliomas are rare central nervous system (CNS) tumors in children. The purpose of this study was to identify prognostic factors for progression free survival (PFS) and overall survival (OS) in pediatric patients with oligodendrogliomas. We retrospectively analyzed clinical data on 37 pediatric patients with oligodendroglial tumors treated at Washington University. Kaplan-Meier method was used to calculate survival rates. Log-rank was used to detect the difference between survival curves. The median age was 11.1 years (range 10 months-18 years), and median follow-up was 4.5 years (range 2 months-30.5 years). The 5-year PFS and OS were 66.4 and 93.4%, respectively. Mixed histology was associated with worse OS compared to patients with pure oligodendroglioma, 5-year OS 77.6 versus 100% (P < 0.01). Patients who underwent gross total resection (GTR) experienced an improved 5-year PFS of 100% compared to 28.8% (P = 0.03) in patients treated with subtotal resection (STR) or biopsy alone. Age >3 years at diagnosis correlated with improved 5-year PFS, 33.3 versus 69.8% (P = 0.01). Neither post-operative chemotherapy nor radiation therapy correlated with improved outcome. GTR and age >3 years at diagnosis remained significant for improved PFS on multivariate analysis. There were no factors correlated with improved overall survival on multivariate analysis. Pediatric oligodendroglial tumors are associated with excellent OS; however, a third of patients developed progressive disease. Our data demonstrate that patients with less than GTR and <3 years at diagnosis are at increased risk for progression and may benefit from more aggressive therapy.

A Radical New Approach for Mental Health Diversion.

The criminalization of mental illness is a national tragedy. Over the past three decades there have been numerous programs and initiatives designed to reduce the number of people with mental illness incarcerated in jails and prisons. Despite such efforts, incarceration rates have not fallen and have actually climbed in many jurisdictions. One major consequence of the criminalization of mental illness has been a large increase in referrals for evaluation for competency to stand trial and, consequently, in the need for competency restoration services. Many states have been unable to keep up with the demand for such services, causing patients to languish in jails with their criminal proceedings suspended, awaiting transfer to a state hospital. Expedited Diversion to Court-Ordered Treatment (EDCOT) is a new model for diversion that has great potential to drastically improve the diversion process, bypass the competency restoration system, and reduce the criminalization of mental illness. Successful implementation of EDCOT would result in more humane treatment of people with mental illness, without jeopardizing public safety; furthermore, it would pay for itself with the savings from reductions in the use of competency restoration services.

Assessing the Role of Cyberbiosecurity in Agriculture: A Case Study.

Agriculture has adopted the use of smart technology to help meet growing food demands. This increased automation and associated connectivity increases the risk of farms being targeted by cyber-attacks. Increasing frequency of cybersecurity breaches in many industries illustrates the need for securing our food supply chain. The uniqueness of biological data, the complexity of integration across the food and agricultural system, and the importance of this system to the U.S. bioeconomy and public welfare suggests an urgency as well as unique challenges that are not common across all industries. To identify and address the gaps in awareness and knowledge as well as encourage collaborations, Virginia Tech hosted a virtual workshop consisting of professionals from agriculture, cybersecurity, government, and academia. During the workshop, thought leaders and influencers discussed 1) common food and agricultural system challenges, scenarios, outcomes and risks to various sectors of the system; 2) cyberbiosecurity strategies for the system, gaps in workforce and training, and research and policy needs. The meeting sessions were transcribed and analyzed using qualitative methodology. The most common themes that emerged were challenges, solutions, viewpoints, common vocabulary. From the results of the analysis, it is evident that none of the participating groups had available cybersecurity training and resources. Participants were uncertain about future pathways for training, implementation, and outreach related to cyberbiosecurity. Recommendations include creating training and education, continued interdisciplinary collaboration, and recruiting government involvement to speed up better security practices related to cyberbiosecurity.

Health related quality of life and cognitive status in patients with glioblastoma multiforme receiving escalating doses of conformal three dimensional radiation on RTOG 98-03.

The Radiation Therapy Oncology Group (RTOG) embarked on a phase I/II study of patients suffering from glioblastoma multiforme (protocol 98-03) to assess the impact of dose escalation with 3-D conformal techniques. The primary endpoints were feasibility and survival. This report describes the outcome of secondary endpoints (quality of life and neurocognitive function). Patients with supratentorial GBM were treated with a combination of carmustine (BCNU) and conformal irradiation (dose levels: 66, 72, 78, 84 Gy, respectively). Quality of Life was assessed with the Spitzer Quality of Life Index. Neurocognitive function was determined by the Mini Mental Status Examination. The latter tests were administered at the start of irradiation, at the end of irradiation and then at 4 month intervals. Relatively high compliance was achieved with both of the tools (SQLI; MMSE). Overall rates of survival between baseline SQLI scores <7 and 7-10 were statistically significantly different [HR = 1.72, 95% CI (1.22, 2.4), P = 0.0015]. The significant impact of high SQLI score on survival was preserved in multivariate analysis. The component of this index which made the greatest contribution was the patient's independence. There was continual deterioration of neurocognitive function within the populations studied. No correlation was seen between dose escalation and the secondary endpoints studied. Radiation dose escalation and assessment of its impact on life quality and neurocognition can be carried out in a large international trial. Baseline SQLI is a statistically significant determinant of survival. Those who maintain independence have superior survival to those who are reliant on others.

Combined surgical resection and stereotactic radiosurgery for treatment of cerebral metastases.

BACKGROUND: Patients with limited intracranial metastatic disease traditionally have been treated with surgery followed by WBRT. However, there is growing concern for the debilitating cognitive effects after WBRT in long-term survivors. We present a series of patients treated with surgery followed by SRS, while reserving WBRT as a salvage therapy for disease progression. METHODS: Medical records from 15 patients with 1 to 2 cerebral metastases who underwent both resection and SRS were reviewed. Outcome measures included overall survival, survival by RPA class, EOR, local tumor control, progression of intracranial disease, need for WBRT salvage therapy, and COD. RESULTS: Fifteen patients with cerebral metastases were treated with the combined surgery-SRS paradigm. Eight of the 15 patients (53.3%) were designated RPA class 1, with 6 of 15 (40.0%) in class 2 and 1 of 15 (6.7%) in class 3. Gross total resection was achieved in 12 cases (80.0%). Overall median survival was 20.0 months, with values of 22.0 and 13.0 months for RPA classes 1 and 2, respectively. Local recurrence occurred in 16.7% of those patients with GTR. Six patients (40.0%) went on to receive WBRT at a median of 8.0 months from initial presentation. Twelve patients (80.0%) had died at the completion of the study, and the COD was CNS progression in 33.3%. CONCLUSIONS: Surgical resection combined with SRS is an effective treatment for selected patients with limited cerebral metastatic disease. Survival using this combined treatment was equivalent to or greater than that reported by other studies using surgery + WBRT or SRS + WBRT.

Time-of-flight magnetic resonance angiography imaging of a residual arteriovenous malformation nidus after Onyx embolization for stereotactic radiosurgery planning. Technical note.

This report demonstrates that time-of-flight (TOF) MR angiography is a useful adjunct for planning stereotactic radiosurgery (SRS) of large arteriovenous malformations (AVMs) after staged embolization with Onyx. Onyx (ethylene vinyl copolymer), a recently approved liquid embolic agent, has been increasingly used to exclude portions of large AVMs from the parent circulation prior to SRS. Limiting SRS to regions of persistent arteriovenous shunting and excluding regions eliminated by embolization may reduce unnecessary radiation doses to eloquent brain structures. However, SRS dosimetry planning presents unique challenges after Onyx embolization because it creates extensive artifacts on CT scans, and it cannot be delineated from untreated nidus on standard MR sequences. During the radiosurgery procedure, MR images were obtained using a GE Signa 1.5-T unit. Standard axial T2 fast spin echo high-resolution images (TR 3000 msec, TE 108 msec, slice thickness 2.5 mm) were generated for optimal visualization of brain tissue and AVM flow voids. The 3D TOF MR angiography images of the circle of Willis and vertebral arteries were subsequently obtained to visualize AVM regions embolized with Onyx (TR 37 msec, TE 6.9 msec, flip angle 20 degrees). Adjunct TOF MR angiography images demonstrated excellent contrast between nidus embolized with Onyx and regions of persistent arteriovenous shunting within a large AVM prior to SRS. Additional information derived from these sequences resulted in substantial adjustments to the treatment plan and an overall reduction in the treated tissue volume.

Electrically Conductive CNT Composites at Loadings below Theoretical Percolation Values.

It is well established that dramatic increases in conductivity occur upon the addition of conductive filler materials to highly resistive polymeric matrices in experimental settings. However, the mechanisms responsible for the observed behavior at low filler loadings, below theoretical percolation limits, of even high aspect ratio fillers such as carbon nanotubes (CNT) are not completely understood. In this study, conductive composites were fabricated using CNT bundles dispersed in epoxy resins at diverse loadings, using different dispersion and curing protocols. Based on electron microscopy observation of the CNTs strands distribution in the polymeric matrices and the corresponding electrical conductivities of those specimens, we concluded that no single electron transfer model can accurately explain the conductive behavior for all the loading values. We propose the existence of two different conductive mechanisms; one that exists close to the percolation limit, from 'low loadings' to higher CNT contents (CNT % wt > 0.1) and a second for 'extremely low loadings', near the percolation threshold (CNT % wt < 0.1). The high conductivity observed for composites at low CNT loading values can be explained by the existence of a percolative CNT network that coexists with micron size regions of non-conductive material. In contrast, samples with extremely low CNT loading values, which present no connectivity or close proximity between CNT bundles, show an electrical conductivity characterized by a current/voltage dependence. Data suggests that at these loadings, conduction may occur via a material breakdown mechanism, similar to dielectric breakdown in a capacitor. The lessons learned from the data gathered in here could guide future experimental research aimed to control the conductivity of CNT composites.

Functional MRI lie detection: too good to be true?

Neuroscientists are now applying a 21st-century tool to an age-old question: how can you tell when someone is lying? Relying on recently published research, two start-up companies have proposed to use a sophisticated brain-imaging technique, functional magnetic resonance imaging (fMRI), to detect deception. The new approach promises significantly greater accuracy than the conventional polygraph--at least under carefully controlled laboratory conditions. But would it work in the real world? Despite some significant concerns about validity and reliability, fMRI lie detection may in fact be appropriate for certain applications. This new ability to peer inside someone's head raises significant questions of ethics. Commentators have already begun to weigh in on many of these questions. A wider dialogue within the medical, neuroscientific, and legal communities would be optimal in promoting the responsible use of this technology and preventing abuses.

Real-World Effectiveness of Chemotherapy in Elderly Patients With Metastatic Bladder Cancer in the United States.

BACKGROUND: Outcomes for patients with metastatic bladder cancer (mBC) are generally poor and progressively worse following first-line (1L) chemotherapy. OBJECTIVE: To evaluate treatment patterns, survival outcomes, and characteristics of a large, real-world US population of elderly patients with advanced mBC receiving 1L and second-line (2L) treatment retrospectively. METHODS: We identified patients with advanced mBC (aged ≥66 years)-newly diagnosed between January 1, 2004, and December 31, 2011-in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program-Medicare linked database and assessed their palliative systemic chemotherapy treatments and survival outcomes. RESULTS: Of 1703 eligible patients, 42% received 1L chemotherapy; 1L-treated patients tended to be younger and healthier than nontreated patients. Only 27% of 1L-treated patients received cisplatin-based chemotherapy, most commonly cisplatin-gemcitabine. Cisplatin-treated patients were younger and had fewer comorbidities than non-cisplatin-treated patients. Thirty-five percent of 1L-treated patients subsequently received 2L chemotherapy. Patients received a variety of 2L agents as combination chemotherapy (52%) or single-agent chemotherapy (39%). Median overall survival durations in 1L-treated and 2L-treated patients were 8.5 and 7.9 months, respectively. CONCLUSIONS: Results from this retrospective SEER-Medicare database analysis underscore the historical inadequacies of 1L and 2L treatments in elderly patients with advanced mBC. Few patients were treated with 1L chemotherapy, a minority of whom received 1L cisplatin-based chemotherapy, and even fewer received 2L chemotherapy. These findings highlight the disconnect between 1L treatment in clinical trials and treatment in the real-world setting and the lack of standard approaches to 2L treatment in the United States.

Bad risk? An overview of laws prohibiting possession of firearms by individuals with a history of treatment for mental illness.

For nearly 40 years, federal law has barred certain individuals with a history of mental health treatment from purchasing, receiving, or possessing firearms. State laws are a patchwork of different regulations, some much more inclusive than the federal statute, others that parallel it closely. In some states, such laws are nonexistent. For the past 20 years, it has been possible to petition for relief from the federal prohibition; however, this is not the case with all state laws. The mechanisms for relief under state laws, when present, vary significantly, and not all require the input of a mental health professional or even of any physician. This article provides an overview of federal and state laws, a discussion of implications of these laws for mental health clinicians and forensic practitioners, and suggestions of directions for future research.

Management of T3N1 glottic carcinoma: therapeutic outcomes.

OBJECTIVE: The aim of the current study was to determine the best total laryngectomy (TL) approach to the treatment of T3N1 glottic cancer, to study the impact of early nodal disease on stage III glottic cancers, and to describe the preliminary results in a group of patients recently treated for laryngeal preservation (LP). METHODS: A retrospective study of Tumor Research Project data were performed on previously untreated patients with T3N1 glottic squamous cell carcinoma who were treated with curative intent by TL and neck dissection (ND) with or without adjuvant radiation therapy (TL +/- RT) from April 1, 1955 to October 8, 1999 at Washington University School of Medicine/Barnes Jewish Hospital. A preliminary analysis of a similar group of patients more recently treated for LP (1-1-2000 to 1-1-2005) is reported. RESULTS: Forty-two patients with T3N1 glottic carcinoma were treated with TL and ND (TL/ND-16) and TL with ND and TL (TL/ND/RT-26). The 5 year observed survival (OS) and disease-specific survival (DSS) for TL/ND were similar at 62.5%. The 5 year OS and DSS for TL/ND/RT were 53.8% and 58.3%, respectively. There was no survival difference between the two methods. The overall local-regional control rate was 73.9% (11/42 recurrences). The overall recurrence rate was 38%, with 7.1% recurrence at both the primary site and neck. Recurrence was not related to treatment method. The overall salvage rate (5 year DSS after retreatment) was 20% with 50% salvage for patients with neck recurrence. No patients with local recurrence were survivors. The incidence of second primary cancers was 6.8%. More recently, 26 similar patients were treated with LP techniques. Preliminary results showed a 3 year OS of 63.5% and DSS of 76.8%. Local-regional control was 85.4%. LP was 88.5%. CONCLUSIONS: The two TL modalities had statistically similar results in terms of survival, recurrence, and complications. Decreased DSS was seen in older patients (>65 years) and in patients with involved resection margins, recurrent disease, and distant metastasis. Patients with T3N1 glottic cancer had an 8% decrease in DSS compared to patients with T3N0 disease. Previously patients with T3N1 disease have been treated with TL resulting in loss of natural voice in all patients. Preliminary results on 26 patients with T3N1 disease, treated between 2000 and 2005 with voice preservation intent, indicate that the OS, DSS, and local-regional control rates were similar to the TL group, whereas 88.5% of patients maintained natural voice and natural breathing. Use of LP techniques should be the initial therapeutic approach for patients with T3N1 glottic cancer.

When Restoration Fails: One State's Answer to the Dilemma of Permanent Incompetence.

The landmark 1972 U.S. Supreme Court decision in Jackson v. Indiana prohibited the indefinite commitment of criminal defendants on grounds of incompetence to stand trial if there was no substantial probability of restoration to competency in the foreseeable future. Such defendants are still subject to ordinary civil commitment; however, not all will meet civil commitment criteria, given that the criteria for a finding of incompetency to stand trial do not map directly onto the general criteria for involuntary psychiatric hospitalization. If a person charged with a serious crime, such as murder, has no substantial probability of being restored to competency, but does not meet standard civil commitment criteria, compliance with Jackson would seem to require release into the community. This article describes a legislative response to this possibility that became law in California four decades ago, as well as the outcome of its main legal challenge a few years later. Although the law has received harsh criticism from some quarters, it has survived, and provides a legally straightforward, if ethically controversial, means of answering the question of what to do with a permanently incompetent defendant who is charged with a serious violent offense and does not meet traditional civil commitment criteria.

Radiation Therapy for Residual or Recurrent Atypical Meningioma: The Effects of Modality, Timing, and Tumor Pathology on Long-Term Outcomes.

BACKGROUND: Optimal use of stereotactic radiosurgery (SRS) vs external beam radiation therapy (EBRT) for treatment of residual/recurrent atypical meningioma is unclear. OBJECTIVE: To analyze features associated with progression after radiation therapy. METHODS: Fifty radiation-naive patients who received SRS or EBRT for residual and/or recurrent atypical meningioma were examined for predictors of progression using Cox regression and Kaplan-Meier analyses. RESULTS: Thirty-two patients (64%) received adjuvant radiation after subtotal resection, 12 patients (24%) received salvage radiation after progression following subtotal resection, and 6 patients (12%) received salvage radiation after recurrence following gross total resection. Twenty-one patients (42%) received SRS (median 18 Gy), and 7 (33%) had tumor progression. Twenty-nine patients (58%) received EBRT (median 54 Gy), and 13 (45%) had tumor progression. Whereas tumor volume (P = .53), SRS vs EBRT (P = .45), and adjuvant vs salvage (P = .34) were not associated with progression after radiation therapy, spontaneous necrosis (hazard ratio [HR] = 82.3, P < .001), embolization necrosis (HR = 15.6, P = .03), and brain invasion (HR = 3.8, P = .008) predicted progression in univariate and multivariate analyses. Tumors treated with SRS/EBRT had 2- and 5-year actuarial locoregional control rates of 91%/88% and 71%/69%, respectively. Tumors with spontaneous necrosis, embolization necrosis, and no necrosis had 2- and 5-year locoregional control rates of 76%, 92%, and 100% and 36%, 73%, and 100%, respectively (P < .001). CONCLUSION: This study suggests that necrosis may be a negative predictor of radiation response regardless of radiation timing or modality. ABBREVIATIONS: AM, atypical meningiomaEBRT, external beam radiation therapyGTR, gross total resectionLC, locoregional controlOS, overall survivalPOE, preoperative embolizationRT, radiation therapySRS, stereotactic radiosurgerySTR, subtotal resection.

Dose distribution outside of a sphere of P-32 chromic phosphorous colloid.

PURPOSE: To evaluate the dose distribution outside of a cyst instilled with phosphorous-32 (P-32, an electron emitter with a short effective range of 2-8 mm and average energy of 0.69 MeV, used to treat cystic craniopharyngioma) as a function of cyst size with and without plating (migration and adhesion of P-32 to the cyst surface). METHODS AND MATERIALS: A cystic craniopharyngioma treated with instillation of P-32 was approximated by a sphere of uniformly distributed and plated chromic P-32 colloid. The percent depth dose was calculated along a radial position vector exterior to the sphere with a three-dimensional convolution integral and a dose point kernel. RESULTS: The percent depth dose variation of surface or volume source external to a family of spheres was plotted. Complex cyst geometry is amenable to evaluation by approximation with simple spheres. Error estimates are calculated for the dose outside of truncated sphere segments. Plating might occur and raise the dose outside the cyst by more than a factor of 5.0. This has the potential to cause damage to adjacent tissues, including the optic chiasm. CONCLUSION: Clinicians are faced with a number of treatment options for cystic craniopharyngioma, including intracystic instillation of colloid P-32. Unfortunately, plating might occur and potentially damage adjacent normal tissues. It is recommended that the propensity for a craniopharyngioma to plate be evaluated before full treatment, especially after previous treatment.

Postoperative radiation therapy for grade II and III intracranial ependymoma.

PURPOSE: To retrospectively determine the long-term outcome of intracranial ependymoma patients treated with surgery and postoperative radiation therapy. METHODS AND MATERIALS: Sixty patients were treated at our institution between 1964 and 2000. Forty patients had World Health Organization Grade II ependymoma, and 20 patients had Grade III ependymoma. The median patient age was 10.7 years. The majority of patients were male (55%), had infratentorial tumors (80%), and had subtotal resections (72%). Postoperative radiation therapy was delivered to all patients to a median total dose of 50.4 Gy. Craniospinal radiation therapy was used in the earlier era in only 12 patients (20%). RESULTS: The median follow-up of surviving patients was 12.5 years. The 5-year and 10-year disease-free survival rates for all patients were 58.4% and 49.5%, respectively. The 5-year and 10-year overall survival rates for all patients were 71.2% and 55.0%, respectively. Supratentorial tumor location was independently associated with a worse disease-free survival. Subtotal resection and supratentorial location predicted a worse overall survival, but this failed to reach statistical significance. No statistically significant effect on prognosis was observed with tumor grade, patient age, or radiation dose or volume. CONCLUSION: Our long-term follow-up indicates that half of ependymoma patients will have disease recurrences, indicating the need for more effective treatments.