A phase III, multicenter, randomized controlled trial of preoperative versus postoperative stereotactic radiosurgery for patients with surgically resectable brain metastases.

BACKGROUND: Postoperative stereotactic radiosurgery (SRS) is a standard management option for patients with resected brain metastases. Preoperative SRS may have certain advantages compared to postoperative SRS, including less uncertainty in delineation of the intact tumor compared to the postoperative resection cavity, reduced rate of leptomeningeal dissemination postoperatively, and a lower risk of radiation necrosis. The recently published ASCO-SNO-ASTRO consensus statement provides no recommendation for the preferred sequencing of radiotherapy and surgery for patients receiving both treatments for their brain metastases. METHODS: This multicenter, randomized controlled trial aims to recruit 88 patients with resectable brain metastases over an estimated three-year period. Patients with ten or fewer brain metastases with at least one resectable, fulfilling inclusion criteria will be randomized to postoperative SRS (standard arm) or preoperative SRS (investigational arm) in a 1:1 ratio. Randomization will be stratified by age (< 60 versus ≥60 years), histology (melanoma/renal cell carcinoma/sarcoma versus other), and number of metastases (one versus 2-10). In the standard arm, postoperative SRS will be delivered within 3 weeks of surgery, and all unresected metastases will receive primary SRS. In the investigational arm, enrolled patients will receive SRS of all brain metastases followed by surgery of resectable metastases within one week of SRS. In either arm, single fraction or hypofractionated SRS in three or five fractions is permitted. The primary endpoint is to assess local control at 12 months in both arms. Secondary endpoints include local control at other time points, regional/distant brain recurrence rates, leptomeningeal recurrence rates, overall survival, neurocognitive outcomes, and adverse radiation events including radiation necrosis rates in both arms. DISCUSSION: This trial addresses the unanswered question of the optimal sequencing of surgery and SRS in the management of patients with resectable brain metastases. No randomized data comparing preoperative and postoperative SRS for patients with brain metastases has been published to date. TRIAL REGISTRATION: Clinicaltrials.gov , NCT04474925; registered on July 17, 2020. Protocol version 1.0 (January 31, 2020). SPONSOR: Alberta Health Services, Edmonton, Canada (Samir Patel, MD).

Atypical Meningioma: Referral Patterns, Treatment and Adherence to Guidelines.

OBJECTIVE: To determine the referral rate to radiation oncologist (RO), use of postoperative radiotherapy (PORT) and the impact of a clinical practice guideline (CPG) on patients with atypical meningioma (AM). METHODS: A retrospective review of meningioma patients (n=526) treated between 2003 and 2013 was undertaken. Patients' characteristics, extent of surgical resection (EOR), RO referral, PORT, date and treatment of first recurrence were collected for all patients >18 years with a new diagnosis of AM after surgical resection (n=83). Progression free survival (PFS) and overall survival (OS) according to EOR were assessed by the Log-Rank test of Kaplan-Meier survival. RESULTS: Median age was 57 years. EOR was gross total (GTR) in 44 patients, subtotal (STR) in 36 patients and 3 patients had unknown EOR. RO referral rate was 26.5% (n=22); 5 patients initially had GTR and 17 had STR. Only 7 patients received PORT. At a median follow up time of 29 months, recurrences occurred in 28 patients, 4 had GTR, 21 had STR and 3 had an unknown EOR. With PORT, 2 patients developed recurrence. 5-year PFS was 62% after GTR and 33% after STR (P=0.002). 5-year OS was 92% after GTR and 83% after STR (P=0.45). CONCLUSION: In this cohort with AM, RO referral rate was low and was not influenced by the CPG. Use of PORT was also low. Given the lack of conclusive evidence supporting PORT in such patients, a multidisciplinary approach, including RO consultation, is needed to provide patients with optimal and individualised care.

Population based analysis ependymoma patients in Alberta from 1975 to 2007.

BACKGROUND: Ependymomas are rare tumors of the central nervous system whose management is controversial. This population-based study of adults and children with ependymoma aims to (1) identify clinical and treatment-related factors that impact survival and (2) determine if postoperative radiotherapy (RT) can improve survival of patients with subtotal resection (STR) to levels similar to patients who had gross total resection (GTR). METHODS: This retrospective population-based study evaluated 158 patients with ependymoma diagnosed between 1975-2007 in Alberta, Canada. RESULTS: Younger patients (<7 years of age) were more likely to be diagnosed with grade III tumors compared with adults in whom grade I tumors were more common (p=0.003). Adults were more likely to have spinally located tumors compared to young children whose tumors were typically found in the brain. Overall, young children with ependymoma were more likely to die than older children or adults (p=0.001). An equivalent number of patients underwent GTR as compared with STR (48% vs 45%, respectively). Overall, older age, spinal tumor location, lower grade, and GTR were associated with improved progression free survival but only GTR was associated with significant improvement in overall survival. Median survival after STR and RT was 82 months compared with 122 months in patients who had GTR (p=0.0022). CONCLUSIONS: This is the first Canadian population-based analysis of patients with ependymoma including adults and children. Extent of resection appears to be the most important factor determining overall survival. Importantly, the addition of RT to patients initially treated with STR does not improve survival to levels similar to patients receiving GTR.

Stereotactic Radiotherapy for Oligoprogression in Metastatic Renal Cell Cancer Patients Receiving Tyrosine Kinase Inhibitor Therapy: A Phase 2 Prospective Multicenter Study.

BACKGROUND: Despite the paucity of prospective evidence, stereotactic radiotherapy (SRT) is increasingly being considered in the setting of oligoprogression to delay the need to change systemic therapy. OBJECTIVE: To determine the local control (LC), progression-free survival (PFS), cumulative incidence of changing systemic therapy, and overall survival (OS) after SRT to oligoprogressive metastatic renal cell carcinoma (mRCC) lesions in patients who are on tyrosine kinase inhibitor (TKI) therapy. DESIGN, SETTING, AND PARTICIPANTS: A prospective multicenter study was performed to evaluate the use of SRT in oligoprogressive mRCC patients. Patients with mRCC who had previous stability or response after ≥3 mo of TKI therapy were eligible if they developed progression of five of fewer metastases. Thirty-seven patients with 57 oligoprogressive tumors were enrolled. INTERVENTION: Oligoprogressive tumors were treated with SRT, and the same TKI therapy was continued afterward. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Competing risk analyses and the Kaplan-Meir methodology were used to report the outcomes of interest. RESULTS AND LIMITATIONS: The median duration of TKI therapy prior to study entry was 18.6 mo; 1-yr LC of the irradiated tumors was 93% (95% confidence interval [CI] 71-98%). The median PFS after SRT was 9.3 mo (95% CI 7.5-15.7 mo). The cumulative incidence of changing systemic therapy was 47% (95% CI 32-68%) at 1 yr, with a median time to change in systemic therapy of 12.6 mo (95% CI 9.6-17.4 mo). One-year OS was 92% (95% CI 82-100%). There were no grade 3-5 SRT-related toxicities. CONCLUSIONS: LC of irradiated oligoprogressive mRCC tumors was high, and the need to change systemic therapy was delayed for a median of >1 yr. PATIENT SUMMARY: The use of stereotactic radiotherapy in metastatic kidney cancer patients, who develop growth of a few tumors while on oral targeted therapy, can significantly delay the need to change to the next line of drug therapy.

The tethered infinitesimal tori and spheres algorithm: a versatile calculator for axisymmetric problems in equilibrium membrane mechanics.

Constrained minimization of energy functionals is a central part, and usually the difficult part, of solving problems in the equilibrium mechanics of biological and biomimetic membranes. The inherent difficulties of the conventional variational-calculus approach prevents the numerical calculation involved from being made routine in the analyses of experimental results. We have developed a simulated annealing-based computational technique for routinizing the task of constrained minimization of energy functionals governing whole, or small patches of whole, fluid membranes with axisymmetry, spherical topology, and no domains of inhomogeneity. In this article, we describe the essential principles of the technique and apply it to five examples to demonstrate its versatility. It gives membrane shapes that are automatically stable to axisymmetric perturbations. Presently, it can account for constraints on 1), the membrane area or the effective membrane tension; 2), the enclosed volume or the effective pressure difference across the membrane thickness; and 3), the axial end-to-end distance or the applied axial point force.

Risk of Venous Thromboembolism in Glioblastoma Patients.

Background Patients with cancer are at increased risk of venous thromboembolic events (VTE) with a particularly high prevalence in patients with glioblastoma (GB). We designed this current study to determine the incidence of symptomatic VTE in patients with GB undergoing first-line chemoradiotherapy and to develop a clinical score to help physicians identify those who are at the highest risk of VTE. Methods A retrospective study cohort included patients diagnosed with GBM treated with radical concurrent chemoradiotherapy between 2005 and 2010 in Southern Alberta. Descriptive statistics were used to characterize the patient population. A predictive value for VTE was assessed by comparing logistic models and using the area under the receiver operating characteristic curve. Results Twenty-three out of 115 patients (20%) experienced a symptomatic VTE. This complication was not associated with overall survival at two years (p=0.06, heart rate (HR)=1.61). Hypertension and smoking were associated with VTE (p-values 0.034 and 0.048, respectively). A scoring system with the following variables was developed to predict the likelihood of developing VTE: (1) Karnofsky performance status (KPS) - 70, 1 point; KPS < 70, 2 points; (2) Age - 45 to 60, 1 point; 61 to 70, 2 points; (3) Current smoking, 1 point; (4) Hypertension, 1 point. Patients with >3 points were 5 times more likely to develop a VTE. Conclusions In our population, our simple scoring system allows the identification of patients with GB receiving first-line therapy, who are at the highest risk of VTE. These results require validation in an independent series.

Camphor-related self-inflicted keratoconjunctivitis complicating delusions of parasitosis.

PURPOSE: To report a case of camphor-related self-inflicted keratoconjunctivitis secondary to delusions of parasitosis. METHODS: A 61-year-old man with delusions of parasitosis suffered from camphor-related self-inflicted ocular trauma that manifested with corneal epithelial defects and secondary anterior chamber reaction. Two episodes of exacerbation of the ocular conditions related to the use of camphor occurred. The left eye had secondary infection with Sternotrophomonas maltophilia and Staphylococcus aureus in the second episode of exacerbation. RESULTS: The right eye recovered well with the treatment of topical lubricants and corticosteroids and had best-corrected visual acuity (BCVA) of 20/25. The infection of the left eye led to corneal perforation, necessitating penetrating keratoplasty; BCVA was hand motions because of a mature cataract. Olanzapine therapy for 1 month to decrease the delusions of parasitosis and 24-hour watch to prevent the use of camphor led to the resolution of self-inflicted keratoconjunctivitis in the patient. CONCLUSIONS: Delusions of parasitosis may lead to vision-threatening self-inflicted ocular trauma. This may be the first case report of pure camphor-related self-inflicted toxic keratoconjunctivitis.

Survival was Significantly Better with Surgical/Medical/Radiation Co-interventions in a Single-Institution Practice Audit of Frameless Stereotactic Radiosurgery.

PURPOSE: To audit outcomes after introducing frameless stereotactic radiosurgery (SRS) for brain metastases, including co-interventions: neurosurgery, systemic therapy, and whole brain radiotherapy (WBRT). We report median overall survival (MS), local failure, and distant brain failure. We hypothesized patients treated with SRS would have clinically meaningful improved MS compared with historic institutional values. We further hypothesized that patients treated with co-interventions would have clinically meaningful improved MS compared with patients treated with SRS alone. METHODS: One hundred twenty patients (N = 120) with limited intracranial disease underwent 130 frameless SRS sessions from April 2010 to May 2013. Median follow-up was 11 months. MS was measured from brain metastases diagnosis, local failure, and distant brain failure from the time of first SRS. RESULTS: Practice pattern during the first year of the study favored upfront WBRT (79%) over SRS (21%) while upfront SRS (45%) was almost as common as upfront WBRT (55%) in the last year of the study. MS was 18 months; 37% received SRS alone as initial radiotherapy (MS 12 months); 63% received WBRT prior to SRS (MS 19 months); 50% received systemic therapy post-SRS (MS 21 months); and 26% had tumor resection then SRS to the surgical cavity (MS 42 months). Local failure occurred in 10% of lesions and radio-necrosis occurred in 4%. Differences in distant brain failure among patients treated with upfront SRS (40% rate), WBRT followed by SRS (33% rate) or systemic therapy post-SRS (37% rate) were not statistically significant. CONCLUSION: Frameless SRS effectively treats surgical cavities, persistent tumors post-WBRT, and can be used as an upfront treatment of brain metastases. Surgery, systemic therapy, and WBRT are associated with longer MS. Patients can live for years while receiving multiple therapies. Systemic therapy for patients with brain metastases is increasingly common, palliative care occurs earlier and improves survival, and WBRT use is not routine. Modern series sometimes produce unexpectedly good results. Classification and treatment protocols are evolving. This practice audit is note-worthy for (i) high median overall survival, (ii) systemic therapy after radiosurgery for patients with tumors treated by radiosurgery, (iii) distant brain failure not significantly related to WBRT, and (iv) neurosurgery, systemic therapy, and WBRT are independently associated with improved MS.

Factors Associated With the Use of Radiation Therapy in Patients With Stage III Non-small Cell Lung Cancer in Alberta, Canada: A Population-based Study.

BACKGROUND: Cancer care in Alberta, Canada is publicly funded and provides patients with access to health care facilities and providers. The distribution of patients and health services across Alberta presents challenges to the delivery of cancer care, especially radiation therapy. In this study, we examined the association between patient and health system factors, the use of radiation therapy and survival outcomes in patients with stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The provincial cancer registry was used to identify all patients who presented with clinical stage III NSCLC, diagnosed from 2005 to 2007, in Alberta. Patient characteristics, diagnostic method, treatment modality and treatment outcomes were collected from provincial health information systems for analyses. Factors influencing overall survival (OS) were analyzed using Cox proportional hazards models. RESULTS: Nine hundred twenty-nine patients were identified. Sixty-two percent of patients received radiation therapy (RT) as part of their initial cancer treatment and had a median OS of 1.04 vs. 0.34 years with a hazard ratio (HR) of 0.54. On multivariable analysis, patients who were less likely to receive any therapy were older, had higher comorbidity scores and were registered in community cancer centers without radiation therapy infrastructure. Patients registered in tertiary cancer centers had a higher likelihood of accessing multimodality treatment than patients in community centers, with a statistical significance of P<0.001 after correcting for age, gender, histology, substage, and comorbidity. INTERPRETATION: Improving access to radiotherapy treatment for patients presenting to non-radiation therapy centers at diagnosis has the potential to decrease variations in cancer care and improve cancer control outcomes in clinical stage III NSCLC.

Toxic keratopathy-related corneal dehydration after laser in situ keratomileusis.

A 33-year-old woman had progressive blurred vision 2 weeks after uneventful laser in situ keratomileusis surgery. Initial satisfactory uncorrected visual acuity (UCVA) was complicated by postoperative dry eye and drug toxicity. Slitlamp biomicroscopy revealed diffuse punctate epithelial keratitis and inferior corneal epithelial defect with rolled-up epithelium on the flaps and the inferior unoperated cornea in both eyes. Diffuse inflammatory cell infiltrates were evident in the stroma. Stromal thinning was evident on serial Orbscan (Bausch & Lomb) and pachymetry examinations, and a hyperopic shift of almost +6 diopters was observed in the refractive error in both eyes. These examinations showed a gradual recovery of stromal thickness after copious hydration with balanced salt solution. The UCVA was 1.0 in both eyes after corneal rehydration.

Secondary pigmentary glaucoma associated with piggyback intraocular lens implantation.

A 51 year-old man developed bilateral pigmentary glaucoma with uncontrolled intraocular pressure (IOP) and signs of pigmentary dispersion syndrome after piggyback intraocular lens (IOL) implantation. Cataract surgery had been performed with in-the-bag implantation of poly(methyl methacrylate) IOLs in both eyes. Increasing myopia was subsequently corrected with implantation of an AcrySofIOL (Alcon Laboratories) in the ciliary sulcus of each eye. After the second implantation, the IOP was unresponsive to antiglaucoma medications, the visual field was damaged, and the visual acuity decreased. Ultrasound biomicroscopy showed that the haptics and the sharp edge of the IOL were chafing the posterior surface of the iris. After the IOL in the sulcus was removed, the IOP was stabilized by medications. This case highlights the importance of the IOL choice for sulcus implantation to avoid the complications of pigmentary dispersion syndrome.

Seizures in elderly patients with dementia: epidemiology and management.

Epileptic seizures occur in patients with dementia at a higher prevalence than among healthy elderly individuals. The incidence of seizures among patients with dementia varies with the aetiology of the dementing illness. In patients with Alzheimer's disease (the most common form of dementia), approximately 10-22% have at least one unprovoked seizure. Seizures usually occur in later stages of Alzheimer's disease, on average, > or =6 years into the course of the disease. Seizures in Alzheimer's disease are more likely to occur with early-onset disease, particularly if there is a familial presenilin I mutation. The incidence of seizures in other dementing diseases is less clear. There are special considerations regarding the management of seizures in the elderly with dementia. First, the presence of cognitive impairment may impede an accurate diagnosis of seizures. Clinicians may also mistake seizure manifestations for symptoms of the underlying dementia. Second, since most dementia patients are elderly, there are pharmacokinetic changes with aging that affect the use of antiepileptic drugs. Third, antiepileptic drugs have potential cognitive adverse effects that may worsen dementia. Although few studies are available, extrapolations from research in young people and elderly patients without dementia provide several recommendations for the management of seizures in patients with dementia: exclude symptomatic causes of seizures before committing to antiepileptic drug therapy; treat after a first seizure if there is evidence of focal neurological involvement or a risk of recurrent seizures; use antiepileptic drugs with minimal cognitive adverse effects, such as carbamazepine, valproic acid, gabapentin and lamotrigine; and use the lowest possible dosage and monitor antiepileptic drug levels, where possible.

The effect of contouring variability on dosimetric parameters for brain metastases treated with stereotactic radiosurgery.

PURPOSE: To quantify the effect of contouring variation on stereotactic radiosurgery plan quality metrics for brain metastases. METHODS AND MATERIALS: Fourteen metastases, each contoured by 8 physicians, formed the basis of this study. A template-based dynamic conformal 5-arc dose distribution was developed for each of the 112 contours, and each dose distribution was applied to the 7 other contours in each patient set. Radiation Therapy Oncology Group (RTOG) plan quality metrics and the Paddick conformity index were calculated for each of the 896 combinations of dose distributions and contours. RESULTS: The ratio of largest to smallest contour volume for each metastasis varied from 1.25 to 4.47, with a median value of 1.68 (n=8). The median absolute difference in RTOG conformity index between the value for the reference contour and the values for the alternative contours was 0.35. The variation of the range of conformity index for all contours for a given tumor varied with the tumor size. CONCLUSIONS: The high degree of interobserver contouring variation strongly suggests that peer review or consultation should be adopted to standardize tumor volume prescription. Observer confidence was not reflected in contouring consistency. The impact of contouring variability on plan quality metrics, used as criteria for clinical trial protocol compliance, was such that the category of compliance was robust to interobserver effects only 70% of the time.

Tumor regression and positional changes in non-small cell lung cancer during radical radiotherapy.

INTRODUCTION: We have used respiratory-correlated cone beam computed tomography (rcCBCT) imaging to study the volumetric and positional changes that occur throughout the course of radical radiotherapy in non-small cell lung cancer (NSCLC). METHODS: Tumor volumes and centers of mass were recorded and analyzed on weekly serial rcCBCT images of NSCLC patients treated with radical radiotherapy to a dose ≥45 Gy with concurrent chemotherapy. RESULTS: Sixty patients with locally advanced NSCLC were included; in 31 patients, the primary tumor was peripheral and thus suitable for contouring. There was a mean percent decrease of 40.2% by fraction 15 and 51.1% by treatment completion. Among all 60 patients, 19 patients (32%) had more than 30% regression by fraction 15 and 25 patients (81%) by treatment completion. Statistically significant tumor migration in at least one direction between the first and the last 2 weeks was demonstrated in 14 of 27 patients. Clinically relevant changes (atelectasis and effusions) were noted in 11 of 29 visually assessed patients. CONCLUSIONS: Current rcCBCT image quality allows assessment of tumors located more peripherally. Significant tumor regression was documented in the majority of patients. In view of these observations, the suitability of adaptive radiotherapy in radical lung cancer treatment should be further investigated.

Sequels, complications and management of a chemical burn associated with cement splash.

We present a case of successful superficial keratectomy and amniotic membrane grafting to re-establish ocular surface from denuded stroma and significant limbal ischemia caused by a cement splash. We fully documented a case report about the sequels, complications and management strategies of a chemical burn to the eyes associated with a cement splash. Slit lamp examination, visual acuity test as well as all common cultures and stains were performed to measure the outcome. Visual acuity significantly improved from 0.2 to best-corrected visual acuity 0.7 at the 5-month postoperative visit. The cornea regained its clarity. Total re-epithelialization of the injured area was observed. It is of primary importance to remove all the debris from a cement splash at the first available opportunity. Superficial keratectomy and amniotic membrane grafting may be the best methods for the re-epithelialization and reconstruction of the ocular surface.

Alterations of the sense of "humanness" in right hemisphere predominant frontotemporal dementia patients.

OBJECTIVE: To evaluate the sense of "humanness" in frontotemporal dementia (FTD) patients with right hemispheric involvement. BACKGROUND: Early in the course, FTD is often asymmetric, and those with predominant right frontotemporal disease have disproportionate disturbances in social behavior and empathy. A disruption in a sense of humanness may underlie these behavioral disturbances. METHOD: Sixteen patients with asymmetric FTD on functional neuroimaging underwent recognition tests of facial masking, human-animal morphing, and facial distortion. Additional tests evaluated facial discrimination and the recognition of famous faces, facial emotions, and animate-inanimate differences. RESULTS: On the distorted and morphed face tasks, 8 FTD patients with predominant right hemisphere involvement were significantly more likely to call morphed and distorted faces "human" as compared with both 8 FTD patients with predominant left hemisphere involvement and normal controls. The FTD groups did not differ on thresholds for recognizing masked faces or on other face recognition measures. CONCLUSIONS: In FTD, right hemispheric involvement may alter the threshold for judging someone as human independent of the recognition of faces or facial affect. These results suggest that a specific sense of humanness facilitates a person recognition network in the right frontotemporal region of the brain.

Hypersexuality after right pallidotomy for Parkinson's disease.

The authors describe hypersexuality following atypical right pallidotomy for intractable Parkinson's Disease (PD). This patient and literature review suggest important roles for the pallidum in sexual behavior and dopamine in sexual arousal.

Fatal and non-fatal machine-related injuries suffered by children in Alberta, Canada, 1990-1997.

BACKGROUND: Children raised on farms are exposed to many hazardous types of machinery. The objective of this study was to describe the magnitude of non-fatal and fatal farm machinery injuries in Alberta children and adolescents (0-17 years) for the years 1990-1997. To date, there have been no published studies of pediatric farm injuries in Western Canada. METHODS: Data were collected through the Canadian Agricultural Injury Surveillance Program (CAISP). Death certificates and hospital charts were audited to provide enhanced information about the circumstances of injuries related to farm machinery for farm persons aged 17 years and younger. RESULTS: A total of 302 farm machinery injuries were recorded for the years 1990-1997. Of these, 14 resulted in death. All-terrain vehicles (ATVs) were the most common cause of injury (n = 76), followed by tractors (n = 72), and power take-offs (n = 15). The predominant injury mechanism was entanglement (n = 69), followed by falls from machines (n = 57), and being pinned/struck by a machine (n = 49). The median length of hospital stay for injuries was 2.0 days. Males (median = 2.0 days) had significantly longer hospital stays than females (median = 1.0 days). There were significantly more injuries reported during the summer and autumn than during the winter and spring. Those injured in the autumn were significantly older (median = 13.0 years) than children injured in the spring (median = 9.0 years). Injury rates dropped significantly during the study period from 119.9/100,000 per year in 1990 to 50.7/100,000 in 1997. CONCLUSIONS: While injury rates have dropped, the number of injuries occurring to children on Alberta farms is of concern. The large number of ATV related injuries suggests that preventative strategies need to be focused in this area. Am. J. Ind. Med. 45:177-185, 2004.