Toxicity and outcomes of melanoma brain metastases treated with stereotactic radiosurgery: the risk of subsequent symptomatic intralesional hemorrhage exceeds that of radiation necrosis.

PURPOSE: We aimed to assess the outcomes and patterns of toxicity in patients with melanoma brain metastases (MBM) treated with stereotactic radiosurgery (SRS) with or without immunotherapy (IO). METHODS: From a prospective registry, we reviewed MBM patients treated with single fraction Gamma Knife SRS between 2008 and 2021 at our center. We recorded all systemic therapies (chemotherapy, targeted therapy, or immunotherapy) administered before, during, or after SRS. Patients with prior brain surgery were excluded. We captured adverse events following SRS, including intralesional hemorrhage (IH), radiation necrosis (RN) and local failure (LF), as well as extracranial disease status. Distant brain failure (DBF), extracranial progression-free survival (PFS) and overall survival (OS) were determined using a cumulative Incidence function and the Kaplan-Meier method. RESULTS: Our analysis included 165 patients with 570 SRS-treated MBM. Median OS for patients who received IO was 1.41 years versus 0.79 years in patients who did not (p = 0.04). Ipilimumab monotherapy was the most frequent IO regimen (30%). In the absence of IO, the cumulative incidence of symptomatic (grade 2 +) RN was 3% at 24 months and remained unchanged with respect to the type or timing of IO. The incidence of post-SRS g2 + IH in patients who did not receive systemic therapy was 19% at 1- and 2 years compared to 7% at 1- and 2 years among patients who did (HR: 0.33, 95% CI 0.11-0.98; p = 0.046). Overall, neither timing nor type of IO correlated to rates of DBF, OS, or LF. Among patients treated with IO, the median time to extracranial PFS was 5.4 months (95% IC 3.2 - 9.1). CONCLUSION: The risk of g2 + IH exceeds that of g2 + RN in MBM patients undergoing SRS, with or without IO. IH should be considered a critical adverse event following MBM treatments.

Anatomical and surgical characteristics correlate with pachymeningeal failure in patients with brain metastases after neurosurgical resection and adjuvant stereotactic radiosurgery.

PURPOSE: Neurosurgery (NS) is an essential modality for large brain metastases (BM). Postoperative stereotactic radiosurgery (SRS) is the standard of care adjuvant treatment. Pachymeningeal failure (PMF) is a newly described entity, distinct from classical leptomeningeal failure (LMF), that is uniquely observed in postoperative patients treated with adjuvant SRS. We sought to identify risk factors for PMF in patients treated with NS + SRS. METHODS: From a prospective registry (2009 to 2021), we identified all patients treated with NS + SRS. Clinical, imaging, pathological, and treatment factors were analyzed. PMF incidence was evaluated using a competing risks model. RESULTS: 144 Patients were identified. The median age was 62 (23-90). PMF occurred in 21.5% (31/144). Female gender [Hazard Ratio (HR) 2.65, p = 0.013], higher Graded Prognostic Assessment (GPA) index (HR 2.4, p < 0.001), absence of prior radiation therapy (HR N/A, p = 0.018), controlled extracranial disease (CED) (HR 3.46, p = 0.0038), and pia/dura contact (PDC) (HR 3.30, p = 0.0053) were associated with increased risk for PMF on univariate analysis. In patients with PDC, wider target volumes correlated with reduced risk of PMF. Multivariate analysis indicated PDC (HR 3.51, p = 0.0053), piecemeal resection (HR 2.38, p = 0.027), and CED (HR 3.97, p = 0.0016) independently correlated with PMF risk. PMF correlated with reduced OS (HR 2.90, p < 0.001) at a lower rate compared to LMF (HR 10.15, p < 0.001). CONCLUSION: PMF correlates with tumor PDC and piecemeal resection in patients treated with NS + SRS. For unclear reasons, it is also associated with CED. In tumors with PDC, wider dural radiotherapy coverage was associated with a lower risk of PMF.

Pachymeningeal disease: a systematic review and metanalysis.

BACKGROUND: Pachymeningeal disease (PMD) is a newly recognized pattern of brain metastasis (BrM) failure that specifically occurs following surgery with adjuvant stereotactic radiosurgery (SRS) and has unique prognostic implications relative to leptomeningeal disease (LMD). Here, we report its prevalence, prognostic implications, and associated risk factors. METHODS: A literature search was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses on PUBMED and Cochrane from January 2000 to June 2023. RESULTS: We identified 12 studies that included a total of 3992 BrM patients, 659 (16.5%) of whom developed meningeal disease (MD) following surgery plus adjuvant SRS, including either PMD or LMD. The mean prevalence of MD across studies was 20.9% (7.9-38.0%), with PMD accounting for 54.6% of this prevalence and LMD comprising the remaining 45.4%. Mean of the median overall survivals following diagnosis of PMD and LMD was 10.6 months and 3.7 months p = 0.007, respectively, a significant difference. Only 2 risk factors for PMD were reported in ≥ 2 studies and also identified as statistically significant per our meta-analysis: infratentorial location and controlled systemic disease status. CONCLUSION: While PMD has a superior prognosis to LMD, it is nevertheless a critical oncologic event associated with significant mortality and remains poorly recognized. PMD is predominantly observed in patients with controlled systemic disease status and infratentorial location. Future treatment strategies should focus on reducing surgical seeding and sterilizing surgical cavities.

Pituitary metastases: a case series and scoping review.

PURPOSE: To understand the natural history and optimal treatment strategy for pituitary gland metastasis. METHODS: We performed both a retrospective chart review of patients treated at our institution and a scoping review of the topic. RESULTS: The retrospective review identified seven patients with an average age of 59.6 years. Primary histologies included breast cancer (4), melanoma (1), renal cell carcinoma (1), and sarcoma (1). Two patients had anterior pituitary endocrine dysfunction, one of whom was the only patient with visual symptoms. All patients were treated with radiosurgery and two also underwent surgical resection. Overall survival ranged from 6.5 to 117 months. Literature review identified 166 patients from 71 studies. The most common primary cancer was lung (27.7%), followed by breast (18.7%) and renal (14.5%) cancer. 107 presented with endocrine dysfunction, including 41 cases of diabetes insipidus and 55 cases of hypopituitarism. 110 presented with visual compromise. 107 patients received radiotherapy, 96 underwent surgical resection and 44 received systemic chemotherapy/immunotherapy. Surgery was significantly associated with an increased likelihood of vision improvement and a decreased likelihood of endocrine normalization. Radiographic regression predicted visual improvement. Median overall survival was 9.9 months (range: 0.2-96). CONCLUSIONS: This scoping review showed that both radiosurgery and surgical resection have been frequently used to treat pituitary metastases with good response. Vision improvement is more likely to happen following surgical resection, likely at the expense of endocrine dysfunction. Despite treatment and radiographic response, patient survival remains less than a year.

Postoperative CT scans after resection of brain metastases: neurosurgical routine or added value?

BACKGROUND: Metastasis is the most common brain tumor in adults. It is the standard of care at most North American centers to obtain an early postoperative imaging after their resection. However, the necessity of this practice in the absence of a new postoperative deficit remains unclear. METHODS: We retrospectively reviewed our surgical cohort of patients who underwent resection of brain metastases from July 2018 to June 2019. We collected demographic data and reviewed results of routine postoperative CT scans and neurological morbidities to examine the diagnostic and therapeutic yield of an early postoperative scan. In addition, we performed a systematic review of the topic. RESULTS: Our review included 130 patients, all of whom underwent gross total resection of one or more brain metastases. On postoperative CT, none had unexpected findings such as cavity hematoma or new ischemia; no changes in management resulted from postoperative imaging. One patient required a higher dose of dexamethasone on postoperative day 4 for delayed hemiparesis and aphasia due to cerebral edema. Three additional patients underwent a wound washout for delayed infection during a subsequent admission. Our systematic review identified three additional studies; in a combined cohort of 450 patients (including our own), no patients had clinically actionable findings on routine postoperative CT. CONCLUSIONS: Following resection of brain metastases, a routine postoperative CT scan has low diagnostic yield and did not change patient management in any cases examined in this work.

Feedback Delivery in an Academic Cancer Centre: Reflections From an R2C2-based Microlearning Course.

Feedback delivery and training have not been characterized in the context of academic cancer centres. The purpose of this study was to assess the feasibility and utility of a microlearning course based on the R2C2 (Relationship, Reaction, Content, Coaching) feedback model and characterize multidisciplinary healthcare provider (HCP) perspectives on existing feedback practices in an academic cancer centre. Five HCP (two radiation oncologists, one medical oncologist, and two allied health professionals) with supervisory roles were selected by purposive sampling to participate in a prospective longitudinal qualitative study. Each participant completed a web-based multimedia course. Semi-structured one-on-one interviews were conducted with each participant at four time points: pre- and immediately post-course, and at one- and three-months post course. All participants found the course to be time feasible and completed it in 10-20 min. Participants expressed that the course fulfilled their need for feedback training and that its adoption may normalize a feedback culture in the cancer centre. Three themes were identified regarding perceptions of existing feedback practices: (1) hierarchical and interdisciplinary relationships modulate feedback delivery, (2) interest in feedback delivery varies by duration of the supervisory relationship, and (3) the transactionality of supervisor-trainee relationships influences feedback delivery. This study demonstrates the perceived feasibility and utility of a digital microlearning approach for development of feedback competencies in an academic cancer centre, perceptions of cultural barriers to feedback delivery, and the need for organizational commitment to developing a feedback culture.

Brain Metastases: A Modern Multidisciplinary Approach.

Brain metastases (BM) are the most common intracranial neoplasm and represent a major clinical challenge across many medical disciplines. The incidence of BM is increasing, largely due to improvements in primary disease therapeutics conferring greater systemic control, and advancements in neuroimaging techniques and availability leading to earlier diagnosis. In recent years, the landscape of BM treatment has changed significantly with the advent of personalized targeted chemotherapies and immunotherapy, the adoption of focal radiotherapy (RT) for higher intracranial disease burden, and the implementation of new surgical strategies. The increasing permutations of options available for the treatment of patients diagnosed with BM necessitate coordinated care by a multidisciplinary team. This review discusses the current treatment regimens for BM as well as examines the salient features of a modern multidisciplinary approach.

Hyperbaric Oxygen for Radiation Necrosis of the Brain.

INTRODUCTION: Hyperbaric oxygen therapy (HBOT) shows promising results in treating radionecrosis (RN) but there is limited evidence for its use in brain RN. The purpose of this study is to report the outcomes of using HBOT for symptomatic brain RN at a single institution. METHODS: This was a retrospective review of patients with symptomatic brain RN between 2008 and 2018 and was treated with HBOT. Demographic data, steroid use, clinical response, radiologic response and toxicities were collected. The index time for analysis was the first day of HBOT. The primary endpoint was clinical improvement of a presenting symptom, including steroid dose reduction. RESULTS: Thirteen patients who received HBOT for symptomatic RN were included. The median time from last brain radiation therapy to presenting symptoms of brain RN was 6 months. Twelve patients (92%) had clinical improvement with median time to symptom improvement of 33 days (range 1-109 days). One patient had transient improvement after HBOT but had recurrent symptomatic RN at 12 months. Of the eight patients with evaluable follow-up MRI, four patients had radiological improvement while four had stable necrosis appearance. Two patients had subsequent deterioration in MRI appearances, one each in the background of initial radiologic improvement and stability. Median survival was 15 months with median follow-up of 10 months. Seven patients reported side effects attributable to HBOT (54%), four of which were otologic in origin. CONCLUSIONS: HBOT is a safe and effective treatment for brain RN. HBOT showed clinical and radiologic improvement or stability in most patients. Prospective studies to further evaluate the effectiveness and side effects of HBOT are needed.

Utilisation de l'oxygénothérapie hyperbare à la suite de séances de radiothérapie entraînant la mort du tissu cérébral. Introduction: Si l'oxygénothérapie hyperbare (OHB) laisse entrevoir des résultats prometteurs dans le traitement des radionécroses (RN), les preuves demeurent limitées quant à son utilisation dans le cas de RN du cerveau. L'objectif de cette étude est de présenter des résultats de recherche liés, dans un seul établissement de santé, à l'utilisation de l'OHB dans le cas de RN symptomatiques du cerveau. Méthodes: Pour ce faire, nous avons effectué une analyse rétrospective des dossiers de patients atteints de RN symptomatiques du cerveau entre 2008 et 2018 et ayant été traités lors de séances d'OHB. Nous avons aussi recueilli des données de nature démographique et d'autres portant sur l'utilisation de stéroïdes, sur la réponse clinique et radiologique des patients et sur les toxicités. Le point de départ (index time) de notre étude a été la première séance d'OHB alors que son principal indicateur de résultat a été l'amélioration sur le plan clinique d'un symptôme particulier, ce qui a inclus une réduction des doses de stéroïdes. Résultats: Au total, treize patients atteints de RN symptomatiques ont été inclus dans cette étude. Le temps médian entre une ultime séance de radiothérapie et l'apparition de symptômes de RN a été de 6 mois. Douze patients (92 %) ont donné à voir une amélioration de leur état médical, la période médiane d'amélioration de leurs symptômes étant de 33 jours (étendue : 1­109 jours). On a observé chez un seul patient une amélioration transitoire à la suite de séances d'OHB, les symptômes de RN étant réapparus au douzième mois. Sur les huit patients ayant subi un examen d'imagerie de suivi, quatre d'entre eux ont montré des signes d'amélioration sur le plan radiologique tandis que quatre autres ont donné à voir une RN stable. Fait à noter, deux patients chez qui l'on avait observé une amélioration radiologique initiale ou une stabilité de leur état ont montré une détérioration ultérieure à la suite d'un examen d'IRM. Le taux de survie médian de ces patients et leur suivi médian ont été respectivement de 15 mois et de 10 mois. Enfin, sept d'entre eux ont signalé des effets secondaires attribuables à l'OHB, dont quatre d'origine otologique. Conclusions: L'OHB demeure un traitement efficace et sécuritaire dans le cas des RN du cerveau. Elle a permis d'observer chez la plupart des patients une amélioration clinique et radiologique ou à tout le moins une stabilité de leurs symptômes. Cela dit, des études prospectives sont nécessaires afin de pouvoir évaluer plus en profondeur son efficacité et ses effets secondaires.

Cognitive rehabilitation for executive dysfunction in brain tumor patients: a pilot randomized controlled trial.

PURPOSE: Patients with brain tumors face unique quality of life challenges. Executive dysfunction is common and functionally limiting, with no established treatments as standard care. This pilot study evaluated the efficacy of Goal Management Training (GMT), a behavioral intervention combining mindfulness and strategy training, for improving executive and real-life functioning in this population. METHODS: Twenty-five primary brain tumor survivors were randomized to GMT, an active control (Brain Health Program, BHP), or a wait-list (WAIT) control group. The BHP was a supportive care intervention offering education and activities to promote general brain health, without cognitive strategy training. Participants in GMT and BHP completed eight individual sessions and homework between sessions; those in WAIT received usual care. Assessments at baseline, immediately post-training, and 4-month follow-up used a battery of objective and subjective measures, including functional goal attainment. RESULTS: Adherence (% sessions completed) was high for both GMT (98.9%) and BHP (84.4%). Executive functions improved with GMT but not BHP or WAIT (repeated measures analysis of variance, time-by-group interaction, post-training P = 0.077, follow-up P = 0.046). Both intervention groups reported fewer cognitive concerns at post-training (P = 0.049) and follow-up (P < 0.001). Functional goal attainment was greatest with GMT (post-training P = 0.027, follow-up P = 0.064). CONCLUSIONS: GMT improved executive and real-life functioning in brain tumor survivors, with gains maintained at 4-month follow-up. Clinical implementation of this adaptable program merits consideration for clinically stable patients with cognitive dysfunction. Further development and larger prospective cognitive rehabilitation trials appear warranted.

Repeat irradiation for children with supratentorial high-grade glioma.

BACKGROUND: There are very few studies about the role of repeat irradiation (RT2) for children with recurrent supratentorial high-grade glioma (HGG). It was the aim of this study to assess the effectiveness and safety of RT2 in this population. PROCEDURE: This was a retrospective cohort study of 40 children age 18 years and under with recurrent supratentorial HGG who had received at least one course of RT. In-field reirradiation volumes included focal or whole brain RT, with doses ranging from 30 to 54 Gy. The primary endpoint was overall survival (OS) from the first day of RT2. RESULTS: Fourteen patients underwent RT2. The median survival of these patients was 6.5 months. Patients with ≥12 months elapsed time between RT1 and RT2 experienced longer OS than patients who had < 12 months (P = 0.009). There was no difference in OS between patients with or without germline mutations (e.g., Lynch, Li-Fraumeni, or constitutional mismatch-repair deficiency, P = 0.20). Ten patients received RT2 that overlapped with RT1 volumes for locally recurrent disease. Of this group, 80% experienced clinical benefit from in-field RT2, defined as clinical/radiologic response or stable disease. Ninety-three percent completed the prescribed course of RT2, with one patient developing grade 3 radiation necrosis four months after RT2. When compared with 26 patients who were not offered reirradiation, those selected for RT2 had improved median survival from the time of first disease progression (9.4 vs 3.8 months, P = 0.005). CONCLUSIONS: Reirradiation for children with recurrent supratentorial HGG is a safe, effective treatment that provides short-term disease control.

National Survey Among Radiation Oncology Residents Related to Their Needs in Geriatric Oncology.

Currently, there is no formal curriculum addressing geriatric oncology within Canadian radiation oncology (RO) residency programs. Knowledge related to geriatric medicine may help radiation oncologists modify RT based on frailty status and geriatric considerations. Understanding specific learning needs allow program coordinators to align the current curriculum with residents' geriatric oncology learning needs. The purpose of this study is to determine the geriatric oncology educational needs of the Canadian RO residents and to inform Canadian RO residency training. A cross-sectional survey, with Likert, multiple choice, and open-ended questions, was pretested and distributed electronically by program directors to Canadian RO residents over 6 weeks. Responses were analyzed with descriptive statistics and common themes. One-hundred and thirty-five Canadian RO residents were contacted and 63 responded (47%). Half (49%) lacked confidence managing the elderly with multiple comorbidities, polypharmacy, functional and cognitive impairment, and challenging social circumstances;73% agreed additional training would be helpful. Forty-four percent lacked confidence regarding psychogeriatric referrals, fall prevention, palliative and hospice care, and community resources preventing re-hospitalization; 63% agreed additional training would be helpful. Seventy-six percent believed discussion groups, continuing education, geriatric oncology electives, and journal clubs would provide learning opportunities. Seventy-one percent agreed integrating geriatric assessment into RO curricula would improve care. Seventy-nine percent believed geriatric oncology principles have not been adequately integrated into radiation oncology curricula. There are significant gaps specific to geriatric assessment and management of older cancer patients in the current Canadian RO curricula. Most residents agreed that it is important to integrate geriatric oncology training to improve and personalize the care of older cancer patients.

Management and Outcomes in the Oldest-Old Population with Glioblastoma.

OBJECTIVES: Glioblastoma is a lethal disease in the elderly population. We aimed to evaluate disease and treatment outcomes in the oldest-old patients. METHODS: Patients >80 years old with histologically confirmed glioblastoma treated between 2004 and 2009 were identified. We included patients managed with best supportive care (BSC), temozolomide (TMZ) alone, radiotherapy (RT) alone, or concomitantly with TMZ (CRT). Survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: Ultimately, 48 patients were analyzed. Median age and Eastern Cooperative Oncology Group (ECOG) Performance Status were 82 years and 2, respectively. The median Age-Adjusted Charlson Index (AAC) was 6. Gross total and subtotal resections were performed in 16.7% and 18.8% of patients, respectively. Biopsy followed by RT alone was the treatment modality for 23/48 (47.9%), while 17/48 (35.4%) received surgery followed by RT alone or CRT. A total of 8 (16.7%) were managed with BSC after biopsy. Median overall survival (OS) and progression-free survival (PFS) were 4.1 (95% confidence interval [95% CI] 3.3-4.9) and 2.7 (95% CI 1.5-3.9) months, respectively. Improved median OS was observed in those treated with surgical resection followed by RT alone or CRT (7.1 months), compared to biopsy followed by RT alone (4.2 months) or BSC (2.0 months; p=0.002). Surgical resection, age≤85, and AAC<6 were associated with better OS (p=0.032, p=0.031, and p=0.02, respectively). Cause of death was neurological progression in 56% of cases. RT was well-tolerated. CONCLUSIONS: PFS and OS outcomes remain poor in the oldest-old patients (>80 years old). Younger age, lower AAC, surgical resection, and adjuvant treatment were associated with improved OS.

Neutrophil-lymphocyte ratio dynamics during concurrent chemo-radiotherapy for glioblastoma is an independent predictor for overall survival.

Elevated neutrophil-lymphocyte ratio (NLR) may predict worse outcomes in cancer, including glioblastoma (GBM). This study assessed whether change in NLR during focal radiotherapy and concomitant temozolomide (RT-TMZ) provides further prognostic information. This was a retrospective review of patients treated with RT-TMZ for histologically confirmed GBM from January 2004 to September 2010. Variables assessed included age, ECOG performance status (PS), dexamethasone use and extent of surgery. Hematological results were collected at baseline, during and 4 weeks post RT-TMZ. Kaplan-Meier method was used to calculate overall survival (OS). Multivariable analysis (MVA) assessed for joint effect of covariates on OS and Pearson Correlation Coefficients assessed for association between dexamethasone dose and NLR change. With a median age of 55 (range 18-70), 369 patients were included. Median follow up was 15.1 month (range 1.6-134.6). The OS was 66.1% (95% CI 61.2-70.6) and 31.4 (95% CI 26.8-36.1) at 1 and 2 years, respectively. On univariate analysis, both decrease in NLR post RT-TMZ (HR 0.641, p < 0.0001) and baseline NLR < 7.5 (HR 0.628, p < 0.0001) were associated with longer OS. On MVA decrease in NLR (HR 0.727, 95% CI 0.578-0.915), age (HR 1.025, 95% CI 1.012-1.038), baseline neutrophil (<8) (HR 0.689, 95% CI 0.532-0.891), total TMZ cycles (HR 0.89, 95% CI 0.867-0.913) and PS (HR 0.476, 95% CI 0.332-0.683) were independent predictors of OS. These findings suggest that a decrease in NLR during RT-TMZ, accounting for known prognostic factors, is an independent prognostic factor for survival in GBM.

Treatment Outcomes in 1p19q Co-deleted/Partially Deleted Gliomas.

BACKGROUND: Radiotherapy with procarbazine, lomustine, and vincristine improves overall survival (OS) in patients with 1p19q co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma. METHODS: This retrospective analysis investigated outcomes in patients with 1p19q co-deleted/partially deleted oligodendroglioma, oligoastrocytoma, anaplastic oligodendroglioma, or anaplastic oligoastrocytoma. OS and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and prognostic factors using the Cox proportional hazard model. RESULTS: A total of 106 patients (between December 1997 and December 2013) were included. Median age was 40 years (19-66), 58 were male (55%), Eastern Cooperative Oncology Group performance status was 0 in 80 patients (75%). 1p19q status was co-deleted in 66 (62%), incompletely co-deleted in 27 (25%), and 1p or 19q loss alone in four (4%) and nine (8%) patients, respectively. Isocitrate dehydrogenase-1 R132H mutation was found in 67 of 85 patients with sufficient material. Upfront treatment was given in 72 (68%) patients and temozolomide alone in 52 (49%). Median time to radiotherapy in 47 patients (44%) was 34.7 months and 41.2 months in 9 patients with co-deleted/incompletely co-deleted anaplastic oligodendroglioma/anaplastic oligoastrocytoma who received upfront temozolomide alone. Median OS was not reached and 5-year OS was 91% for all groups (median follow-up, 5.1 years). On multivariable analysis for all patients, receipt of therapy upfront versus none (p=0.04), PS 1 versus 0 (p<0.001) and 1p19q co-deletion/incomplete deletion versus 1p or 19q loss alone (p=0.005) were prognostic for PFS. Isocitrate dehydrogenase-1 status was not prognostic for PFS. CONCLUSIONS: With similar survival patterns in low-grade/anaplastic gliomas, molecular characteristics may be more important than histological grade. Longer follow-up and results of prospective trials are needed for definitive guidance on treatment of these patients.

A mandala of faculty development: using theory-based evaluation to explore contexts, mechanisms and outcomes.

Demonstrating the impact of faculty development, is an increasingly mandated and ever elusive goal. Questions have been raised about the adequacy of current approaches. Here, we integrate realist and theory-driven evaluation approaches, to evaluate an intensive longitudinal program. Our aim is to elucidate how faculty development can work to support a range of outcomes among individuals and sub-systems in the academic health sciences. We conducted retrospective framework analysis of qualitative focus group data gathered from 79 program participants (5 cohorts) over a 10-year period. Additionally, we conducted follow-up interviews with 15 alumni. We represent the interactive relationships among contexts, mechanisms, and outcomes as a "mandala" of faculty development. The mandala illustrates the relationship between the immediate program context, and the broader institutional context of academic health sciences, and identifies relevant change mechanisms. Four primary mechanisms were collaborative-reflection, self-reflection and self-regulation, relationship building, and pedagogical knowledge acquisition. Individual outcomes, including changed teaching practices, are described. Perhaps most interestingly, secondary mechanisms-psychological and structural empowerment-contributed to institutional outcomes through participants' engagement in change leadership in their local contexts. Our theoretically informed evaluation approach models how faculty development, situated in appropriate institutional contexts, can trigger mechanisms that yield a range of benefits for faculty and their institutions. The adopted methods hold potential as a way to demonstrate the often difficult-to-measure outcomes of educational programs, and allow for critical examination as to how and whether faculty development programs can accomplish their espoused goals.

Impact of glycemia on survival of glioblastoma patients treated with radiation and temozolomide.

Evidence suggests hyperglycemia is associated with worse outcomes in glioblastoma (GB). This study aims to confirm the association between glycemia during radiotherapy (RT) and temozolomide (TMZ) treatment and overall survival (OS) in patients with newly diagnosed GB. This retrospective study included GB patients treated with RT and TMZ from 2004 to 2011, randomly divided into independent derivation and validation datasets. Time-weighted mean (TWM) glucose and dexamethasone dose were collected from start of RT to 4 weeks after RT. Univariate (UVA) and multivariable (MVA) analyses investigated the association of TWM glucose and other prognostic factors with overall survival (OS). In total, 393 patients with median follow-up of 14 months were analyzed. In the derivation set (n = 196) the median OS was 15 months and median TWM glucose was 6.3 mmol/L. For patients with a TWM glucose ≤6.3 and >6.3 mmol/L, median OS was 16 and 13 months, respectively (p = 0.03). On UVA, TWM glucose, TWM dexamethasone, age, extent of surgery, and performance status were associated with OS. On MVA, TWM glucose remained an independent predictor of OS (p = 0.03) along with TWM dexamethasone, age, and surgery. The validation set (n = 197), with similar baseline characteristics, confirmed that TWM glucose ≤6.3 mmol/L was independently associated with longer OS (p = 0.005). This study demonstrates and validates that glycemia is an independent predictor for survival in GB patients treated with RT and TMZ.

Factors impacting survival following second surgery in patients with glioblastoma in the temozolomide treatment era, incorporating neutrophil/lymphocyte ratio and time to first progression.

Patients with progressive glioblastoma (GBM) have a poor prognosis. Neutrophil/lymphocyte ratio (NLR), a host inflammatory marker, is prognostic in several solid tumors. The prognostic impact of either NLR, or time from first surgery for GBM to first progression (TTP), in patients undergoing second surgery, has not been assessed. Patients undergoing second surgery for GBM were retrospectively reviewed. Primary outcome was overall survival (OS) and Cox proportional hazard models were used to assess the prognostic value of baseline characteristics including TTP and NLR. Univariable and multivariable analysis (MVA) of OS from second surgery were performed using accelerated failure time Weibull model. Of 584 patients with GBM, 107 (18 %) underwent second surgery between 01/04 and 12/11. Patients who underwent second surgery had longer OS versus those having primary surgery alone; 20.9 versus 9.9 months (P < 0.001). Median OS from second surgery in patients with NLR ≤ 4 versus NLR > 4 was 9.7 versus 5.9 months (log rank P = 0.02). The NLR retained its prognostic significance for survival on MVA (time ratio [TR] 1.65, 95 % confidence interval [CI] 1.15-2.35, P < 0.01). No chemotherapy post second surgery (TR 0.23, 95 % CI 0.16-0.33, P < 0.001) portended worse survival. In patients undergoing second surgery, when TTP was ≤ 12 months, 12-24 months, or >24 months, median OS from second surgery was 7.2, 7.0 and 6.3 months, respectively (P = 0.6). A NLR > 4 prior to second surgery is a poor prognostic factor in GBM and later progression is associated with longer survival in patients but not in longer survival after second surgery.

Conditional probability of survival and post-progression survival in patients with glioblastoma in the temozolomide treatment era.

With standard treatment for glioblastoma (GBM) consisting of surgery followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ), median survival is ~14.6 months. This is not as informative to patients who have survived for some time. Conditional probability of survival may offer more relevant survival estimates. Outcomes/conditional probability of survival and post-progression survival (PPS) estimates were retrospectively reviewed in the TMZ treatment era of 882 consecutive patients with a diagnosis of GBM from January 2004 to August 2010. Median age of entire cohort was 62 years including 62 % males. Baseline performance status (PS) was 0-1 in 67, 23 % had frontal lobe tumors, 58 % received concurrent RT/TMZ ± adjuvant TMZ. Survival (OS) was similar for those with frontal lobe tumors versus other locations (P = 0.25). OS for patients receiving standard RT/TMZ ± TMZ was 14.2 months. Age, PS, extent of surgery, therapy post-surgery had significant effects on OS. OS for entire cohort at 1, 2, 3, 4, 5 years was 43.4, 17.9, 10.4, 8.4, 7.2 % respectively. Conditional probability of survival of an additional year given survival to 1, 2, 3, 4, 5 years was 41.4, 58, 80.7, 85.7, 81.5 % respectively. Conditional probability of survival for those patients receiving concurrent RT/TMZ ± adjuvant TMZ was similar. Patients who progress >18 months after their initial treatment for GBM had significantly greater 2 and 5 year PPS as well as OS. Conditional probabilities of survival may provide more meaningful life expectancy predictions for survivors of GBM than conventional survival outcomes.

Glioblastoma treatment in the elderly in the temozolomide therapy era.

BACKGROUND: optimal treatment of glioblastoma (gBM) in the elderly remains unclear. the impact of age on treatment planning, toxicity, and efficacy at a Canadian Cancer Centre was retrospectively reviewed. METHODS: glioblastoma patients treated consecutively between 2004 and 2008 were reviewed. utilizing 70 years as the threshold for definition of an elderly patient, treatments and outcome were compared in younger and elderly populations. RESULTS: four hundred and twenty one patients were included in this analysis and median overall survival (oS) for the entire cohort was 9.8 months. 290 patients were aged <70 (median age 57, range 17- 69) and 131 were aged ≥ 70 (median age 76, range 70-93). patients ≥ 70 were more likely to receive best supportive care (BSC) and all patients >70 who were treated with radiotherapy received <60 gy (P<0.001), except one. patients aged >70 demonstrated inferior survival (one year oS 16% versus 54% for those <70, hr 3.46, P<0.001). in patients treated with BSC only, age had no impact on survival (median survival two months in both groups, hr 0.89, P=0.75). for those treated with higher doses of radiotherapy (>30 gy to <60 gy), one year survival was 19% versus 24% in patients aged >70 versus <70 (hr 1.47, P=0.02) respectively. CONCLUSION: in this retrospective single institution series, elderly patients were more likely to be treated with BSC or palliative doses of radiotherapy. randomized phase iii study results are required for guidance in treatment of this population of patients.

Rate of pachymeningeal failure following adjuvant WBRT vs SRS in patients with brain metastases.

Background: Stereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as standard-of-care adjuvant treatment following surgery for brain metastasis (BrM). Concomitant with the adoption of adjuvant SRS, a new pattern of failure termed "Pachymeningeal failure" (PMF) has emerged. Methods: We reviewed a prospective registry of 264 BrM patients; 145 and 119 were treated adjuvantly with WBRT and SRS, respectively. The Cox proportional hazards model was used to identify variables correlating to outcomes. Outcomes were calculated using the cumulative incidence (CI) method. Univariate (UVA) and multivariate analyses (MVA) were done to identify factors associated with PMF. Results: CI of PMF was 2 % and 18 % at 12 months, and 2 % and 23 % at 24 months for WRBT and SRS, respectively (p < 0.001). The CI of classic leptomeningeal disease (LMD) was 3 % and 4 % at 12 months, and 6 % and 6 % at 24 months for WBRT and SRS, respectively (P = 0.67). On UVA, adjuvant SRS [HR 9.75 (3.43-27.68) (P < 0.001)]; preoperative dural contact (PDC) [HR 6.78 (1.64-28.10) (P = 0.008)]; GPA score [HR 1.64 (1.11-2.42) (P = 0.012)]; and lung EGFR/ALK status [HR 3.11 (1.02-9.45) (P = 0.045)]; were associated with PMF risk. On MVA, adjuvant SRS [HR 8.15 (2.69-24.7) (P < 0.001)]; and PDC [HR 6.28 (1.51-26.1) (P = 0.012)] remained associated with PMF. Conclusions: Preoperative dural contact and adjuvant SRS instead of adjuvant WBRT were associated with an increased risk of PMF. Strategies to improve pachymeningeal radiation coverage to sterilize at risk pachymeninges should be investigated.