Metastatic Melanoma of the Optic Nerve Sheath.

A 23-year-old man with a history of metastatic melanoma developed painful vision loss to counting fingers with enhancement of optic nerve on contrast-enhanced magnetic resonance imaging (MRI) and received a diagnosis of optic neuritis from an outside hospital. Despite empiric corticosteroid therapy, the patient worsened and developed secondary central retinal vein occlusion with further deterioration of vision. Repeat MRI demonstrated optic nerve sheath (ONS) involvement suggestive of optic perineuritis (OPN) and an ONS biopsy confirmed a rare case of isolated metastatic melanoma. Our case highlights the clinical and radiographic features that can mimic OPN and delay diagnosis and treatment.

Prostate cancer pathology audits: is central pathology review still warranted?

INTRODUCTION: Estimating the risk of extraprostatic extension and the probability of recurrence with different treatment modalities is common practice in cancer management. A strong predictor of recurrence and organ-confined disease is tumor grade. However, differences exist between genitourinary and non-specialist pathologists in grading prostate cancer. As such, the primary objective of this study was to assess the accuracy of non-specialist prostate cancer biopsies at our institution by analyzing the proportion of cases changing pathologic risk category upon expert review. MATERIALS AND METHODS: Log books from 2003 where our genitourinary pathologists reviewed prostate needle-core biopsies were used to identify cases. A retrospective chart review was completed and descriptive statistics were used to summarize the results for the following synoptic variables: 10 and 20 Gleason Score, number of biopsy sites, overall % involvement, perineural invasion--PNI (present/absent), extracapsular extension--ECE (present/absent). RESULTS: A total of 151 patients were reviewed. Twenty eight percent of cases (42/151) had a change in risk category after expert review. Of the 98 low risk cases, 33% were upgraded in risk category. Of the 24 intermediate risk cases, 12% were upgraded to high risk and none were downgraded. Of the 29 high risk cases, 24% were downgraded in risk category. CONCLUSION: All referred patients should continue to have their pathology centrally reviewed. This practice will help facilitate optimal prostate cancer management and improve quality of care. While these findings are dated given pathologic practice change, such changes do not necessarily equate with disparity elimination or reduction; conclusions can only be drawn with a more recent audit to see if such disparities still exist.

Spine Stereotactic Radiosurgery for Metastatic Pheochromocytoma.

PURPOSE:  Despite aggressive primary treatment, up to 13.5% of patients diagnosed with pheochromocytoma may develop metastases, most often affecting the axial skeleton. Given that systemic therapy options are often inadequate, local therapy remains the cornerstone of palliation for these patients. Historically poor responses to standard fractionated radiotherapy have led to the consideration of stereotactic radiosurgery as an option to overcome potential radioresistance and provide durable local control of these tumors. Here we report our institutional experience in treating spine metastases from pheochromocytoma with spine stereotactic radiosurgery (SSRS). METHODS AND MATERIALS: Our clinical databases were retrospectively reviewed for patients with metastatic pheochromocytoma treated with SSRS from 2000-2017. Seven patients with 16 treated metastatic spinal lesions were identified. Local control was evaluated using magnetic resonance imaging (MRI). Pain and symptom data were assessed to evaluate toxicity using Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The Kaplan-Meier method was used to assess local control and overall survival (OS). RESULTS: Median follow-up for treated lesions was 11 months (range 2.2 - 70.8). Most lesions were treated to a dose of 27 Gy in three fractions (62.5%). Other fractionation schemes included 24 Gy in one fraction (25%), 16 Gy in one fraction (6.3%), and 18 Gy in three fractions (6.3%). Treatment sites included the cervical spine (18.8%), thoracic spine (37.5%), lumbar spine (31.3%), and sacrum (12.5%). The crude local control rate was 93.7%, with one thoracic spine lesion progressing 20.7 months after treatment with 24 Gy in one fraction. Kaplan-Meier OS rates at 1 and 2 years after SSRS were 71.4% and 42.9%, respectively. Most common toxicities included acute grade 1-2 pain and fatigue. There was one case of vertebral fracture in a cervical spine lesion treated to 27 Gy in three fractions, which was managed non-surgically. CONCLUSION: Very few studies have explored the use of SSRS in metastatic pheochromocytoma. Our data suggest this modern radiation modality is effective, safe, and provides durable local control to palliate symptoms and potentially limit further metastatic seeding. Larger patient numbers and longer follow-up will further define the role of SSRS as a treatment option in these patients.

Multi-institutional Investigation: Circulating CD4:CD8 ratio is a prognosticator of response to total skin electron beam radiation in mycosis fungoides.

BACKGROUND AND PURPOSE: A lower proportion of CD8+ tumor infiltrating lymphocytes in mycosis fungoides (MF) patients is associated with worse survival. However, it is not known whether circulating CD4:CD8 ratio is a prognosticator of response to total skin electron beam therapy (TSEBT). METHODS AND MATERIALS: We identified 126 MF patients treated with TSEBT from 2001 to 20014 at two high-volume academic centers. Circulating CD4:CD8 ratio was obtained within 1 week before TSEBT. TSEBT was delivered with 6-9mEV electrons with low (12 Gy) or conventional (≥12 Gy) doses. Treatment response was assessed with the modified Severity Weighted Assessment Tool (mSWAT). Post-treatment mSWAT decrease of ≥75% was classified as near complete response (CR) while mSWAT decrease of <75% was considered partial response (PR). Receiver operating characteristic analysis determined an optimal CD4:CD8 threshold value to predict TSEBT response in the derivation cohort and was applied to an external validation cohort. RESULTS: 71.4% and 28.6% of patients achieved CR and PR after TSEBT. Higher CD4:CD8 ratio predicted poorer response: median CD4:CD8 in patients with PR vs. CR was 4.84 vs. 1.97 (p = 0.002). A threshold CD4:CD8 of 4.42 optimally discriminated in the discovery cohort patients with PR vs. XR (sensitivity 90%, specificity 59%, area under curve (AUC) = 0.71; p = 0.002). Within an independent test cohort (n = 32), 73.9% of patients with CD4:CD8 <4.42 achieved CR vs. 33.3% of those with CD4:CD8 ≥4.42 (p = 0.033). Among all patients with CD4:CD8 <4.42 (n = 73), 74% achieved CR with low-dose TSEBT vs. 93% with conventional dose TSEBT (p = 0.02). On multivariable logistic regression, CD4:CD8 remained a significant independent predictor of TSEBT response in all patients (OR = 0.107, 95% CI 0.395-0.290, p < 0.001). CONCLUSION: Peripheral blood CD4:CD8 ratio was a significant independent predictor of TSEBT response of MF patients as validated in an independent cohort at separate academic center. The potential for CD4:CD8 ratio as a biomarker to inform radiation treatment dosing warrants further investigation.

The contrasting roles of creep and stress relaxation in the time-dependent deformation during in-situ cooling of a nickel-base single crystal superalloy.

Time dependent plastic deformation in a single crystal nickel-base superalloy during cooling from casting relevant temperatures has been studied using a combination of in-situ neutron diffraction, transmission electron microscopy and modelling. Visco-plastic deformation during cooling was found to be dependent on the stress and constraints imposed to component contraction during cooling, which mechanistically comprises creep and stress relaxation. Creep results in progressive work hardening with dislocations shearing the γ' precipitates, a high dislocation density in the γ channels and near the γ/γ' interface and precipitate shearing. When macroscopic contraction is restricted, relaxation dominates. This leads to work softening from a decreased dislocation density and the presence of long segment stacking faults in γ phase. Changes in lattice strains occur to a similar magnitude in both the γ and γ' phases during stress relaxation, while in creep there is no clear monotonic trend in lattice strain in the γ phase, but only a marginal increase in the γ' precipitates. Using a visco-plastic law derived from in-situ experiments, the experimentally measured and calculated stresses during cooling show a good agreement when creep predominates. However, when stress relaxation dominates accounting for the decrease in dislocation density during cooling is essential.

Bevacizumab as an effective treatment for radiation necrosis after radiotherapy for melanoma brain metastases.

Radiation necrosis (RN) is a potential late complication of radiotherapy for intracranial malignancy, which is often associated with significant neurological morbidity. Prolonged treatment with high-dose corticosteroids or surgical resection has been the standard care for RN, but protracted steroid use can lead to significant side effects and surgical resection is not always feasible. The antivascular endothelial growth factor monoclonal antibody bevacizumab induces clinical and radiographic improvements in RN, with overall good tolerance. However, evidence supporting its use for RN in melanoma brain metastases is minimal, likely secondary to concern for intracranial bleeding. Immunotherapy is now one of the most commonly used and effective therapies for metastatic melanoma. A higher risk of RN has been reported with immunotherapy, making alternative treatment for RN in this population a priority, especially as prolonged use of steroids may counteract the treatment efficacy of immunotherapy. We report on seven melanoma patients who developed RN after stereotactic radiosurgery with or without whole-brain radiation therapy who were treated with 2-6 doses of bevacizumab. All patients experienced improvements in symptoms and quality of life, with a concurrent improvement in imaging in six patients. Furthermore, bevacizumab was well tolerated and none of the seven patients experienced intracranial or extracranial bleeding. Our series suggests that in selected melanoma brain metastases patients, bevacizumab may be a safe and effective treatment for RN, especially for those who are undergoing immunotherapy, and should be further evaluated in a prospective setting.

Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control.

BACKGROUND: Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. MATERIAL AND METHODS: Multi-institutional retrospective analysis was conducted of ninety-nine metastatic melanoma patients from 2007 to 2014 treated with ipilimumab who later received stereotactic radiosurgery (SRS) for new brain metastases that developed after starting immunotherapy. All patients had complete blood count acquired before SRS. Primary outcomes were intracranial disease control and overall survival (OS). RESULTS: The median follow-up time was 15.5months. In the MD Anderson cohort, patients who received SRS after 5.5months (n=20) of their last dose of ipilimumab had significantly worse intracranial control than patients who received SRS within 5.5months (n=51) (median 3.63 vs. 8.09months; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.03-4.16, p=0.041). OS was not different between the two arms. The improvement in intracranial control was confirmed in an independent validation cohort of 28 patients treated at Yale-New Haven Hospital. Circulating absolute lymphocyte count before SRS predicted for treatment response as those with baseline counts >1000/µL had reduced risk of intracranial recurrence compared with those with ≤1000/µL (HR 0.46, 95% CI 0.0.23-0.94, p=0.03). CONCLUSIONS: In this multi-institutional study, patients who received SRS for new brain metastases within 5.5months after ipilimumab therapy had better intracranial disease control than those who received SRS later. Moreover, higher circulating lymphocyte count was associated with improved intracranial disease control.

Combining Radiation Therapy with Immune Checkpoint Blockade for Central Nervous System Malignancies.

Malignancies of the central nervous system (CNS), particularly glioblastoma and brain metastases from a variety of disease sites, are difficult to treat despite advances in multimodality approaches consisting of surgery, chemotherapy, and radiation therapy (RT). Recent successes of immunotherapeutic strategies including immune checkpoint blockade (ICB) via anti-PD-1 and anti-CTLA-4 antibodies against aggressive cancers, such as melanoma, non-small cell lung cancer, and renal cell carcinoma, have presented an exciting opportunity to translate these strategies for CNS malignancies. Moreover, via both localized cytotoxicity and systemic proinflammatory effects, the role of RT in enhancing antitumor immune response and, therefore, promoting tumor control is being re-examined, with several preclinical and clinical studies demonstrating potential synergistic effect of RT with ICB in the treatment of primary and metastatic CNS tumors. In this review, we highlight the preclinical evidence supporting the immunomodulatory effect of RT and discuss the rationales for its combination with ICB to promote antitumor immune response. We then outline the current clinical experience of combining RT with ICB in the treatment of multiple primary and metastatic brain tumors. Finally, we review advances in characterizing and modifying tumor radioimmunotherapy responses using biomarkers and microRNA (miRNA) that may potentially be used to guide clinical decision-making in the near future.

Teaching facial fracture repair: A novel method of surgical skills training using three-dimensional biomodels.

BACKGROUND: The facial fracture biomodel is a three-dimensional physical prototype of an actual facial fracture. The biomodel can be used as a novel teaching tool to facilitate technical skills training in fracture reduction and fixation, but more importantly, can help develop diagnostic and management competence. OBJECTIVE: To introduce the 'facial fracture biomodel' as a teaching aid, and to provide preliminary evidence of its effectiveness in teaching residents the principles of panfacial fracture repair. METHODS: Computer three-dimensional image processing and rapid prototyping were used to generate an accurate physical model of a panfacial fracture, mounted in a silicon 'soft tissue' base. Senior plastic surgery residents in their third, fourth and fifth years of training across Canada were invited to participate in a workshop using this biomodel to simulate panfacial fracture repair. A short didactic presentation outlining the 'patient's' clinical and radiological findings, and key principles of fracture repair, was given by a consultant plastic surgeon before the exercise. The residents completed a pre- and postbiomodel questionnaire soliciting information regarding background, diagnosis and management, and feedback. RESULTS: A total of 29 residents completed both pre- and postbiomodel questionnaires. Statistically significant results were found in the following areas: diagnosis of all fracture patterns (P=8.2×10(-7) [t test]), choice of incisions for adequate exposure (P=0.04 [t test]) and identifying sequence of repair (P=0.019 [χ(2) test]). Subjective evaluation of workshop effectiveness revealed a statistically significant increase in 'comfort level' only among third year trainees. Overall, positive feedback was reported among all participants. CONCLUSIONS: Biomodelling is a promising ancillary teaching aid that can assist in teaching residents technical skills, as well as how to assess and plan surgical repair.

HISTORIQUE: Le biomodèle de fracture au visage est un prototype physique tridimensionnel de véritable fracture au visage. Il peut être utilisé comme outil d'enseignement novateur pour faciliter l'enseignement des habiletés techniques afin de réduire et fixer les fractures, mais surtout, pour acquérir des compétences de diagnostic et de prise en charge. OBJECTIF: Présenter le « biomodèle de fracture au visage ¼ comme aide à l'enseignement et fournir des données préliminaires de son efficacité à enseigner aux résidents les principes de la réparation des fractures panfaciales. MÉTHODOLOGIE: Le traitement informatique d'images tridimensionnelles et le prototypage rapide ont été utilisés pour générer un modèle physique précis de fracture panfaciale, monté sur une base de « tissus mous ¼ de silicone. Les résidents seniors en chirurgie plastique de troisième, quatrième et cinquième années du Canada ont été invités à participer à un atelier au moyen de ce biomodèle pour simuler la réparation d'une fracture panfaciale. Avant l'exercice, un plasticien consultant a fait une courte présentation didactique soulignant les observations cliniques et radiologiques du « patient ¼ et les principaux principes de la réparation de la fracture. Les résidents ont rempli un questionnaire avant et après avoir utilisé le biomodèle, contenant leurs commentaires et de l'information sur l'expérience, le diagnostic et la prise en charge. RÉSULTATS: Au total, 29 résidents ont rempli le questionnaire avant et après le biomodèle. Des résultats statistiquement significatifs ont été constatés dans les secteurs suivants : diagnostic de tous les profils de fracture (P=8,2×10−7 [test t]), choix d'incisions pour une exposition adéquate (P=0,04 [test t]) et détermination de la séquence de réparation (P=0,019 [test χ2]). D'après l'évaluation subjective de l'efficacité de l'atelier, seuls les résidents de troisième année présentaient une augmentation statistiquement significative du « niveau de confort ¼. Dans l'ensemble, tous les participants ont fait des commentaires positifs. CONCLUSIONS: Le biomodélisation est une aide auxiliaire à l'enseignement prometteuse qui peut contribuer à enseigner aux résidents les habiletés techniques, de même que l'évaluation et la planification des réparations chirurgicales.

Safety of laparoscopic and open approaches for repair of the unilateral primary inguinal hernia: an analysis of short-term outcomes.

BACKGROUND: Primary laparoscopic repair of unilateral inguinal hernias has not achieved widespread recognition mainly because of concerns over safety. METHODS: Prospective cohort study using the American College of Surgeons National Surgery Quality Improvement Program between 2005 and 2010. Complications in patients undergoing unilateral first-time, elective laparoscopic unilateral inguinal hernia repair (LIHR) were compared with open inguinal hernia repair (OIHR). RESULTS: Of 37,645 identified patients, 6,356 (16.9%) underwent LIHR and 31,289 (83.1%) underwent OIHR. Both groups had similar 30-day overall complications, major complications, and mortality rates: 62 (1.0%) vs 307 (1.0%), P = 1.00; 31 (.5%) vs 173 (.5%), P = .57; and 1 (.02%) vs 16 (.05%), P = .34, respectively. Using multivariable logistic regression, overall complications showed no difference, OR 1.01 (95% CI .76 to 1.34; P = .94), as did major complications, OR .90 (95% CI .61 to 1.34; P = .62), although favoring the LIHR group, where OR and CI represent the odss ratio and confidence intervals. CONCLUSION: These data demonstrate no significant difference between elective unilateral LIHR and OIHR with regard to 30-day morbidity and mortality.

Radiation treatment of bladder squamous cell carcinoma in a patient with spina bifida: A case report.

Bladder cancer is the sixth most common cancer in Canada. While most patients present with transitional cell carcinoma, few present with squamous cell carcinoma (SCC). Risk factors for SCC include a history of chronic urinary tract infection, urothelial inflammation and indwelling catheters. We present the management of a patient with locally advanced SCC of the bladder.

Modern palliative radiation treatment: do complexity and workload contribute to medical errors?

PURPOSE: To examine whether treatment workload and complexity associated with palliative radiation therapy contribute to medical errors. METHODS AND MATERIALS: In the setting of a large academic health sciences center, patient scheduling and record and verification systems were used to identify patients starting radiation therapy. All records of radiation treatment courses delivered during a 3-month period were retrieved and divided into radical and palliative intent. "Same day consultation, planning and treatment" was used as a proxy for workload and "previous treatment" and "multiple sites" as surrogates for complexity. In addition, all planning and treatment discrepancies (errors and "near-misses") recorded during the same time frame were reviewed and analyzed. RESULTS: There were 365 new patients treated with 485 courses of palliative radiation therapy. Of those patients, 128 (35%) were same-day consultation, simulation, and treatment patients; 166 (45%) patients had previous treatment; and 94 (26%) patients had treatment to multiple sites. Four near-misses and 4 errors occurred during the audit period, giving an error per course rate of 0.82%. In comparison, there were 10 near-misses and 5 errors associated with 1100 courses of radical treatment during the audit period. This translated into an error rate of 0.45% per course. An association was found between workload and complexity and increased palliative therapy error rates. CONCLUSIONS: Increased complexity and workload may have an impact on palliative radiation treatment discrepancies. This information may help guide the necessary recommendations for process improvement for patients who require palliative radiation therapy.

Outcome and toxicity of postoperative short course adjuvant radiation and chemotherapy following resection of adenocarcinoma of the rectum.

A retrospective review has been performed to assess the outcome and toxicity of post-operative adjuvant therapy of 25 Gy/5 fractions/1 week following resection of stage II and III rectal cancer. Forty patients were treated between August 1992 and May 1995. The ages ranged from 42 to 79 (median 63); 32 were male (80%). At last follow up 32 were alive with 0.9 to 11.3 years of follow-up (median 6.6 years). The 5-year actuarial survival was 76% (95% CI: 62-91%). The local relapse free rate was 73% (95% CI: 58-88). Seven patients experienced grade 3 or 4 early toxicity. Three patients had grade 2 or 3 late toxicity. Although treatment was well tolerated, the local relapse rate observed was high. In view of the changes in surgical and pathological techniques in the last decade, further studies are required to determine the merits or otherwise of postoperative Short Course Adjuvant Radiation.