Publications by authors named "Shun Wong"

83 Publications

Spatiotemporal Mapping of Early Volume Loss in the Mouse Brain after Cranial Irradiation.

Radiat Res 2021 10;196(4):394-403

Departments of Medical Biophysics, University of Toronto, Ontario, Canada.

Sequelae after pediatric cranial radiotherapy (CRT) result in long-term changes in brain structure. While past evidence indicates regional differences in brain volume change, it remains unclear how these manifest in the time course of change after CRT. In this study, we spatiotemporally characterized volume losses induced by cranial irradiation in a mouse model, with a dense sampling of measurements over the first week postirradiation. Wild-type mice received whole-brain irradiation (7 Gy) or sham irradiation (0 Gy) at 16 days of age. In vivo magnetic resonance imaging was performed at one time point before, and 2-4 time points postirradiation in each mouse, with a particular focus on sampling during the first week after cranial irradiation. Volume changes across the brain were measured, and the degree and timing of volume loss were quantified across structures from a predefined atlas. Volume measurements across the brain after cranial irradiation revealed a ∼2-day delay in which volume is not significantly altered, after which time volume change proceeds over the course of four days. Volume losses were 3% larger and emerged 40% slower in white matter than in gray matter. Large volume loss was also observed in the ventricles. Differences in the timing and magnitude of volume change between gray and white matter after cranial irradiation were observed. These results suggest differences in the mechanism and/or kinetics underlying the associated radio-response, which may have implications in development.
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http://dx.doi.org/10.1667/RADE-21-00013.1DOI Listing
October 2021

Metformin effects on brain development following cranial irradiation in a mouse model.

Neuro Oncol 2021 09;23(9):1523-1536

Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

Background: Cranial radiation therapy (CRT) is a mainstay of treatment for malignant pediatric brain tumors and high-risk leukemia. Although CRT improves survival, it has been shown to disrupt normal brain development and result in cognitive impairments in cancer survivors. Animal studies suggest that there is potential to promote brain recovery after injury using metformin. Our aim was to evaluate whether metformin can restore brain volume outcomes in a mouse model of CRT.

Methods: C57BL/6J mice were irradiated with a whole-brain radiation dose of 7 Gy during infancy. Two weeks of metformin treatment started either on the day of or 3 days after irradiation. In vivo magnetic resonance imaging was performed prior to irradiation and at 3 subsequent time points to evaluate the effects of radiation and metformin on brain development.

Results: Widespread volume loss in the irradiated brain appeared within 1 week of irradiation with limited subsequent recovery in volume outcomes. In many structures, metformin administration starting on the day of irradiation exacerbated radiation-induced injury, particularly in male mice. Metformin treatment starting 3 days after irradiation improved brain volume outcomes in subcortical regions, the olfactory bulbs, and structures of the brainstem and cerebellum.

Conclusions: Our results show that metformin treatment has the potential to improve neuroanatomical outcomes after CRT. However, both timing of metformin administration and subject sex affect structure outcomes, and metformin may also be deleterious. Our results highlight important considerations in determining the potential benefits of metformin treatment after CRT and emphasize the need for caution in repurposing metformin in clinical studies.
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http://dx.doi.org/10.1093/neuonc/noab131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408860PMC
September 2021

Metabolic Regulation of Hippocampal Neuronal Development and Its Inhibition After Irradiation.

J Neuropathol Exp Neurol 2021 Apr;80(5):467-475

From the Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

5'-Adenosine monophosphate-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis, plays a role in cell fate determination. Whether AMPK regulates hippocampal neuronal development remains unclear. Hippocampal neurogenesis is abrogated after DNA damage. Here, we asked whether AMPK regulates adult hippocampal neurogenesis and its inhibition following irradiation. Adult Cre-lox mice deficient in AMPK in brain, and wild-type mice were used in a birth-dating study using bromodeoxyuridine to evaluate hippocampal neurogenesis. There was no evidence of AMPK or phospho-AMPK immunoreactivity in hippocampus. Increase in p-AMPK but not AMPK expression was observed in granule neurons and subgranular neuroprogenitor cells (NPCs) in the dentate gyrus within 24 hours and persisted up to 9 weeks after irradiation. AMPK deficiency in Cre-lox mice did not alter neuroblast and newborn neuron numbers but resulted in decreased newborn and proliferating NPCs. Inhibition of neurogenesis was observed after irradiation regardless of genotypes. In Cre-lox mice, there was further loss of newborn early NPCs and neuroblasts but not newborn neurons after irradiation compared with wild-type mice. These results are consistent with differential negative effect of AMPK on hippocampal neuronal development and its inhibition after irradiation.
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http://dx.doi.org/10.1093/jnen/nlab014DOI Listing
April 2021

Round Cell Sarcoma with EWSR1-PATZ1 Fusion in the Face of a Five-Year-Old Boy: Report of a Case with Unusual Histologic Features.

Head Neck Pathol 2021 Dec 18;15(4):1350-1358. Epub 2021 Jan 18.

Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.

Round cell sarcomas with EWSR1-PATZ1 fusion are rare polyphenotypic sarcomas that typically show both neural and myogenic differentiation on immunohistochemistry. The histology features lobular admixture of cellular fascicles of relatively monotonous spindle cells and small blue round cells separated by fibrotic stroma. The clinical behavior of EWSR1-PATZ1 sarcoma is uncertain currently with mixed outcomes reported even in cases with metastases. We herein report an additional case of EWSR1-PATZ1 fusion-related round cell sarcoma in the face of a 5-year-old boy with unusual histologic features of pale zones, rosette/gland-like structures and expression of epithelial markers. Fluorescent in-situ hybridization study (FISH) using EWSR1 breakapart probes was negative and molecular study with RNA sequencing was required to confirm the diagnosis. These findings highlight the diagnostic challenge and potential pitfall of FISH study in EWSR1-PATZ1 sarcoma. Further studies are required to increase the understanding of their behavior, morphologic spectrum and molecular features that will help devise new treatment strategies to these rare tumours.
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http://dx.doi.org/10.1007/s12105-021-01285-wDOI Listing
December 2021

Salvage surgery for locally recurrent anal cancer after intensity modulated radiation therapy with concurrent chemotherapy.

Cancer Treat Res Commun 2021 17;26:100287. Epub 2020 Dec 17.

Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada. Electronic address:

Introduction: Chemoradiation (CRT) with intensity modulated radiation treatment (IMRT) has become the standard for anal cancer. In patients who fail this treatment modality, salvage surgery with abdominal perineal resection can result in long term cancer control. We aimed to evaluate a single centre's experience of salvage surgery for local recurrence since the introduction of IMRT.

Materials And Methods: A retrospective chart review was performed of all patients who underwent definitive CRT for anal carcinoma at a single tertiary referral center since IMRT became standard in 2009. Patients with recurrent or persistent disease after treatment who underwent salvage surgery were included. Details of CRT, salvage surgery and surgical complications, patterns of recurrence after surgery, and survival data were collected and described.

Results: Between 2009-2018, 181 patients underwent definitive treatment using IMRT for anal carcinoma. Of 26 patients who had locoregional recurrent or persistent disease, 14 underwent salvage surgery. Nine had multi-visceral resection and 8 required autologous flap reconstruction. Twelve patients had resections with clear margins and 2 had microscopic positive margins. Twelve patients (86%) experienced post-operative complications, and eight (57%) had perineal wound complications. After salvage, four patients (29%) recurred locally. None of the 8 patients with rpT2 disease recurred. After salvage surgery, 5-year disease free survival was 68.4% and 5-year overall survival was 75%.

Conclusion: Following IMRT based chemoradiation, salvage surgery has high rates of surgical complications; however disease free and overall survival results are excellent particularly for small recurrences.
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http://dx.doi.org/10.1016/j.ctarc.2020.100287DOI Listing
December 2020

Clinical and pathological characterization of FLNC-related myofibrillar myopathy caused by founder variant c.8129G>A in Hong Kong Chinese.

Clin Genet 2020 05 23;97(5):747-757. Epub 2020 Feb 23.

Department of Pathology, Queen Elizabeth Hospital, Hong Kong.

FLNC-related myofibrillar myopathy could manifest as autosomal dominant late-onset slowly progressive proximal muscle weakness; involvements of cardiac and/or respiratory functions are common. We describe 34 patients in nine families of FLNC-related myofibrillar myopathy in Hong Kong ethnic Chinese diagnosed over the last 12 years, in whom the same pathogenic variant c.8129G>A (p.Trp2710*) was detected. Twenty-six patients were symptomatic when diagnosed; four patients died of pneumonia and/or respiratory failure. Abnormal amorphous material or granulofilamentous masses were detected in half of the cases, with mitochondrial abnormalities noted in two-thirds. We also show by haplotype analysis the founder effect associated with this Hong Kong variant, which might have occurred 42 to 71 generations ago or around Tang and Song dynasties, and underlain a higher incidence of myofibrillar myopathy among Hong Kong Chinese. The late-onset nature and slowly progressive course of the highly penetrant condition could have significant impact on the family members, and an early diagnosis could benefit the whole family. Considering another neighboring founder variant in FLNC in German patients, we advocate development of specific therapies such as chaperone-based or antisense oligonucleotide strategies for this particular type of myopathy.
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http://dx.doi.org/10.1111/cge.13715DOI Listing
May 2020

Intensity Modulated Radiation Therapy Plus Etoposide/Cisplatin for Patients With Limited Advanced Unresectable Thymic Epithelial Tumors: A Prospective Phase 2 Study.

Int J Radiat Oncol Biol Phys 2020 05 25;107(1):98-105. Epub 2020 Jan 25.

Department of Radiation Oncology, Shanghai Cancer Center, Fudan University, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Electronic address:

Purpose: This prospective phase 2 study evaluated the efficacy and safety of intensity modulated radiation therapy plus etoposide/cisplatin (EP) for patients with unresectable thymic epithelial tumors (TETs).

Methods And Materials: Patients with limited advanced unresectable TETs whose lesions could be encompassed within radiation fields were enrolled in this study. Two cycles of EP (75 mg/m etoposide and 25 mg/m cisplatin on days 1-3 and days 29-31) were administered concurrently with radiation therapy, followed by 2 cycles after radiation therapy. The primary endpoint was the objective response rate. The secondary endpoints were the progression-free survival rate, overall survival rate, and incidence of adverse events.

Results: Fifty-six patients were enrolled between June 2011 and May 2018. Twenty-two and 34 patients had thymomas and thymic carcinomas, respectively. The median age was 52 (range, 21-76) years, and 30 patients (53.6%) were men. Eight patients (14.3%) had stage III tumors, 6 (10.7%) had stage IVA tumors, and 42 (75.0%) had stage IVB tumors. The objective response rate was 85.7% (95% confidence interval, 76.3%-95.2%). With a median follow-up of 46 (range, 7-101) months, the 1-, 2-, and 5-year progression-free survival rates were 66.1%, 48.0%, and 29.5%, and the 1-, 2-, and 5-year overall survival rates were 91.0%, 76.2%, and 56.2%, respectively. The most common grade 3 to 4 adverse event was leukopenia (42.9%). Pulmonary fibrosis was also observed (5.3%).

Conclusions: Because intensity modulated radiation therapy with EP is effective and safe for limited advanced unresectable TETs, it could be a suitable treatment option for such patients.
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http://dx.doi.org/10.1016/j.ijrobp.2019.12.045DOI Listing
May 2020

Metabolic Regulation of Hippocampal Neuroprogenitor Apoptosis After Irradiation.

J Neuropathol Exp Neurol 2020 03;79(3):325-335

From the Sunnybrook Health Sciences Centre.

The tumor suppressor p53 is an important regulator of cell fate response after DNA damage. Cell fate response following metabolic stresses has also been linked to p53-dependent pathways. In this study, we asked if 5'-adenosine monophosphate-activated protein kinase (AMPK), the master sensor of cellular energy balance, played a role in p53-dependent apoptosis of neural progenitor cells (NPCs) in the hippocampus after irradiation. Adult mice with targeted disruption of p53 or prkaa2 (gene that encodes AMPKα) in the brain were used to determine the role of p53 and AMPK, respectively, in radiation-induced apoptosis of NPCs in the hippocampus. The p53-dependent apoptosis of NPCs was associated with an increase in phospho-AMPK expression in the dentate gyrus at 8 hours after irradiation. Activation of AMPK was seen in granule neurons and subgranular NPCs. Compared with wildtype mice, apoptosis of NPCs was significantly attenuated in AMPK deficient (nestinCre: prkaa2fl/fl) mice after irradiation. AMPK deficiency did not however alter p53 activation in NPCs after irradiation. We conclude that AMPK may regulate apoptosis of hippocampal NPCs after irradiation. These findings suggest that cellular metabolism may play a role in determining cell fate response such as apoptosis after DNA damage in NPCs.
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http://dx.doi.org/10.1093/jnen/nlz108DOI Listing
March 2020

Spinal Cord Dose Tolerance to Stereotactic Body Radiation Therapy.

Int J Radiat Oncol Biol Phys 2021 05 10;110(1):124-136. Epub 2019 Oct 10.

Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, New York.

Spinal cord tolerance data for stereotactic body radiation therapy (SBRT) were extracted from published reports, reviewed, and modelled. For de novo SBRT delivered in 1 to 5 fractions, the following spinal cord point maximum doses (D) are estimated to be associated with a 1% to 5% risk of radiation myelopathy (RM): 12.4 to 14.0 Gy in 1 fraction, 17.0 Gy in 2 fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4 fractions, and 25.3 Gy in 5 fractions. For reirradiation SBRT delivered in 1 to 5 fractions, reported factors associated with a lower risk of RM include cumulative thecal sac equivalent dose in 2 Gy fractions with an alpha/beta of 2 (EQD2) D ≤70 Gy; SBRT thecal sac EQD2 D ≤25 Gy, thecal sac SBRT EQD2 D to cumulative EQD2 D ratio ≤0.5, and a minimum time interval to reirradiation of ≥5 months. Larger studies containing complete institutional cohorts with dosimetric data of patients treated with spine SBRT, with and without RM, are required to refine RM risk estimates.
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http://dx.doi.org/10.1016/j.ijrobp.2019.09.038DOI Listing
May 2021

Outcomes of extra-cranial stereotactic body radiotherapy for metastatic colorectal cancer: Dose and site of metastases matter.

Radiother Oncol 2020 01 19;142:236-245. Epub 2019 Sep 19.

Sunnybrook Odette Cancer Centre, Department of Radiation Oncology, University of Toronto, Canada.

Background And Purpose: To review the clinical outcomes following the use of stereotactic body radiotherapy (SBRT) in patients with metastatic colorectal cancer (mCRC) from a large academic institution.

Materials And Methods: Patients with mCRC treated with extracranial SBRT between 2008 and 2016 were identified from an institutional database. Treatment indications were oligometastases, oligoprogression, and local control of dominant tumors. Endpoints included local progression (LP), overall survival (OS), progression-free survival (PFS), and cumulative incidence of starting or changing systemic therapy (SCST). Univariate and multivariable analyses (MVA) were performed to identify predictive factors.

Results: One hundred and sixty-five patients (262 lesions treated) were included. The 2-year cumulative incidence of LP was 23.8%. Lower SBRT doses and tumor location in the liver were significant predictors of LP on MVA. Median OS was 49.3 months, 19.3 months, and 9.0 months for oligometastases, oligoprogression, and local control of dominant tumors, respectively. Primary tumor not in situ, smaller tumors, fewer lines of previous systemic therapy, lower CEA, and oligometastases treatment indications were significant predictors of higher OS on MVA. For the entire cohort, median PFS was 9.9 months, while oligometastatic patients had a median PFS of 12.4 months. 2-year cumulative incidence of SCST was 41.7%.

Conclusions: Survival outcomes are favorable after SBRT for mCRC patients. A significant proportion of patients did not have a change in systemic therapy after SBRT. Higher doses are required to obtain the best local control. Efforts should be made to better optimize SBRT delivery for liver metastases given their higher local failure rate.
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http://dx.doi.org/10.1016/j.radonc.2019.08.018DOI Listing
January 2020

Founder Mutation c.1516A>C in KLHL40 Is a Frequent Cause of Nemaline Myopathy With Hyponatremia in Ethnic Chinese.

J Neuropathol Exp Neurol 2019 09;78(9):854-864

Department of Pathology, Princess Margaret Hospital.

KLHL40-related nemaline myopathy is a severe autosomal recessive muscle disorder. The current study describes 4 cases of KLHL40-related nemaline myopathy in Hong Kong ethnic Chinese presenting within 3 years, which are confirmed with clinicopathologic features and genetic studies. The incidence is estimated to be at least 1 in 45 226 livebirths (at least 1 in 41 608 among ethnic Chinese livebirths) in Hong Kong. Hyponatremia appears to be another common feature in these patients. Salient histological features include nemaline bodies ranging from 200 to 500 nm in diameters on ultrastructural examination as well as negative KLHL40 immunohistochemistry; type II fiber predominance is obvious in 2 cases. We demonstrate the founder effect associated with genetic variant c.1516A>C (p.Thr506Pro) by polymorphic marker analysis, which revealed a 0.56-0.75-Mb or 0.41-0.78-cM shared haplotype encompassing the disease allele. The mutation is believed to have occurred around 412 generations ago or 6220 BCE, as estimated using DMLE+ and a formula described by Boehnke. We believe the founder variant might possibly underlie a sizable portion of nemaline myopathy in ethnic Chinese. Analysis of the KLHL40 gene may be considered as the first-tier testing of congenital myopathy in this ethnic group.
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http://dx.doi.org/10.1093/jnen/nlz056DOI Listing
September 2019

A Humanist Neurosurgeon: A Legacy of Dr. Roy Selby.

World Neurosurg 2019 Aug 28;128:149-157. Epub 2019 Apr 28.

N.N. Burdenko National Medical Research Centre for Neurosurgery, Moscow, Russia.

The article is dedicated to the life and work of Dr. Roy Selby (1930-2002), an American neurosurgeon who founded neurosurgery in Malaysia. Dr. Selby stayed in Malaysia from July 1963 to May 1970. He opened the first neurosurgical department at the general hospital in Kuala Lumpur and established a training program under which Malaysian physicians and nurses were sent to neurosurgery centers in the United States and Canada. Some physicians came back and headed local neurosurgical units. On his return to the United States, Dr. Selby practiced neurosurgery until 1986, when he had to give it up due to the impact of progressive congestive heart failure. From 1986 to 1994, Dr. Selby taught graduate courses in the Department of Psychology at East Texas State University, Texarkana, Texas. He was a pioneer of spinal surgery and founded the Lumbar Spine Society. Dr. Selby was a world citizen neurosurgeon and advocated international standards of training in neurosurgery. From 1985 to 1994, he was chairman of the Archives Committee of the American Association of Neurological Surgeons. Dr. Selby serves as a model of a physician as a humanist.
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http://dx.doi.org/10.1016/j.wneu.2019.04.178DOI Listing
August 2019

Flexi-Myo Panel Strategy: Genomic Diagnoses of Myopathies and Muscular Dystrophies by Next-Generation Sequencing.

Genet Test Mol Biomarkers 2020 Feb 22;24(2):99-104. Epub 2019 Mar 22.

Department of Pathology, Princess Margaret Hospital, Hong Kong, China.

Muscle disorders are clinically and genetically heterogeneous. Investigations, including plasma creatine kinase, electromyography, and nerve conduction velocity studies are often nonspecific, whereas muscle biopsy might be limited by sampling bias and variable histopathology. Next-generation sequencing is now generally considered an important diagnostic tool for muscle disorders, with decreased costs and improved diagnostic yield. Inclusion of a large number of genes in the analysis might, however, generate a large number of ambiguous results and create unnecessary confusion for clinicians and patients. An ethnic Chinese patient presented at age 10 with tip-toe walking. Upon examination the patient had a waddling gait, a tight Achilles tendon with . A muscle biopsy showed the presence of minicores with disruption of the myofibrillary network and Z-bands. Sequencing was performed using the Flexi-Myo panel, which provides coverage for 85 myopathic genes. Reporting of sequencing results was decided by the responsible chemical pathologists based on the available clinical and genetic information. A previously identified heterozygous in-frame deletion was detected in , which confirmed the diagnosis of Laing myopathy. No variants of uncertain significance required reporting. We describe the effectiveness of our Flexi-Myo panel approach for the diagnosis of muscle disorders, which confirmed diagnosis of Laing myopathy in what had been a clinically ambiguous presentation. This approach enables efficient genomic testing for muscle diseases in adults and children with satisfactory diagnostic yield and sufficient sensitivity, whereas avoiding the reporting of ambiguous results. Similar strategies might also be implemented for other groups of disorders.
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http://dx.doi.org/10.1089/gtmb.2018.0185DOI Listing
February 2020

p53 Loss Mitigates Early Volume Deficits in the Brains of Irradiated Young Mice.

Int J Radiat Oncol Biol Phys 2019 02 20;103(2):511-520. Epub 2018 Sep 20.

Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Translational Medicine, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Electronic address:

Purpose: Pediatric cranial radiation therapy results in lasting changes in brain structure. Though different facets of radiation response have been characterized, the relative contributions of each to altered development is unclear. We sought to determine the role of radiation-induced programmed cell death, as mediated by the Trp53 (p53) gene, on neuroanatomic development.

Methods And Materials: Mice having a conditional knockout of p53 (p53KO) or wildtype p53 (WT) were irradiated with a whole-brain dose of 7 Gy (IR; n = 30) or 0 Gy (sham; n = 28) at 16 days of age. In vivo magnetic resonance imaging was performed before irradiation and at 4 time points after irradiation, until 3 months posttreatment, followed by ex vivo magnetic resonance imaging and immunohistochemistry. The role of p53 in development was assessed at 6 weeks of age in another group of untreated mice (n = 37).

Results: Neuroanatomic development in p53KO mice was normal. After cranial irradiation, alterations in neuroanatomy were detectable in WT mice and emerged through 2 stages: an early volume loss within 1 week and decreased growth through development. In many structures, the early volume loss was partially mitigated by p53KO. However, p53KO had a neutral or negative impact on growth; thus, p53KO did not widely improve volume at endpoint. Partial volume recovery was observed in the dentate gyrus and olfactory bulbs of p53KO-IR mice, with corresponding increases in neurogenesis compared with WT-IR mice.

Conclusions: Although p53 is known to play an important role in mediating radiation-induced apoptosis, this is the first study to look at the cumulative effect of p53KO through development after cranial irradiation across the entire brain. It is clear that apoptosis plays an important role in volume loss early after radiation therapy. This early preservation alone was insufficient to normalize brain development on the whole, but regions reliant on neurogenesis exhibited a significant benefit.
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http://dx.doi.org/10.1016/j.ijrobp.2018.09.014DOI Listing
February 2019

Synchronous anal canal carcinoma in a heterosexual couple.

BMC Cancer 2018 Sep 10;18(1):884. Epub 2018 Sep 10.

Department of Radiation Oncology, Sunnybrook Health Sciences Centre T-Wing, University of Toronto, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada.

Background: Sexually transmitted Human Papilloma Virus (HPV) infection is a known risk factor for cancer of the anal canal in both men and women.

Case Presentation: We describe a report of synchronous carcinoma of the anal canal in a heterosexual couple. High risk type 16 HPV DNA was detected in both tumors.

Conclusion: Longstanding sexual partners may share risk of HPV-associated anal canal cancer.
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http://dx.doi.org/10.1186/s12885-018-4785-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131756PMC
September 2018

A prospective cohort study of patient-reported vomiting, retching, nausea and antiemetic use during neoadjuvant long-course radiation therapy and concurrent 5-fluorouracil-based chemotherapy for rectal adenocarcinoma.

Clin Transl Radiat Oncol 2018 Mar 5;10:42-46. Epub 2018 Apr 5.

Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

Background And Purpose: Antiemetic guidelines suggest daily prophylaxis with a serotonin receptor antagonist (5-HTRA) as an option for patients receiving long-course neoadjuvant radiation therapy and concurrent 5-fluorouracil-based chemotherapy for rectal cancer, despite the risks that 5-HTRA-induced constipation may pose. We explored the incidence of patient-reported vomiting, retching, nausea and antiemetic intake among patients in this setting to determine if these risks are justified.

Materials And Methods: We carried out a single-centre non-randomised prospective cohort study of adult patients receiving long-course neoadjuvant radiation therapy and concurrent 5-fluorouracil-based chemotherapy for rectal adenocarcinoma. Patients recorded symptoms and medication intake daily until 7 days following treatment completion.

Results: From 33 evaluable patients, we collected 1407 days of patient-reported data. Vomiting was reported by 7 patients (21%), retching by 5(15%) and nausea by 21(64%). No patients were administered prophylactic antiemetics. The median number of days with vomiting was 2, and the cumulative number of days for all affected patients was 22 (1.6% of 1407 evaluable days). There were no differences in PTV or small bowel loop V15Gy, V45Gy and V50Gy volumes between patients that did and did not vomit.

Conclusions: The cumulative incidence of days with vomiting was only 1.6%. 5-HTRA prophylaxis during long-course neoadjuvant treatment seems unnecessary.
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http://dx.doi.org/10.1016/j.ctro.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909027PMC
March 2018

Mapping the contribution and strategic distribution patterns of neuroimaging features of small vessel disease in poststroke cognitive impairment.

J Neurol Neurosurg Psychiatry 2018 09 17;89(9):918-926. Epub 2018 Apr 17.

Chow Yuk Ho Technology Centre for Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China.

Objectives: Individual neuroimaging features of small vessel disease (SVD) have been reported to influence poststroke cognition. This study aimed to investigate the joint contribution and strategic distribution patterns of multiple types of SVD imaging features in poststroke cognitive impairment.

Methods: We studied 145 first-ever ischaemic stroke patients with MRI and Montreal Cognitive Assessment (MoCA) examined at baseline. The local burdens of acute ischaemic lesion (AIL), white matter hyperintensity, lacune, enlarged perivascular space and cross-sectional atrophy were quantified and entered into support vector regression (SVR) models to associate with the global and domain scores of MoCA. The SVR models were optimised with feature selection through 10-fold cross-validations. The contribution of SVD features to MoCA scores was measured by the prediction accuracy in the corresponding SVR model after optimisation.

Results: The combination of the neuroimaging features of SVD contributed much more to the MoCA deficits on top of AILs compared with individual SVD features, and the cognitive impact of different individual SVD features was generally similar. As identified by the optimal SVR models, the important SVD-affected regions were mainly located in the basal ganglia and white matter around it, although the specific regions varied for MoCA and its domains.

Conclusions: Multiple types of SVD neuroimaging features jointly had a significant impact on global and domain cognitive functionings after stroke on top of AILs. The map of strategic cognitive-relevant regions of SVD features may help clinicians to understand their complementary impact on poststroke cognition.
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http://dx.doi.org/10.1136/jnnp-2017-317817DOI Listing
September 2018

Altered brain morphology after focal radiation reveals impact of off-target effects: implications for white matter development and neurogenesis.

Neuro Oncol 2018 05;20(6):788-798

Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Children with brain tumors treated with cranial radiation therapy (RT) often exhibit cognitive late effects, commonly associated with reduced white matter (WM) volume and decreased neurogenesis. The impact of radiation damage in particular regions or tissues on brain development as a whole has not been elucidated.

Methods: We delivered whole-brain or focal radiation (8 Gy single dose) to infant mice. Focal treatments targeted white matter (anterior commissure), neuronal (olfactory bulbs), or neurogenic (subventricular zone) regions. High-resolution ex vivo MRI was used to assess radiation-induced volume differences. Immunohistochemistry for myelin basic protein and doublecortin was performed to assess associated cellular changes within white matter and related to neurogenesis, respectively.

Results: Both whole-brain and focal RT in infancy resulted in volume deficits in young adulthood, with whole-brain RT resulting in the largest deficits. RT of the anterior commissure, surprisingly, showed no impact on its volume or on brain development as a whole. In contrast, RT of the olfactory bulbs resulted in off-target volume reduction in the anterior commissure and decreased subventricular zone neurogenesis. RT of the subventricular zone likewise produced volume deficits in both the olfactory bulbs and the anterior commissure. Similar off-target effects were found in the corpus callosum and parietal cortex.

Conclusions: Our results demonstrate that radiation damage locally can have important off-target consequences for brain development. These data suggest that WM may be less radiosensitive than volume change alone would indicate and have implications for region-sparing radiation treatments aimed at reducing cognitive late effects.
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http://dx.doi.org/10.1093/neuonc/nox211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5961122PMC
May 2018

The effect of prone and supine treatment positions for the pre-operative treatment of rectal cancer on organ-at-risk sparing and setup reproducibility using volumetric modulated arc therapy.

Radiat Oncol 2017 Dec 5;12(1):180. Epub 2017 Dec 5.

Sunnybrook Health Sciences Centre/Odette Cancer Centre, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada.

Background And Purpose: To compare organ-at-risk doses and setup reproducibility using the prone and supine orientations in volumetric modulated arc therapy (VMAT) for rectal cancer.

Materials And Methods: Seventeen consecutive rectal cancer patients undergoing preoperative radiation were selected and setup in either the prone (N = 8) or supine (N = 9) position. All patients were treated using posteriorly-applied VMAT. Bladder and small bowel dose and cone beam CT (CBCT) reproducibility metrics were retrospectively collected.

Results: Dose metrics for bladder and small bowel did not show significant differences between the prone and supine orientations. The prone data had a trend for smaller irradiated volumes than supine for the small bowel at lower doses-V20 (prone: 135 ± 99 cm; supine: 201 ± 162 cm) and V30 (prone: 78 ± 71 cm; supine: 105 ± 106 cm). At higher doses, the trend reversed as exemplified by the small bowel V50.4 (prone: 20 ± 28 cm; supine: 10 ± 14 cm). CBCT data showed that rotational errors in pitch and roll were significantly larger for the prone vs. supine orientation (pitch: 2.0° ± 1.3° vs. 0.8° ± 1.1° p < 0.001; roll: 1.0° ± 0.9° vs. 0.3° ± 0.5°, p < 0.001).

Conclusions: Bladder and small bowel doses were not significantly different when comparing VMAT plans developed for the prone and supine orientations. The supine orientation demonstrated improved setup reproducibility.
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http://dx.doi.org/10.1186/s13014-017-0918-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715653PMC
December 2017

A systematic review of methodologies, endpoints, and outcome measures in randomized trials of radiation therapy-induced nausea and vomiting.

Support Care Cancer 2017 06 31;25(6):2019-2033. Epub 2017 Mar 31.

Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

Purpose: Clinical trials in radiation therapy-induced nausea and vomiting (RINV) appear to have varied methodologies, endpoints, and outcome measures. This complicates trial comparisons, weakens practice guideline recommendations, and contributes to variability in supportive care patterns of practice. We systematically reviewed RINV trials to describe and compare their pertinent design features.

Materials And Methods: Ovid versions of the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, EMBASE, and MEDLINE to January/February 2017 were searched for adult phase III trials of RINV management strategies. Key abstracted data included trial interventions and eligibility criteria, standard radiation therapy (RT) metrics, symptom assessment procedures, symptom definitions and grading systems, pre-specified and reported endpoints, and other outcome measures.

Results: From 1166 references identified in the initial database search, we selected 34 trials for analysis that collectively randomized 4529 patients (median 61, range 11-1492). Twenty-eight trials (82%) were published prior to the year 2000. Twenty-seven trials (79%) involved multiple fraction RT and 7 (21%) single fraction RT. Twenty-four trials (71%) evaluated prophylactic interventions, 9 (26%) rescue interventions, and 1 trial did not specify. Thirty-three trials (97%) evaluated pharmacologic interventions. Twenty trials (59%) had patient report symptoms, 5 (15%) healthcare professionals or researchers, and 10 (29%) did not specify. Nausea was not defined in any trial but was reported as a stand-alone symptom in 26 trials (76%) and was graded in 20 (59%), with categorical qualitative scales being the most common method. Vomiting was defined in 3 trials (9%), was reported as a stand-alone symptom in 17 (47%), and was graded in 7 (21%), with continuous numerical scales being the most common method. Retching was defined in 3 trials, was not reported as a stand-alone symptom in any trial, and was graded in 1 (3%). Twenty-one trials (62%) created compound symptom measures that combined individual symptoms. Fifteen trials (44%) reported "emetic episode/event" measures but only 9 defined them. Seventeen trials (50%) reported complicated endpoints (e.g., "response," "control," "success") that combined multiple symptom or compound symptom measures, but 7 did not define them comprehensively. Ten trials (29%) defined a primary endpoint a priori.

Conclusions: Methodologies, endpoints, and outcome measures varied considerably among 34 randomized trials in RINV.
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http://dx.doi.org/10.1007/s00520-017-3685-9DOI Listing
June 2017

Cellular Senescence in Mouse Hippocampus After Irradiation and the Role of p53 and p21.

J Neuropathol Exp Neurol 2017 04;76(4):260-269

University of Toronto, The Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

Diverse stress signals including irradiation may trigger cellular senescence. We asked whether irradiation induced senescence in mouse hippocampus, and whether p53 or p21 played a role in this response. Following whole-brain irradiation, polymerase chain reaction (PCR) arrays for senescence-associated genes showed increased expression of CDKN1A (p21) and CDKN2A (p19ARF) in mouse hippocampus at 9 weeks. Upregulation of p21 and p19ARF was confirmed using real-time PCR, which also demonstrated increased CDKN2A/p16INKa expression after irradiation. No altered regulation of another 17 senescence-associated genes was observed after irradiation. Immunohistochemistry revealed increased nuclear expression of p16INK4A, p19ARF, p53, p21, phosphorylated p38 (pp38), 4-hydroxy-2-nonenal, and interleukin-6 (IL6) in granule cells of dentate gyrus after irradiation. Increased p16 nuclear immunoreactivity was further observed in type -1 cells, the putative neural stem cells. γ-phosphorylated-histone-2A nuclear foci were also seen in dentate gyrus 9 weeks postirradiation. In nonirradiated mice knockout of the TRP53 or p21 gene, there was increased p16INK4A, p19ARF, and IL6, but not pp38 in dentate gyrus. We conclude that irradiation induces transcript and protein expression profile alterations in mouse dentate gyrus consistent with the senescence phenotype. Absence of p53 or p21 results in increase in baseline expression of senescence markers with no further increase in expression after irradiation.
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http://dx.doi.org/10.1093/jnen/nlx006DOI Listing
April 2017

Catalytic Direct C2-Alkenylation of Oxazoles at Parts per Million Levels of Palladium/PhMezole-Phos Complex.

Org Lett 2016 Oct 11;18(20):5300-5303. Epub 2016 Oct 11.

State Key Laboratory of Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University , Hung Hom, Kowloon 852, Hong Kong.

General direct C2-alkenylation of oxazoles is reported using alkenyl tosylates at parts per million levels of palladium catalyst. From a series of ligands screened, PhMezole-Phos emerged as the promising ligand candidate to facilitate this reaction. Significantly, the method is scalable and exhibits excellent substrate tolerance. Highly sterically hindered substrates and small vinyl tosylate can be coupled successfully. Moreover, our method enables a rapid diversification of oxazole-based C^N ligands which can be readily derived into new group 9 organometallic compounds.
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http://dx.doi.org/10.1021/acs.orglett.6b02619DOI Listing
October 2016

Differential Apoptosis Radiosensitivity of Neural Progenitors in Adult Mouse Hippocampus.

Int J Mol Sci 2016 Jun 20;17(5). Epub 2016 Jun 20.

Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada.

Mammalian tissue-specific stem cells and progenitors demonstrate differential DNA damage response. Neural progenitors in dentate gyrus of the hippocampus are known to undergo apoptosis after irradiation. Using a mouse model of hippocampal neuronal development, we characterized the apoptosis sensitivity of the different neural progenitor subpopulations in adult mouse dentate gyrus after irradiation. Two different bromodeoxyuridine incorporation paradigms were used for cell fate mapping. We identified two apoptosis sensitive neural progenitor subpopulations after irradiation. The first represented non-proliferative and non-newborn neuroblasts and immature neurons that expressed doublecortin, calretinin or both. The second consisted of proliferative intermediate neural progenitors. The putative radial glia-like neural stem cells or type-1 cells, regardless of proliferation status, were apoptosis resistant after irradiation. There was no evidence of radiation-induced apoptosis in the absence of the Trp53 (p53) gene but absence of Cdkn1a (p21) did not alter the apoptotic response. Upregulation of nuclear p53 was observed in neuroblasts after irradiation. We conclude that adult hippocampal neural progenitors may demonstrate differential p53-dependent apoptosis sensitivity after irradiation.
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http://dx.doi.org/10.3390/ijms17060970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926502PMC
June 2016

Effects of Aging on Hippocampal Neurogenesis After Irradiation.

Int J Radiat Oncol Biol Phys 2016 Apr 29;94(5):1181-9. Epub 2015 Dec 29.

Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Departments of Radiation Oncology and Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Purpose: To assess the influence of aging on hippocampal neuronal development after irradiation (IR).

Methods And Materials: Male mice, 2, 4, 6, 12, and 18 months of age, were given a single dose of 0 or 5 Gy of IR. A bromodeoxyuridine (BrdU) incorporation study was used to label newborn cells. Neural progenitors, newborn neurons, and microglia in dentate gyrus (DG) were identified by phenotypic markers, and their numbers were quantified by nonbiased stereology 9 weeks after IR.

Results: BrdU-positive or newborn cells in DG decreased with aging and after IR. The number of neuroblasts and newborn neurons decreased with aging, and a further significant reduction was observed after IR. Total type 1 cells (the putative neural stem cells), and newborn type 1 cells decreased with aging, and further reduction in total type 1 cells was observed after IR. Aging-associated activation of microglia in hippocampus was enhanced after IR.

Conclusions: The aging-associated decline in hippocampal neurogenesis was further inhibited after IR. Ablation of neural progenitors and activation of microglia may contribute to the inhibition of neuronal development after IR across all ages.
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http://dx.doi.org/10.1016/j.ijrobp.2015.12.364DOI Listing
April 2016

Comparison of the EORTC STO-22 and the FACT-Ga quality of life questionnaires for patients with gastric cancer.

Ann Palliat Med 2016 Jan;5(1):13-21

European Organisation for Research & Treatment of Cancer Headquarters, Brussels, Belgium.

This review compares the development, characteristics, validity, and reliability of two well-known quality of life (QOL) assessment tools used in patients with gastric cancer: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Stomach (EORTC QLQ-STO22) and the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga). A literature search was conducted using MEDLINE, EMBASE, and Cochrane CENTRAL (inception to April 2015) to identify studies that discussed the development, characteristics, validity and reliability of the EORTC QLQ-STO22 or the FACT-Ga. The QLQ-STO22 was developed with collaboration with patients, healthcare professionals and literature review and was mainly field tested in European countries. Conversely, items on the FACT-Ga were generated from interviews with patients and healthcare professionals concurrently in North America and Asia. While both modules involve a 7-day recall period and use Likert scales, the QLQ-STO22 and FACT-Ga differ in terms of QOL domain focus, quantity and presentation of items, response options, and scoring. However, both tools show good internal consistency, test-retest reliability, sensitivity to change and construct validity. In addition, both questionnaires have been internationally validated within a large sample of patients undergoing a variety of treatments, thus demonstrating their cross-cultural applicability. The EORTC QLQ-STO22 and FACT-Ga are both valid and reliable tools with unique strengths and weaknesses. Selection between instruments should consider specific patient characteristics and goals of the study.
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http://dx.doi.org/10.3978/j.issn.2224-5820.2016.01.02DOI Listing
January 2016

Cut points for mild, moderate, and severe pain among cancer and non-cancer patients: a literature review.

Ann Palliat Med 2015 Oct;4(4):176-83

Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada.

Defining cut points (CPs) for varying levels of pain intensity is important for assessing changes in patient's functional status, and guiding the development and evaluation of treatment options. We aimed to summarize CPs identified in the literature for mild, moderate, and severe pain on the numeric rating scale (NRS), and recommend optimal CPs for cancer and non-cancer patients. We searched MEDLINE and EMBASE (inception to May 2015) for studies that used CPs to classify pain intensity on the NRS among patients with cancer or non-cancer conditions leading to acute or chronic pain. A CP was defined as the upper bound of a mild or moderate pain category. Of 1,556 identified articles, 27 were included for review. Among patients with cancer pain, mild-moderate pain CPs ranged from 1 to 4 (mean, 3.5±1.08), with CP4 being the most recommended CP (80%). For moderate-severe pain, CPs ranged from 4 to 7 (mean, 6.2±0.92), and CP6 (50%) was the optimal CPs. Among patients with non-cancer pain, mild-moderate pain CPs ranged from 2 to 5 (mean, 3.62±0.78), and CP4 was the most frequently used CP (52.9%). For moderate-severe non-cancer pain, CPs ranged from 4 to 8 (mean, 6.5±0.99), and CP6 (41.2%) was the most frequently recommended CP. A wide range of CPs for mild, moderate, and severe pain categories were identified in the literature among both cancer and non-cancer patient populations. Further studies are needed to delineate more accurate and precise CPs for pain intensity.
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http://dx.doi.org/10.3978/j.issn.2224-5820.2015.09.04DOI Listing
October 2015

A novel prospective descriptive analysis of nausea and vomiting among patients receiving gastrointestinal radiation therapy.

Support Care Cancer 2016 Apr 16;24(4):1545-61. Epub 2015 Sep 16.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.

Purpose: Nausea and vomiting are common side effects from radiotherapy that can interfere with gastrointestinal (GI) cancer patients' quality of life (QOL). This study described the subjective experience of patients with radiation-induced nausea and vomiting (RINV) and its relation to QOL.

Methods: Forty-eight patients treated with abdominal radiotherapy alone or with concomitant chemoradiotherapy were followed in a prospective study. All episodes of nausea, vomiting, and antiemetic use were recorded daily for the treatment period and the week following completion of therapy. QOL was assessed weekly using the Functional Living Index-Emesis QOL Tool (FLIE) and the EORTC QLQ-C30 core questionnaire (C30).

Results: In total, 351 episodes of nausea severity, duration, onset time, and 154 outcomes of vomiting onset times and contents were documented. The median nausea severity experienced per episode was 5 (on a scale from 1 to 10), and the most common durations of nausea were 30 min or less and constant nausea all day and night. The most common location of nausea was the abdomen. Longer nausea duration, great nausea severities, and the location of nausea experienced had significant adverse relationships to multiple QOL items on both the FLIE and the C30. In addition, the onset timing and number of vomiting episodes were related to the majority of all FLIE and QOL scores.

Conclusion: Patient's subjective experiences of RINV directly correlated to the worsening of QOL outcomes. The identification and amelioration of these RINV experiences could improve QOL.
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http://dx.doi.org/10.1007/s00520-015-2942-zDOI Listing
April 2016

IKBB tumor suppressive role in nasopharyngeal carcinoma via NF-κB-mediated signalling.

Int J Cancer 2016 Jan 10;138(1):160-70. Epub 2015 Aug 10.

Department of Clinical Oncology, University of Hong Kong, People's Republic of China.

Tumor suppressor genes (TSGs) play a prominent role in cancer and are important in the development of nasopharyngeal carcinoma (NPC), which is endemic in Southern China as well as Southeast Asia. Apart from TSGs, aberrant signalling pathways are also commonly associated with tumor progression. Unsurprisingly, the NF-κB pathway is frequently associated with angiogenesis and promoting tumor growth and development. Functional complementation studies using microcell-mediated chromosome transfer helped to identify IKBB as a putative TSG in NPC. IKBB, an inhibitor of NF-κB, has recently been shown to be inversely associated with tumor growth and metastasis via inactivation of the NF-κB pathway, but its suppressive role is still only poorly understood. This study takes the lead in revealing the suppressive role of IKBB in NPC. IKBB is silenced in the majority of NPC tumor tissues in all stages. Its suppressive role is substantiated by perturbation in tumor formation, cell migration and angiogenesis. Interestingly, IKBB not only affects the 'seed', but also influences the 'soil' by downregulating the transcriptional level of proangiogenic factors Rantes, Upar, IL6, and IL8. For the first time, our data establish the importance of a novel tumor suppressive IKBB gene in abrogating angiogenesis in NPC via the NF-κB signalling pathway, which is likely mediated by crosstalk with the Akt/Gsk3β signalling pathway.
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http://dx.doi.org/10.1002/ijc.29702DOI Listing
January 2016

Treatment age, dose and sex determine neuroanatomical outcome in irradiated juvenile mice.

Radiat Res 2015 May 4;183(5):541-9. Epub 2015 May 4.

a  Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada.

Pediatric cranial radiation therapy can induce long-term neurocognitive deficits, the risk and severity of these deficits are amplified in females and in those individuals exposed at a younger age and/or those irradiated at higher doses. To investigate the developmental consequences of these factors in greater detail, male and female C57Bl/6J mice between infancy and late childhood (16 and 36 days) were irradiated at a single time point with a whole-brain dose of 0, 3, 5 or 7 Gy. In vivo and ex vivo magnetic resonance imaging (MRI) and deformation-based morphometry was used to identify radiation-induced volume differences. As expected, exposure to 7 Gy of radiation at 16 days of age induced widespread volume deficits that were largely mitigated by increasing treatment age or decreasing dose. Notable exceptions were regions in the olfactory bulbs and hippocampus that displayed both a detectable difference in volume and a loss in neurogenesis for most doses and ages. Furthermore, white matter regions located at the front of the brain remained sensitive to radiation at later treatment ages, compared to regions at the back. Differences due to sex were subtle, with increased radiosensitivity in females detectable only in the mammillary bodies and fornix. Our results reveal anatomical alterations in brain development consistent with expectations based on pediatric patient neurocognitive outcomes. This data demonstrates that neuroimaging of the mouse is an effective tool for investigating radiation-induced late effects.
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http://dx.doi.org/10.1667/RR13854.1DOI Listing
May 2015

The safety of allogeneic innate lymphocyte therapy for glioma patients with prior cranial irradiation.

Cancer Immunol Immunother 2015 May 13;64(5):551-62. Epub 2015 Feb 13.

Division of Hematology and Oncology, School of Medicine, University of Alabama at Birmingham (UAB), 1824 6th Ave S, WTI 510C, Birmingham, AL, 35294, USA,

The standard treatment of high-grade glioma presents a combination of radiotherapy, chemotherapy and surgery. Immunotherapy is proposed as a potential adjunct to standard cytotoxic regimens to target remaining microscopic disease following resection. We have shown ex vivo expanded/activated γδ T cells to be a promising innate lymphocyte therapy based on their recognition of stress antigens expressed on gliomas. However, successful integration of γδ T cell therapy protocols requires understanding the efficacy and safety of adoptively transferred immune cells in the post-treatment environment. The unique features of γδ T cell product and the environment (hypoxia, inflammation) can affect levels of expression of key cell receptors and secreted factors and either promote or hinder the feasibility of γδ T cell therapy. We investigated the potential for the γδ T cells to injure normal brain tissue that may have been stressed by treatment. We evaluated γδ T cell toxicity by assessing actual and correlative toxicity indicators in several available models including: (1) expression of stress markers on normal primary human astrocytes (as surrogate for brain parenchyma) after irradiation and temozolomide treatment, (2) cytotoxicity of γδ T cells on normal and irradiated primary astrocytes, (3) microglial activation and expression of stress-induced ligands in mouse brain after whole-brain irradiation and (4) expression of stress-induced markers on human brain tumors and on normal brain tissue. The lack of expression of stress-induced ligands in all tested models suggests that γδ T cell therapy is safe for brain tumor patients who undergo standard cytotoxic therapies.
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http://dx.doi.org/10.1007/s00262-015-1662-zDOI Listing
May 2015
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