Publications by authors named "William Chu"

128 Publications

Gantry-based 5-fraction Elective Nodal Irradiation in Unfavorable-Risk Prostate Cancer: Outcomes from 2 Prospective Studies comparing SABR Boost with MR Dose Painted HDR Brachytherapy Boost.

Int J Radiat Oncol Biol Phys 2021 Oct 9. Epub 2021 Oct 9.

Odette Cancer Centre, Sunnybrook Health Sciences Centre; Department of Radiation Oncology, University of Toronto; Institute of Health Policy, Management and Evaluation. Electronic address:

Background: ASCO/CCO guidelines recommend brachytherapy boost for intermediate-risk (IR) or high-risk (HR) prostate cancer (PCa) patients. Stereotactic ablative body radiotherapy (SABR) is an emerging technique for PCa but its use in HR disease is limited. We compare efficacy, toxicity, and quality-of-life (QoL) in patients treated on 2 prospective protocols that used SABR boost or MR-guided HDR brachytherapy boost (MR-HDR) with 6-18 months of androgen deprivation therapy (ADT).

Methods: In XXXXXX study (study 1), patients received 40Gy to prostate and 25Gy to pelvis in 5 weekly fractions. In XXXXXX (study 2), patients received HDR-BT 15Gy x 1 to the prostate and ≤22.5Gy to the MRI nodule, followed by 25Gy in 5 weekly fractions to pelvis. All patients received between 6 and 18 months of androgen deprivation therapy.

Results: Thirty patients (NCCN 7% unfavorable IR, and 93% HR) completed study 1 while 31 patients (NCCN 3% favorable IR, 47% Unfavorable IR and 50% HR) completed treatment as per study 2. Median follow-up was 72 and 62 months, respectively. In study 2, 6 patients had BF and all 6 developed metastatic disease. Actuarial 5-year BF was 0% for study 1 and 18.2% for study 2 (p=0.005). There was no significant difference in worst acute or late GI or GU toxicity. Grade 3 late GU toxicity was noted in 3% of the patients in study 2 (HDR-BT boost). There was no significant difference in QoL or minimally clinical important change.

Conclusions: In the context of 5-fraction pelvic radiotherapy and ADT, there does not appear to be a significant difference in toxicity or QoL between SABR vs. HDR BT boost. While efficacy favored the SABR boost cohort, this should be viewed in the context of limitations and biases associated with comparing two sequential phase II studies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.10.003DOI Listing
October 2021

Elective nodal ultra hypofractionated radiation for prostate cancer: Safety and efficacy from four prospective clinical trials.

Radiother Oncol 2021 Sep 4;163:159-164. Epub 2021 Sep 4.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Canada; Department of Radiation Oncology, University of Toronto, Canada; Institute of Health Policy, Management and Evaluation, Canada. Electronic address:

Background And Purpose: The role of elective nodal irradiation (ENI) in localized prostate cancer (PCa) is controversial. With increasing use of SBRT to the prostate, data is needed regarding the safety and efficacy of ENI using ultra-hypofractionated radiation (UHRT).

Materials And Methods: Between 2013-2020, 4 prospective clinical trials of intermediate or high-risk PCa receiving dose-escalated RT to the prostate (via HDR brachytherapy or SBRT boost) and ENI using UHRT (25 Gy in 5 weekly fractions) were conducted. Primary endpoints included acute genitourinary and gastrointestinal toxicities (CTCAE v3.0/4.0), and secondary endpoints included late genitourinary and gastrointestinal toxicities, patient-reported quality of life (EPIC) and biochemical failure (Phoenix definition).

Results: One-hundred sixty-five patients were enrolled, of whom 98 (59%) had high-risk disease. ADT was used in 141 (85%). Median follow-up was 38 months (IQR 10-63). The worst acute genitourinary and gastrointestinal toxicities respectively were 48% and 7.5% for grade 2, and 2.7% and 0% for grade 3. Cumulative incidence of late grade 2+ genitourinary and gastrointestinal toxicities at 36 months were 58% and 11.3% and for late grade 3+ toxicities were 1% and 0%, respectively. No grade 4+ acute or late toxicities were observed. Bowel and sexual toxicity significantly worsened up to 1-year compared to baseline. Over time, urinary (p < 0.0001), bowel (p = 0.0018) and sexual (p < 0.0001) scores significantly improved. The 3-year biochemical recurrence-free survival was 98%.

Conclusion: ENI using UHRT is associated with low incidence of grade 3+ toxicity, while grade 1-2 acute genitourinary and gastrointestinal toxicity is common. Randomized phase 3 trials are needed.
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http://dx.doi.org/10.1016/j.radonc.2021.08.017DOI Listing
September 2021

Physical and psychological health outcomes of a sitting light volleyball intervention program on adults with physical disabilities: a non-randomized controlled pre-post study.

BMC Sports Sci Med Rehabil 2021 Aug 28;13(1):100. Epub 2021 Aug 28.

School of Educational Sciences and Psychology, University of Eastern Finland, Kuopio, Finland.

Background: People with physical disabilities (PWPD) have limited opportunities to participate in sport activities. Sitting light volleyball (SLVB) is an adapted sport that combines light volleyball and paralympic sitting volleyball. This study examined the effectiveness of an SLVB intervention program to improve the physical and psychological health outcomes of PWPD in Hong Kong, China.

Methods: Thirty-two PWPD [13 women; SLVB group, n = 18; control group (CG), n = 14] with an average age of 48.89 years (SD = 14.42 years) participated in a 16-week intervention consisting of basic SLVB skills, and they also received instructions on the required posture, team tactics, and SLVB rules. Physical (i.e., muscular strength, muscular endurance, body composition, flexibility, and aerobic endurance) and psychological (i.e., physical activity enjoyment and quality of life) health outcomes were measured before and after the intervention.

Results: Individuals in the SLVB group exhibited statistically significant improvements in cardiovascular endurance [F(1,29) = 4.23, p = .049], body composition [F(1,23) = 6.67, p = .017], and physical activity enjoyment [F(1,29) = 16.94, p = .001] compared with adults in the CG.

Conclusions: Participating in SLVB has physical and psychological benefits for adults with physical disabilities in this study. Registration number of trial registry: The trial is registered at chictr.org.cn, number ChiCTR2000032971 on 17/05/2020.
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http://dx.doi.org/10.1186/s13102-021-00328-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403424PMC
August 2021

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

Eur Urol 2021 Aug 13. Epub 2021 Aug 13.

Division of Medical Oncology, Department of Medicine, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Despite the paucity of prospective evidence, stereotactic radiotherapy (SRT) is increasingly being considered in the setting of oligoprogression to delay the need to change systemic therapy.

Objective: To determine the local control (LC), progression-free survival (PFS), cumulative incidence of changing systemic therapy, and overall survival (OS) after SRT to oligoprogressive metastatic renal cell carcinoma (mRCC) lesions in patients who are on tyrosine kinase inhibitor (TKI) therapy.

Design, Setting, And Participants: A prospective multicenter study was performed to evaluate the use of SRT in oligoprogressive mRCC patients. Patients with mRCC who had previous stability or response after ≥3 mo of TKI therapy were eligible if they developed progression of five of fewer metastases. Thirty-seven patients with 57 oligoprogressive tumors were enrolled.

Intervention: Oligoprogressive tumors were treated with SRT, and the same TKI therapy was continued afterward.

Outcome Measurements And Statistical Analysis: Competing risk analyses and the Kaplan-Meir methodology were used to report the outcomes of interest.

Results And Limitations: The median duration of TKI therapy prior to study entry was 18.6 mo; 1-yr LC of the irradiated tumors was 93% (95% confidence interval [CI] 71-98%). The median PFS after SRT was 9.3 mo (95% CI 7.5-15.7 mo). The cumulative incidence of changing systemic therapy was 47% (95% CI 32-68%) at 1 yr, with a median time to change in systemic therapy of 12.6 mo (95% CI 9.6-17.4 mo). One-year OS was 92% (95% CI 82-100%). There were no grade 3-5 SRT-related toxicities.

Conclusions: LC of irradiated oligoprogressive mRCC tumors was high, and the need to change systemic therapy was delayed for a median of >1 yr.

Patient Summary: The use of stereotactic radiotherapy in metastatic kidney cancer patients, who develop growth of a few tumors while on oral targeted therapy, can significantly delay the need to change to the next line of drug therapy.
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http://dx.doi.org/10.1016/j.eururo.2021.07.026DOI Listing
August 2021

Elective pelvic nodal irradiation with a simultaneous hypofractionated integrated prostate boost for localized high risk prostate cancer: Long term results from a prospective clinical trial.

Radiother Oncol 2021 Jul 26;163:21-31. Epub 2021 Jul 26.

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

Background: To report on long-term results of elective pelvic nodal irradiation (EPNI) and a simultaneous hypofractionated prostate boost for high-risk prostate cancer.

Materials And Methods: This was a prospective single-arm study. Patients with high-risk disease (cT3, PSA >20 ng/mL, or Gleason score 8-10) were eligible. Patients received 45 Gy in 25 fractions to the prostate and pelvic lymph nodes with a simultaneous intensity-modulated radiotherapy boost of 22.5 Gy to the prostate (total dose 67.5 Gy in 25 fractions), with androgen deprivation therapy (ADT) for 2-3 years. The primary endpoint was biochemical failure. Secondary endpoints included distant metastases and overall survival. Multivariable analysis was performed to look for predictive factors. Late toxicity was assessed using CTCAE v3.0.

Results: 230 patients enrolled. Median follow-up was 11.2 years (IQR 8.1-12.9). At 10 years, cumulative incidence of biochemical failure was 33.4%, distant metastasis was 16.5%, and overall survival was 76.3%. On multivariable analysis, PSA nadir ≥0.05 ng/mL was associated with biochemical failure (HR 6.8, 95% CI 4-11.8, p < 0.001) and distant metastases (HR 7.5, 95% CI 3.9-14.5, p < 0.0001). PSA nadir ≥0.1 ng/mL (HR 5.2, 95% 2.2-12, p = 0.0001) and ADT use ≤12 months (versus >24 months) (HR 2.3, 95% CI 1.3-3.9, p = 0.004) were associated with worse survival. The 5-year cumulative incidence of any late grade ≥3 gastrointestinal and genitourinary toxicity was 2.3% and 7.5%, respectively.

Conclusion: EPNI and a simultaneous hypofractionated prostate boost combined with long-term ADT for high-risk prostate cancer resulted in acceptable 10-year biochemical control and survival with low grade ≥3 toxicity.
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http://dx.doi.org/10.1016/j.radonc.2021.07.018DOI Listing
July 2021

Outcomes of extra-cranial stereotactic body radiotherapy for metastatic breast cancer: Treatment indication matters.

Radiother Oncol 2021 08 10;161:159-165. Epub 2021 Jun 10.

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

Background And Purpose: To summarize the clinical outcomes of stereotactic body radiotherapy (SBRT) for metastatic breast cancer (mBC) from a large institution.

Materials And Methods: Patients with mBC who received extra-cranial SBRT to metastatic lesions from 2011 to 2017 were identified. Treatment indications were: oligometastases, oligoprogression, and local control of dominant tumor (CDT). Endpoints included overall survival (OS), progression-free survival (PFS), local control (LC) and cumulative incidence of starting/changing chemo or hormonal therapy (SCT). Univariate and multivariate analyses were used to identify predictive factors.

Results: We analyzed 120 patients (193 treated metastatic lesions) with a median follow up of 15.25 months. 1-and 2-year LC rates were 89% and 86.6%, respectively. 1-and 2-year OS rates were 83.5% and 70%, respectively, with treatment indication and molecular subtype being the predictive factors on MVA. 1-year OS was 91.0%, 78.5% and 63.9% for oligometastases, oligoprogression and CDT, respectively (p = 0.003). The worst OS was seen in basal subtype with 1-and 2-year OS rates of 59.2% and 39.5% (p = 0.01). Treatment indication was found to be predictive for PFS and lower rates of SCT on MVA. 1-and 2-year PFS rates were 45% and 32%, respectively. The 1-year PFS for oligometastases, oligoprogression, and CDT was 66%, 19.6%, and 14.3%, respectively (p < 0.001). The cumulative incidence of SCT at 1-year was 12% for oligometastases, 39.7% for oligoprogression and 53.3% for CDT (p < 0.001).

Conclusion: Patients treated for oligometastases have better OS and PFS than those treated for oligoprogression or CDT. SBRT may delay SCT in mBC patients, particularly those with oligometastases. SBRT provided an excellent LC in mBC patients.
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http://dx.doi.org/10.1016/j.radonc.2021.06.012DOI Listing
August 2021

Comparison of different predicting models to assist the diagnosis of spinal lesions.

Inform Health Soc Care 2021 Jun 11:1-11. Epub 2021 Jun 11.

School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.

In neurosurgical or orthopedic clinics, the differential diagnosis of lower back pain is often time-consuming and costly. This is especially true when there are several candidate diagnoses with similar symptoms that might confuse clinic physicians. Therefore, methods for the efficient differential diagnosis can help physicians to implement the most appropriate treatment and achieve the goal of pain reduction for their patients.In this study, we applied data-mining techniques from artificial intelligence technologies, in order to implement a computer-aided auxiliary differential diagnosis for a herniated intervertebral disc, spondylolithesis, and spinal stenosis. We collected questionnaires from 361 patients and analyzed the resulting data by using a linear discriminant analysis, clustering, and artificial neural network techniques to construct a related classification model and to compare the accuracy and implementation efficiency of the different methods.Our results indicate that a linear discriminant analysis has obvious advantages for classification and diagnosis, in terms of accuracy.We concluded that the judgment results from artificial intelligence can be used as a reference for medical personnel in their clinical diagnoses. Our method is expected to facilitate the early detection of symptoms and early treatment, so as to reduce the social resource costs and the huge burden of medical expenses, and to increase the quality of medical care.
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http://dx.doi.org/10.1080/17538157.2021.1939355DOI Listing
June 2021

Stereotactic pelvic radiotherapy with HDR boost for dose escalation in intermediate and high-risk prostate cancer (SPARE): Efficacy, toxicity and quality of life.

Radiother Oncol 2021 08 3;161:40-46. Epub 2021 Jun 3.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Canada; Department of Radiation Oncology, University of Toronto, Canada; Institute of Health Policy, Management and Evaluation, Canada. Electronic address:

Background: The ASCO/CCO guidelines recommend brachytherapy (BT) boost for eligible intermediate- (IR) or high-risk (HR) prostate cancer (PCa) patients. We present efficacy, toxicity and quality-of-life (QoL) outcomes in patients treated on a prospective protocol of MRI dose-painted high-dose-rate BT boost (HDR-BT) followed by 5-fraction pelvic radiotherapy (RT) and 6-18 months of androgen deprivation therapy (ADT).

Methods: In this phase I/II study, IR or HR PCa patients received HDR-BT 15 Gy × 1 to prostate and up to 22.5 Gy to MRI nodule, followed by 25 Gy in 5, weekly fractions to pelvis. Toxicity was assessed using CTCAEv3.0, and QoL was captured using EPIC questionnaire. Biochemical failure (BF; nadir + 2.0), and proportion of patients with PSA < 0.4 ng/ml at 4-years (4yPSARR) were evaluated. A minimally clinically important change (MCIC) was recorded if QoL score decreased >0.5 standard deviation of baseline scores.

Results: Thirty-one patients (NCCN 3.2% favorable IR, 48.4% unfavorable IR and 48.4% HR) completed treatment with a median follow-up of 61 months. Median D90 to MR nodule was 19.0 Gy and median prostate V100% was 96.5%. The actuarial 5-year BF rate was 18.2%, and the 4yPSARR was 71%. One patient died of PCa. Acute grade 2 and 3 toxicities: GU: 50%, 7%, and GI: 3%, none, respectively. Late grade 2 and 3 toxicities were: GU: 23%, 3%, and GI: 7%, none, respectively. Proportion of patients with MCIC was 7.7% for urinary domain and 32.0% for bowel domain.

Conclusions: This novel treatment protocol incorporating MRI dose-painted HDR-BT boost and 5-fraction pelvic RT with ADT is well tolerated.
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http://dx.doi.org/10.1016/j.radonc.2021.05.024DOI Listing
August 2021

Adaptive Magnetic Resonance-Guided Stereotactic Body Radiotherapy: The Next Step in the Treatment of Renal Cell Carcinoma.

Front Oncol 2021 11;11:634830. Epub 2021 May 11.

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

Adaptive MR-guided radiotherapy (MRgRT) is a new treatment paradigm and its role as a non-invasive treatment option for renal cell carcinoma is evolving. The early clinical experience to date shows that real-time plan adaptation based on the daily MRI anatomy can lead to improved target coverage and normal tissue sparing. Continued technological innovations will further mitigate the challenges of organ motion and enable more advanced treatment adaptation, and potentially lead to enhanced oncologic outcomes and preservation of renal function. Future applications look promising to make a positive clinical impact and further the personalization of radiotherapy in the management of renal cell carcinoma.
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http://dx.doi.org/10.3389/fonc.2021.634830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144516PMC
May 2021

Effects and Safety of Lumbar Fusion Techniques in Lumbar Spondylolisthesis: A Network Meta-Analysis of Randomized Controlled Trials.

Global Spine J 2021 Mar 23:2192568221997804. Epub 2021 Mar 23.

Department of Orthopedics, 38007Cheng Hsin General hospital, Taipei.

Study Design: Network meta-analysis of randomized controlled trials.

Objectives: Lumbar spondylolisthesis is a common indication for spinal fusion. Lumbar interbody fusion (LIF) is popular method to achieve arthrodesis, but previous syntheses usually used head-to-head comparison of 2 surgical methods, and no of them pooled analysis with high-quality. This network meta-analysis of randomized controlled trials was carried out to simultaneously compare fusion techniques in the treatment of lumbar spondylolisthesis.

Methods: Three databases were searched for randomized controlled trials (RCTs) on this topic. After critical appraisal, fusion rate, overall adverse events, operative time, Oswestry Disability Index, and pain were extracted for analysis. We conduced network meta-analysis using contrast-based method. Primary outcomes were reported as risk ratio (RR) with 95% confidence interval (CI).

Results: Fifteen RCTs (n = 992) met our eligibility criteria. The RCTs treated patients posterolateral fusion (PLF), posterior LIF (PLIF), transforaminal LIF (TLIF), minimally invasive (MIS) TLIF, extreme lateral LIF (XLIF), and circumferential fusion. The pooled estimate showed that circumferential fusion led to significantly higher fusion rate than PLF (RR = 2.15, 95%CI:1.41-3.28), PLIF (RR = 2.11, 95%CI:1.38-3.22), TLIF (RR = 2.13, 95%CI:1.39-3.27), MIS-TLIF (RR = 2.13, 95%CI:1.35-3.35), and XLIF (RR = 2.01, 95%CI: 1.25-3.22). Moreover, circumferential fusion exhibited the best balance in probability between fusion rate and adverse event rate. No evidence showed inconsistency or small-study effect in the results.

Conclusions: Collectively, circumferential fusion might be worth to be recommended because it exhibits the best balance between fusion rate and overall adverse event. PLF is still an inferior procedure and requires shorter operative time.
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http://dx.doi.org/10.1177/2192568221997804DOI Listing
March 2021

Stereotactic Ablative Radiotherapy for the Management of Liver Metastases from Neuroendocrine Neoplasms: A Preliminary Study.

Neuroendocrinology 2021 Feb 2. Epub 2021 Feb 2.

Introduction: Liver metastases are common in patients with neuroendocrine neoplasms. The role of stereotactic ablative radiotherapy (SABR) is not well understood in this population.

Objective: To evaluate the safety and efficacy of SABR in treating well-differentiated neuroendocrine liver metastases (WD-NELM).

Methods: A retrospective review of patients with WD-NELM treated with SABR between January 2015-July 2019. Demographic, treatment and clinical/radiographic follow-up data were abstracted. RECIST 1.1 criteria were applied to each individual target to evaluate the response to treatment. Local control (LC) and progression free survival (PFS) were determined using Kaplan-Meier methodology. Toxicity was reported according to CTCAE v5.0.

Results: Twenty-five patients with a total of 53 liver metastases treated with SABR were identified. Most patients (68%) had midgut tumors, were Grade II (80%) and had high volume intrahepatic and/or extrahepatic disease (76%). Median number of liver metastases treated was 2 with a median size of 2.5 cm. Median radiation dose delivered was 50Gy/5 fractions. Median follow-up was 14 months; 24 of the 25 patients were alive at time of analysis. The objective response rate (ORR) was 32%, with improvement or stability in 96% of lesions treated. The median time to best response was 9 months. The 1-year LC and PFS were 92% and 44% respectively. No Grade III/IV acute or late toxicity was identified.

Conclusions: Liver SABR is a safe and promising means of providing local control for WD-NELM. This treatment modality should be evaluated in select patients in concert with strategies to manage systemic disease.
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http://dx.doi.org/10.1159/000514914DOI Listing
February 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

Prostate high dose-rate brachytherapy as monotherapy for prostate cancer: Late toxicity and patient reported outcomes from a randomized phase II clinical trial.

Radiother Oncol 2021 03 4;156:160-165. Epub 2021 Jan 4.

Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Canada. Electronic address:

Background And Purpose: Long-term toxicity of high dose-rate brachytherapy as monotherapy for prostate cancer is not well defined. We report late toxicity and health related quality of life (HRQOL) changes from a randomized phase II clinical trial of two different fractionation schemes.

Materials And Methods: Eligible patients had NCCN low or intermediate risk prostate cancer. 170 patients were randomized to receive either a single 19 Gy or two-fractions of 13.5 Gy one week apart. Toxicity was measured using Common Terminology for Adverse Events (CTCAE) v4.0, and HRQOL was measured using the Expanded Prostate Index Composite (EPIC).

Results: Median follow-up was 63 months. The 5-year cumulative incidence of Grade 2 or higher genitourinary (GU) and gastrointestinal (GI) toxicity was 62% and 12% in the single-fraction arm, and 47% and 9% in the two-fraction arm, respectively. Grade 3 GU toxicity was only seen in the single fraction arm with a cumulative incidence of 2%. The 5-year prevalence of Grade 2 GU toxicity was 29% and 21%, in the single- and two-fraction arms, respectively, with Grade 2 GI toxicity of 1% and 2%. Beyond the first year, no significant differences in mean urinary HRQOL were seen compared to baseline in the two-fraction arm, in contrast to the single-fraction arm where a decline in urinary HRQOL was seen at 4 and 5 years. Sexual HRQOL was significantly reduced in both treatment arms at all timepoints, with no changes in the bowel domain.

Conclusions: HDR monotherapy is well tolerated with minimal impact on HRQOL.
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http://dx.doi.org/10.1016/j.radonc.2020.12.021DOI Listing
March 2021

Prevalence, mortality and healthcare economic burden of tuberous sclerosis in Hong Kong: a population-based retrospective cohort study (1995-2018).

Orphanet J Rare Dis 2020 09 25;15(1):264. Epub 2020 Sep 25.

Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, SAR, People's Republic of China.

Background: We aim to elucidate the disease impact by accounting the prevalence, survival rate, genetics, mTOR inhibitor use and direct costs of tuberous sclerosis complex (TSC) in our local setting. TSC patients with documented visits to our local public hospitals in 1995-2018 were identified. The public hospitals captured most if not all local TSC patients. Demographics such as age, sex, death, genetic profiles were retrieved from the central electronic database. Data including prevalence, age distribution and survival rate were analysed. Direct cost was calculated with reference to the drug use and number of visits to various public hospital facilities.

Results: We identified 284 surviving TSC patients (55.3% male) in Hong Kong. The age range was from 4.5 months to 89.9 years, with a median age of 27.2 years. Paediatrics (< 18 years) to adult (≥18 years) ratio was 1:2.84. The overall prevalence of TSC patients was 3.87 in 100,000 (i.e. 1 in 25,833). Genetically, TSC1:TSC2 ratio is 1:2.7. Thirty seven patients died within the study period. The age of death ranged from 7.6 years to 77.8 years, with a median age of death at 36.6 years (IQR: 24.7-51.1 years). Most patients survived till adulthood. Survival rate at 20 and 50 years follow-up was 98.6 and 79.5% respectively. Two hundred and twenty nine TSC patients (71.3%) had neurological manifestations, sixteen patients (5.0%) had chronic kidney diseases and five patients (1.6%) had pulmonary lymphangioleiomyomatosis. Forty seven (16.5%) TSC patients were prescribed with mTOR inhibitors within the study period. Healthcare facility utilization was further analysed in the 2008-2018 cohort. In particular, the mean number of specialist out-patient clinic visits per patient-year was 9.23 per patient-year, which was 4.91 times more than that of local general population.

Conclusions: Prevalence of local TSC patients is within the range of that reported in the literature. Local TSC patients have fair long term survival, but they require disproportionally high healthcare cost when compared with the general population, particularly in terms of outpatient (OP) visits. Although effective disease-modifying agent (i.e. mTOR inhibitor) is available, it was not widely used yet in Hong Kong despite the fact that Government approved and supported its use recently. Further research on quality of life and setting up a comprehensive patient registry are necessary for more accurate assessment of cost and benefit.
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http://dx.doi.org/10.1186/s13023-020-01517-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523393PMC
September 2020

Single-fraction HDR brachytherapy as monotherapy in low and intermediate risk prostate cancer: Outcomes from two clinical trials with and without an MRI-guided boost.

Radiother Oncol 2021 01 10;154:29-35. Epub 2020 Sep 10.

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

Purpose: Single-fraction HDR monotherapy for the treatment of localized prostate cancer is appealing, but published outcomes are discouraging. An approach to improve local control is MRI-guided focal dose-escalation to the dominant intraprostatic lesion (DIL). Here we report a comparison of outcomes from two phase II clinical trials with and without a focal boost.

Methods: Patients had low or intermediate-risk disease. Patients in Trial1 received a single 19 Gy HDR implant to the whole prostate. Trial2 incorporated an additional MRI-guided focal DIL boost to at least 23 Gy. ADT was not allowed. Toxicities (CTCAEv4.0) and quality of life (EPIC) were collected. Biochemical failure (BF) was defined as nadir +2. Univariate and multivariate logistic regression analysis was conducted to search for predictors of BF.

Results: Trial1 had 87 patients with a median follow-up of 62 months, while Trial2 had 60 patients with a median follow-up of 50 months. The five-year cumulative BF rate was 32.6% and 31.3%, respectively (p = 0.9). 77.5% of failures were biopsy-confirmed local failures, all of which underwent local salvage therapy. The addition of a DIL boost was not associated with worse toxicity or QOL. Baseline PSA and Gleason score correlated with BF, but none of the dosimetric parameters was a significant predictor of BF.

Conclusions: MRI-guided focal boost was safe and well tolerated, but did not improve local control after 19 Gy single-fraction HDR monotherapy, and the control rates were unacceptable. Single-fraction HDR monotherapy for prostate cancer should not be offered outside of clinical trials.
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http://dx.doi.org/10.1016/j.radonc.2020.09.007DOI Listing
January 2021

Evaluation of a sitting light volleyball intervention to adults with physical impairments: qualitative study using social-ecological model.

BMC Sports Sci Med Rehabil 2020 8;12:41. Epub 2020 Jul 8.

Department of Sport and Physical Education, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong.

Background: This study was a part of 16-week sitting light volleyball (SLVB) intervention program which examined the effects of the intervention on the physical and psychological attributes of adults with physical impairments (PWPI) in Hong Kong. Gaining a deeper understanding of the perceptions and experiences of PWPI in the SLVB intervention is critical to the development of SLVB as a physical activity and a sport. The aims of this study were (a) to assess participants' experiences of the intervention and (b) to examine the suitability and feasibility of SLVB intervention for PWPI.

Methods: Twenty participants (mean age = 53.52 years, standard deviation 9.02 years; 60% female; 25% with at least a college degree) participated in semi-structured interviews.

Results: Content analysis revealed features of their experiences at the or level (physical and psychological health, enjoyment, novelty, competence, autonomy), level (socialization and teamwork, social support), and levels (perceived sport venue environment, venue accessibility, safety, dissemination of information), and level (resources allocation by the government). The participants also commented on the suitability and feasibility of the SLVB intervention for PWPI, its content and coaching, the modified rules, the duration of sessions, scheduling, and the number of participants and coaches.

Conclusions: This study identified several themes relevant to the promotion of PWPI engagement with SLVB and demonstrated that adopting a multilevel approach to the intervention resulted in positive outcomes for participants. Playing SLVB is suitable and feasible for PWPI. The findings contribute to the understanding of the experiences PWPI had of the SLVB intervention, which is critical to the further development of SLVB as a physical activity and a sport.
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http://dx.doi.org/10.1186/s13102-020-00187-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346623PMC
July 2020

Stereotactic Ablative Radiotherapy for ≥T1b Primary Renal Cell Carcinoma: A Report From the International Radiosurgery Oncology Consortium for Kidney (IROCK).

Int J Radiat Oncol Biol Phys 2020 11 17;108(4):941-949. Epub 2020 Jun 17.

Department of Radiation Oncology, London Regional Cancer Program, London, Ontario, Canada; Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.

Purpose: Patients with larger (T1b, >4 cm) renal cell carcinoma (RCC) not suitable for surgery have few treatment options because thermal ablation is less effective in this setting. We hypothesize that SABR represents an effective, safe, and nephron-sparing alternative for large RCC.

Methods And Materials: Individual patient data from 9 institutions in Germany, Australia, USA, Canada, and Japan were pooled. Patients with T1a tumors, M1 disease, and/or upper tract urothelial carcinoma were excluded. Demographics, treatment, oncologic, and renal function outcomes were assessed using descriptive statistics. Kaplan-Meier estimates and univariable and multivariable Cox proportional hazards regression were generated for oncologic outcomes.

Results: Ninety-five patients were included. Median follow-up was 2.7 years. Median age was 76 years, median tumor diameter was 4.9 cm, and 81.1% had Eastern Cooperative Oncology Group performance status of 0 to 1 (or Karnofsky performance status ≥70%). In patients for whom operability details were reported, 77.6% were defined as inoperable as determined by the referring urologist. Mean baseline estimated glomerular filtration rate (eGFR) was 57.2 mL/min (mild-to-moderate dysfunction), with 30% of the cohort having moderate-to-severe dysfunction (eGFR <45mL/min). After SABR, eGFR decreased by 7.9 mL/min. Three patients (3.2%) required dialysis. Thirty-eight patients (40%) had a grade 1 to 2 toxicity. No grade 3 to 5 toxicities were reported. Cancer-specific survival, overall survival, and progression-free survival were 96.1%, 83.7%, and 81.0% at 2 years and 91.4%, 69.2%, 64.9% at 4 years, respectively. Local, distant, and any failure at 4 years were 2.9%, 11.1%, and 12.1% (cumulative incidence function with death as competing event). On multivariable analysis, increasing tumor size was associated with inferior cancer-specific survival (hazard ratio per 1 cm increase: 1.30; P < .001).

Conclusions: SABR for larger RCC in this older, largely medically inoperable cohort, demonstrated efficacy and tolerability and had modest impact on renal function. SABR appears to be a viable treatment option in this patient population.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.014DOI Listing
November 2020

Accelerating prostate stereotactic ablative body radiotherapy: Efficacy and toxicity of a randomized phase II study of 11 versus 29 days overall treatment time (PATRIOT).

Radiother Oncol 2020 08 27;149:8-13. Epub 2020 Apr 27.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada; Institute of Health Policy Management and Evaluation, University of Toronto, Canada. Electronic address:

Background: Prostate stereotactic ablative radiotherapy (SABR) regimens differ in time, dose, and fractionation. We report an update of a multicentre, Canadian randomized phase II study to investigate the impact of overall treatment time on quality of life (QOL), efficacy, and toxicity.

Methods: Men with intermediate risk prostate cancer were randomized to 40 Gy in 5 fractions delivered every other day (EOD) versus once per week (QW). Primary outcome was proportion of patients experiencing a minimally clinically important change (MCIC) in acute bowel QOL using EPIC. Secondary outcomes were toxicity, biochemical failure (BF), other QOL domains, and the rate of salvage therapy.

Findings: 152 men from 3 centers were randomized; the median follow-up was 62 months. Results are described for EOD versus QW. Acute bowel and urinary QOL was reported previously. Late changes in QOL were not significantly different between the two arms. There were 1 (1.3%) vs 3 (2.7%) late grade 3 + GI toxicities (p = 0.36) and 5 (6.7%) vs 2 (2.7%) late grade 3 GU toxicities (p = 0.44). Two and 5 patients had BF (5-year failure rate 3.0 vs 7.2%, p = 0.22); 0 and 4 patients received salvage therapy (p = 0.04). 5-Year OS and CSS was 95.8% and 98.6% with no difference between arms (p = 0.49, p = 0.15). 3 patients in the QW arm developed metastases.

Interpretation: Although we previously reported that weekly prostate SABR had better bowel and urinary QOL compared to EOD, the updated results show no difference in late toxicity, QOL, BF, or PSA kinetics. Patients should be counseled that QW SABR reduces short-term toxicity compared to QW SABR.
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http://dx.doi.org/10.1016/j.radonc.2020.04.039DOI Listing
August 2020

Primary Renal Carcinoid Tumor: Report of Two Cases.

Perm J 2020 13;24. Epub 2020 Mar 13.

Department of Urology, West Los Angeles Medical Center, CA.

Introduction: Primary renal carcinoid tumors are a rare subset of neuroendocrine tumors arising in the kidneys. Although carcinoid syndrome has occasionally been described, most patients are asymptomatic at presentation.

Case Presentations: We present 2 cases of primary renal carcinoid tumor and describe the workup, immunohistochemical analysis, treatment, and surveillance of each female patient. The first patient was found to have a renal mass on imaging during a workup of chronic abdominal pain and subsequently underwent a robotic radical nephrectomy. The second patient was found to have an incidental renal mass on imaging and subsequently underwent renal biopsy, followed by robot-assisted laparoscopic partial nephrectomy. In both cases, a gallium dotatate Ga 68-enhanced positron emission tomography/computed tomography scan was used to further assess disease burden.

Discussion: This report describes 2 cases of primary renal carcinoid tumor with unique presentations and management in our regional health care system. Because primary renal carcinoid tumors are quite uncommon, there are no clear established guidelines on preoperative imaging or posttreatment surveillance in patients with these tumors. There remains a large amount of variability in the diagnosis, workup, immunohistochemical analysis, treatment, and surveillance of patients with primary renal carcinoid tumors. As we learn more about this disease, we hope to optimize patient outcomes and standardize pretreatment workup and posttreatment surveillance.
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http://dx.doi.org/10.7812/TPP/19.147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089591PMC
May 2021

Proof of concept for stereotactic body radiation therapy in the treatment of functional neuroendocrine neoplasms.

J Radiosurg SBRT 2020 ;6(4):321-324

Division of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto. 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada.

Dysregulated hormonal production remains a challenge in the management of neuroendocrine neoplasms (NEN). We report 4 cases of patients with functional NEN treated with stereotactic body radiation therapy (SBRT) to either the primary/dominant metastatic site of disease or the end organ of hormonal release. No significant toxicities were observed during or after treatment. Each patient has had biochemical, clinical and radiographic response to therapy, providing proof of concept that SBRT is an effective therapeutic strategy for functional neuroendocrine neoplasms.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065890PMC
January 2020

Deep Phenotyping by Mass Cytometry and Single-Cell RNA-Sequencing Reveals LYN-Regulated Signaling Profiles Underlying Monocyte Subset Heterogeneity and Lifespan.

Circ Res 2020 05 10;126(10):e61-e79. Epub 2020 Mar 10.

From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada.

Rationale: Monocytes are key effectors of the mononuclear phagocyte system, playing critical roles in regulating tissue homeostasis and coordinating inflammatory reactions, including those involved in chronic inflammatory diseases such as atherosclerosis. Monocytes have traditionally been divided into 2 major subsets termed conventional monocytes and patrolling monocytes (pMo) but recent systems immunology approaches have identified marked heterogeneity within these cells, and much of what regulates monocyte population homeostasis remains unknown. We and others have previously identified LYN tyrosine kinase as a key negative regulator of myeloid cell biology; however, LYN's role in regulating specific monocyte subset homeostasis has not been investigated.

Objective: We sought to comprehensively profile monocytes to elucidate the underlying heterogeneity within monocytes and dissect how deficiency affects monocyte subset composition, signaling, and gene expression. We further tested the biological significance of these findings in a model of atherosclerosis.

Methods And Results: Mass cytometric analysis of monocyte subsets and signaling pathway activation patterns in conventional monocytes and pMos revealed distinct baseline signaling profiles and far greater heterogeneity than previously described. deficiency led to a selective expansion of pMos and alterations in specific signaling pathways within these cells, revealing a critical role for LYN in pMo physiology. LYN's role in regulating pMos was cell-intrinsic and correlated with an increased circulating half-life of -deficient pMos. Furthermore, single-cell RNA sequencing revealed marked perturbations in the gene expression profiles of monocytes with upregulation of genes involved in pMo development, survival, and function. deficiency also led to a significant increase in aorta-associated pMos and protected mice from high-fat diet-induced atherosclerosis.

Conclusions: Together our data identify LYN as a key regulator of pMo development and a potential therapeutic target in inflammatory diseases regulated by pMos.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315708DOI Listing
May 2020

Prostate high dose-rate brachytherapy as monotherapy for low and intermediate risk prostate cancer: Efficacy results from a randomized phase II clinical trial of one fraction of 19 Gy or two fractions of 13.5 Gy.

Radiother Oncol 2020 05 5;146:90-96. Epub 2020 Mar 5.

Sunnybrook Odette Cancer Centre, University of Toronto, Canada.

Background And Purpose: High dose-rate (HDR) brachytherapy as monotherapy is a treatment option for localized prostate cancer, but optimal dose and fractionation is unknown. We report efficacy results of a randomized phase II trial of HDR monotherapy delivered as either one or two fractions.

Materials And Methods: Eligible patients had low or intermediate risk prostate cancer, prostate volume <60 cc, and no androgen deprivation use. 170 patients were randomized to receive HDR as either a single fraction of 19 Gy or as two fractions of 13.5 Gy one week apart. Median age was 65 years, median PSA was 6.33 ng/ml, and Grade Group 1, 2 and 3 was present in 28%, 60%, and 12%, respectively. There was no difference in baseline factors between arms and 19%, 51% and 30% had low risk, favourable intermediate and unfavourable intermediate risk disease, respectively. The Phoenix definition was used to define biochemical failure, all local failures were confirmed by biopsy and toxicity was assessed using CTCAE v.4.

Results: Median follow-up was 60 months. PSA decreased more quickly in the 2-fraction arm (p = 0.009). Median PSA at 5-years was 0.65 ng/ml in the single fraction and 0.16 ng/ml in the 2-fraction arm. The 5-year biochemical disease-free survival and cumulative incidence of local failure was 73.5% and 29% in the single fraction arm and 95% (p = 0.001) and 3% (p < 0.001) in the 2-fraction arm, respectively. Recurrence was not associated with initial stage, grade group, or risk group. Grade 2 late rectal toxicity occurred in 1% while the incidence of grade 2 and 3 urinary toxicity was 45% and 1%, respectively, with no difference between arms.

Conclusions: HDR monotherapy delivered as two fraction of 13.5 Gy is well tolerated with a high cancer control rate at 5 years. Single fraction monotherapy is inferior and should not be used.
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http://dx.doi.org/10.1016/j.radonc.2020.02.009DOI Listing
May 2020

Evaluating the Tolerability of a Simultaneous Focal Boost to the Gross Tumor in Prostate SABR: A Toxicity and Quality-of-Life Comparison of Two Prospective Trials.

Int J Radiat Oncol Biol Phys 2020 05 25;107(1):136-142. Epub 2020 Jan 25.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Purpose: Dose-escalated stereotactic ablative radiotherapy (SABR) to the whole prostate may be associated with better outcomes but has a risk of increased toxicity. An alternative approach is to focally boost the dominant intraprostatic lesion (DIL) seen on magnetic resonance imaging. We report the toxicity and quality-of-life (QOL) outcomes of 2 phase 2 trials of prostate and pelvic SABR, with or without a simultaneous DIL boost.

Methods And Materials: The first trial treated patients with high-risk prostate cancer to a dose of 40 Gy to the prostate and 25 Gy to the pelvis in 5 fractions. The second trial treated patients with intermediate-risk and high-risk prostate cancer to a dose of 35 Gy to the prostate, 25 Gy to the pelvis, and a DIL boost up to 50 Gy in 5 fractions. Acute toxicities, late toxicities, and QOL were assessed.

Results: Thirty patients were enrolled in each trial. In the focal boost cohort, the median DIL D90% was 48.3 Gy. There was no significant difference in acute grade ≥2 gastrointestinal or genitourinary toxicity between the 2 trials or in cumulative worst late gastrointestinal or genitourinary toxicity up to 24 months. There was no significant difference in QOL domain scores or minimally clinical important change between the 2 trials.

Conclusions: Prostate and pelvic SABR with a simultaneous DIL boost was feasible. Acute grade ≥2 toxicity, late toxicity, and QOL seemed to be comparable to a cohort that did not receive a focal boost. Further follow-up will be required to assess long-term outcomes, and randomized data are required to confirm these findings.
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http://dx.doi.org/10.1016/j.ijrobp.2019.12.044DOI Listing
May 2020

Dosimetric predictors of toxicity and quality of life following prostate stereotactic ablative radiotherapy.

Radiother Oncol 2020 03 3;144:135-140. Epub 2019 Dec 3.

Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada; Institute of Health Policy Management and Evaluation, University of Toronto, Canada. Electronic address:

Purpose: SABR offers an effective treatment option for clinically localized prostate cancer. Here we report the dosimetric predictors of late toxicity and quality of life (QOL) in a pooled cohort of patients from four phase II trials.

Methods: The combined cohort included all three prostate cancer risk groups. The prescription dose was 35-40 Gy in 5 fractions. Toxicity (CTCAE) and QOL (EPIC) were collected. Multiple dosimetric parameters for the bladder, rectum and penile bulb were collected. Univariate (UVA) followed by multivariate (MVA) logistic regression analysis was conducted to search for significant dosimetric predictors of late GI/GU toxicity, or minimal clinically important change in the relevant QOL domain.

Results: 258 patients were included with median follow up of 6.1 years. For QOL, bladder Dmax, V38, D1cc, D2cc, D5cc and rectal V35 were predictors of urinary and bowel MCIC on UVA. On MVA, only bladder V38 remained significant. For late toxicity, various parameters were significant on UVA but only rectal Dmax, V38 and bladder D2cc were significant predictors on MVA.

Conclusions: This report confirms that the high-dose regions in the bladder and rectum are more significant predictors of late toxicity and QOL after prostate SABR compared to low-dose regions. Caution must be taken to avoid high doses and hotspots in those organs.
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http://dx.doi.org/10.1016/j.radonc.2019.11.017DOI Listing
March 2020

Correction to: Unequivocal imaging of aluminium in human cells and tissues by an improved method using morin.

Histochem Cell Biol 2019 Dec;152(6):465

Aluminium and Silicon Research Group, The Birchall Centre, Lennard-Jones Laboratories, Keele University, Keele, Staffordshire, ST5 5BG, UK.

After publication of our article, it has come to our attention that our Conflict of Interest statement should read.
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http://dx.doi.org/10.1007/s00418-019-01828-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943385PMC
December 2019

IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations.

Brain Pathol 2020 05 3;30(3):541-553. Epub 2019 Dec 3.

Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China SAR.

In the 2016, WHO classification of tumors of the central nervous system, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower grade astrocytomas and IDH-mutated astrocytomas is now regarded as a single group with longer survival. However, the molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated. In this study, we recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (P = 0.036) and low-risk (P < 0.0001) groups. One limitation of this study is the relatively short follow-up period, a common confounding factor for studies on low-grade tumors. Our data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.
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http://dx.doi.org/10.1111/bpa.12801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018138PMC
May 2020

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

Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial.

Lancet Oncol 2019 11 17;20(11):1531-1543. Epub 2019 Sep 17.

The Royal Marsden Hospital, London, UK; The Institute of Cancer Research, London, UK. Electronic address:

Background: Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer.

Methods: PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing.

Findings: Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred.

Interpretation: Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity.

Funding: Accuray and National Institute of Health Research.
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http://dx.doi.org/10.1016/S1470-2045(19)30569-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838670PMC
November 2019

Unequivocal imaging of aluminium in human cells and tissues by an improved method using morin.

Histochem Cell Biol 2019 Dec 28;152(6):453-463. Epub 2019 Aug 28.

Aluminium and Silicon Research Group, The Birchall Centre, Lennard-Jones Laboratories, Keele University, Keele, Staffordshire, ST5 5BG, UK.

Aluminium is biologically reactive and its ability to potentiate the immune response has driven its inclusion in both veterinary and human vaccines. Consequently, the need for unequivocal visualisation of aluminium in vivo has created a focused research effort to establish fluorescent molecular probes for this purpose. The most commonly used direct fluorescent labels for the detection of aluminium are morin (2',3,4',5,7-pentahydroxyflavone) and lumogallion [4-chloro-3-(2,4-dihydroxyphenylazo)-2-hydroxybenzene-1-sulphonic acid]. While the former has gained popularity in the detection of aluminium in plants and predominantly within root tips, the latter boasts greater sensitivity and selectivity for the detection of aluminium in human cells and tissues. Herein, we have developed a simplified morin staining protocol using the autofluorescence quenching agent, Sudan Black B. This modified protocol improves tissue morphology and increases analytical sensitivity, which allows intracellular aluminium to be detected in monocytes and when co-localised with senile plaques in human brain tissue of donors diagnosed with familial Alzheimer's disease. Overall, our results demonstrate a simple approach to minimise false positives in the use of morin to unequivocally detect aluminium in vivo.
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http://dx.doi.org/10.1007/s00418-019-01809-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881412PMC
December 2019
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