Publications by authors named "Vincent LaPointe"

17 Publications

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Functionalized Polyhydroquinolines from Amino Acids Using a Key One-Pot Cyclization Cascade and Application to the Synthesis of (±)-Δ-Mesembrenone.

Org Lett 2021 Oct 25. Epub 2021 Oct 25.

Département de chimie, Université de Sherbrooke, 2500, boulevard de l'Université, Sherbrooke, Québec, Canada J1K 2R1.

Substituted polyhydroquinolines are ubiquitous skeletal cores found in drugs and bioactive natural products. As a new route to access this motif, we successfully developed a one-pot cyclization cascade with high chemocontrol and diastereoselectivity. The sequence generates two cycles, three carbon-carbon bonds, and an all-carbon quaternary center in a highly convergent process. Functionalized polyhydroquinolines and congeners can be accessed from commercially available amino acids. This versatile and robust strategy was applied to the synthesis of (±)-Δ-mesembrenone.
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http://dx.doi.org/10.1021/acs.orglett.1c03323DOI Listing
October 2021

Patient-reported outcome measures in patients undergoing radiotherapy for head and neck cancer.

Support Care Cancer 2021 May 19;29(5):2537-2547. Epub 2020 Sep 19.

Univeristy of British Columbia, Vancouver, BC, Canada.

Objectives: Head and neck (H&N) cancer patients experience significant acute side effects from treatment. This study evaluates prospectively collected patient-reported outcomes (PROs) in H&N patients undergoing radiotherapy (RT) to assess feasibility of electronically collecting PROs and to objectively document symptom acuity and trajectory during RT.

Materials And Methods: H&N patients undergoing radical RT at our multicentre institution completed a 12-item partial survey of the Vanderbilt Head & Neck Symptom Survey 2.0 prior to RT and weekly on RT. Between October 2016 and October 2018, 318 of 333 patients completed a baseline survey and at least one weekly survey.

Results: The average number of weekly questionnaires completed was 5 (range 1-8). The mean maximum symptom scores were highest for dysgeusia (5.8/10), pain (5.4/10), mucositis (4.8/10), weight loss due to swallowing (4.5/10) and mucus causing choking/gagging (4.3/10). On multivariate analysis, female gender, sinonasal, nasopharynx and oropharynx primaries were associated with a greater risk of moderate-severe pain (p < 0.05). Sinonasal, nasopharynx, oral cavity, oropharynx and thyroid primaries were associated with a greater risk of moderate-severe mucositis during radiation (p < 0.0001). Salivary gland, sinonasal, nasopharynx and oropharynx primaries and higher radiation dose were associated with a greater risk of moderate-severe dysgeusia (all p < 0.05).

Conclusions: Electronic PRO collection during H&N cancer RT is feasible. H&N cancer patients experience significant symptoms during RT, and the most severe symptoms reported were dysgeusia, pain and mucositis. Oropharynx cancer patients reported the highest symptom scores during RT.
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http://dx.doi.org/10.1007/s00520-020-05778-2DOI Listing
May 2021

Pain response in a population-based study of radium-223 (Ra223) for metastatic castration-resistant prostate cancer.

Can Urol Assoc J 2019 Oct;13(10):E311-E316

Radiation Oncology, British Columbia Cancer Agency, BC, Canada.

Introduction: Clinical trials have shown that radium-223 (Ra223) can prolong survival and improve quality of life in patients with metastatic castration-resistant prostate cancer (mCRPC). The objectives of this study were to evaluate pain responses with Ra223 at a population-based level and to determine if there is an association between pain response and alkaline phosphatase (ALP) response.

Methods: All patients from the Vancouver and Kelowna Cancer Centers (CC) in British Columbia who were treated with Ra223 between June 2015 and December 2016 were identified. Patients completed the Brief Pain Inventory (BPI) just prior to each Ra223 injection. Pain response was defined as a two or more point improvement in worst pain relative to baseline, without an increase in pain medication level. ALP was determined at each visit, with a response threshold defined as a 30% decrease from baseline, consistent with the definition of response used in the ALSYMPCA trial.

Results: A total of 65 patients in Vancouver and Kelowna CC received Ra223 during the study period and 56 patients had at least one BPI record, of which 44 (79%) patients were assessable for change in worst pain. Of the assessable patients, 23 (52%, 95% confidence interval [CI] 38-67) had a pain response, although the use of concurrent external beam radiotherapy was a confounder in four cases. Of the 44 patients assessable for change in worst pain, 59% had ALP responses greater than 30%. An ALP response was seen in 56% of pain-responders vs. 43% of non-pain-responders. There was no association between pain response and ALP response (Phi =-0.05; p=0.77).

Conclusions: Ra223 administration was associated with a meaningful pain response rate in this cohort. There was no correlation between pain response and ALP response.
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http://dx.doi.org/10.5489/cuaj.5685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788917PMC
October 2019

Consistent Biopsy Quality and Gleason Grading Within the Global Active Surveillance Global Action Plan 3 Initiative: A Prerequisite for Future Studies.

Eur Urol Oncol 2019 05 13;2(3):333-336. Epub 2018 Sep 13.

Kan-tonsspital Baden, Baden, Switzerland.

Within the Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative, 25 centers across the globe collaborate to standardize active surveillance (AS) protocols for men with low-risk prostate cancer (PCa). A centralized PCa AS database, comprising data of more than 15000 patients worldwide, was created. Comparability of the histopathology between the different cohorts was assessed by a centralized pathology review of 445 biopsies from 15 GAP3 centers. Grade group 1 (Gleason score 6) in 85% and grade group ≥2 (Gleason score ≥7) in 15% showed 89% concordance at review with moderate agreement (κ=0.56). Average biopsy core length was similar among the analyzed cohorts. Recently established highly adverse pathologies, including cribriform and/or intraductal carcinoma, were observed in 3.6% of the reviewed biopsies. In conclusion, the centralized pathology review of 445 biopsies revealed comparable histopathology among the 15 GAP3 centers with a low frequency of high-risk features. This enables further data analyses-without correction-toward uniform global AS guidelines for men with low-risk PCa. PATIENT SUMMARY: Movember Foundation's Global Action Plan Prostate Cancer Active Surveillance (GAP3) initiative combines data from 15000 men with low-risk prostate cancer (PCa) across the globe to standardize active surveillance protocols. Histopathology review confirmed that the histopathology was consistent with low-risk PCa in most men and comparable between different centers.
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http://dx.doi.org/10.1016/j.euo.2018.08.017DOI Listing
May 2019

Provincial development of a patient-reported outcome initiative to guide patient care, quality improvement, and research.

Healthc Manage Forum 2018 Jan;31(1):13-17

8 BC Cancer Agency, Vancouver Island Centre, Victoria, British Columbia, Canada.

The BC Cancer Agency Radiotherapy (RT) program started the Prospective Outcomes and Support Initiative (POSI) at all six centres to utilize patient-reported outcomes for immediate clinical care, quality improvement, and research. Patient-reported outcomes were collected at time of computed tomography simulation via tablet and 2 to 4 weeks post-RT via either tablet or over the phone by a registered nurse. From 2013 to 2016, patients were approached on 20,150 attempts by POSI for patients treated with RT for bone metastases (52%), brain metastases (11%), lung cancer (17%), gynecological cancer (16%), head and neck cancer (2%), and other pilots (2%). The accrual rate for all encounters was 85% (n = 17,101), with the accrual rate varying between the lowest and the highest accruing centre from 78% to 89% ( P < .001) and varying by tumour site ( P < .001). Using the POSI database, we have performed research and quality improvement initiatives that have changed practice.
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http://dx.doi.org/10.1177/0840470417715478DOI Listing
January 2018

Comparison of patient-reported outcomes with single versus multiple fraction palliative radiotherapy for bone metastasis in a population-based cohort.

Radiother Oncol 2016 05 9;119(2):202-7. Epub 2016 Apr 9.

Department of Surgery, University of British Columbia, Canada; BC Cancer Agency, Centre for the North, Prince George, Canada. Electronic address:

Background: Despite randomized control trials showing equivalent efficacy between single-fraction (SF) and multiple-fraction (MF) radiation therapy (RT) for bone metastases (BoM), considerable variation in fractionation exists. We compared patient-reported outcomes (PROs) following SF versus MF RT in a population-based cohort.

Methods: PROs were chosen to assess patients' perception of pain, function, and symptom frustration. Total score was the sum of the 3 questions.

Results: 968 patients completed pre and post-RT PROs, 35% (335) had complicated BoM. Overall, there were no differences in total score improvement (79% vs. 83%; p=0.13), nor for complicated BoM (77% vs. 84%; p=0.12), SFRT and MFRT respectively. On multivariate analysis no differences in improvement in total score were observed between SFRT and MFRT overall (OR=0.71; 95% CI 0.49-1.02; p=0.06), nor for complicated BoM (OR=0.74; 95% CI 0.39-1.39; p=0.35). In the complicated BoM subset, pain complete response (CR) (19% vs. 33%; p=0.01) and functional improvement occurred more commonly in the MFRT group (69% vs. 81%; p=0.04).

Conclusion: Improvements in PROs for pain, function and symptom frustration were similar between SFRT and MFRT supporting the use of hypofractionated regimens. Using a simple, 3-question, telephone-based questionnaire to assess response to palliative RT is a feasible strategy to collect PROs.
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http://dx.doi.org/10.1016/j.radonc.2016.03.025DOI Listing
May 2016

Effect of aging and long-term erectile function after iodine-125 prostate brachytherapy.

Brachytherapy 2015 May-Jun;14(3):334-41. Epub 2015 Feb 14.

Vancouver Cancer Center, The British Columbia Provincial Prostate Brachytherapy Program, University of British Columbia, British Columbia Cancer Agency, Canada.

Purpose: To evaluate long-term erectile function (EF) in men treated with iodine-125 prostate brachytherapy (PB) and to determine factors predictive for erectile dysfunction (ED), including natural decline because of aging.

Methods: Two thousand nine hundred twenty-nine patients (implanted July 1989-June 2012) with baseline EF and greater than 10-month followup (FU) are included. About 78.9% had full and 7.9% had partial EF at baseline. EF was assessed on a physician-reported three-point scale. Poisson regression with generalized estimating equations was used to assess predictors of ED and Kaplan-Meier curves time to ED. The effect of aging was calculated from the declining rate of baseline EF seen in sequential 5-year age cohorts and from the Massachusetts Male Aging Study.

Results: The median age was 66 years and median FU 3.5 years (maximum 14 years). About 1142 patients had more than 5 years of FU, and 43% had received 6 months of androgen deprivation therapy (ADT). Significant drop in EF was seen at 6 weeks after PB, with gradual decline thereafter. EF preservation at 5 years for age younger than 55, 56-59, 60-64, 65-69, and 70 year and older was 82%, 73%, 58%, 39%, and 23%, respectively. Comparisons of the 5-year age-related and treatment-related EF decline show that 50% of the long-term EF decline is related to aging. On univariate and multivariate analyses, age at implant, length of FU, hypertension, diabetes, and use of ADT (all p < 0.01) were significant predictors of ED.

Conclusion: More than 80% of young men have EF preserved 5 years after PB. Age, ADT, history of hypertension, and the natural decline in EF have negative impact on long-term EF after PB.
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http://dx.doi.org/10.1016/j.brachy.2015.01.001DOI Listing
December 2015

Late urinary side effects 10 years after low-dose-rate prostate brachytherapy: population-based results from a multiphysician practice treating with a standardized protocol and uniform dosimetric goals.

Int J Radiat Oncol Biol Phys 2014 Nov 20;90(3):570-8. Epub 2014 Aug 20.

British Columbia Provincial Prostate Brachytherapy Program, British Columbia Cancer Agency, Vancouver, BC, Canada.

Purpose: To determine late urinary toxicity (>12 months) in a large cohort of uniformly treated low-dose-rate prostate brachytherapy patients.

Methods And Materials: From 1998 to 2009, 2709 patients with National Comprehensive Cancer Network-defined low-risk and low-tier intermediate-risk prostate cancer were treated with Iodine 125 ((125)I) low-dose-rate prostate brachytherapy; 2011 patients with a minimum of 25 months of follow-up were included in the study. Baseline patients, treatment, implant factors, and late urinary toxicity (Radiation Therapy Oncology Group [RTOG] grading system and International Prostate Symptom Score [IPSS]) were recorded prospectively. Time to IPSS resolution, late RTOG genitourinary toxicity was examined with Kaplan-Meier and log-rank tests. Cox proportional hazards regression was done for individual covariates and multivariable models.

Results: Median follow-up was 54.5 months (range, 2-13 years). Actuarial toxicity rates reached 27% and 10% (RTOG ≥2 and ≥3, respectively) at 9-13 years. Symptoms resolved quickly in the majority of patients (88% in 6-12 months). The prevalence of RTOG 0, 1, 2, 3, and 4 toxicity with a minimum of 7 years' follow-up was 70%, 21%, 6.4%, 2.3%, and 0.08%, respectively. Patients with a larger prostate volume, higher baseline IPSS, higher D90, acute toxicity, and age >70 years had more late RTOG ≥2 toxicity (all P≤.02). The IPSS resolved slower in patients with lower baseline IPSS and larger ultrasound prostate volume, those not receiving androgen deprivation therapy, and those with higher D90. The crude rate of RTOG 3 toxicity was 6%. Overall the rate of transurethral resection of the prostate was 1.9%; strictures, 2%; incontinence, 1.3%; severe symptoms, 1.8%; late catheterization, 1.3%; and hematuria, 0.8%. The majority (80%) resolved their symptoms in 6-12 months.

Conclusion: Long-term urinary toxicity after brachytherapy is low. Although actuarial rates increase with longer follow-up (27% RTOG 2 and 10% RTOG 3 at 13 years), symptoms resolve relatively quickly; between 5 and 13 years' follow-up, >90% of patients have minimal urinary toxicity. Refining patient selection criteria, planning, and treatment delivery may further reduce toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2014.06.037DOI Listing
November 2014

Prostate-specific antigen at 4 to 5 years after low-dose-rate prostate brachytherapy is a strong predictor of disease-free survival.

Int J Radiat Oncol Biol Phys 2014 Jan;88(1):87-93

Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Medical Physics, British Columbia Cancer Agency Vancouver Centre, Vancouver, British Columbia, Canada.

Purpose: To determine (1) the prognostic utility of prostate-specific antigen (PSA) concentration at 45 to 60 months (48mPSA) after low-dose-rate prostate brachytherapy (LDR-PB); (2) the predictors of 48mPSA; and (3) the prognostic utility of directional trends between PSA levels at 24, 36, and 48 months after LDR-PB.

Methods And Materials: Between 1998 and 2008, 2223 patients with low- and intermediate-risk prostate cancer received LDR-PB monotherapy. A cohort of 1434 of these patients was identified with a documented 48mPSA and no evidence of disease relapse prior to the 48mPSA. In addition, a subset of this cohort (n=585) was identified with ≥72 months of follow-up and documented PSA values at both 24 and 36 months after implantation.

Results: Median follow-up time was 76 months. Eight-year Kaplan-Meier disease-free survival (DFS) rates were 100% vs 73.4% for patients with 48mPSA≤0.2 vs those with >0.2 ng/mL; 99.1% versus 53.8% for a 48mPSA threshold of ≤0.4 versus >0.4 ng/mL, respectively; and 97.3% versus 0% for a threshold of ≤1.0 versus >1.0 ng/mL, respectively. On multivariate analysis, the only factor predictive of DFS was 48mPSA (P<.0001). On subset analysis (n=585), 29 patients had a PSA rise (defined as >0.2 ng/mL) between 24 and 36 months, 24 patients had a rise between 36 and 48 months, and 11 patients had rises over both intervals. Failure rates in these patients were 52%, 79%, and 100%, respectively. On multivariate analysis, initial PSA, androgen deprivation therapy, and dose to 90% of the prostate significantly correlated with 48mPSA but together accounted for only ∼5% of its total variance.

Conclusions: The 48mPSA after LDR-PB is highly predictive of long-term DFS. Patients with 48mPSA≤0.4 ng/mL had a <1% risk of disease relapse at 8 years, whereas all patients with 48mPSA>1.0 ng/mL relapsed. Consecutive PSA rises of >0.2 ng/mL from 24 to 36 months and from 36 to 48 months were also highly predictive of subsequent failure.
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http://dx.doi.org/10.1016/j.ijrobp.2013.10.010DOI Listing
January 2014

Decline in acute urinary toxicity: a long-term study in 2011 patients with prostate brachytherapy within a provincial institution.

Brachytherapy 2014 Jan-Feb;13(1):46-52. Epub 2013 Nov 7.

Department of Radiation Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.

Purpose: To determine whether acute urinary toxicity rates improve with the overall experience of a large prostate brachytherapy program.

Methods And Materials: From 1998 to 2009, 2937 patients were treated with prostate brachytherapy at the British Columbia Cancer Agency. Baseline patient, treatment, and implant factors were recorded prospectively. Acute urinary toxicity data were prospectively recorded at baseline and each follow-up visit. Patients with ≥2 years of follow-up data were grouped into cohorts of 500 for analysis.

Results: Two thousand eleven patients met the above criteria. Acute urinary retention (AUR) in the acute period (within 6 months of implant) occurred in 9.1% of patients overall and was prolonged (catheterization >20 days) in 3.4%. Both overall AUR and prolonged AUR decreased across implant cohorts (p ≤ 0.001 in both cases). Overall acute Radiation Therapy Oncology Group (RTOG) Grades 0 and 1 urinary toxicity rate was 57.5% and RTOG Grades 2 and 3 urinary toxicity rates were 34.3% and 8.1%, respectively. Acute toxicity improved over time for both RTOG Grades ≥2 and ≥3 toxicity (p < 0.0001). International prostate symptom score resolution to baseline was achieved in 80.5% of patients with a median time of 12.2 months.

Conclusions: Acute AUR and RTOG urinary toxicity rates continue to decline with the increasing experience of our provincial prostate brachytherapy program, despite its expansion to new centers and addition of members. This is likely due to better patient selection, refinement in treatment planning and implantation technique, and mentorship and training process.
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http://dx.doi.org/10.1016/j.brachy.2013.10.005DOI Listing
May 2014

Biological consequences of MLC calibration errors in IMRT delivery and QA.

Med Phys 2012 Apr;39(4):1917-24

British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, British Columbia, Canada.

Purpose: The purpose of this work is threefold: (1) to explore biological consequences of the multileaf collimator (MLC) calibration errors in intensity modulated radiotherapy (IMRT) of prostate and head and neck cancers, (2) to determine levels of planning target volume (PTV) and normal tissue under- or overdose flagged with clinically used QA action limits, and (3) to provide biologically based input for MLC QA and IMRT QA action limits.

Methods: Ten consecutive prostate IMRT cases and ten consecutive head and neck IMRT cases were used. Systematic MLC offsets (i.e., calibration error) were introduced for each control point of the plan separately for X1 and X2 leaf banks. Offsets were from - 2 to 2 mm with a 0.5 mm increment. The modified files were imported into the planning system for forward dose recalculation. The original plan served as the reference. The generalized equivalent uniform dose (gEUD) was used as the biological index for the targets, rectum, parotid glands, brainstem, and spinal cord. Each plan was recalculated on a CT scan of a 27 cm diameter cylindrical phantom with a contoured 0.6 cc ion chamber. Dose to ion chamber and 3D gamma analysis were compared to the reference plan. QA pass criteria: (1) at least 95% of voxels with a dose cutoff of 50% of maximum dose have to pass at 3 mm/3% and (2) dose to chamber within 2% of the reference dose.

Results: For prostate cases, differences in PTV and rectum gEUD greater than 2% were identified. However, a larger proportion of plans leading to greater than 2% difference in prostate PTV gEUD passed the ion chamber QA but not 3D gamma QA. A similar trend was found for the rectum gEUD. For head and neck IMRT, the QA pass criteria flagged plans leading to greater than 4% differences in PTV gEUD and greater than 5% differences in the maximum dose to brainstem. If pass criteria were relaxed to 90% for gamma and 3% for ion chamber QA, plans leading to a 5% difference in PTV gEUD and a 5%-8% difference in brainstem maximum dose would likely pass IMRT QA. A larger proportion of head and neck plans with greater than 2% PTV gEUD difference passed 3D gamma QA compared to ion chamber QA.

Conclusions: For low modulation plans, there is a better chance to catch MLC calibration errors with 3D gamma QA rather than ion chamber QA. Conversely, for high modulation plans, there is a better chance to catch MLC calibration errors with ion chamber QA rather than with 3D gamma QA. Ion chamber and 3D gamma analysis IMRT QA can detect greater than 2% change in gEUD for PTVs and critical structures for low modulation treatment plans. For high modulation treatment plans, ion chamber and 3D gamma analysis can detect greater than 2% change in gEUD for PTVs and a 5% change in critical structure gEUD since either QA methods passes the QA criteria. For gEUD changes less than those listed above, either QA method has the same proportion of passing rate.
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http://dx.doi.org/10.1118/1.3692177DOI Listing
April 2012

Outcomes following iodine-125 brachytherapy in patients with Gleason 7, intermediate risk prostate cancer: a population-based cohort study.

Radiother Oncol 2012 May 10;103(2):228-32. Epub 2012 Feb 10.

Department of Radiation Oncology, BC Cancer Agency, Vancouver, Canada.

Background And Purpose: To evaluate outcome in patients with Gleason 7 prostate cancer treated with iodine-125 brachytherapy at the British Columbia Cancer Agency.

Materials And Methods: Between 20th July 1998 and 7th February 2006, 1500 patients underwent I-125 prostate brachytherapy without supplemental external beam radiation therapy. Of these, 439 had Gleason 7 disease; 362 had Gleason 3+4 and 77 had 4+3 disease. Generally, patients received 6 months of androgen suppression. We compared biochemical no evidence of disease (bNED) between patients with Gleason ≤ 6 and Gleason 7 and between Gleason 3+4 and 4+3 using the Phoenix definition of biochemical recurrence.

Results: Median follow-up was 60 months. Estimated 5 year bNED was 97% for patients with Gleason score ≤ 6 and 94% for patients with Gleason 7 disease (p=0.037). Estimated bNED was 95% and 94% for 3+4 and 4+3, respectively (p=0.791). There was no difference in bNED between implants achieving D90 ≥ versus
Conclusions: I-125 brachytherapy with 6 months of ADT demonstrates excellent bNED rates in Gleason 7 disease. We found no evidence of a difference between patients with Gleason 3+4 versus 4+3 disease.
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http://dx.doi.org/10.1016/j.radonc.2012.01.006DOI Listing
May 2012

The effect of loose versus stranded seeds on biochemical no evidence of disease in patients with carcinoma of the prostate treated with iodine-125 brachytherapy.

Brachytherapy 2011 Nov-Dec;10(6):442-8. Epub 2011 Mar 12.

Department of Radiation Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada.

Purpose: The British Columbia Cancer Agency has been performing iodine-125 prostate brachytherapy since 1998, initially using loose seeds and phasing into the exclusive use of RAPIDStrand (RS) (Oncura Inc., Plymouth Meeting, PA) by November 2000. The aim of this study was to investigate rates of biochemical no evidence of disease (bNED) in patients treated with loose seeds compared with RS from this population-based cohort.

Methods And Materials: Between July 1998 and February 2006, 1500 implants were performed (327 loose and 1173 RS). Biochemical failure is reported using the Phoenix definition and prostate-specific antigen (PSA) >0.4ng/mL at ≥48 months postimplant. Actuarial estimates were calculated by the Kaplan-Meier method. Analysis was repeated with the first 100 loose and stranded implants excluded to assess the learning curve effect. Log-rank test was used to evaluate differences in bNED. Variables showing association with bNED were included in a multivariate model.

Results: There was no difference between loose and stranded seeds. Estimated rate of bNED was 93.5% (95% confidence interval [CI], 90.6-96.4) at 7 years for patients treated with loose seeds and 94.0% (95% CI, 91.8-96.2) for patients treated with RS according to Phoenix definition (p=0.846). Using the PSA >0.4ng/mL definition, estimated rates were 91.3% (95% CI, 88.0-94.6) and 91.9% (95% CI, 89.7-94.1) for loose and stranded seeds, respectively (p=0.871). Exclusion of the first 100 loose and stranded implants also revealed no difference in bNED.

Conclusion: This study of 1500 patients treated with iodine-125 brachytherapy demonstrates no difference in bNED between loose and stranded seeds, using either Phoenix or PSA >0.4ng/mL definitions of biochemical failure.
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http://dx.doi.org/10.1016/j.brachy.2011.01.011DOI Listing
February 2012

Evaluating the Phoenix definition of biochemical failure after (125)I prostate brachytherapy: Can PSA kinetics distinguish PSA failures from PSA bounces?

Int J Radiat Oncol Biol Phys 2010 Oct 3;78(2):415-21. Epub 2010 Feb 3.

British Columbia Cancer Agency, Vancouver, BC, Canada.

Purpose: To evaluate the prostate-specific antigen (PSA) kinetics of PSA failure (PSAf) and PSA bounce (PSAb) after permanent (125)I prostate brachytherapy (PB).

Methods And Materials: The study included 1,006 consecutive low and "low tier" intermediate-risk patients treated with (125)I PB, with a potential minimum follow-up of 4 years. Patients who met the Phoenix definition of biochemical failure (nadir + 2 ng/mL(-1)) were identified. If the PSA subsequently fell to ≤0.5 ng/mL(-1)without intervention, this was considered a PSAb. All others were scored as true PSAf. Patient, tumor and dosimetric characteristics were compared between groups using the chi-square test and analysis of variance to evaluate factors associated with PSAf or PSAb.

Results: Median follow-up was 54 months. Of the 1,006 men, 57 patients triggered the Phoenix definition of PSA failure, 32 (56%) were true PSAf, and 25 PSAb (44%). The median time to trigger nadir + 2 was 20.6 months (range, 6-36) vs. 49 mo (range, 12-83) for PSAb vs. PSAf groups (p < 0.001). The PSAb patients were significantly younger (p < 0.0001), had shorter time to reach the nadir (median 6 vs. 11.5 months, p = 0.001) and had a shorter PSA doubling time (p = 0.05). Men younger than age 70 who trigger nadir +2 PSA failure within 38 months of implant have an 80% likelihood of having PSAb and 20% chance of PSAf.

Conclusions: With adequate follow-up, 44% of PSA failures by the Phoenix definition in our cohort were found to be benign PSA bounces. Our study reinforces the need for adequate follow-up when reporting PB PSA outcomes, to ensure accurate estimates of treatment efficacy and to avoid unnecessary secondary interventions.
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http://dx.doi.org/10.1016/j.ijrobp.2009.07.1724DOI Listing
October 2010

Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) export-competent RNP.

EMBO J 2009 Apr 5;28(8):1087-98. Epub 2009 Mar 5.

Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada.

The eukaryotic translation initiation factor 4E (eIF4E) controls gene expression through its effects on mRNA export and cap-dependent translation, both of which contribute to its oncogenic potential. In contrast to its translation function, the mRNA export function of eIF4E is poorly understood. Using an RNP isolation/mass spectrometry approach, we identified candidate cofactors of eIF4E mRNA export including LRPPRC. This protein associates with mRNAs containing the eIF4E-sensitivity element (4E-SE), and its overexpression alters the nuclear export of several eIF4E-sensitive mRNAs. LRPPRC-mediated alteration of eIF4E's mRNA export function requires the integrity of its eIF4E-binding site and it coincides with the subcellular re-distribution of eIF4E. The eIF4E export RNP is distinct in composition from the bulk mRNA export pathway, in that eIF4E- and eIF4E-sensitive mRNAs do not associate with general mRNA export factors such as TAP/NXF1 or REF/Aly. Our data indicate that mRNA export pathways have evolved for specific mRNAs enabling the differential regulation of biochemical pathways by modulating the expression of groups of genes at the level of their export.
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http://dx.doi.org/10.1038/emboj.2009.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683702PMC
April 2009

Urinary symptom flare in 712 125I prostate brachytherapy patients: long-term follow-up.

Int J Radiat Oncol Biol Phys 2009 Nov 11;75(3):649-55. Epub 2009 Feb 11.

Department of Surgery, University of British Columbia, Provincial Prostate Brachytherapy Program, British Columbia Cancer Agency, 600 W. 10th Avenue, Vancouver, BC, Canada.

Purpose: To describe the late transient worsening of urinary symptoms ("urinary symptom flare") in 712 consecutive prostate brachytherapy patients, associated predictive factors, association with rectal and urinary toxicity, and the development of erectile dysfunction.

Methods And Materials: Patients underwent implantation between 1998 and 2003 (median follow-up, 57 months). International Prostate Symptom Score (IPSS), Radiation Therapy Oncology Group (RTOG) toxicity, and erectile function data were prospectively collected. Flare was defined as an increase in IPSS of > or =5 and of > or =8 points greater than the post-treatment nadir. The relationships between the occurrence of flare and the patient, tumor, and treatment characteristics were examined. The Cox proportional hazards method was used to test individual variables and the multivariate models.

Results: The incidence of flare was 52% and 30% using the flare definition of an IPSS of > or =5 and > or =8 points greater than the postimplant nadir, respectively. Of the patients with symptoms, 65% had resolution of their symptoms within 6 months and 91% within 1 year. Flares most commonly occurred 16-24 months after implantation. On multivariate analysis, a greater baseline IPSS and greater maximal postimplant IPSS were the predictors of flare, regardless of the flare definition used. Androgen suppression was a predictor for fewer flares (IPSS > or =5). Diabetes and prostate edema predicted for more frequent flares (IPSS >/=8). Patients with flare had a greater incidence of RTOG Grade 3 urinary toxicity and RTOG Grade 2 or greater rectal toxicity. No association was found between erectile dysfunction and the occurrence of flare.

Conclusion: Urinary symptom flare is a common, transient phenomenon after prostate brachytherapy. A greater baseline IPSS and maximal postimplant IPSS were the strongest predictive factors. Flare was associated with a greater incidence of late RTOG Grade 3 urinary toxicity and greater rate of late RTOG Grade 2 or greater rectal toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2008.11.043DOI Listing
November 2009

Predictive factors for acute and late urinary toxicity after permanent prostate brachytherapy: long-term outcome in 712 consecutive patients.

Int J Radiat Oncol Biol Phys 2009 Mar 26;73(4):1023-32. Epub 2008 Dec 26.

Vancouver Cancer Center, Vancouver, BC, Canada.

Purpose: To describe the frequency of acute and late Radiation Therapy Oncology Group (RTOG) urinary toxicity, associated predictive factors, and resolution of International Prostate Symptom Score (IPSS) in 712 consecutive prostate brachytherapy patients.

Methods And Materials: Patients underwent implantation between 1998 and 2003 (median follow-up, 57 months). The IPSS and RTOG toxicity data were prospectively collected. The patient, treatment, and implant factors were examined for an association with urinary toxicity. The time to IPSS resolution was examined using Kaplan-Meier curves, and multivariate modeling of IPSS resolution was done using Cox proportional hazards regression analysis. Logistic regression analysis was used to examine the factors associated with urinary toxicity.

Results: The IPSS returned to baseline at a median of 12.6 months. On multivariate analysis, patients with a high baseline IPSS had a quicker resolution of their IPSS. Higher prostate D90 (dose covering 90% of the prostate), maximal postimplant IPSS, and urinary retention slowed the IPSS resolution time. The rate of the actuarial 5-year late urinary (>12 months) RTOG Grade 0, 1, 2, 3, and 4 was 32%, 36%, 24%, 6.2%, and 0.1%, respectively. At 7 years, the prevalence of RTOG Grade 0-1 was 92.5%. Patients with a larger prostate volume, greater number of needles, greater baseline IPSS, and use of hormonal therapy had more acute toxicity. On multivariate analysis, the significant predictors for late greater than or equal to RTOG toxicity 2 were a greater baseline IPSS, maximal postimplant IPSS, presence of acute toxicity, and higher prostate V150 (volume of the prostate covered by 150% of the dose). More recently implanted patients had less acute urinary toxicity and patients given hormonal therapy had less late urinary toxicity (all p < 0.02).

Conclusion: Most urinary symptoms resolved within 12 months after prostate brachytherapy, and significant long-term urinary toxicity was very low. Refined patient selection and greater technical experience in prostate brachytherapy were associated with less urinary toxicity.
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http://dx.doi.org/10.1016/j.ijrobp.2008.05.022DOI Listing
March 2009
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