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1.
Pract Radiat Oncol ; 10(3): 186-194, 2020.
Article in English | MEDLINE | ID: mdl-31978591

ABSTRACT

PURPOSE: Previously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit. METHODS AND MATERIALS: Clinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed. RESULTS: Rectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines. CONCLUSIONS: There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.


Subject(s)
Prostate/surgery , Prostatic Neoplasms/surgery , Rectum/surgery , Aged , Aged, 80 and over , Humans , Male , Middle Aged , Prostate/radiation effects , Prostatic Neoplasms/radiotherapy , Rectum/radiation effects
2.
Pract Radiat Oncol ; 8(1): e7-e15, 2018.
Article in English | MEDLINE | ID: mdl-28951089

ABSTRACT

BACKGROUND: We previously reported the results of a phase 3 trial evaluating a prostate/rectal hydrogel spacer during prostate intensity modulated radiation therapy, which resulted in decreased rectal dose and toxicity and less decline in bowel quality of life (QOL). A secondary analysis was performed to correlate penile bulb dose and sexual QOL. METHODS AND MATERIALS: Sexual QOL was measured with the Expanded Prostate Cancer Index Composite (EPIC) by mean scores, the proportion of patients with a minimal clinically important difference (MID), and analyses of the different items composing the sexual domain. RESULTS: A total of 222 men enrolled with median follow-up of 37 months. Hydrogel reduced penile bulb mean dose, maximum dose, and percentage of penile bulb receiving 10 to 30 Gy (all P < .05) with mean dose indirectly correlated with erections sufficient for intercourse at 15 months (P = .03). Baseline EPIC was low (53 [standard deviation ± 24]) with no difference between arms (P > .1). A total of 41% (88/222) of men had adequate baseline sexual QOL (EPIC >60 (mean, 77 [± 8.3]). This subgroup at 3 years had better sexual function (P = .03) with a spacer with a smaller difference in sexual bother (P = .1), which resulted in a higher EPIC summary on the spacer arm (58 [±24.1] vs control 45 [± 24.4]) meeting threshold for MID without statistical significance (P = .07). There were statistically nonsignificant differences favoring spacer for the proportion of men with MID and 2× MID declines in sexual QOL with 53% vs 75% having an 11-point decline (P = .064) and 41% vs 60% with a 22-point decline (P = .11). At 3 years, more men potent at baseline and treated with spacer had "erections sufficient for intercourse" (control 37.5% vs spacer 66.7%, P = .046) as well as statistically higher scores on 7 of 13 items in the sexual domain (all P < .05). CONCLUSIONS: The use of a hydrogel spacer decreased dose to the penile bulb, which was associated with improved erectile function compared with the control group based on patient-reported sexual QOL.


Subject(s)
Prostatic Neoplasms/radiotherapy , Quality of Life/psychology , Radiotherapy, Intensity-Modulated/psychology , Sexual Behavior/psychology , Humans , Male , Radiotherapy, Intensity-Modulated/methods
3.
Int J Radiat Oncol Biol Phys ; 97(5): 976-985, 2017 04 01.
Article in English | MEDLINE | ID: mdl-28209443

ABSTRACT

PURPOSE: SpaceOAR, a Food and Drug Administration-approved hydrogel intended to create a rectal-prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years. METHODS AND MATERIALS: Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds. RESULTS: The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P=.028) and grade ≥2 (5.7% vs 0%; P=.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favored the spacer group (P=.002), with the difference at 3 years (5.8 points; P<.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P<.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02). CONCLUSIONS: The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy.


Subject(s)
Prostatic Neoplasms/epidemiology , Prostatic Neoplasms/radiotherapy , Radiation Injuries/epidemiology , Radiation Injuries/prevention & control , Radiation Protection/statistics & numerical data , Rectal Diseases/epidemiology , Rectal Diseases/prevention & control , Adult , Aged , Causality , Dose Fractionation, Radiation , Follow-Up Studies , Humans , Longitudinal Studies , Male , Middle Aged , Organs at Risk/radiation effects , Prevalence , Prostatic Neoplasms/psychology , Quality of Life/psychology , Radiation Injuries/psychology , Radiation Protection/instrumentation , Radiotherapy, Conformal/methods , Radiotherapy, Conformal/psychology , Radiotherapy, Conformal/statistics & numerical data , Radiotherapy, Image-Guided/psychology , Radiotherapy, Image-Guided/statistics & numerical data , Rectal Diseases/psychology , Risk Factors , Treatment Outcome , United States/epidemiology
4.
Gut ; 65(3): 456-64, 2016 Mar.
Article in English | MEDLINE | ID: mdl-25645662

ABSTRACT

OBJECTIVE: ATG16L1 is an autophagy gene known to control host immune responses to viruses and bacteria. Recently, a non-synonymous single-nucleotide polymorphism in ATG16L1 (Thr300Ala), previously identified as a risk factor in Crohn's disease (CD), was associated with more favourable clinical outcomes in thyroid cancer. Mechanisms underlying this observation have not been proposed, nor is it clear whether an association between Thr300Ala and clinical outcomes will be observed in other cancers. We hypothesised that Thr300Ala influences clinical outcome in human colorectal cancer (CRC) and controls innate antiviral pathways in colon cancer cells. DESIGN: We genotyped 460 patients with CRC and assessed for an association between ATG16L1 Thr300Ala and overall survival and clinical stage. Human CRC cell lines were targeted by homologous recombination to examine the functional consequence of loss of ATG16L1, or introduction of the Thr300Ala variant. RESULTS: We found an association between longer overall survival, reduced metastasis and the ATG16L1 Ala/Ala genotype. Tumour sections from ATG16L1 Ala/Ala patients expressed elevated type I interferons (IFN-I)-inducible, MxA, suggesting that differences in cytokine production may influence disease progression. When introduced into human CRC cells by homologous recombination, the Thr300Ala variant did not affect bulk autophagy, but increased basal production of type I IFN. Introduction of Thr300Ala resulted in increased sensitivity to the dsRNA mimic poly(I:C) through a mitochondrial antiviral signalling (MAVS)-dependent pathway. CONCLUSIONS: The CD-risk allele, Thr300Ala, in ATG16L1 is associated with improved overall survival in human CRC, generating a rationale to genotype ATG16L1 Thr300Ala in patients with CRC. We found that Thr300A alters production of MAVS-dependent type I IFN in CRC cells, providing a mechanism that may influence clinical outcomes.


Subject(s)
Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Carrier Proteins/genetics , Colorectal Neoplasms/genetics , Interferon Type I/metabolism , Polymorphism, Single Nucleotide , Adenocarcinoma/metabolism , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Autophagy-Related Proteins , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/mortality , Female , Follow-Up Studies , Humans , Male , Middle Aged , Survival Analysis
5.
Int J Radiat Oncol Biol Phys ; 92(5): 971-977, 2015 Aug 01.
Article in English | MEDLINE | ID: mdl-26054865

ABSTRACT

PURPOSE: Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation. METHODS AND MATERIALS: Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months. RESULTS: Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption. CONCLUSIONS: Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols.


Subject(s)
Hydrogel, Polyethylene Glycol Dimethacrylate/administration & dosage , Organs at Risk/radiation effects , Prostatic Neoplasms/radiotherapy , Radiation Injuries/prevention & control , Radiation Protection/instrumentation , Radiotherapy, Image-Guided/instrumentation , Radiotherapy, Intensity-Modulated/instrumentation , Rectum/radiation effects , Aged , Fiducial Markers , Humans , Male , Prospective Studies , Prostate , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology , Quality of Life , Radiation Dosage , Radiography , Radiotherapy Dosage , Radiotherapy, Image-Guided/methods , Radiotherapy, Intensity-Modulated/adverse effects , Radiotherapy, Intensity-Modulated/methods , Urinary Tract/radiation effects
7.
BMJ Open ; 3(6)2013 Jun 20.
Article in English | MEDLINE | ID: mdl-23794574

ABSTRACT

OBJECTIVE: A common genetic coding variant in the core autophagy gene ATG16L1 is associated with increased susceptibility to Crohn's disease (CD). The variant encodes an amino acid change in ATG16L1 such that the threonine at position 300 is substituted with an alanine (ATG16L1 T300A). How this variant contributes to increased risk of CD is not known, but studies with transfected cell lines and gene-targeted mice have demonstrated that ATG16L1 is required for autophagy, control of interleukin-1-ß and autophagic clearance of intracellular microbes. In addition, studies with human cells expressing ATG16L1 T300A indicate that this variant reduces the autophagic clearance of intracellular microbes. DESIGN/RESULTS: We demonstrate, using somatically gene-targeted human cells that the ATG16L1 T300A variant confers protection from cellular invasion by Salmonella. In addition, we show that ATG16L1-deficient cells are resistant to bacterial invasion. CONCLUSIONS: These results suggest that cellular expression of ATG16L1 facilitates bacterial invasion and that the CD-associated ATG16L1 T300A variant may confer protection from bacterial infection.

8.
Med Phys ; 39(6): 3051-9, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22755690

ABSTRACT

PURPOSE: To investigate using 3D γ analysis for IMRT and VMAT QA. METHODS: We explored and studied 3D γ-analysis by comparing TPS computed and EPID back-projection reconstructed doses in patient's CT images. Two 3D γ quantities, γ(PTV) and γ(10), were proposed and studied for evaluating the QA results, and compared to 2D γ (MapCheck composite: γ(MC)). RESULTS: It was found that when 3%(global)/3 mm criteria was used, all IMRT and 90% of VMAT plans passed QA with a γ pass rate ≥90%. A significant statistical correlation was observed between 3D and 2D γ-analysis results for IMRT QA if γ(10) and γ(MC) are concerned, but no significant relation is found between γ(PTV) and γ(MC). CONCLUSIONS: 3D γ analysis based on EPID dose back-projection may provide a feasible tool for IMRT and VMAT pretreatment plan QA.


Subject(s)
Gamma Rays , Imaging, Three-Dimensional/methods , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy, Intensity-Modulated/methods , Humans , Male , Prostatic Neoplasms/radiotherapy , Quality Control , Radiotherapy Planning, Computer-Assisted/standards , Radiotherapy, Intensity-Modulated/standards , Software
9.
J Immunol ; 184(12): 7001-9, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20483768

ABSTRACT

The TNF alpha-induced protein 3 (TNFAIP3) is an ubiquitin-modifying enzyme and an essential negative regulator of inflammation. Genome-wide association studies have implicated the TNFAIP3 locus in susceptibility to autoimmune disorders in European cohorts, including rheumatoid arthritis, coronary artery disease, psoriasis, celiac disease, type 1 diabetes, inflammatory bowel disease, and systemic lupus erythematosus (SLE). There are two nonsynonymous coding polymorphisms in the deubiquitinating (DUB) domain of TNFAIP3: F127C, which is in high-linkage disequilibrium with reported SLE-risk variants, and A125V, which has not been previously studied. We conducted a case-control study in African-American SLE patients using these coding variants, along with tagging polymorphisms in TNFAIP3, and identified a novel African-derived risk haplotype that is distinct from previously reported risk variants (odds ratio=1.6, p=0.006). In addition, a rare protective haplotype was defined by A125V (odds ratio=0.31, p=0.027). Although A125V was associated with protection from SLE, surprisingly the same allele was associated with increased risk of inflammatory bowel disease. We tested the functional activity of nonsynonymous coding polymorphisms within TNFAIP3, and found that the A125V coding-change variant alters the DUB activity of the protein. Finally, we used computer modeling to depict how the A125V amino acid change in TNFAIP3 may affect the three-dimensional structure of the DUB domain to a greater extent than F127C. This is the first report of an association between TNFAIP3 polymorphisms and autoimmunity in African-Americans.


Subject(s)
Autoimmunity/genetics , Genetic Predisposition to Disease , Intracellular Signaling Peptides and Proteins/genetics , Lupus Erythematosus, Systemic/genetics , Nuclear Proteins/genetics , Black or African American/genetics , Case-Control Studies , DNA-Binding Proteins , Genome-Wide Association Study , Humans , Immunoblotting , Immunoprecipitation , Intracellular Signaling Peptides and Proteins/chemistry , Nuclear Proteins/chemistry , Polymerase Chain Reaction , Polymorphism, Genetic , Polymorphism, Single Nucleotide , Protein Structure, Quaternary , Transfection , Tumor Necrosis Factor alpha-Induced Protein 3
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