In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of ...progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4–6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT.
The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0–1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8–70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8–25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing.
Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 PBRT alone, 602 to group 2 PBRT plus short-term ADT, and 598 to group 3 PLNRT plus PBRT plus short-term ADT). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6–9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0–74·9) in group 1, 81·3% (78·0–84·6) in group 2, and 87·4% (84·7–90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 44% of 563 patients) than in group 2 (201 36% of 563; p=0·0034), which, in turn, were more common than in group 1 (98 18% of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group.
The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer.
National Cancer Institute.
Pediatric cervical spine injuries (CSIs) are rare and differ from adult CSIs. Our objective was to describe CSIs in a large, representative cohort of children.
We conducted a 5-year retrospective ...review of children <16 years old with CSIs at 17 Pediatric Emergency Care Applied Research Network hospitals. Investigators reviewed imaging reports and consultations to assign CSI type. We described cohort characteristics using means and frequencies and used Fisher's exact test to compare differences between 3 age groups: <2 years, 2 to 7 years, and 8 to 15 years. We used logistic regression to explore the relationship between injury level and age and mechanism of injury and between neurologic outcome and cord involvement, injury level, age, and comorbid injuries.
A total of 540 children with CSIs were included in the study. CSI level was associated with both age and mechanism of injury. For children <2 and 2 to 7 years old, motor vehicle crash (MVC) was the most common injury mechanism (56%, 37%). Children in these age groups more commonly injured the axial (occiput-C2) region (74%, 78%). In children 8 to 15 years old, sports accounted for as many injuries as MVCs (23%, 23%), and 53% of injuries were subaxial (C3-7). CSIs often necessitated surgical intervention (axial, 39%; subaxial, 30%) and often resulted in neurologic deficits (21%) and death (7%). Neurologic outcome was associated with cord involvement, injury level, age, and comorbid injuries.
We demonstrated a high degree of variability of CSI patterns, treatments and outcomes in children. The rarity, variation, and morbidity of pediatric CSIs make prompt recognition and treatment critical.
Adult prediction rules for cervical spine injury (CSI) exist; however, pediatric rules do not. Our objectives were to determine test accuracies of retrospectively identified CSI risk factors in a ...prospective pediatric cohort and compare them to a de novo risk model.
We conducted a 4-center, prospective observational study of children 0 to 17 years old who experienced blunt trauma and underwent emergency medical services scene response, trauma evaluation, and/or cervical imaging. Emergency department providers recorded CSI risk factors. CSIs were classified by reviewing imaging, consultations, and/or telephone follow-up. We calculated bivariable relative risks, multivariable odds ratios, and test characteristics for the retrospective risk model and a de novo model.
Of 4091 enrolled children, 74 (1.8%) had CSIs. Fourteen factors had bivariable associations with CSIs: diving, axial load, clotheslining, loss of consciousness, neck pain, inability to move neck, altered mental status, signs of basilar skull fracture, torso injury, thoracic injury, intubation, respiratory distress, decreased oxygen saturation, and neurologic deficits. The retrospective model (high-risk motor vehicle crash, diving, predisposing condition, neck pain, decreased neck mobility (report or exam), altered mental status, neurologic deficits, or torso injury) was 90.5% (95% confidence interval: 83.9%-97.2%) sensitive and 45.6% (44.0%-47.1%) specific for CSIs. The de novo model (diving, axial load, neck pain, inability to move neck, altered mental status, intubation, or respiratory distress) was 92.0% (85.7%-98.1%) sensitive and 50.3% (48.7%-51.8%) specific.
Our findings support previously identified pediatric CSI risk factors and prospective pediatric CSI prediction rule development.
Purpose To evaluate the effects of a novel ab interno trabeculectomy device on human trabecular meshwork (TM). Design Laboratory evaluation. Methods The TM from human cadaveric corneal rim tissue was ...incised using 3 instruments: (1) novel dual-blade device; (2) microvitreoretinal (MVR) blade; and (3) Trabectome. Tissue samples underwent histologic processing and comparative analyses. Subsequently, human eye perfusion studies were performed to evaluate intraocular pressure (IOP)-lowering effects of each device. Main outcome measures were degree of TM removal by histology and IOP in a perfusion model. Results The MVR blade exhibited minimal removal of TM and obvious injury to the adjacent sclera. The Trabectome removed a large portion of the central TM, but leaflets of residual tissue remained and thermal injury was noted in all samples. The dual-blade device achieved a more complete removal of TM without injury to surrounding tissues. All devices resulted in statistically significant lowering of IOP during perfusion model studies. MVR blade treatment across 170.0 ± 14.1 degrees of TM resulted in a decrease of IOP from 18.5 ± 1.9 mm Hg to 12.8 ± 2.2 mm Hg ( P < .01). Trabectome treatment across 117.5 ± 12.6 degrees resulted in a decrease of IOP from 18.8 ± 1.7 mm Hg to 11.3 ± 1.0 mm Hg ( P < .01). Dual-blade device treatment across 157.5 ± 26.3 degrees resulted in a decrease of IOP from 18.3 ± 3.0 mm Hg to 11.0 ± 2.2 mm Hg ( P < .01). Conclusions The novel dual-blade device demonstrated a more complete removal of TM without residual TM leaflets or damage to surrounding tissues and significantly reduced IOP in a human eye perfusion model.
Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate ...that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver of tumor progression and metastases, and nominate DNA-PKcs as a therapeutic target for advanced malignancies.
•Identification of DNA-PKcs-modulated transcriptional networks and consequence•DNA-PKcs-mediated gene regulation promotes migration, invasion, and metastases•DNA-PKcs is upregulated and highly activated in aggressive human tumors•DNA-PKcs independently predicts for metastases, recurrence, and poor survival
Goodwin et al. identify DNA-PKcs as a promising therapeutic target that drives prostate cancer progression and metastasis through transcriptional regulation. DNA-PKcs is significantly elevated in advanced disease and is an independent predictor of metastasis, recurrence, and poor survival.
The optimal timing of postoperative radiotherapy (RT) after radical prostatectomy (RP) is unclear. We hypothesized that a genomic classifier (GC) would provide prognostic and predictive insight into ...the development of clinical metastases in men receiving post-RP RT and inform decision making.
GC scores were calculated from 188 patients with pT3 or margin-positive prostate cancer, who received post-RP RT at Thomas Jefferson University and Mayo Clinic between 1990 and 2009. The primary end point was clinical metastasis. Prognostic accuracy of the models was tested using the concordance index for censored data and decision curve analysis. Cox regression analysis tested the relationship between GC and metastasis.
The cumulative incidence of metastasis at 5 years after RT was 0%, 9%, and 29% for low, average, and high GC scores, respectively (P = .002). In multivariable analysis, GC and pre-RP prostate-specific antigen were independent predictors of metastasis (both P < .01). Within the low GC score (< 0.4), there were no differences in the cumulative incidence of metastasis comparing patients who received adjuvant or salvage RT (P = .79). However, for patients with higher GC scores (≥ 0.4), cumulative incidence of metastasis at 5 years was 6% for patients treated with adjuvant RT compared with 23% for patients treated with salvage RT (P < .01).
In patients treated with post-RP RT, GC is prognostic for the development of clinical metastasis beyond routine clinical and pathologic features. Although preliminary, patients with low GC scores are best treated with salvage RT, whereas those with high GC scores benefit from adjuvant therapy. These findings provide the first rational selection of timing for post-RP RT.
Low-grade brain tumors (pilocytic astrocytomas) arising in the neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome are hypothesized to result from a combination of germline and ...acquired somatic NF1 tumor suppressor gene mutations. However, genetically engineered mice (GEM) in which mono-allelic germline Nf1 gene loss is coupled with bi-allelic somatic (glial progenitor cell) Nf1 gene inactivation develop brain tumors that do not fully recapitulate the neuropathological features of the human condition. These observations raise the intriguing possibility that, while loss of neurofibromin function is necessary for NF1-associated low-grade astrocytoma development, additional genetic changes may be required for full penetrance of the human brain tumor phenotype. To identify these potential cooperating genetic mutations, we performed whole-genome sequencing (WGS) analysis of three NF1-associated pilocytic astrocytoma (PA) tumors. We found that the mechanism of somatic NF1 loss was different in each tumor (frameshift mutation, loss of heterozygosity, and methylation). In addition, tumor purity analysis revealed that these tumors had a high proportion of stromal cells, such that only 50%-60% of cells in the tumor mass exhibited somatic NF1 loss. Importantly, we identified no additional recurrent pathogenic somatic mutations, supporting a model in which neuroglial progenitor cell NF1 loss is likely sufficient for PA formation in cooperation with a proper stromal environment.
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