Validation of a Chin Retrusion Scale for Chinese Subjects.

ABSTRACT: Chin augmentation procedures are gaining in popularity. The purpose of this study was to validate the China (Allergan) Chin Retrusion Scale (CACRS) and to evaluate the reliability of the scale. A team of 10 physicians based in Beijing, China, consisting of 1 principal investigator and 9 independent raters, assessed a pool of subject images. Using standardized equipment to capture 2-dimensional images, 100 subjects were photographed from a left, lateral, 90° view. Two measures were used to assess the validity of the scale: rater evaluations of clinically significant differences in 52 pairs of images and rater assessment of chin retrusion using the CACRS to grade the 100 images. The CACRS demonstrated almost perfect inter-rater agreement during 2 validation sessions, with intraclass correlation coefficients of 0.89 and 0.90 at sessions 1 and 2, respectively. Overall inter-rater agreement for all 9 raters was almost perfect, with a weighted kappa of 0.82. Based on inter- and intra-rater agreement, the CACRS was validated for physician ratings of chin retrusion in Chinese subjects. Results from clinical significance evaluations indicated that a 1-grade difference between image pairs was considered clinically meaningful for the CACRS. The CACRS is a validated and reliable photonumeric scale for the assessment of chin retrusion in Chinese men and women. The scale is a clinically significant reference tool for evaluating the effect of chin augmentation.

Safe and Effective Chin Augmentation With the Hyaluronic Acid Injectable Filler, VYC-20L.

BACKGROUND: VYC-20L is a hyaluronic acid soft tissue filler with lidocaine designed to restore facial volume. OBJECTIVE: Evaluate the safety and effectiveness of VYC-20L in patients with chin retrusion. MATERIALS AND METHODS: Adults with chin retrusion were randomized (3:1) to receive VYC-20L in the chin at study onset (treatment group) or 6 months later (control group). The primary effectiveness end point was ≥1-point improvement on the Allergan Chin Retrusion Scale (ACRS) from baseline at Month 6. Safety assessments included injection site responses (ISRs) and adverse events (AEs). RESULTS: VYC-20L was administered to 192 participants (treatment group, n = 144; control group, n = 48). At Month 6, significantly more participants had an ACRS response in the treatment versus control group (56.3% vs 27.5%; p = .0019). Effectiveness was also demonstrated by the proportion of participants with improved/much improved Global Aesthetic Improvement Scale scores and responses on the FACE-Q Satisfaction with Chin questionnaire and FACE-Q Psychological Wellbeing module. Treatment benefit remained evident at Month 12. Most common ISRs were tenderness (81.1%) and firmness (75.1%). One participant (0.5%) discontinued the study due to 2 treatment-related serious AEs of facial cellulitis and injection site inflammation, both resolved without sequelae. CONCLUSION: VYC-20L significantly improved an ACRS response and was generally safe and well tolerated.

Tau overexpression exacerbates neuropathology after repeated mild head impacts in male mice.

Repeated mild traumatic brain injury (rmTBI) can lead to development of chronic traumatic encephalopathy (CTE), which is characterized by progressive neurodegeneration with presence of white matter damage, gliosis and hyper-phosphorylated tau. While animal models of rmTBI have been documented, few characterize the molecular pathogenesis and expression profiles of relevant injured brain regions. Additionally, while the usage of transgenic tau mice in rmTBI is prevalent, the effects of tau on pathological outcomes has not been well studied. Here we characterized a 42-impact closed-head rmTBI paradigm on 3-4 month old male C57BL/6 (WT) and Tau-overexpressing mice (Tau58.4). This injury paradigm resulted in chronic gliosis, T-cell infiltration, and demyelination of the optic nerve and associated white matter tracts at 1-month post-injury. At 3-months post-injury, Tau58.4 mice showed progressive neuroinflammation and neurodegeneration in multiple brain regions compared to WT mice. Corresponding to histopathology, RNAseq of the optic nerve tract at 1-month post-injury showed significant upregulation of inflammatory pathways and downregulation of myelin synthetic pathways in both genotypes. However, Tau58.4 mice showed additional changes in neurite development, protein processing, and cell stress. Comparisons with published transcriptomes of human Alzheimer's Disease and CTE revealed common signatures including neuroinflammation and downregulation of protein phosphatases. We next investigated the demyelination and T-cell infiltration phenotypes to determine whether these offer potential avenues for therapeutic intervention. Tau58.4 mice were treated with the histamine H3 receptor antagonist GSK239512 for 1-month post-injury to promote remyelination of white matter lesions. This restored myelin gene expression to sham levels but failed to repair the histopathologic lesions. Likewise, injured T-cell-deficient Rag2/Il2rg (R2G2) mice also showed evidence for inflammation and loss of myelin. However, unlike immune-competent mice, R2G2 mice had altered myeloid cell gene expression and fewer demyelinated lesions. Together this data shows that rmTBI leads to chronic white matter inflammatory demyelination and axonal loss exacerbated by human tau overexpression but suggests that immune-suppression and remyelination alone are insufficient to reverse damage.

VYC-25L Hyaluronic Acid Injectable Gel Is Safe and Effective for Long-Term Restoration and Creation of Volume of the Lower Face.

BACKGROUND: Juvéderm Volux (VYC-25L; Allergan plc) is an injectable hyaluronic acid gel designed to restore and create facial volume. OBJECTIVE: The aim of this study was to evaluate the safety and effectiveness of Volux for chin retrusion over 18 months and after repeat treatment. METHODS: This prospective, single-blind, controlled study enrolled subjects aged ≥18 years with chin retrusion (glabella-subnasale-pogonion facial angle 145°-165°). Subjects were randomized (3:1) to Volux at study onset or 3 months later (control group), and could receive a single repeat treatment during months 18 to 24. Assessments included mean facial-angle change from baseline, Global Aesthetic Improvement Scale (GAIS) responder rates (improved/much improved), improvements in 3 subject-reported FACE-Q scales, and safety. RESULTS: Of 132 enrolled subjects, 119 received initial Volux treatment and 89 received repeat treatment. Mean changes (95% confidence interval) in glabella-subnasale-pogonion angle from baseline for treatment and control groups, respectively, were: 1.15° (0.75°, 1.56°) and 1.16° (0.57°, 1.75°) at month 18, and 3.14° (2.68°, 3.61°) and 2.72° (1.78°, 3.66°) 1 month after repeat treatment. Investigators rated 52.5%/60.0% of treated/control subjects at month 18 and 96.9%/100% after retreatment as GAIS responders; subject-reported rates were 62.0%/64.0% and 93.8%/100%. Durable improvements in Satisfaction with Chin, Satisfaction with Lower Face and Jawline, and Psychological Well-Being were reported in 82.1%, 78.2%, and 60.3% of subjects, respectively, at month 18, and 92.3%, 93.8%, and 67.7% of subjects after retreatment. The safety profile was as expected. CONCLUSIONS: Volux injectable gel is a safe, effective, and durable alternative to surgical treatments for increasing chin projection and jaw volume, and results in high patient satisfaction.

Lip and Perioral Enhancement With Hyaluronic Acid Dermal Fillers in Individuals With Skin of Color.

BACKGROUND: Individuals with skin of color are underrepresented in studies of lip and perioral enhancement. OBJECTIVE: To examine the effectiveness and safety of hyaluronic acid (HA) dermal filler treatment for lip and perioral enhancement in subjects with skin of color. METHODS: Data were pooled from subjects with Fitzpatrick skin phototypes IV, V, or VI in 2 pivotal studies of HA dermal fillers. Photonumeric scales were used to assess lip fullness (5-point scale) and perioral lines and oral commissures severity (each 4-point scales). Safety was assessed by injection site responses recorded in patient diaries and adverse events (AEs). RESULTS: The cohort comprised 72 subjects (median age: 49.5 years; 95.8% female). Mean lip fullness improved from baseline by 1.1 points at 3 months after treatment; 85.0% of subjects were responders (≥1-point improvement). Of subjects treated for perioral lines (n = 12) and oral commissures (n = 56), 90.9% and 46.4%, respectively, were responders. Injection site responses were generally mild or moderate in severity, resolved within 2 weeks, and were consistent with those expected for HA dermal filler treatment. The most common AEs were injection site mass (19.4%) and bruising (12.5%). CONCLUSION: Lip and perioral enhancement with HA dermal fillers is effective and safe in subjects with skin of color.

Safe, Effective Chin and Jaw Restoration With VYC-25L Hyaluronic Acid Injectable Gel.

BACKGROUND: VYC-25L, a hyaluronic acid soft-tissue filler with lidocaine, is designed to restore and create facial volume in the chin and jaw. OBJECTIVE: To evaluate the safety and effectiveness of VYC-25L in subjects with chin retrusion. METHODS: Adults with chin retrusion (145°-165° glabella-subnasale-pogonion facial angle) were randomized (3:1) to receive VYC-25L in the chin/jaw at study onset (treatment group) or 3 months later (control group). Primary effectiveness end point was mean change in facial angle from baseline at Month 3. Safety assessments included injection site responses (ISRs), recorded in a subject diary, and adverse events (AEs). RESULTS: VYC-25L was administered to 119 subjects (treatment group: n = 90; control group: n = 29). Mean change in facial angle from baseline at Month 3 was significantly greater in the treatment versus control group (difference: 2.51°; p < .0001). Effectiveness was also demonstrated by the proportion of subjects with improved/much improved Global Aesthetic Improvement Scale scores and responses on FACE-Q Satisfaction and Psychological Well-Being Scales. Treatment benefit remained evident at Month 12. Common ISRs were firmness (95.8%), tenderness (95.8%), and swelling (91.6%). No serious treatment-related AEs were reported. CONCLUSION: VYC-25L significantly improved glabella-subnasale-pogonion facial angle and was generally safe and well tolerated.

Lactation Outcomes in More Than 3500 Women Following Primary Augmentation: 5-Year Data From the Breast Implant Follow-Up Study.

BACKGROUND: Women with breast implants may have concerns about their ability to successfully breast-feed. The Breast Implant Follow-up Study (BIFS-001) is a large, 10-year observational study evaluating the performance and safety of Natrelle round silicone gel-filled breast implants. OBJECTIVES: This analysis compared lactation outcomes in women enrolled in BIFS-001 who gave birth after they underwent primary augmentation with Natrelle round silicone implants or saline implants. METHODS: At baseline and annually after surgery (>5-year visit window), patients completed questionnaires regarding pregnancy and lactation. Comparisons were made using summary statistics and odds ratios with 90% confidence intervals (OR [90% CI]). RESULTS: A total of 4679 subjects gave birth at least once after primary augmentation for a total of 5736 live births during the study (silicone, 3695 births; saline, 2041 births). Of these, 3715 (79.4%) women breast-fed at least 1 child, resulting in 80.0% (silicone) and 75.9% (saline) of babies being breast-fed. The most common complication was insufficient milk production, which was reported for 19.6% (silicone) and 19.8% (saline) of single births (OR, 0.94 [0.83, 1.06]). Complications occurred at similar rates in each group when evaluated by incision type, implant size, pocket location, and age. CONCLUSIONS: In this large group of women who gave birth after primary breast augmentation with Natrelle round silicone implants or saline implants, most were able to breast-feed their infants without complications. Lactation complications were comparable between the silicone and saline cohorts, and the incidence was comparable to reports in the general population of women who breast-feed.

Safety and Effectiveness of Repeat Treatment With VYC-15L for Lip and Perioral Enhancement: Results From a Prospective Multicenter Study.

BACKGROUND: VYC-15L (Juvéderm Volbella XC) is a nonanimal crosslinked hyaluronic acid (HA) gel with lidocaine. OBJECTIVES: To evaluate safety and effectiveness of repeat treatment with VYC-15L administered 1 year after treatment for lip and perioral enhancement. METHODS: In this prospective multicenter study, 124 subjects with minimal, mild, or moderate lip fullness on the validated 5-point Allergan Lip Fullness Scale (LFS) who received initial/touch-up treatment with VYC-15L received repeat treatment with VYC-15L 1 year after initial treatment. Effectiveness endpoints included LFS responder rates (≥1-point improvement from baseline) and scores on the FACE-Q Satisfaction With Lips and Appraisal of Lip Lines scales at 1 month after repeat treatment. Subjects completed safety diaries for 30 days after repeat treatment. RESULTS: LFS responder rates were 86.2%, 80.3%, and 65.3% at months 1 and 3 and 1 year, respectively, after initial/touch-up treatment. The responder rate improved to 94.3% 1 month after repeat treatment with VYC-15L and required less median volume vs initial/touch-up treatment (1.5 vs 2.6 mL). FACE-Q scores doubled from baseline at 3 months, remained high through 1 year, and doubled from baseline after repeat treatment. At 1 month after repeat treatment, 96.7% and 89.3% of subjects showed improvement over baseline in FACE-Q Satisfaction With Lips and Appraisal of Lip Lines, respectively. Severe injection site responses were less frequent after repeat treatment than initial/touch-up treatment. CONCLUSIONS: Repeat treatment with VYC-15L at 1 year was safe and effective for lip and perioral enhancement, and required less product volume to achieve similar effectiveness to initial/touch-up treatment.

Enhanced proteolytic clearance of plasma Aß by peripherally administered neprilysin does not result in reduced levels of brain Aß in mice.

Accumulation of ß-amyloid (Aß) in the brain is believed to contribute to the pathology of Alzheimer's Disease (AD). Aß levels are controlled by the production of Aß from amyloid precursor protein, degradation by proteases, and peripheral clearance. In this study we sought to determine whether enhancing clearance of plasma Aß with a peripherally administered Aß-degrading protease would reduce brain Aß levels through a peripheral sink. Neprilysin (NEP) is a zinc-dependent metalloprotease that is one of the key Aß-degrading enzymes in the brain. We developed a NEP fusion protein with in vitro degradation of Aß and a 10 day plasma half-life in mouse. Intravenous administration of NEP to wild-type and APP23 transgenic mice resulted in dose-dependent clearance of plasma Aß. However, this did not correspond to reduced levels of soluble brain Aß with treatment up to 5 weeks in WT mice or formic acid-extractable brain Aß with 3 month treatment in aged APP23. In contrast, intracranial injection of NEP resulted in an acute decrease in soluble brain Aß. We found no change in amyloid precursor protein gene expression in mice treated with intravenous NEP, suggesting that the lack of effects in the brain following this route of administration was not caused by compensatory upregulation of Aß production. Taken together, these results suggest a lack of a robust peripheral Aß efflux sink through which brain amyloid burdens can be therapeutically reduced.

3D inversion recovery ultrashort echo time MRI can detect demyelination in cuprizone-treated mice.

Purpose: To test the ability of inversion-recovery ultrashort echo time (IR-UTE) MRI to directly detect demyelination in mice using a standard cuprizone mouse model. Methods: Non-aqueous myelin protons have ultrashort T2s and are "invisible" with conventional MRI sequences but can be detected with UTE sequences. The IR-UTE sequence uses an adiabatic inversion-recovery preparation to suppress the long T2 water signal so that the remaining signal is from the ultrashort T2 myelin component. In this study, eight 8-week-old C57BL/6 mice were fed cuprizone (n = 4) or control chow (n = 4) for 5 weeks and then imaged by 3D IR-UTE MRI. The differences in IR-UTE signal were compared in the major white matter tracts in the brain and correlated with the Luxol Fast Blue histochemical marker of myelin. Results: IR-UTE signal decreased in cuprizone-treated mice in white matter known to be sensitive to demyelination in this model, such as the corpus callosum, but not in white matter known to be resistant to demyelination, such as the internal capsule. These findings correlated with histochemical staining of myelin content. Conclusions: 3D IR-UTE MRI was sensitive to cuprizone-induced demyelination in the mouse brain, and is a promising noninvasive method for measuring brain myelin content.

Acellular Dermal Matrices in Breast Reconstruction: CARE Trial 5-Year Outcomes Data for More Than 9500 Patients.

Few studies have assessed long-term complications in women undergoing implant-based breast reconstruction with use of an acellular dermal matrix (ADM). This study compared outcomes over 5 years in women undergoing breast reconstruction procedures with and without ADM. Methods: Complications data in patients enrolled in the prospective Continued Access Reconstruction/Revision Expansion trial were segregated by use of ADM versus no ADM in patients undergoing primary breast reconstruction or revision-reconstruction. Continued Access Reconstruction/Revision Expansion trial evaluated long-term safety and effectiveness of shaped, textured, silicone implants. Results: Of the 9502 women, 257 had primary (n = 160) or revision-reconstruction (n = 97) with ADMs; 9245 had primary (n = 6977) or revision-reconstruction (n = 2268) without ADMs. Capsular contracture rates in primary reconstruction were lower with ADM than without at year 5 (3.2% versus 7.4%); rates were similar at year 1 (≤2.4%). Capsular contracture rates in revision-reconstruction were lower with ADM than without at year 5 (1.4% versus 8.9%); rates were similar at year 1 (≤2.5%). Seroma rates were low and sustained for all cohorts throughout the 5 years (≤2.9%). Reoperation rates increased over time in all cohorts, with similar rates between groups (2.4%-47.3% from week 4 to year 5 across cohorts). Other trends over time included lower rates for asymmetry and implant malposition with ADM than without. Conclusion: These long-term data suggest that the use of ADM in breast reconstruction procedures may provide a benefit in reducing complications, such as capsular contracture, and may sustain low rates of seroma.

Pericellular activation of hepatocyte growth factor by the transmembrane serine proteases matriptase and hepsin, but not by the membrane-associated protease uPA.

HGF (hepatocyte growth factor) is a pleiotropic cytokine homologous to the serine protease zymogen plasminogen that requires canonical proteolytic cleavage to gain functional activity. The activating proteases are key components of its regulation, but controversy surrounds their identity. Using quantitative analysis we found no evidence for activation by uPA (urokinase plasminogen activator), despite reports that this is a principal activator of pro-HGF. This was unaffected by a wide range of experimental conditions, including the use of various molecular forms of both HGF and uPA, and the presence of uPAR (uPA receptor) or heparin. In contrast the catalytic domains of the TTSPs (type-II transmembrane serine proteases) matriptase and hepsin were highly efficient activators (50% activation at 0.1 and 3.4 nM respectively), at least four orders of magnitude more efficient than uPA. PS-SCL (positional-scanning synthetic combinatorial peptide libraries) were used to identify consensus sequences for the TTSPs, which in the case of hepsin corresponded to the pro-HGF activation sequence, demonstrating a high specificity for this reaction. Both TTSPs were also found to be efficient activators at the cell surface. Activation of pro-HGF by PC3 prostate carcinoma cells was abolished by both protease inhibition and matriptase-targeting siRNA (small interfering RNA), and scattering of MDCK (Madin-Darby canine kidney) cells in the presence of pro-HGF was abolished by inhibition of matriptase. Hepsin-transfected HEK (human embryonic kidney)-293 cells also activated pro-HGF. These observations demonstrate that, in contrast with the uPA/uPAR system, the TTSPs matriptase and hepsin are direct pericellular activators of pro-HGF, and that together these proteins may form a pathway contributing to their involvement in pathological situations, including cancer.

Metabolic Risk Factors Associated with Early-Onset Colorectal Adenocarcinoma: A Case-Control Study at Kaiser Permanente Southern California.

BACKGROUND: The incidence of early-onset colorectal cancer (eoCRC) diagnosed among individuals under age 50 has been rising. However, risk factors for eoCRC are unclear. We investigated whether metabolic abnormalities are risk factors for eoCRC adenocarcinoma. METHODS: Invasive colorectal adenocarcinoma cases diagnosed between ages 15 and 49 from 2008 to 2018 at Kaiser Permanente Southern California (KPSC) were identified. Those with a history of inflammatory bowel disease were excluded. Noncancer controls were selected 5:1 for each case matched by age, sex, and length of membership prior to index date. Data were collected from KSPC's electronic medical records. The exposures of interest included obesity, type II diabetes, hypertension, and dyslipidemia, assessed from ≥1 year prior to eoCRC diagnosis/index date. Conditional logistic regressions were used to evaluate the associations between these metabolic risk factors and risk of eoCRC adenocarcinoma, adjusting for race/ethnicity, smoking, family history, neighborhood socioeconomic status, and health care utilization. RESULTS: A total of 1,032 cases and 5,128 controls were included. Risk of colorectal adenocarcinoma was significantly associated with obesity [odds ratio (OR) = 1.41; 95% confidence interval (CI), 1.15-1.74], but not diabetes, hypertension or dyslipidemia. In analysis stratified by tumor location, obesity was significantly associated with risk of colon adenocarcinoma OR = 1.56 (1.17-2.07), but its association with rectal adenocarcinoma was less clear OR = 1.19 (0.85-1.68). No significant interaction was detected between obesity and age (≥40 vs. <40), and obesity and sex. CONCLUSIONS: Obesity was associated with risk for eoCRC adenocarcinoma. IMPACT: This finding could help inform early-onset colorectal adenocarcinoma screening and prevention recommendations.See related commentary by Hayes, p. 1775.

A Dual Inhibitor of DYRK1A and GSK3ß for ß-Cell Proliferation: Aminopyrazine Derivative GNF4877.

Loss of ß-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase ß-cell mass are less developed. Promoting ß-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring ß-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3ß (GSK3ß) was previously reported to induce primary human ß-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring ß-cell proliferation.

Selective DYRK1A Inhibitor for the Treatment of Type 1 Diabetes: Discovery of 6-Azaindole Derivative GNF2133.

Autoimmune deficiency and destruction in either ß-cell mass or function can cause insufficient insulin levels and, as a result, hyperglycemia and diabetes. Thus, promoting ß-cell proliferation could be one approach toward diabetes intervention. In this report we describe the discovery of a potent and selective DYRK1A inhibitor GNF2133, which was identified through optimization of a 6-azaindole screening hit. In vitro, GNF2133 is able to proliferate both rodent and human ß-cells. In vivo, GNF2133 demonstrated significant dose-dependent glucose disposal capacity and insulin secretion in response to glucose-potentiated arginine-induced insulin secretion (GPAIS) challenge in rat insulin promoter and diphtheria toxin A (RIP-DTA) mice. The work described here provides new avenues to disease altering therapeutic interventions in the treatment of type 1 diabetes (T1D).

A time-resolved fluorescence resonance energy transfer-based assay for DEN1 peptidase activity.

Neural precursor cell expressed, developmentally down-regulated gene 8 (NEDD8) is a recently discovered ubiquitin-like posttranslational modifier. NEDD8 acts predominantly as a regulator of ubiquitin-protein ligases and as a decoy for proteins targeted for proteasomal degradation. It thereby controls key events in cell cycle progression and embryogenesis. Deneddylase-1 (DEN1/NEDP1/SENP8) features a selective peptidase activity converting the proNEDD8 precursor to its mature form and an isopeptidase activity deconjugating NEDD8 from substrates such as cullins and p53. In this study, we describe a high-throughput screening (HTS)-compatible time-resolved fluorescent resonance energy transfer (TR-FRET) assay measuring the peptidase activity of DEN1.

Radical Prostatectomy and Pelvic Lymph Node Dissection in Kaiser Permanente Southern California: 15-Year Experience.

INTRODUCTION: Radical prostatectomy (RP) with pelvic lymph node dissection (PLND) is the standard treatment of high-risk prostate cancer. High-risk patients and those with lymph node metastasis (LNM) require further treatment. We review outcomes of RP+PLND in Kaiser Permanente Southern California (KPSC). METHODS: Patients who underwent RP+PLND in KPSC from January 1, 2001, to July 1, 2015 were included. Patient charts were retrospectively reviewed for demographic information and clinicopathologic data which were used to calculate positive surgical margin rate, LNM, adjuvant treatment, 5-year biochemical recurrence, and overall survival. Univariate and multivariate logistic regression analyses were used to identify factors associated with margin positivity. RESULTS: Patients (N = 1829) underwent RP+PLND (241 high-risk, 943 intermediate-risk, 645 low-risk). Positive margin rates were 17.8%, 14.8%, and 11.9% in the high, intermediate- and low-risk groups. Biochemical recurrence rates were 22% in high-risk and 12.1% in the low-risk category. Androgen deprivation use was 4.1% in the high-risk group and 0.9% in the low-risk group. Five-year overall survival was 92.5% in lymph node-positive patients and 94.9% in lymph node-negative patients (p = 0.8). On multivariate analysis, age (odds ratio [OR] = 1.02, p = 0.02), prebiopsy prostate-specific antigen (OR = 1.02, p < 0.001), and clinical T stage (OR = 1.49, p = 0.01) were associated with margin positivity. CONCLUSION: In KPSC, RP+PLND was performed in patients with low-, intermediate-, and high-risk prostate cancer. Age, prebiopsy prostate-specific antigen, and clinical stage were associated with positive surgical margins in patients with LNM. Recipients of RP+PLND with LNM and positive surgical margins required adjuvant treatment.

Radiographic nodal prognostic factors in stage I HPV-related oropharyngeal squamous cell carcinoma.

BACKGROUND: The updated AJCC Cancer Staging Manual groups all p16-positive oropharyngeal squamous cell carcinoma (OPSCC) with unilateral nodal involvement within 6 cm into the new clinical N1 classification, consolidating a heterogeneous group of disease with varying radiographic findings. METHODS: A central radiological review was conducted identifying 233 patients with stage I node-positive (cT1-2N1) disease who underwent definitive concurrent chemoradiation. Factors evaluated included lymph node size, low-neck lymphadenopathy, retropharyngeal lymphadenopathy, overt radiographic extracapsular extension, and matted lymphadenopathy. RESULTS: On multivariate analysis adjusted for age, smoking history, and chemotherapy regimen, low-neck lymphadenopathy (hazard ratio (HR) = 6.55; P < .001) and retropharyngeal lymphadenopathy (HR = 3.36; P = .009) predicted for inferior progression-free survival (PFS). low-neck lymphadenopathy (HR = 6.38; P = .001) and retropharyngeal lymphadenopathy (HR = 3.32; P = .02) also predicted for inferior overall survival (OS). All other radiographic characteristics showed no prognostic impact for PFS or OS. CONCLUSIONS: This analysis suggests that caution should be advised against de-intensification efforts among patients with stage I node-positive p16-positive OPSCC with low-neck lymphadenopathy or retropharyngeal lymphadenopathy.

Long-Term Outcomes of Newly Diagnosed Resected Atypical Meningiomas and the Role of Adjuvant Radiotherapy.

OBJECTIVE: The role of adjuvant radiotherapy (ART) in patients with World Health Organization Grade II atypical meningiomas (AMs) remains controversial. METHODS: We retrospectively reviewed 149 patients with newly diagnosed resected AMs from 2000 to 2012. Gross total resection (GTR) was defined as Simpson Grades I-III and subtotal resection (STR) as Grades IV and V. Kaplan-Meier analyses of local control (LC), progression-free survival (PFS), and overall survival were performed with the log-rank test, and risk factors for progression/recurrence (P/R) were analyzed with multivariate Cox regression. RESULTS: Median follow-up was 74.2 months. GTR was achieved in 98 patients and STR in 51 patients. Fifty-three (35%) patients received ART. Overall, 46 patients (31%) experienced P/R with a median time to P/R of 32.4 months. ART was associated with a trend toward improved PFS (P = 0.0669) in the GTR subset but significantly improved LC (P = 0.0183) and PFS (P = 0.0034) in the STR subset. Age, tumor size, and STR were significant risk factors for worse PFS, whereas receiving ART was associated with improved PFS on multivariate analyses. Thirty-nine of the 46 progressive/recurrent patients underwent salvage therapy with only 22 patients experiencing long-term control. Five patients experienced transformation to World Health Organization Grade III malignant meningioma. CONCLUSIONS: Patients who undergo STR for newly diagnosed AM should receive ART based on improvements in LC and PFS. GTR patients should be considered for ART, but active surveillance is a reasonable management approach with the recognition that progressive/recurrent disease can act aggressively. Prospective, randomized trials are currently underway to evaluate the role of ART.

Phase I and Pharmacology Study of Ropidoxuridine (IPdR) as Prodrug for Iododeoxyuridine-Mediated Tumor Radiosensitization in Advanced GI Cancer Undergoing Radiation.

PURPOSE: Iododeoxyuridine (IUdR) is a potent radiosensitizer; however, its clinical utility is limited by dose-limiting systemic toxicities and the need for prolonged continuous infusion. 5-Iodo-2-pyrimidinone-2'-deoxyribose (IPdR) is an oral prodrug of IUdR that, compared with IUdR, is easier to administer and less toxic, with a more favorable therapeutic index in preclinical studies. Here, we report the clinical and pharmacologic results of a first-in-human phase I dose escalation study of IPdR + concurrent radiation therapy (RT) in patients with advanced metastatic gastrointestinal (GI) cancers. PATIENTS AND METHODS: Adult patients with metastatic GI cancers referred for palliative RT to the chest, abdomen, or pelvis were eligible for study. Patients received IPdR orally once every day × 28 days beginning 7 days before the initiation of RT (37.5 Gy in 2.5 Gy × 15 fractions). A 2-part dose escalation scheme was used, pharmacokinetic studies were performed at multiple time points, and all patients were assessed for toxicity and response to Day 56. RESULTS: Nineteen patients were entered on study. Dose-limiting toxicity was encountered at 1,800 mg every day, and the recommended phase II dose is 1,200 mg every day. Pharmacokinetic analyses demonstrated achievable and sustainable levels of plasma IUdR ≥1 µmol/L (levels previously shown to mediate radiosensitization). Two complete, 3 partial, and 9 stable responses were achieved in target lesions. CONCLUSIONS: Administration of IPdR orally every day × 28 days with RT is feasible and tolerable at doses that produce plasma IUdR levels ≥1 µmol/L. These results support the investigation of IPdR + RT in phase II studies.